TAB 4 Research Ethics Milestones in Research Ethics 1946 Nuremburg Code. (Subject's consent required.) 1962 Federal Food, Drug, and Cosmetic Act. (Requires consent of research subjects.) 1964 Declaration of Helsinki. (Differentiates clinical from non-clinical biomedical research.) 1966 Public Health Service policy. (Specifies institutional committee peer review of research; benefits of experiment must outweigh risks; informed consent.) 1966- Henry K. Beecher's article published in the New England Journal of Medicine cataloguing unethical human experimentation. Other unethical experiments publicized subsequently (e.g., Jewish Chronic Disease Hospital, Tuskegee, and Wiliowbrook). 1974 45 CFR 46. (Specifies structure add procedures for "Institutional Review Boards" and the review of proposed investigations.) 1974-8 US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Issues the Belmont Report as well as reports on research involving vulnerable populations. Department of Health, Education, and Welfare promulgates regulations for such populations (e.g., children, pregnant women, and prisoners). 1979-80 Department of Health, Education, and Welfare Ethics Advisory Board. (To review certain research such as in vitro fertilization.) 1978-83 President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. (Assure implementation of regulations regarding protection of human subjects and discussion of compensation for research related injury.) 1985-89 US Congress Biomedical Ethics Advisory Committee Topic specific initiatives including: National Commission on Acquired Immune Deficiency Syndrome; National Institutes of Health Human Fetal Tissue Transplantation Research Panel; National Institutes of Health Recombinant DNA Advisory Committee; National Institutes of Health and US Department of Energy Ethical, Legal and Social Issues Programs; Presidential Commission on the Human Immunodeficiency Virus Epidemic; US Department of Health and Human Services Organ Transplantation Task Force. Derived from: Beauchamp TL, Walters L. Contemporary Issues in Bioethics, 2nd ed. Belmont, CA: Wadsworth Publ Co, 1982. McCarthy CR. "Experience with Boards and Commissions Concerned with Research Ethics in the United States." In: K Berg, KE Tranoy, eds. Research Ethics. New York: Alan R. Liss, 1983, pp 111-122. U.S. Congress, Office of Technology Assessment., Biomedical Ethics in US Public Policy-Background Paper, OTA-BP-BBS-105 - Washington, DC: US Govt Printing Office, 1993. TAB 4 RESEARCH ETHICS U.S. V. KARL BRANT EXCERPT (NUREMBERG CODE) List of Attachments For Briefing Book Volume 1 Tab 4 Attachment 1: Research Ethics: U.S. v. Karl Brant Excerpt (Nuremberg Code) Attachment 2: Research Ethics: Nuremberg Code Attachment 3: Research Ethics: Declaration of Helsinki Attachment 4: Research Ethics: Henry K. Beecher,"Ethics and Clinical Research," New England Journal of Medicine (274;1354-60, 1966) Attachment 5: Final Report of the Tuskegee Syphilis Study Ad Hoc Advisory Panel (1973) Attachment 6: The National Commission For the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, 4/18/79. Attachment 7: Research Ethics: Federal Policy for the Protection of Human Subjects. TAB 4 Research Ethics: Nuremberg Code Codes of Research Ethics The Nuremberg Code The great weight of the evidence before us is to the effect that certain types of medical experiments on human beings, when kept within reasonably well-defined bounds, conform to the ethics of the medical profession generally. The protagonists of the practice of human experimentation justify their views on the basis that such experiments yield results for the good of society that are unprocurable by other methods or means of study. All agree, however, that certain basic principles must be observed in order to satisfy moral, ethical and legal concepts. 1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problems under study that the anticipated results will justify the performance of the experiment. 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except perhaps, in those experiments where the experimental physicians also serve as subjects. 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. From Trials of War Criminals Before the Nuremberg Military Tribunals Under Control Council Law No. 10. Vol. II, Nuremberg, October 1946 - April 1949. UNITED STATES V. KARL BRANDT 305 We of a prison can form a sufficiently clear opinion of the risks of an experiment made with pernicious malaria. These facts will be confirmed by any sincere and decent scientist in a personal conversation, though he would not like to make such a statement in public.... * * * 6. Judgment * * * BEALS, SEBRING, CRAWFORD, J.J.: . . . Judged by any standard of proof the record clearly shows the commission of war crimes and crimes against humanity substantially as alleged in counts two and three of the indictment. Beginning with the outbreak of World War II criminal medical experiments on non-German nationals, both prisoners of war and civilians, including Jews and "asocial" persons, were carried out on a large scale in Germany and the occupied countries. These experiments were not the isolated and casual acts of individual doctors and scientists working solely on their own responsibility, but were the product of coordinated policy-making and planning at high governmental, military, and Nazi Party levels, conducted as an integral part of the total war effort. They were ordered, sanctioned, permitted, or approved by persons in positions of authority who under all principles of law were under duty to know about these things and to take steps to terminate or prevent them. The great weight of the evidence before us is to the effect that certain types of medical experiments on human beings, when kept within reasonably well defined bounds, conform to the ethics of the medical profession generally. The protagonists of the practice of human experimentation justify their views on the basis that such experiments yield results for the good of society that are unprocurable by other methods or means of study. All agree, however, that certain basic principles [*] must be observed in order to satisfy moral, ethical, and legal concepts: 1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise the free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, direct, or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. ____________ [*]These ten principles are now known as the Nuremberg Code. 306 EXPERIMENTATION WITHOUT RESTRICTION 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. Of the ten principles which have been enumerated our judicial concern, of course, is with those requirements which are purely legal in nature - or which at least are so clearly related to matters legal that they assist us in determining criminal culpability and punishment. To go beyond that point would lead us into a field that would be beyond our sphere of competence. However, the point need not be labored. We find from the evidence that in the medical experiments which have been proved, these ten principles were much more frequently honored in their breach than in their observance. Many of the concentration camp inmates who were the victims of these atrocities were citizens of countries other than the German Reich. They were non-German nationals, including Jews and "asocial persons," both prisoners of war and civilians, who had been imprisoned and forced to submit to these tortures and barbarities without so much as a semblance of trial. In every single instance appearing in the record, subjects were used who did not consent to the experiments; indeed, as to some of the experiments, it is not even contended by the defendants that the subjects occupied the status of volunteers. In no case was the experimental subject at liberty of his own free choice to withdraw from any experiment. In many cases experiments were performed by unqualified persons; were conducted at random for no adequate scientific reason, and under revolting physical conditions. All of the experiments were conducted with unnecessary suffering and injury, and but very little, if any, precautions were taken to protect or safeguard the human subjects from the possibilities of injury, disability, or death. In every one of the experiments the subjects experienced extreme pain or torture, and in most of them they suffered permanent injury, mutilation or death, either as a direct result of the experiments or because of lack of adequate follow-up care. Obviously all of these experiments involving brutalities, tortures, disabling injury, and death were performed in complete disregard of international conventions, the laws and customs of war [and] the general principles of criminal law as derived from the criminal law: of all civilized nations...Manifestly human experiments under such conditions are contrary to "the principles of the law of nations as they result from the usages established among civilized peoples, from the laws of humanity, and from the dictates of public conscience." * * * There is some evidence to the effect that the camp inmates used as subjects in the first series submitted to being used as subjects after being told that the experiments were harmless and that additional food would be given to volunteers. But these victims were not informed that they would be artificially infected with a highly virulent virus nor that they might die as a result. Certainly no one would seriously suggest that under the circumstances these men gave their legal consent to act as subjects. One does not ordinarily consent to be the special object of a murder, and if one did, such consent would not absolve his slayer. * * * [Sixteen of the twenty-three defendants were found guilty of war crimes and crimes against humanity. Seven, including Karl Brandt, Rudolf Brandt, and Joachim Mrugowsky, were sentenced to death by hanging: the other nine, including Siegfried Handloser and Gerhard Rose, to imprisonment varying from ten years to life.] C.Epilogue-Experiments Subsequent to 1945 In 1966 Dr. Henry K. Beecher, Dorr Professor of Research in Anesthesia at the Harvard Medical School, surveyed the tremendous, postwar increase in research involving human subjects and charged that "many of the patients [who were used in these experiments.] TAB 4 RESEARCH ETHICS: Declaration of Helsinki TAB 4 Research Ethics: Henry K. Beecher, Ethics and Clinical Research," New England Journal of Medicine (274; 1354-60, 1966) TAB 4 Final Report of the Tuskegee Syphilis Study Ad Hoc Advisory Panel" (1973) FINAL REPORT of the Tuskegee Syphilis Study Ad Hoc Advisory Panel CENTER FOR BIOETHICS LIBRARY KENNEDY INSTITUTE GEORGETOWN UNIVERSITY U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE TABLE OF CONTENTS PANEL CHARTERS First Panel Charter ..............................1 Second Panel Charter .............................2 PANEL MEMBERS ..........................................3 DATES AND PLACES OF MEETINGS ...........................4 FINAL REPORT Section I - Report on Charge I ...................5 Addenda to Charge I ............................14 Section II - Report on Charge II ...............16 Addenda to Charge II ...........................20 Section III - Report on Charge III ..............21 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE C H A R T E R Tuskegee Syphilis Study Ad Hoc Advisory Panel to the Assistant Secretary for Health and Scientific Affairs Purpose To fulfill the public pledge of the Assistant Secretary for Health and Scientific Affairs to investigate the circumstances surrounding the Tuskegee, Alabama, study of untreated syphilis in the male Negro initiated by the United States Public Health Service in 1932. Authority The committee is established under the provisions of Section 222 of the Public Health Service Act, as amended, 42 US Code 217a, and in accordance with the provisions of Executive Order 11671, which sets forth standards for the formation and use of advisory committees. Function The committee will advise the Assistant Secretary for Health and Scientific Affairs on the following specific aspects of the Tuskegee Syphilis Study: Determine whether the study was justified in 1932 and whether it should have been continued when penicillin became generally available. Recommend whether the study should be continued at this point in time, and if not, how it should be terminated in a way consistent with the rights and health needs of its remaining participants. Determine whether existing policies to protect the rights of patients participating in health research conducted or supported by the Department of Health, Education, and Welfare are adequate and effective and to recommend improvements in these policies, if needed. Structure The committee will consist of nine members, including the Chairman, not otherwise in the full-time employ of the Federal Government. Members will be selected by the Assistant Secretary for Health and Scientific Affairs from citizens representing medicine, law, religion, labor, education, health administration, and public affairs. The Panel members will be invited to serve for a period not to extend beyond December 31, 1972, unless an extension beyond that time is approved by the Assistant Secretary for Health and Scientific Affairs. The Assistant Secretary of Health and Scientific Affairs will designate the Chairman. Management and staff services will be provided by the Office of the Assistant Secretary for Health and Scientific Affairs. Meetings Meetings will be held at the call of the Chairman, with the advance approval of a Government official who shall also approve the agenda. A Government official will be present at all meetings. Meetings shall be conducted, and records of the proceedings kept as required by Executive Order 11671 and applicable Departmental regulations. Compensation Members who are not full-time Federal employees will be paid at the rate of $100 per day for time spent at meetings, plus per diem and travel expenses in accordance with Standard Government Travel Regulations. Annual Cost Estimate Estimated annual cost for operating the committee, including compensation and travel expenses of members but excluding staff support, is $74,000. Estimate of annual man years of staff support required is one year at an estimated annual cost of $16,000. Report A final report based on the committee's investigation will be made to the Assistant Secretary for Health and Scientific Affairs. A copy of this report shall be provided to the Department Committee Management Officer. The Tuskegee Syphilis Study Ad Hoc Advisory Panel to the Assistant Secretary for Health and Scientific Affairs will terminate on December 31, 1972, unless extension beyond that date is requested and approved. FORMAL DETERMINATION By authority delegated to me by the Secretary on September 29, 1969, I hereby determine that the formation of the Tuskegee Syphilis Study Ad Hoc Advisory Panel to the Assistant Secretary for Health and Scientific Affairs is in the public interest in connection with the performance of duties imposed on the Department by law, and that such duties can best be performed through the advice and counsel of such a group. 8/28/72 (sgd.) Merlin K. DuVal, M.D. Date Assistant Secretary for Health and Scientific Affairs 1 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE C H A R T E R Tuskegee Syphilis Study Ad Hoc Advisory Panel to the Assistant Secretary for Health Purpose To fulfill the public pledge of the Assistant Secretary for Health to investigate the circumstances surrounding the Tuskegee, Alabama, study of untreated syphilis in the male Negro initiated by the United States Public Health service in 1932. Authority The Panel is established under the provisions of Section 222 of the Public Health Service Act, as amended, 42 US Code 217a; the Panel is governed by provisions of Executive Order 11671, which sets forth standards for the formation and use of advisory committees. Function The Panel will advise the Assistant Secretary for Health on the following specific aspects of the Tuskegee Syphilis Study: Determine whether the study was justified in 1932 and whether it should have been continued when penicillin became generally available. Recommend whether the study should be continued at this point in time, and if not, how it should be terminated in a way consistent with the rights and health needs of its remaining participants. Determine whether existing policies to protect the rights of patients participating in health research conducted or supported by the Department of Health, Education, and Welfare are adequate and effective and to recommend improvements in these policies, if needed. Structure The Tuskegee Syphilis Study Ad Hoc Advisory Panel to the Assistant Secretary for Health consists of nine members, including the Chairman, not otherwise in the full-time employ of the Federal Government. Members will be selected by the Assistant Secretary for Health from citizens representing medicine, law, religion, labor, education, health administration, and public affairs. The Chairman is designated by the Assistant Secretary for Health. The Panel members will be invited to serve for a period not to extend beyond March 31, 1973, unless an extension beyond that time is approved by the Assistant Secretary for Health. Management and staff services will be provided by the Office of the Assistant Secretary for Health which supplies the Executive Secretary. Meetings Meetings will be held at the call of the Chairman, with the advance approval of a Government official who shall also approve the agenda. A Government official will be present at all meetings. Meetings are open to the public except as determined otherwise by the Secretary; notice of all meetings is given to the public. Meetings are conducted, and records of the proceedings kept as required by applicable laws and Departmental regulations. Compensation Members who are not full-time Federal employees will be paid at the rate of $100 per day for time spent at meetings, plus per diem and travel expenses in accordance with Standard Government Travel Regulations. Annual Cost Estimate Estimated annual cost for operating the committee, including compensation and travel expenses of members but excluding staff support, is $74,000. Estimate of annual man years of staff support required is one year at an estimated annual cost of $16,000. Report A final report based on the Panel's investigation will be made to the Assistant Secretary for Health, not later than April 30, 1973, which contains as a minimum a list of members and their business addresses, the dates and places of meetings, and a summary of the Panel's activities and recommendations. A copy of this report shall be provided to the Department Committee Management Officer. Termination Date Unless renewed by appropriate action prior to its expiration, the Tuskegee Syphilis Study Ad Hoc Advisory Panel to the Assistant Secretary for Health will terminate on March 31, 1973. APPROVED: 1/4/73 (sgd.) Richard L. Seggel Date Acting Assistant Secretary for Health 2 P A N E L M E M B E R S Seward Hiltner, Phd.,D.D. Chairman: Professor Theology Broadus N. Butler, Ph.D. Princeton Theological Seminary President, Dillard University Princeton, New Jersey 08540 2601 Gentilly Boulevard New Orleans, Louisiana 70122 Jay Katz, M.D. Professor (adjunct) Members: of Law and Psychiatry Yale Law School Mr. Ronald H. Brown 127 Wall Street General Counsel New Haven, Connecticut 06520 National Urban League 55 East 52nd Street Jeanne C. Sinkford, D.D.S. New York, New York 10022 Associate Dean for Graduate and Post graduate Affairs Vernal Cave, M.D. College of Dentistry Director, Bureau of Venereal Howard University Disease Control 600 W Street, N. W. New York City Health Department Washington, D. C. 20001 93 Worth Street New York, New York 10022 Jean L. Harris, M.D., F.R.S.H. Mr. Fred Speaker Executive Director Attorney at Law National Medical Association 2 North Market Square Foundation, Inc. Harrisburg, Pennsylvania 17108 1150 17th Street, N.W. Washington, D.C. 20036 Mr. Barney H. Weeks President, Alabama Labor Council AFL-CIO 1018 South 18th Street Birmingham, Alabama 35205 3 MEETINGS Subcommittee Meeting on TUSKEGEE SYPHILIS STUDY AD HOC Charge III ADVISORY PANEL National Institute of Health Bethesda, Maryland 7. December 19, 1972 1. September 22, 1972 Panel Meeting Subcommittee Meeting on National Institute of Health Charge III Bethesda, Maryland Holiday Inn - La Guardia Airport New York, New York 8. January 24, 1973 2. September 27, 1972 Subcommittee Meeting on Charge Panel Meeting III National Institute of Health 55 East 52nd Street Bethesda, Maryland New York, New York 3. October 25, 1972 9. February 23, 1973 Panel Meeting Subcommittee Meeting on Charge National Institute of Health National Institute of Health Bethesda, Maryland Bethesda, Maryland 4. November 2, 1972 10. March 1, 1973 Panel Meeting Panel Meeting National Institute of Health Parklawn Building Bethesda, Maryland Rockville, Maryland 5. November 30, 1972 11. March 20, 1973 Panel Meeting Subcommittee Meeting Charge III National Institute of Health 26 Federal Plaza Bethesda, Maryland New York, New York 6. December 18, 1972 12. March 28, 1973 Subcommittee Meeting on Panel Meeting Charge I National Institute of Health Bethesda, Maryland 4 REPORT ON CHARGE I April 24, 1973 Tuskegee Sypilis Study Ad Hoc Advisory Panel Acknowledgements Subcommittee for Charge I The Co-Chairmen wish to acknowledge the input of members of the subcommittee and panel members whose input and deliberations were essential to the final report for Charge l: Members of the Subcommittee for Charge l Mr. Ronald H. Brown Mr. Vernal Cave Mr. Barney H. Weeks Dr. Jean L. Harris, Co-Chairman Dr. Jeanne C. Sinkford, Co-Chairman and Mr. Fred Speaker, Panel Member Also, our sincere appreciation to staff members who assisted in editing, typing and distributing the final report: Dr. Robert C. Backus Mrs. Bernice M. Lee Mrs. Jacqueline Eagle 5 FINAL REPORT TUSKEGEE SYPHILIS STUDY AD HOC ADVISORY PANEL REPORT ON CHARGE I-A Statement of Charge I-A: Determine whether the study was justified in 1932 Background Data The Tuskegee Study was one of several investigations that were taking place in the 1930's with the ultimate objective of venereal disease control in the United States. Beginning in 1926, the United States Public Health Service, with the cooperation of other organizations, actively engaged in venereal disease control work.1 In 1929, the United States Public Health Service entered into a cooperative demonstration study with the Julius Rosewald fund and state and local departments of health in the control of venereal disease in six southern states2: Mississippi (Bolivar County); Tennessee (Tipton County); Georgia (Glynn County); Alabama (Macon County); North Carolina (Pitt County); Virginia (Albermarle County). These syphilis control demonstrations took place from 1930-1932 and disclosed a high prevalence of syphilis (35%) in the Macon County survey. Macon County was 82.4% Negro. The cultural status of this Negro population was low and the illiteracy rate was high. During the years 1928-1942 the Cooperative Clinical Studies in the Treatment of Syphilis3 were taking place in the syphilis clinics of Western Reserve University of Pennsylvania, and the University of Michigan. The Division of Venereal Disease, USPHS provided statistical support, and financial support was provided by the USPHS and a grant from the Milbank Memorial Fund. These studies included a focus on effects of treatment in latent syphilis which had not been clinically documented before 1932. A report issued in 1932 indicated a satisfactory clinical outcome in 35% of untreated latent syphilitics. The findings of Bruusgaard of Oslo on the results of untreated syphilis became available in 19294. The Oslo study was classic retrospective study involving the analysis of 473 patients at three to forty years after infection. For the first time, as a result of the Oslo study, clinical data were available to suggest the probability of spontaneous cure, continued latency, or serious or fatal outcome. Of the 473 patients included in the Oslo study, 309 were living and examined and 164 were deceased. Among the 473 patients, 27.7 percent were clinically free from symptoms and Wassermann negative; 14.8 percent had no clinical symptoms with Wassermann positive; 14.1 percent had heart and vessel disease; 2.76 percent had general paresis and 1.27 percent had tabes dorsalis. Thus in 1932, as the Public Health Service put forth a major effort toward control and treatment, much was still unknown regarding the latent stages of the disease especially pertaining to its natural course and the epidemiology of late and latent syphilis. Facts and Documentation Pertaining to Charge I-A 1. There is no protocol which documents the original intent of the study. None of the literature searches or interviews with participants in the study gave any evidence that a written protocol ever existed for this study. The theories postulated from time to time include the following purposes either by direct statement or implication:5-7 a. Study of the natural history of the disease. b. Study of the course of treated and untreated syphilis (Annual Report of the Surgeon General of the Public Health Service of the United States 1935-36). c. Study of the differences in histological and clinical course of the disease in black versus white subjects. d. Study with an "acceptance" of the postulate that there was a benign course of the disease in later stages vis-a- vis the dangers of available therapy. e. Short term study (6 months or longer) of the incidence and clinical course of late latent syphilis in the Negro male (From letter of correspondence from T. Clark, Assistant Surgeon General, to M.M. Davis of the Rosenwald Fund, October 29, 1932) --Original plan of procedure is stated herein. f. A Study which would provide valuable data for a syphilis control program for a rural impoverished community. In the absence of an original protocol, it can only be assumed that between 1932 and 1936 (when the first report5 of the study was made) the decision was made to continue the study as a long-term study. The Annual Report of the Surgeon General for 1935-36 included the statement: "Plans for the continuation of this study are underway. During the last 12 months, success has been obtained in gaining permission for the performance of autopsies on 11/15 individuals who died." 2. There is no evidence that informed consent was gained from the human participants in this study. Such consent would and should have included knowledge of the risk of human life for the involved parties and information re possible infections of innocent, 6 nonparticipating parties such as friends and relatives. Reports such as "Only individuals giving a history of infection who submitted voluntarily to examination were included in the 399 cases" are the only ones that are documentable.5 Submitting voluntarily is not informed consent. 3. In 1932, there was a known risk to human life and transmission of the disease in latent and late syphilis* was believed to be possible. Moore 3 1932 reported satisfactory clinical outcome in 85% of patients with latent syphilis that were treated in contrast to 35% if no treatment is given. 4. The study as announced and continually described as involving "untreated" male Negro subjects was not a study of "untreated" subjects. Caldwell8 in 1971 reported that: All but one of the originally untreated syphilitics seen in 1968-1970 have received therapy, although heavy metals and/or antibiotics were given for a variety of reasons by many non-study physicians and not necessarily in doses considered curative for syphilis. Heller6 in 1946 reported "about one-fourth of the syphilitic individuals received treatment for their infection. Most of these, however, received no more than 1 or 2 arsenical injections; only 12 received as many as 10." The "untreated" group in this study is therefore a group of treated and untreated male subjects. 5. There is evidence that controL subjects who became syphilitic were transferred to the "untreated" group. This data is present in the patient files at the Center for Disease Control in Atlanta. Caldwell8 reports 12 original controls either acquired syphilis or were found to have reactive treponemal tests (unavailable prior to 1953). Heller,6 also, reported that "it is known that some of the control group have a acquired syphilis although the exact number cannot be accurately determined at present." Since this transfer of patients from the control group to the syphilitic group did occur, the study is not one of late latent syphilis. Also, it is not certain that this group of patients did in fact receive adequate therapy. 6. In the absence of a definitive protocol, there is no evidence of assurance that standardization of evaluative procedures, which are essential to the validity and reliability of a scientific study, existed at any time. This fact leaves open to question the true scientific merits of a longitudinal study of this nature. Standardization of evaluative procedures and clinical judgment of the investigators are considered essential to the valid interpretation of clinical data.9 It should be noted that, in 1932, orderly and well planned research related to latent syphilis was justifiable since a. Morbidity and * Vonderlehr to T. Clark - Memorandum - June 10, 1932. ------- mortality had not been documented for this population and the significance of the survey procedure had just been reported in findings of the prevalence studies for 6 southern counties;1 b. Epidemiologic knowledge of syphilis at the time had not produced facts so that it could be scientifically documented "just how and at what stage the disease is spread."* c. There was a paucity of knowledge re clinical aspects and spontaneous cure in latent syphilis3 and the Oslo study4 had just reported spontaneous remission of the disease in 27.7% of the patients studied. If perhaps a higher "cure" rate could have been documented for the latent syphilitics, then the treatment priorities and recommendations may have been altered for this community where funds and medical services were already inadequate. The retrospective summary of the "Scientific Contributions of the Tuskegee Study" from the Chief, Venereal Disease Branch, USPHS (dated November 21, 1972) includes the following merits of the study: "Knowledge already gained or potentially able to be gained from this study may be categorized as contributing to improvements in the following areas: 1. Care of the surviving participants, 2. Care of all persons with latent syphilis 3. The operation of a national syphilis control program 4. Understanding of the disease of syphilis. 5. Understanding of basic disease producing mechanisms." Panel Judgments on Charge 1-A 1. In retrospect, the Public Health Service Study of Untreated Syphilis in the Male Negro in Macon Country, Alabama, was ethically unjustified in 1932. This judgment made in 1973 about the conduct of the study in 1932 is made with the advantage of hindsight acutely sharpened over some forty years,concerning an activity in a different age with different social standards. Nevertheless one fundamental ethical rule is that a person should not be subjected to avoidable risk of death or physical harm unless he freely and intelligently consents. There is no evidence that such consent was obtained from the participants in this study. 2. Because of the paucity of information available today on the manner in which the study was conceived, designed and sustained, a scientific justification for a short term demonstration study cannot be ruled out. However, the conduct of the longitudinal study as initially reported in 1936 and through the years is ------- *Letter from L. Usilton, VD Program 1930-32 and memorandum from Vonderienr to T. Clark (Assistant surgeon General) June 10, 1932. 7 judged to be scientifically unsound and its results are disproportionately meager compared with known risks to human subjects involved. Outstanding weaknesses of this study, supported by the lack of written protocol, include lack of validity and reliability assurances; lack of calibration of investigator responses; uncertain quality of clinical judgments between various investigators; questionable data base validity and questionable value of the experimental design for along term study of this nature. The position of the Panel must not be construed to be a general repudiation of scientific research with human subjects. It is possible that a scientific study in 1932 of untreated syphilis, properly conceived with a clear protocol and conducted with suitable subjects who fully understood the implications of their involvement, might have been justified in the pre-penicillin era. This is especially true when one considers the uncertain nature of the results of treatment of late latent syphilis and the highly toxic nature of therapeutic agents then available. 8 REPORT ON CHARGE 1-B Statement of Charge 1-B: Determine whether the study should have been continued when penicillin became generally available. Background Data In 1932, treatment of syphilis in all stages was being provided through the use of a variety of chemotherapeutic agents including mercury, bismuth, arsphenamine, neoarsphenamine, iodides and various combinations thereof. Treatment procedures being used in the early 1930's extended over long periods of time (up to two years) and were not without hazard to the patient.10 As of 1932, also treatment was widely recommended and treatment schedules specifically for late latent syphilis were published and in use.3 10 The rational for treatment at that time was based on the clinical judgment "that the latent syphilis patient must abe regarded as potential carrier of the disease and should be treated for the sake of the Community's health."3 The aims of treatment in the treatment of latent syphilis were stated to be: 1) to increase the probability of "cure" or arrest, 2) to decrease the probability of progression or relapse over the probable result if no treatment were given and 3) the control of potential infectiousness from contact of the patient with adults of either sex, or in the case of women with latent syphilis, for unborn children. According to Pfeiffer (1935, 11 treatment of late syphilis is quite individualistic and requires the physician's best judgment based upon sound fundamental knowledge of internal medicine and experience, and should not be undertaken as a routine procedure. Thus, treatment was being recommended in the United States for all stages of syphilis as of 1932 despite the "spontaneous" cure concept that was being justified by interpretations of the Oslo study, the potential hazards of treatment due to drug toxicity and to possible Jarisch-Herxheimer reactions in acute late syphilis.12 Documented reports of the effects of penicillin in the 1940's and early 1950's vary from outright support and endorsement of the use of penicillin in late and latent syphilis, 13-15 to statements of possible little or no value, 16-17 to expressions of doubts and uncertainty 18-19 related to its value, the potency of penicillin, absence of control of the rate of absorption, and potential hazard related to severe Herxheimer effects. Although the mechanism of action of penicillin is not clear from available scientific reports of late latent syphilis, the therapeutic benefits were clinically documented by the early 1950's and have been widely reported from the mid 1950's to the present. In fact, the Center for Disease Control of the USPHS has reported treatment of syphilitic mothers in all stages of infection with penicillin as of 195320 and has demonstrated that penicillin is the most effective treatment yet known for neurosyphilis(1960).21 Facts and Documentation re Charge 1-B 1. Treatment schedules recommending the use of arsenical and bismuth in the treatment of late latent syphilis were available in 1932.3 Penicillin therapy was recommended for treatment of late latent syphilis in the late 1940's14-15 which was before it became readily available for public use (estimated to have be 1952-53). 2. It was "known as early as 1932 that 85% of patients treated in late latent syphilis would enjoy prolonged maintenance of good health and freedom from disease as opposed to 35 percent if left untreated."3 Scientists in this study,5 reported in 1936, that morbidity in male Negroes with untreated syphilis far exceeds that in a comparable non-syphilitic group and that cardiovascular and central nervous system involvements were two to three times as common. Moreover, Wenger,22 in 1950, reported: "We know now, where we could only surmise before, that we have contributed to their ailments and shortened their lives. I think the least we can say is that we have a high moral obligation to those that have died to make this the best study possible." The effect of syphilis in shortening life was published from observations made by Usilton et al. in 1937.23 The study by Rosahn24 at Yale in 1947 reported strong clinical evidence that syphilis ran a more fatal course in Negroes than in Caucasians. 3. Reports regarding the withholding of treatment from patients in this study are varied and are still subject to controversy. Statements received from personal interviews conducted by Panel members with participants in this study cannot be considered as conclusive since there are varied opinions concerning what actually happened. In written letters and in open interviews, the panel received reports that treatment was deliberately withheld on the one hand and on the other, we were told that individuals seeking treatment were not denied treatment (in transcript and correspondence documents). What is clearly documentable (in a sense of letters between Vonderiehr and Health officials in Tuskegee taking place between February 1941 and August 1942) is that known seropositive, untreated males under 45 years of age from the Tuskegee Study had been called for army duty and rejected on account of positive blood. The local board was furnished with a list of 256 9 names of men under 45 years of age and asked that these men be excluded from the list of draftees needing treatment! According to the letters, the board agreed with this arrangement in order to make it possible to continue this study on an effective basis. It should be noted that some of these patients had already received notices from the Local Selective Service Board "to begin their antisyphilitic treatment immediately." According to Wenger,22 the patients in the study "received no treatment on our recommendation." At the present time, we know that most of the participants in this study received some form of treatment with heavy metals and/or antibiotics.8 Although the adequacy of treatment received is not known, it is clear that the treatment received was provided by physicians who were not a part of the study and who were individually sought by the individual patients related to their own medical symptoms and pursuit of treatment. 4. The five survey periods in this study occurred in 1932, 1938- 39, 1948, 1952-53 and 1968-70.8-25 This study lacks continuity except through the public health nurse and at these isolated survey periods. In 1969 an Ad Hoc Committee reviewed the Tuskegee Study with the purpose: to examine data from the Tuskegee Study and offer advice on continuance of this study. Participants of the February 6, 1969 meeting included: Committee Members: Dr. Gene Stollerman Chairman, Dept. of Medicine University of Tennessee, Memphis Dr. Johannes Ipsen, Jr. Professor Dept. of Community Medicine University of Pennsylvania, Philadelphia Dr. Ira Myers State Health Officer Montgomery Dr. J. Lawton Smith Associate Professor or Ophthalmology University of Miami Dr. Clyde Kaiser Senior Member Technical Staff Milbank Memorial Fund New York City Resource Persons: Dr. Bobby C. Brown, VDRL,NCDC Mrs. Eleanor V. Price, VD Branch, NCDC Dr. Joseph Caldwell, VD Branch, NCDC Dr. Paul Cohen, VDRL,NCDC Dr. Sidney Olansky Professor of Medicine Dept. of Internal Medicine Emory University Clinic, Atlanta Recorders: Dr. Leslie C. Norins Chief, VDRL, NCDC Mrs. Doris J. Smith Secretary to Dr. Norins, VDRL, NCDC Attending: Dr. David J. Sencer Director, NCDC Dr. William J. Brown Chief, VD Branch, NCDC Dr. U.S.G. Kuhn,III, VDRL,NCDC Miss Genevieve W. Stout, VDRL, NCDC Dr. H. Bruce Dull Assistant Director, NCDC The meeting was convened at 1:00 p.m. and adjourned at 4:10 p.m. A summary report of the meeting includes the following: The purpose of the meeting was to determine if the Tuskegee Study should be terminated or continued. Considerations were: 1. How the study was setup in 1932 2. Are the participants all available 3. How are the survivors faring At the time of this study there were only seven patients whose primary cause of death was ascribed to syphilis. It was determined that benefits to be achieved from the study at this time were: 1. Relationship of serology to morbidity from syphilis 2. Relationship of known pathology to syphilis 3. Various epidemiological considerations Full treatment of the survivors was also considered and the following liabilities listed. Danger of late Herxheimer's reaction which would worsen or possibly kill those syphilitic patients suffering cardiovascular or neurological conditions. At this time it was mentioned that both Macon County Health Department and Tuskegee Institute were cognizant of the study. The meeting was terminated with several salient points. 10 1. This type of study would never be repeated. 2. There were certain medical facts to be learned by continuing the present study. 3. Treatment for these patients was not indicated unless they had signs of active syphilitic disease. 4. More contact should be established between PHS and Macon County Health Department and Medical Society so they would cooperate in the continuance of the study. It should be noted that the Committee was eminently represented from the medical community. However, legal representatives and others from the non-medical community of scholars were not adequately represented for so sensitive a study. This is especially true since the Tuskegee Study was being continued at a time when Department of Health, Education, and Welfare guidelines for the Protection of Human Subjects were being widely disseminated for the compliance by all institutions receiving grant support. The three hours and ten minutes were not adequate for in-depth study of the broad issues, implications and ramifications of this study. In 1970, Drs. Anne Yobs and Arnold L. Schroeter in separate memoranda (to the Director, Center for Disease Control and to the Chief, Venereal Disease Branch) recommended procedures for orderly termination of this study. Dr. James Lucas, Assistant Chief of the Venereal Disease Branch, in a memorandum to the Chief of the Venereal Disease Branch dated September 10, 1970 states: It must be full realized that the remaining contribution from this study will be largely of historical interest. Nothing learned will prevent, find, or cure a single case of infectious syphilis or bring us closer to our basic mission of controlling venereal disease in the United States. 5. There is a crucial absence of evidence that patients were give a "choice"of continuing in the study once penicillin became readily available. This fact serves to amplify the magnitude of encroachment on the human lives and well-being of the participants in this study. This is especially significant when there is uncertainty as to the whole issue of "consent" of the participants. Panel Judgments on Charge I-B The ethical, legal and scientific implications which are evoked from the facts presented in the previous section led the Panel to the following judgment: That penicillin therapy should have made available to the participants in this study especially as of 1953 when penicillin became generally available. Withholding of penicillin, after it became generally available, amplified the injustice to which this group of human beings had already been subjected. The scientific merits of the Tuskegee Study are vastly overshadowed by the violation of basic ethical principles pertaining to human dignity and human life imposed on the experimental subjects. 11 REPORT ON CHARGE 1 SUMMARY This section of the Advisory Panel's report deals specifically with Charge codes I-A and I-B. Statement of Charge Codes Charge I-A. Determine whether the study was justified in 1932, and Charge I-B. Determine whether it should have been continued when penicillin became generally available. Introduction The Background Paper on the Tuskegee Study, prepared by the Venereal Disease Branch of the Center for Disease Control, July 27, 1972, included the following statements: "Because of the lack of knowledge of the pathogenesis of syphilis, a long-term study of untreated syphilis was considered desirable in establishing a more knowledgeable syphilis control program." "A prospective study was begun late in 1932 in Macon County, Alabama, a rural area with a static population and a high rate of untreated syphilis. An untreated population such as this offered an unusual opportunity to follow and study the disease over a long period of time. In 1932, a total of 26 percent of the male population tested, who were 25 years of age or older, were serologically reactive for syphilis by at least two tests, usually on two occasions. The original study group was composed of 399 of these men who had received no therapy and who gave historical and laboratory evidence of syphilis which had progressed beyond the infectious stages. A total of 201 men comparable in age and environment and judged by serology, history, and physical examination to be free of syphilis were selected to be the control group." Panel Conclusions re Charge 1-A and I-B of the Tuskegee Study After extensive review of the available documents, interviews with associated parties and pursuit of various other avenues of documentation, the Panel concludes that: 1. In retrospect, the Public Health Service Study of Untreated Syphilis in the Male Negro in Macon County, Alabama was ethically unjustified in 1932. 2. Because of the paucity of information available today on the manner in which the study was conceived, designed and sustained, scientific justification for short-term demonstration study in 1932 cannot be ruled out. However, the conduct of the longitudinal study as initially reported in 1936 and through the years is judged to be scientifically unsound and its results are disproportionately meager compared with known risks to the human subjects involved. 3. Penicillin therapy should have been made available to the participants in this study not later than 1953. The Panel qualifies its conclusions with several position statements summarized as follows: a. The judgements in 1973 about the conduct of the Tuskegee Study in 1932 are made with the advantage of hindsight, acutely sharpened over some forty years concerning an activity in a different age with different social standards. Nevertheless one fundamental ethical rule is that a person should not be subjected to avoidable risk of death or physical harm unless he freely and intelligently consents. There was no evidence that such consent was obtained from the participants in this study. b. History has shown that certain people under psychological, social or economic duress are particularly acquiescent. These are the young, the mentally impaired, the institutionalized, the poor and persons of racial minority and other disadvantaged groups. These are the people who may be selected for human experimentation and who, because of their station in life, may not have an equal chance to withhold consent. c. The Tuskegee Syphilis Study, placed in the perspective of its early years, is not an isolated event in terms of the generally accepted conditions and practices that prevailed in the 1930's. d. The position of the Panel must not be construed to be a general repudiation of scientific research with human subjects. It is possible that a scientific study in 1932 of untreated syphilis, properly conceived with a clear protocol and conducted with suitable subjects who full understood the implications of their involvement, might have been justified int he pre-penicillin era because of the uncertain nature of results of treatment of late latent syphilis with the highly toxic therapeutic agents then available. REFERENCES 1. Clark, T. The Control of Syphilis in Southern Rural Areas. Julius Rosenwald Fund, Chicago, 1932. p. 27 2. Ibid. pp.6-36 3. Moore, Joseph Earle. Latent Syphilis Cooperative Clinical Studies in the Treatment of Syphilis. Reprint No. 45 from Venereal Disease Information, Vol XIII, Nos. 8-12, 1932 and Vol XIV, No. 1, 1933 pp. 1-56. 12 4. Bruusgaard, E. The Fate of Syphilitics Who are not Given Specific Treatment. Archiv tur Dermatologie und Syphilis 1929, 157, p. 309. 5. Vonderlehr, R.A. et al. Untreated Syphilis in the Male Negro. Venereal Disease Information 17:260-265, 1936. 6. Heller, J.R. and Bruyere, P.T.: Untreated Syphilis in Male Negro: II. Mortality During 12 Years of Observation. Venereal Disease Information 27: 34-38, 1946. 7. Shafer, J.K., Usilton, L.J., and Gleason, G.A. Untreated Syphilis in Male Negro: Prospective Study of Effect on Life Expectancy. Public Health Reports 69:684-690, 1954 Milbank Memorial Fund Quarterly. 32:262-274, July 1954. 8. Caldwell, J.G., Price, E.V., Shroeter, A.L. and Fletcher, G.F. Aortic Regurgitation in a Study of Aged Males with Previous Syphilis. Presented in part at American Venereal Disease Association Annual Meeting, 22 June 1971. 9. Feinstein, A.R. Clinical Judgment. Baltimore, William and Wilkins Co., 1967, pp. 45-48 10. Gaupin, C.E. The Treatment of Latent Syphilis. Kentucky Medical Journal 30: 74-77, February 1932. 11. Pfeiffer, A. Medical Aspects in the Prevention and Management of Late and Latent Syphilis, Psychiatric Quarterly 9:185-193, April 1935. 12. Greenbaum, S.C. The "Bismuth Approach" in the Treatment of Acute (late) Syphilis. Journal of Chemotherapy 13: 5-8, April 1936. 13. Stokes, J.H. et al. The Action of Penicillin in Late Syphilis. J.A.M.A. 126: 73-79, September 1944. 14. Dexter, D.C. and Tucker, H.A. Penicillin Treatment of Benign Late Gummaatous Syphilis, Report of Twenty-one Cases. American Journal of Syphilis, Gonorrhea, and Venereal Disease 30: 211-226, May 1946. 15. Committee on Medical Research: The Changing Character of Commercial Penicillin with Suggestions as to the Use of Penicillin in Syphilis. U.S. Health Service and Food and Drug Administration. J.A.M.A. 131: 271-275, May 1946. 16. Barnett, C.W. The Publich Health Aspects of Late Latent Syphilis. Stanford Medical Bulletin 10: 152-156, August 1952. 17. Reynolds, F.W. Treatment Failures Following the Use of Penicillin in Late Syphilis. American Journal of Syphilis, Gonorrhea, and Venereal Disease 32:233-242, May 1948. 18. McElligott, G.L.M. The Management of Late and Latent Syphilis. British Medical Journal 1:829-830, April 1953. 19. Barnett, C.W. Epstein, N.J., Brewer, A.F. et al. Effect of Treatment in Late Latent Syphilis. Arch Dermat Syph 69: 91- 99, January 1954. 20. VD Fact Sheet. No. 10. U.S. Publich Health Service Publication, December 1953, p. 20. 21. VD Fact Sheet. No. 17. U.S. Public Health Service Publication, December 1960, p. 19. 22. Wenger, O.C. Untreated Syphilis in Negro Male. Hot Springs Seminar, 9-18-50 (From CDC Files) 23. Usilton, L. et al. A Tentative Death Curve for Acquired Syphilis in White and Colored Males in the United States. Venereal Disease Information 18: pp. 231-234, 1937. 24. Rosahn, P.D. Autopsy Studies in Syphilis. Journal of Venereal Disease Information 28: Supplement No. 21, pp. 32-39, 1949. 25. Rivers, E. Schuman, S., Simpson, L., and Olansky, S. Twenty Years of Follow-up Experience in a Long Range Medical Study. Public Health Reports 68: (4), 391-395, April 1953. Respectfully Submitted, Ronald H. Brown Jean L. Harris, MD Seward Hiltner, PhD., D.D. Jeanne C. Sinkford, D.D.S., Ph.D. Fred Speaker Barney H. Weeks Approval with Reservations (See addendum for reservation statement) Jay Katz, M.D. Vernal Cave, M.D. Abstention: Broadus N. Butler, Ph.D. 13 YALE LAW SCHOOL NEW HAVEN, CONNECTICUT 06520 TO: THE ASSISTANT SECRETARY FOR HEALTH AND SCIENTIFIC AFFAIRS FROM: JAY KATZ, M.D. TOPIC: RESERVATIONS ABOUT THE PANEL REPORT ON CHARGE 1 I should like to add the following findings and observations to the majority opinion: (1) There is ample evidence in the records available to us that the consent to participation was not obtained from the Tuskegee Syphilis Study subjects, but that instead they were exploited, manipulated, and deceived. They were treated not as human subjects but as objects of research. The most fundamental reason for condemning the Tuskegee Study at its inception and throughout its continuation is not that all the subjects should have been treated, for some might not have wished to be treated, but rather that they were never fairly consulted about the research project, its consequences for them, and the alternatives available to them. Those who for reasons of intellectual incapacity could not have been so consulted should not have been invited to participate in the study in the first place. (2) It was already known before the Tuskegee Syphilis Study was begun, and reconfirmed by the study itself, that persons with untreated syphilis have a higher death rate than those who have been treated. The life expectancy of at least forty subjects in the study was markedly decreased for lack of treatment. (3) In addition, the untreated and the "inadvertently" (using the work frequently employed by the investigators) but inadequately treated subjects suffered many complications which could have been ameliorated with treatment. This fact was noted on occasion in the published reports of the Tuskegee Syphilis Study and as late as 1971. However, the subjects were not apprised of this possibility. (4) One of the senior investigators wrote in 1936 that since "a considerable portion of the infected Negro population remained untreated during he entire course of syphilis, an unusual opportunity (arose) to study the untreated syphilitic patient from the beginning of the disease to the death of the infected person." Throughout, the investigators seem to have confused the study with an "experiment in nature." But syphilis was not a condition for which no beneficial treatment was available, calling for experimentation to learn more about the condition in the hope of finding a remedy. The persistence of the syphilitic disease from which the victims of the Tuskegee Study suffered resulted from the unwillingness or incapacity of society to mobilize the necessary resources for treatment. The investigators, the USPHS, and the private foundations who gave support to this study should not have exploited this situation in the fashion they did. Unless they could have guaranteed knowledgeable participation by the subjects, they all should have disappeared from the research scene ore else utilized their limited research resources for therapeutic ends. Instead, the investigators believed that the persons involved in the Tuskegee Study would never seek out treatment; a completely unwarranted assumption which ultimately led the investigators deliberately to obstruct the opportunity for treatment of a number of the participants. (5) In theory if not in practice, it has long been "a principle of medical and surgical morality (never to perform) on man an experiment which might be harmful to him at any extent, even though the result might be highly advantageous to science"" (Claude Bernard 1865), at least without the knowledgeable consent of the subject. This was one basis on which the German physicians who had conducted medical experiments in concentration camps were tried by the Nuremberg Military Tribunal for crimes against humanity. Testimony at their trial by official representatives of the American Medical Association clearly suggested that research like the Tuskegee Syphilis Study would have been intolerable in this country or anywhere in the civilized world. yet the Tuskegee study was continued after the Nuremberg findings and the Nuremberg Code had been widely disseminated to the medical community. Moreover, the study was not reviewed in 1966 after the Surgeon General of the USPHS promulgated his guidelines for the ethical conduct of research, even though this study was carried on within the purview of his department. (6) The Tuskegee Syphilis Study finally was reviewed in 1969. A lengthier transcript of the proceedings, not quoted by the majority, reveals the tone of the five members of the reviewing committee repeatedly emphasized that a moral obligation existed to provide treatment for the "patients". His plea remained unheeded. Instead the Committee, which was in part concerned with the possibility of adverse criticism, seemed to be reassured by the observation that "if we established good liaison with the local medical society, there would be no need to answer criticism." (7) The controversy over the effectiveness and the dangers of arsenic and heavy metal treatment in 1932 and of penicillin treatment when it was introduced as a method of therapy is beside the point. For the real issue is that the participants in this study were never informed of the availability of treatment because 14 the investigators were never in favor of such treatment. Throughout the study the responsibility rested heavily on the shoulders of the investigators to make every effort to apprise the subjects of what could be done for them if they so wished. In 1937 the then Surgeon General of the USPHS wrote: "(f) or late syphilis no blanket prescription can be written. Each patient is a law unto himself. For every syphilis patient, late and early, a careful physical examination is necessary before starting treatment and should be repeated frequently during its course." Even prior to that, in 1932, ranking USPHS physicians stated in a series of articles that adequate treatment "will afford a practical, if not complete guaranty of freedom from the development of any late lesions.." In conclusion, I note sadly that the medical profession, through its national association, its many individual societies, and its journals, has on the whole not reacted to this study except by ignoring it. One lengthy editorial appeared in the October 1972 issue of the Southern Medical Journal which exonerated the study and chastised the "irresponsible press" for bringing it to public attention. When will we take seriously our responsibilities, particularly to the disadvantaged in our midst who so consistently throughout history have been the first to be selected for human research? Respectfully submitted, (sgd) Jay Katz, M.D. 15 REPORT ON CHARGE Il Transmittal Note from Chairman of Subcommittee on Charge II This report on Charge II was prepared by the Subcommittee on Charge II (Ronald H. Browns J.D., Jean L. Harris, M.D., F.R.S.H., Jay Katz, M.D., F.A.C.P., Fred Speaker, J.D., Jeanne C. Sinkford, D.D.S. PhD., Secretary, Vernal G. Cave, M.D., F.A.C.P., Chairman). The provisional basis for this report which was the result of the earliest deliberations the panel dealt with is now amply substantiated by our documentations, conclusions, and recommendations under Charges I and III. On behalf of the entire subcommittee, the Chairman expresses deep thanks and appreciation for their splendid cooperation to Dr. Robert C. Backus, Mr. Robert Rawles, Mr. James Morant, Mrs. Jacqueline Eagle, and Mrs. Bernice M. Lee. 16 LETTER OF TRANSMISSION October 27, 1972 Merlin K. DuVal, M.D. Assistant Secretary for Health and Scientific Affairs Department of Health, Education, and Welfare Washington, D.C. 20201 Dear Dr. DuVal: As Chairman of the Tuskegee Syphilis Study Ad Hoc Advisory Panel, I enclose our first report to you, relating only to the second charge of the three assigned to the Panel. Although one member of the Panel was in hospital on the day this report was put into form for transmission to you, her written suggestions concerning an earlier draft have been incorporated. Hence, the report represents concurrence of the Panel as a whole. You will note that our initial recommendations call for some very early steps on your part. We as a Panel, along with the excellent staff that is assisting our work, stand ready to help you to implement the recommendations in any way. It is our understanding, on the basis of the statements you made to us at out orientation meeting, that our reports to you, including this initial one, will be made public only by you whether or not you decide to accept and implement our recommendations. Since agreeing on the enclosed report, two-thirds of our Panel have been able to engage in a first-hand investigation for two days, in Macon County, Alabama. Nothing that we have discovered through this recent field visit has afforded us cause to alter any part of the enclosed report concerning the second charge. The first-hand investigation, brief as it has been, has provided us with information and new understandings that will prove of great value in our subsequent work on charges 1 and 3. Sincerely, (sgd.) Broadus N. Butler, Ph.D. Chairman Tuskegee Syphilis Study Ad Hoc Advisory Panel 17 October 25, 1972 INITIAL RECOMMENDATION OF THE TUSKEGEE SYPHILIS STUDY AD HOC ADVISORY PANEL The Charter of the Tuskegee Syphilis Study Ad Hoc Advisory Panel, issued on August 28, 1972, mandates advice on three specific aspects of the study of untreated syphilis initiated by the Public Health Service in 1932. Item two of three charges requires the Panel to: "Recommend whether the study should be continued at this point in time, and if not, how it should be terminated in a way consistent with the rights and health needs of its remaining participants." Initially, the Panel has limited its deliberations and recommendations exclusively to this charge, and the recommendations contained in this report are intended to respond solely to this specific issue. In determining our initial recommendations, the Panel has made inquiries which have led us to accept certain evidence outlined here. Though our research on the background conduct of the Tuskegee Syphilis Study has not been completed, the Panel is satisfied that in light of its preliminary findings, which will be full documented at a later date, the recommendations set forth below are fully justified. BACKGROUND Since 1932, under the leadership, direction and guidance of the Untied States Public Health Service, there has been a continuing study, centered in Macon County, Alabama, of the effect of untreated syphilitic infection in approximately 400 Black male human beings previously infected with syphilis as subjects. In the pursuit of this study approximately 200 Black male human beings without syphilis were followed as controls. No convincing evidence has been presented to this Panel that participants in this study were adequately informed about he nature of the experiment, either at its inception or subsequently. The United States Public Health Service from the onset of the study has maintained a continuous policy of withholding treatment for syphilis from the infected subjects. There was common medical knowledge, before this study, that untreated syphilitic infection produces disability and premature mortality. To date, including its earliest reports, this study has confirmed that untreated syphilitic infection produces disability and premature mortality. Since the late 1940's numerous medical authorities have recommended treatment for syphilis with penicillin in all stages of the disease, including late latent syphilis and tertiary syphilis. A technical and medical advisory panel convened in 1969 by the United States Public Health Service is reported to have recommended with some ambiguity, that the participants surviving at that time should not be treated. It is estimated that approximately 125 of the participants, including 50 of the controls, are still alive; and the current health status of the participants in the Tuskegee Study is not known. RECOMMENDATIONS I. Termination The study of untreated syphilis in Black males in Macon County, Alabama, now known as the "Tuskegee Syphilis Study", should be terminated immediately. With this most basic recommendation, the participants involved in this study are to be given the care now required to treat an disabilities resulting from their participation. In furtherance of this goal we recommend: A. That Select Specialists Group, composed of competent doctors and other appropriate persons, with experience in the problems arising from this study, be appointed by the Assistant Secretary for Health and Scientific Affairs, DHEW, no later than fifteen days after the adoption of these recommendations. B. That the members of the Select Specialists Group have had no prior involvement in the Tuskegee Syphilis Study. C. That the Select Specialists Group be composed of, but not necessarily be limited to, a dermatologist with experience in syphilogy who will serve as Chairman, tow internists (at least one of whom shall be a cardiologist), a radiologist, a neurologist, an ophthalmologist, a psychiatrist, a doctor of dental surgery, and a social worker. D. That the Select Specialists Group be solely charged to apply its expert diagnostic and therapeutic skills in order to safeguard the best interests of the participants and of others who may have been infected as a result of the withholding of treatment from the participants. E. That the Select Specialists Group be vested with the full legally permissible medical authority, medical supervision and medical judgment with regard to the treatment or referral of all of the surviving participants and others within and outside Macon County who may be identified, in cooperation with the 18 appropriate medical societies and Health Departments. F. That the Public Health Service immediately inform all surviving participants of the nature of their participation in the study, and the desire of the Public Health Service to assess their current health status. G. That the members of the "Subcommittee on Medical Care" of the Tuskegee Syphilis Study Ad Hoc Advisory Panel be ex-officio members of the Select Specialists Group to function primarily as liaison between the Select Specialists Group and the entire Panel. H. That on completion of its charge, the Select Specialists Group submit a detailed report about its activities to the Tuskegee Syphilis Study Ad Hoc Advisory Panel through its Chairman. This report shall include, but by no means be limited to, the reasons for administering or withholding penicillin and other drug treatment for syphilis from untreated participants who are infected with syphilis. I. That the highest priorities be given to this mission so that the charge to the Select Specialists Group shall be completed at the earliest possible date consistent with the best interests of the participants and the ethical responsibilities of the Department of Health, Education, and Welfare. II. Assessment, Treatment and Care A. That arrangements be made with all speed for the immediate health assessment, treatment and care of all persons included in the study in a suitably adequate facility easily accessible to the surviving participants. That whenever a participant expresses the wish to be cared for or treated by physicians of his own choice, such choices be respected and given all necessary support. B. That every effort be made to preserve confidentiality with respect to the identification of any participant. C. That the United States Public Health Service's epidemiologists be mobilized, on a highest priority basis, to assist in locating all surviving participants as well as others who may have been infected as a result of the withholding of treatment from the participants. III. Encouragement of Participation A. That adequate arrangements be provided for maintaining present standards of living during the evaluation and treatment periods in order to minimize any economic barriers to the cooperation of the participants. B. That at a minimum, any benefits which have been promised to the participants in the past continue to remain in effect. Respectfully submitted, Broadus N. Butler, Ph.D. Ronald H. Brown Vernal Cave, M.D. Jean L. Harris, M.D. Seward Hiltner, Ph.D., D.D. Jay Katz, M.D. Jeanne C. Sinkford, D.D.S., Ph.D. Fred Speaker Barney H. Weeks 19 October 27, 1972 TO: ASSISTANT SECRETARY FOR HEALTH AND SCIENTIFIC AFFAIRS FROM: JAY KATZ, M.D. SUBJECT: ADDENDUM TO PANEL REPORT ON CHARGE II I entirely concur in the Panel's recommendations and in the reasons given therefor. However, one additional piece of evidence lends even greater conviction, if any is still needed, to the decision to terminate the Tuskegee Syphilis Study. We have been informed that no scientific knowledge of any consequence would be derived form its continuation. The Panel felt that recording this fact might create the impression that it was the major reason for terminating the study. I believe that its inclusion should not, and would not, be so construed. There are cogent reasons for not dismissing the issue of scientific merit. As long as society continues to favor the pursuit of medical knowledge for the possible benefit of the patients participating in research or for the benefit of future patients, a balancing of risks and benefits is inevitable. We must acknowledge this reality in order to confront such questions as: Do we wish to preserve this balancing process and, if we do, how might we learn to minimize inevitable harm to subjects and science? We urgently need to establish an orderly process which will permit the assessment of the conflicting claims inherent in decisions to initiate, continue or terminate research projects. Such an assessment might proceed in four steps: (1) a relentless inquiry into the harmful consequences to the participants; (2) an appraisal fo the benefits which may accrue to science as well as to society: (3) a balancing of the risks to the participants against he benefits to them and/or science; and (4) an anticipatory rebuttal to the charge that either the interests of the participants or of science have not been sufficiently considered. In the light of the finding that no interests of science are surrendered by terminating the Tuskegee Syphilis Study, there is nothing to balance and nothing to rebut, and continuance of the study would for this reason alone be inadmissible. I appreciate that had the conclusion been otherwise, the study would in all probability still have to be terminated because of the other findings set fort in the Panel's report, findings which will be further explored in our deliberations with respect to Charge One ("whether the study was justified"). Moreover, I should note that the four factors, listed above, do not directly address themselves to such other important considerations as: who should be selected for research, what disclosures must be made to participants in research, etc. This will surely be considered in our response to Charge Three ("whether existing (research) policies are adequate and effective"). Finally, I also leave unconsidered for now another question which emerges from the finding of "no scientific merit": why was the study not terminated at a time prior to the appointment of this Panel? One of the benefits of including a finding of scientific merit in every assessment is that many more projects might be terminated sooner, because the reviewer would be hard pressed to make an affirmative finding on this issue. Respectfully submitted, (sgd.) Jay Katz, M.D. 20 REPORT ON CHARGE III TO: THE ASSISTANT SECRETARY FOR HEALTH FROM: TUSKEGEE SYPHILIS STUDY AD HOC ADVISORY PANEL TOPIC: FINAL REPORT ON CHARGE III I. INTRODUCTION In his third charge to the Tuskegee Syphilis Study Ad Hoc Advisory Panel, Dr. Merlin K. DuVal, the HEW Assistant Secretary for Health and Scientific Affairs, has asked us to determine whether existing policies to protect the rights of patients participating in health research conducted or supported by the Department of Health, Education, and Welfare are adequate and effective and to recommend improvements in these policies, if needed. Our response to this charge, embodied in this report, should not be viewed simply as a reaction to a single ethically objectionable research project. For the Tuskegee Syphilis Study, despite its widespread publicity was not an isolated phenomenon. We believe that the revelations from Macon County merely brought to the surface once again the unresolved problems which have long plagued medical research activities. Indeed, we hasten to add that although we refer to this report almost exclusively to physicians and to biomedical investigations, the issues we explore also arise int he context of non-medical investigations with human beings, conducted by psychologists, sociologists, educators, lawyers and others. The scope of the DHEW Policy on Protection of Human Subjects, broadened in 1971 to encompass such research , attests to the increasing significance of non-medical investigations with human beings. Our initial determination that the protection of human research subject is a current and widespread problem should not be surprising, especially in light of the recent Congressional hearings and bills focusing on the regulation of experimentation. In the past decade the press has publicized and debated a number of experiments which raised ethical questions: for example, the injection of cancer cells into aged patients at the Jewish Chronic Disease Hospital in Brooklyn, the deliberate infection of mentally retarded children with hepatitis at Willowbrook, the development of heart transplantation techniques, the enormous amount of drug research conducted in American prisons, the whole- body irradiation treatment of cancer patients at the University of Cincinnati, the advent and spread of "psychosurgery," and the Tuskegee Syphilis Study itself. With so many dramatic projects coming to the attention of the general public, more must lie beneath the surface. Evidence for this too has been forthcoming. In 1966, Dr. Henry K. Beecher, the eminent Dorr Professor of Research in Anesthesia at the Harvard Medical School, charged in the prestigious New England Journal of Medicine that "many of the patients (used in experiments which Dr. Beecher investigated and reported) never had the risk satisfactorily explained to them, and... further hundreds have not known that they were the subjects of an experiment although grave consequences have been suffered as the direct result.."1 Dr. Beecher concluded that "unethical or questionably ethical procedures are not uncommon."2 Quite recently this charge has been corroborated by the sociologist Bernard Barber and his associates, who interviewed biomedical researchers about their own research practices.3 Despite the expected tendency of researchers to minimize ethical problems in their own work, Barber et al. were able to conclude that "while the large majority fo our samples of biomedical researchers seems to hold and live up to high ethical standards, a significant minority may not."4 The problem of ethical experimentation is the product of the unresolved conflict between two strongly held values: the dignity and integrity of the individual, and the freedom of scientific inquiry. Professionals of many disciplines, and researchers especially, exercise unexamined discretion to intervene in the lives of their subjects for the sake of scientific progress. Although exposure to needless harm and neglect of the duty to obtain the subject's consent have generally been frowned upon in theory, the inflection of unnecessary harm and infringements on informed consent are frequently accepted, in practice, as the price to be paid for the advancement of knowledge. How have investigators come to claim this sweeping prerogative? If the answer to this question is that "society" has authorized professionals to choose between scientific progress and * This report was prepared by the Subcommittee on Charge III (Jay Katz, M.D., chairman, Ronald H. Brown, J.D., Seward Hiltner, Ph.D. and Fred Speaker, J.D.). The subcommittee chairman wishes to thank his research assistant Stephen H. Glickman, a third year law student at Yale University, for his valuable contributions to this report. Special thanks go also to Dr. Robert C. Backus, Mrs. Bernice M. Lee and Ms. Jackie Eagle who in many was facilitated the work of the subcommittee. 21 individual human dignity and welfare should not "society" retain some control over the research enterprise? We agree with the philosopher Hans Jonas that a slower progress in the conquest of disease would not threaten society, grievous as it is to those who have to deplore that their particular disease be not yet conquered, but that society would indeed be threatened by the erosion of those moral values whose loss, possibly caused by too ruthless a pursuit of scientific progress, would make its most dazzling triumphs not worth having.5 We have, as will be seen, made far-reaching recommendations for change. We do not propose these changes lightly. But throughout, in accordance with our mandate, our concern has not been just to define the ethical issues, but also to examine the structures and policies thus far devised to deal with those issues. In urging greater societal involvement in the research enterprise, we believe that the goal of scientific progress can be harmonized with the need to assure the protection of human subjects. ______________ 1. Beecher, "Ethics and Clinical Research," 274 New Eng. J. Med. 1354 (1966) 2. Ibid., p. 1355. 3. Barber,, Lally, Makarushka, and Sullivan, Research on Human Subjects: Problems of Social Control in Medical Experimentation (Russell Sage Foundation 1973) (hereinafter, Barber et al.) 4. Barber et al., supra, footnote 3, at 52. 5. Jonas, "Philosophical Reflections on Experimenting with Human Subjects," 98 Daedalus 219, 245 (1969). 22 II. SUMMARY OF CONCLUSIONS AND RECOMMENDATIONS A. Evaluation of Current DHEW Policies for the Protection of Human Research Subjects 1. No uniform Departmental policy for the protection of research subjects exists. Instead one policy governs "extramural" research - research supported by DHEW grants or contracts to institutions outside the Federal Government and conducted by private researchers - and another policy governs "intramural" research - research conducted by personnel of the Public Health Service. Furthermore, Food and Drug Administration (FDA) regulations promulgated to protect subjects in drug research, whether or not supported by DHEW or conducted by PHS, incorporate variations of their own. The lack of uniformity in DHEW policies creates confusion, and denies some subjects the protection they deserve. Moving to the next higher level, no uniform Federal policies exist for the protection of subjects in Government-sponsored research. Other agencies wholly separate from DHEW - most notably, the Department of Defense - support or conduct human research. DHEW policies do not govern such research. Here too, the Federal Government's failure to develop a uniform policy has been detrimental to the welfare of research subjects. 2. Under current DHEW policies for the protection of research subjects, regulation of research practices is largely left to the biomedical professions. Since the conduct of human experimentation raises important issues social policy, greater participation in decision-making by representatives of other professions and of the general public is required. 3. The present reliance by DHEW on the institutional review committee as the primary mechanism for the protection of research subjects was an important advance in the continuing effort to guarantee ethical experimentation. Prior peer review of research protocols is a requirement which should be retained. 4. The existing review committee system suffers from the basic defects which seriously undermine the accomplishment of the task assigned to the committees: a. The governing standards promulgated by DHEW which are intended to guide review committee decisions in specific cases are vague and overly general. b. No provisions are made for the dissemination or publication of review committee decisions. Their low level of visibility hampers efforts to evaluate and learn from committee attempts to resolve the complex problems of human research. c. Although the informed consent of the research subject is one of the most important requirements of research ethics, DHEW policies for obtaining consent are poorly drafted and contain critical loopholes. As a result, one crucial task of institutional review committees - the implementation of the informed consent requirement - is commonly performed inadequately. In particular, consent is far too often obtained in form alone and not in substance. d. DHEW policies do not give sufficient attention to the protection of such special research subjects as children, prisoners and the mentally incompetent. The use of these subjects in human experimentation presents grave dangers of abuse. e. The obligation of institutional review committees to conduct continuing review of research projects after their initial approval is undefined and as a consequence often neglected. f. Inefficient utilization of institutional review committees contributes to their ineffectiveness. Committees are overburdened with a variety of separate functions, and could operate best if their tasks were narrowly defined to encompass mainly the implementation of research policies adequately formulated by others. g. Effective procedures for enforcing DHEW policies, when those policies are disregarded, have not been devised. 5. No policy for the compensation of research subjects harmed as a consequence of their participation in research has been formulated, despite the fact that no matter how careful investigators may be, unavoidable injury to a few is the price society must pay for the privilege of engaging in research which ultimately benefits the many. Remitting injured subjects to the uncertainties of the law court is not a solution. B. Policy Recommendations 1. Congress should establish a permanent body with the authority to regulate at least all Federally supported research involving human subjects, whether it is conducted in intramural or extramural settings, or sponsored DHEW or other government agencies, such as the Department of Defense. Ideally, the authority of this body should extend to all research activities, even those not Federally supported. But such a proposal may raise major jurisdictional problems. This body could be called the National Human Investigation Board. The Board should be independent of DHEW, for we do not 23 believe that the agency which both conducts a great deal of research itself and supports much of the research that is carried on elsewhere is a position to carry out dispassionately the functions we have in mind. The members of the Board should be appointed from diverse professional and scientific disciplines, and should include representatives from he public at large. 2. The primary responsibility of the National Human Investigation Board should be to formulate research policies, in much greater detail and with much more clarity than is presently the case. The Board must promulgate detailed procedures to govern the implementation of its policies by institutional review committees. It must also promulgate procedures for the review of research decisions and their consequences. In particular, this Board should establish procedures for the publication of important institutional committee and Board decisions. Publication of such decisions would permit their intensive study both inside and outside the medical profession and would be a first step toward the case-by-case development of policies governing human experimentation. We regard such a development, analogous to the experience of the common law, as the best hope for ultimately providing workable standards for the regulation of the human experimentation process. 3. The National Human Investigation Board should develop appeals procedures for the adjudication of disagreements between investigators and the institutional review committees. 4. The National Human Investigation Board should also develop a "no fault" clinical research insurance plan to assure compensation for subjects harmed as a result of their participation in research. Institutions which sponsor Federally supported research activities should be required to participate in such a plan. 5. With the establishment of adequate policy formulation and review mechanisms, the structure and functions of the institutional review committees should be altered to enhance the effectiveness of prior review. In place of the amorphous institutional review committee as it now exists, we propose the creation of an Institutional Human Investigation Committee (IHIC) with two distinct subcommittees. The IHIC should be the direct link between the institution and the National Human Investigation Board, and should establish local regulations consistent with national policies. The IHIC should also assume an educational role in its institutions, informing participants in the research enterprise of their rights and obligations. The implementation of research policies should be left to the two subcommittees of the IHIC: a. A Protocol Review Group (PRG) should be responsible for the prior review of research protocols. The PRG should be composed mainly of competent biomedical professionals. b. A Subject Advisory Group (SAG) should be responsible for aiding subjects in their decision-making whenever they request its services. Subject must be made aware of the existence of the SAG. The primary concern of the SAG should be with procedures for obtaining consent, and with the quality of consents obtained. The SAG should be composed of both professionals and laymen. 24 III. DEVELOPMENT OF CURRENT DHEW POLICIES A. Historical Background Experimentation with human beings is not a modem phenomenon; it dates back to the beginning of recorded history. However, until the advent of scientific medicine, "research" was largely conducted unsystematically in the context of clinical practice which benefited, harmed or did nothing to untold patients. Indeed, harmful consequences most often accrued to countless patients who were given treatments whose value had not been established by carefully controlled clinical investigations.6 Since the individuals involved in "research" were generally also considered potential recipients of the knowledge gained, few questions were raised about the propriety of these interventions by either the medical or legal profession. As far as the medical profession was concerned, the systematic use of human beings for research purposes, a trend which began in the late nineteenth century and has accelerated ever since, did not lead until relatively recently to a sustained exploration of the need to safeguard research subjects. A notable exception was Claude Bernard who in 1865 published his influential An Introduction to the Study of Experimental Medicine,7 in which he not only demonstrated the need for experimentation on human subjects by also began to formulate rules of ethical conduct. Similarly the law has had little to say about the rights of human subjects in the research enterprise. Indeed prior to the nineteen-sixties, no specific federal or state statutes regulated research institutions or investigators in their use of human subjects for experimental purposes. Though beginning with the English case of Slater v. Baker and Stapleton8 in 1767 and the American case of Carpenter v. Blake9 in 1871, courts were from time to time confronted with the claim of experimentation in malpractice actions, the resulting opinions evinced concern about "experimentation" but did not provide any meaningful legal guidelines for investigators to follow. Perhaps the fact situations in these cases, which often raised other important issues besides experimentation, precluded judges from speaking out more clearly on the legal limits to human research. Through the first third of the twentieth century, the generally accepted legal rule seemed to be that a physician experimented "at his peril" if his patients were harmed thereby.10 Eventually, the distinction between rash human experimentation and careful, scientific and ethical experimental practice was acknowledged by the courts. In 1935, the Supreme Court of Michigan stated in a malpractice case: We recognize the fact that if the general practice of medicine and surgery is to progress, there must be a certain amount of experimentation carried on; but such experiments must be done with the knowledge and consent of the patient or those responsible for him and must not vary too radically from the accepted method of procedure.11 Although this dictum was a broad generalization, made in a therapeutic context, and was not directed at non-therapeutic investigations, it signalled the ascendancy of a more balanced judicial attitude toward medical research involving human beings. This posture was sorely tested by the revelations of the horrifying atrocities perpetrated under the Nazis by German physicians and scientists in the name of clinical research.12 The disclosures at the Nuremberg disturbed the medical community, and many physicians and research scientists called for worldwide acceptance of ethical standards to assure the protection of subjects in biomedical research. However, the impact of their concern was blunted by the cruelty of the concentration camp experiments which obscured the fundamental fact that similar problems of research ethics, though not of the same magnitude, had characterized the research enterprise from its beginnings. Nonetheless, the trial of the Nazi physicians led the Military Tribunal to set forth ten basic principles, the so-called Nuremberg Code,13 which must be observed in human experimentation "in order to satisfy moral, ethical, and legal concepts." The following principles illustrate the nature of the Code: 1. The voluntary consent of the human subject is absolutely essential... 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods of study, and not random and unnecessary experiments in nature. 3. The degree of risk to be taken should never ___________ 6. See, e.g., Modell, "Let Each New Patient Be a Complete Experience," 174 J.A.M.A. 1717 (1960) 7. Bernard, An Introduction to the Study of Experimental Medicine, H.C. Greene (Transl.) (Macmillan, 1927). 8. 95 Eng. Rep. 860 (1767). 9. 60 Barb, 488 (N.Y. 1871). 10. See Curran, "Governmental Regulation of the Use of Human Subjects in Medical Research: The Approach of Two Federal Agencies. 98 Daedalus 542, 543 (1969). 11. Fortner v. Koch, 272 Mich, 273, 282; 261 N.W. 762, 765 (1935). 12. See Trials of War Criminals Before the Nuremberg Military Tribunals. Volumes I and II. The Medical Case. Washington, D.C.: U.S. Government Printing Office (1948). For excerpts which indicate the nature of the offenses and the resulting judgements, see Katz, Experimentation with Human Beings, pp. 292-306 (Russell Sage Foundation, 1972) (Hereinafter Katz). 13. Katz, supra footnote 12, at 305. 25 exceed that determined by the humanitarian importance of the problem to be solved by the experiment. The widely felt need to supplement and modify the provisions fo the Nuremberg Code led to the proliferation of other "improved" codes of research ethics. The World Medical Association's Helsinki Declaration (1964),14 the American Medical Association's Ethical Guidelines for Clinical Investigation (1966)15 and the draft code of the American Psychological Association (1972)16 are three which have received the most attention. The promulgation of such documents helped to focus attention on the ethical problems inherent in research activities involving human subjects. However, as the number of documents increased their limitation become more evident to concerned observers. As one of us has elsewhere remarked: The proliferation of such codes testifies to the difficulty of promulgating a set of rules which do not immediately raise more questions than they answer. By necessity these codes have to be succinctly worded and, being devoid of commentary, their meaning is subject to a variety of interpretations. Moreover, since they generally aspire to ideal practices, they invite judicious and injudicious neglect. Consequently, as long as they remain unliberated tablets of exhortation, codes will at best have limited usefulness in guiding the daily behavior of investigators.17 Furthermore, discrepancies between codes have helped to sow confusion. Discussing the Helsinki Declaration and the A.M.A. Guidelines, Professors Katz and Caprol observed: The significant discrepancies between those two documents highlight the need for mechanisms which would permit their reconciliation...Unlike the Helsinki Declaration, the AMA guidelines propose that"(m)inors or mentally incompetent subjects may be used as subjects only if (t)the nature of the investigation is such that mentally incompetent subjects may be used as subjects only if (t)the nature of the investigation is such that mentally competent adults would not be competent subjects." On the other hand, the Declaration of Helsinki states, and the AMA guidelines do not, that "(a)t any time during the course of clinical research the subject or his guardian should be free to withdraw permission for research to be continued." No explanation is provided for the differences nor is any mechanism available to guide physician-investigators in adopting or rejecting part or all of either document, based on its disagreement with the other or for any additional reasons.18 In retrospect, the promulgation of so many varying codes of ethics can be viewed as a tacit recognition within the professions that self-regulation by investigators could not be relied on to control research practices. When it was also realized that the codes themselves had serious shortcomings, new and quite different proposals for ordering the research process began to emerge. Procedures were gradually developed to apply the general principles contained in codes of research ethics in the formal evaluation of individual research projects by institutional review committees. The National Institutes of Health (NIH) first developed such procedures in order to regulate clinical research performed at its Clinical Center in Bethesda, Maryland. Since 1953, human research has not been conducted there without prior approval of a review committee responsible for the protection of subjects.19 In 1966, Surgeon General William H. Stewart extended the requirement of prior review by "a committee of (the investigator's) institutional associates" to all "extra-mural" research supported by United states Public Health Service (PHS) grants and awards.20 This review was to assure an independent determination: (1) of the rights and welfare of the individual or individuals involved, (2) of the appropriateness of the methods used to secure informed consent, and (3) of the risks and potential medical benefits of the investigation.21 Prior committee review was also instituted, in 1967, for all "intramural" research programs of the Public Health Service.22 The tuskegee Syphilis Study, conducted by PHS investigators, was an intramural activity. _____________ 14. 271 N. Eng. J. Med. 473 (1964). 15. American Medical Association, Opinions and Reports of the Judicial Council, pp. 9-11 (Chicago, 1969). 16. American Psychological Association, Ethical Principles in the Conduct of Research with Human Participants (Draft Document, 1972). 17. Katz. "The Education of the Physician-Investigator," 98 Daedalus 480, 482-3 (1969). 18. Katz and Caprol, Social Factors Affecting the Modern Treatment of Catastrophic Diseases (Unpublished Manuscript, 1973) (hereinafter, Katz and Capron). 19. Sessoms, "Guiding Principles in Medical Research Involving Humans, National Institutes of Health," 32 Hospitals, Journal of American Hospital Association 44 (1958). 20. Memorandum of Surgeon General William H. Stewart to the Heads of Institutions Conduction Research with Public Health Grants, (February 8, 1966). 21. Ibid. 22. DHEW - Public Health Service, Protection of the Individual as a Research Subject - Intramural Programs (May 1, 1969) (hereinafter Intramural Guidelines). 26 In 1971, the Department of Health, Education, and Welfare formulated its policy for the protection of human subjects23 which superseded the Public Health Service extramural program guidelines. Institutional committee review was retained as the central feature of the new DHEW policy. The DHEW regulations apply to all research supported by Departmental grants or contracts, regardless of whether the research is medical in nature. However, the new regulations do not apply to intramural PHS activities, which are still governed by separate and sometimes divergent PHS guidelines. Also in 1971, the Food and Drug Administration promulgated additional regulations,24 patterned on the DHEW framework, to govern the testing of "investigational new drugs." And recently, in response to the Tuskegee Syphilis Study revelations, Senator Jacob Javits introduced a bill which would enact most of the current DHEW requirements into law.25 Senator Hubert Humphrey also responding to the Tuskegee Study, introduced another bill, quite different in conception.26 It would create within the executive branch a independent board to establish guidelines for human experimentation, to review research practices and to enjoin the conduct of certain investigations. Due to the Federal Government's prominent role in funding biomedical research, the PHS-DHEW regulations have had a noticeable impact on the conduct of human research in this country. Over 700 American research institutions have established review committees in order to satisfy DHEW or PHS requirements.27 Although these committees are required to review only Federally-funded research, they often have extended their review to all research on human subjects conducted at their institutions.28 B. Description of DHEW Policy29 At present DHEW policies vest primary responsibility for the protection of research subjects in institutional review committees. These committees are charged with the initial review of all project proposals and are also expected to subject research activities to "continuing review". Once a committee has approved a research protocol, its decision is reviewed again by the DHEW study section which considers the protocol for funding. When either group disapproves a protocol, that decision cannot be appealed to the Department, and the protocol cannot be Federally funded. In contrast to the DHEW requirements, PHS intramural policy does not require continuing review. Instead, the burden is on the investigator to bring "significant proposed changes in protocol and emergent problems of investigation...to the attention of the review group involved."30 Nor does PHS intramural policy specify distinct stages of protocol review. DHEW requires institutional committees to review all aspects of "any activity" which might expose a subject to the possibility of harm if the activity "goes beyond the application of those established and accepted methods necessary to meet his needs."31 Recognizing that this jurisdictional standard leaves much to the discretion of committees and investigators the Department concedes that"(a)cceptance is a matter of professional response, and determination as to when a method passes from the experimental stage and becomes `established and accepted' is a matter of judgement."32 Before the committee can approve an activity under review, it must "determine that the rights and welfare of the subjects involved are adequately protected, that the risks to an individual are outweighed by the potential benefits to him or by the importance of the knowledge to be gained, and that informed consent is to be obtained by methods that are adequate and appropriate."33 Like the jurisdictional standard, these review standards are phrased in general terms, although the "basic elements" of "informed consent" are set forth in greater detail.34 DHEW policy also requires each institution to provide written assurance that it will abide by DHEW policy. The assurance must include "a statement of compliance with DHEW requirements for initial and continuing committee review of the supported activities; a set of implementing guidelines, including identification of the committee, and a description of its review procedures."35 As part of the "implementing guidelines," each institution is asked to adopt a "statement of principles that will assist the institution in the discharge of its responsibilities for protecting the rights and welfare of subjects."36 These statements are typically derived from existing codes of ethics not much more explicit that the DHEW review standards themselves.37 _______________ 23. DHEW Grants Administration Manual Chapter 1-40 (1971) (hereinafter Grants Administration Manual). The Department publishes The Institutional Guide to DHEW Policy on Protection of Human Subjects (1971) (hereinafter Institutional Guide) to help institutions sponsoring research to implement DHEW policy. 24. 36 Fed. Reg. 5037-38 (1971). 25. S. 3935, 92nd Cong., 2d Sess (1972). 26. S. 3951, 92nd Cong., 2d Sess. (1972). 27. For a description of the spread of institutional review committees they surveyed review "all clinical research" conducted at their institutions, regardless of funding. Barber et al., supra, footnote 3, at 149. 29. This description is based on the Intramural Guidelines, supra, footnote 23, and the Institutional Guide, supra, footnote. 23. Hereinafter, the policy of the Manual and the Guide will be referred to as "DHEW" policy, while the policy of the Intramural Guidelines will be referred to as "PHS intramural" policy. 30. Intramural Guidelines, supra, footnote 22, at 5. 31. Grants Administration Manual, supra, footnote 23, 1-40-10. 32. Institutional Guide, supra, footnote 23 at 3. 33. Grants administration Manual, supra, footnote 23, 1-40-20(A). The PHS Intramural Guidelines, supra, footnote 22, contain essentially equivalent standards for review, at 4-5. 34. See infra., pp. 31-32. 35. Grants Administration Manual, supra, footnote 23, 1-40-40(A). 36. Grants Administration Manual, supra, footnote 23, 1-40- 40(C)(2)(a). 37. Ibid. See also Institutional Guide, supra, footnote 23, at 5, footnote 2, and at 23. 27 Unlike DHEW policy, the intramural guidelines of the PHS make specific, albeit limited, reference to "(s)tudies involving children, the mentally ill or the mentally defective."38 Such studies "shall be carried out only when there is no significant risk of physical or mental harm to the subject or when direct benefit to the subject is anticipated."39 The intramural guidelines also explicitly provide that"(s)tudies of individuals with limited civil freedom shall also be subject to group consideration and approval."40 Although the references to minors, incompetents, and prisoners do not impose addition substantive restrictions on research, they may alert review committees and investigators to the special problems presented by research with such subjects.41 Since institutional review committees are entrusted with such difficult decision-making responsibilities, their composition is a matter of Departmental concern: The committee must be composed of sufficient members with varying backgrounds to assure complete and adequate review of projects and activities commonly conducted by the institution. The committee's membership, maturity, experience, and expertise should be such as to justify respect for its advice and counsel. No member of an institutional committee shall be involved in either the initial or continuing review of an activity in which he has a professional responsibility, except to provide information requested by the committee. In addition to possessing the professional competence to review specific activities, the committee should be able to determine acceptability of the proposal in terms of institutional commitments and regulations, applicable law, standards of professional conduct and practice, and community attitudes. The committee may therefore need to include persons whose primary concerns lie in these areas rather than in the conduct of research, development, and service programs of the types supported by the DHEW.42 Beyond this, the Department does not specify any particular size or membership requirements, believing instead that disparity in institutional situations demands flexibility. For the same reason the Department does not provide any directions for the conduct of initial or continuing review. Instead, as already noted, institutions are required to submit for Departmental approval a description of the procedures their committees will follow to implement review. When DHEW funding is sough, a research proposal approved by an institutional committee is reviewed again within the Department.43 A study section, composed of scientists not connected with the proposal or its sponsoring institution, examines the proposal and transmits its recommendation to the particular National Advisory Council Authorized to grant the requested research funds. This Departmental review is not restricted to a reconsideration of the "ethical soundness" of the proposed research. Instead, it encompasses all other factors which enter into any research funding decision, such as the scientific rigor of the proposal, the scientific significance of the proposed project, and the relationship of budgetary estimates to the proposed study. As a result, the review of ethical issues at this stage cannot be as thorough as it is intended to be at the institutional level. The adoption of this institutional review committee approach promised to be a significant advance toward the goal of ethical human research. For the first time, codes of research ethics were to be applied in concrete situations by means of a definite procedure providing for independent scrutiny of individual research proposals. moreover, a decentralized, pluralistic approach, emphasizing decision-making at the institutional level, seemed to offer other advantages. The exploration of problems from different points of view could ultimately lead to a fuller appreciation of the issues requiring resolution. Concern for the rights and welfare of subjects could be more easily communicated to individual investigators. The review of research protocols could be handled in depth and yet with dispatch. Despite these hopes, the present DHEW regulatory framework can only be considered a qualified success. The continued existence of two varying sets of guidelines to govern intramural and extramural human research activities respectively serves no purpose and generates confusion. As to the content of the guidelines, although from a historical perspective institutional committee review was a major improvement over prior practices, many deficiencies, to which we now turn, have precluded successful supervision of human experimentation for the protection of human subjects. ____________ 38. Intramural Guidelines, supra, footnote 22, at 10. 39. Ibid. 40. Ibid. 41. PHS intramural policy does impose stricter consent requirements for experiments with such subjects. These consent requirements are discussed infra, at pp. 25 ff. 42. Grants Administration Manual, supra, footnote 23, 1-40-40 (C) (2) (b). 43. Grants Administration Manual, supra, footnote 23, 1-40-20 (B) and 1-40-50 (B). See also NIH Manual 4107 "Grants Involving Human Subjects," 4107 (G) (1972). 28 IV. CRITIQUE OF DHEW POLICY A. Vagueness of Standards At bottom, the difficulties which face review committees derive from the generality of the standards which are to guide their determinations in specific cases under either the intramural or extramural policies. To illustrate, if a review committee had evaluated the Tuskegee Syphilis Study under current guidelines, questions calling for searching examination would have surfaced. (1) If the requirement of informed consent44 is to be taken seriously, should impoverished and uneducated Blacks from rural Alabama have been selected as subjects in the first place? Or should a concerted effort have been made to find subjects from among the most educated within the population at large, or at least to select from the given subgroup those subjects most capable of giving "informed consent" Put more generally, what general principles should guide the selection of subjects? The philosopher Hans Jonas has given one answer to this question: "(O)ne should look for (subjects) among the most highly motivated; the most highly educated, and the least `captive' members of the community."45 (2) If "(t)he welfare of the individual is paramount (and) the subject must have available to him the facilities and professional attention necessary for the protection of his health and safety,"46 what special efforts should have been made by investigators to provide medical treatment beyond the economic reach of the subjects before enlisting them in the Tuskegee Study? Or should the institutional review committee have turned down the Tuskegee Syphilis Study because no adequate treatment facilities were available in Macon County? (3) How should "continuing review" operate? For example, at what point in time, after penicillin treatment for syphilis became available, should the subjects of the Tuskegee Syphilis Study have been apprised of this new development? Since it generally takes time before medical consensus is reached on the value of a new medication and is reported in the medical literature, when should the subjects have been told that a drug was available which at least some competent physicians considered effective treatment? (4) How should the risks inherent in this study have been weighed against the predicted advancement of medical knowledge? The rule that "the risks to an individual...(must be) outweighed by the potential benefits to him or by the importance of the knowledge to be gained,"47 is perhaps the most difficult guideline for review committees to implement. The seeming simplicity of this command belies its complexity. How are such tangibles as "risks", "benefits", and "importance of knowledge" to be measured and weighed? Can serious harm to research subjects ever be outweighed solely by additions to the sum of human knowledge?48 If so, what kind of knowledge, in what circumstances, would outweigh what risks to subjects? The difficulties inherent in evaluating the scientific merits of a particular study are demonstrated by the ongoing differences of opinion among scientists of the PHS as to whether continuation of the Tuskegee Syphilis Study can still be defended on the ground of scientific merit. It is necessary for review committees to scrutinize carefully the research design of every proposed study if the requirement that risks be balanced against benefits is to be taken seriously, for the acquisition of knowledge depends so much on the soundness of the research protocol.49 Does the informed willingness of the subject to accept certain risks have any bearing on the committee's balancing of risks against benefits? Finally, since the design of he Tuskegee Study could not completely exclude the possibility that non-subjects might contract syphilis from untreated subjects, how should a review committee have balanced risks to non-subjects against benefits to society?50 (5) Review committees are also required to "determine that the rights and welfare of the subjects involved are adequately protected."51 What rights did the Tuskegee Study subjects possess? The tremendous confusion which exists in the area of patient subjects' rights is in part the result of the traditional but largely unexamined prerogative of professionals ___________ 44. The requirement of informed consent is analyzed in greater detail infra, at pp. 31 ff. 45. Jonas, "Philosophical Reflections on Experimenting with Human Subjects," 98 Daedalus 219, 235 (1969). 46. Intramural Guidelines, supra, footnote 22, at 1. 47. Grants Administration Manual, supra footnote 23, 1-40-20 (A); see also Intramural Guidelines, supra, footnote 22, at 2, 4-5. 48. Although PHS policy does prescribe seriously risky experimentation which cannot benefit the subject, Intramural Guidelines, supra, footnote 22 at 2, DHEW policy for extramural research does not categorically prohibit such research. The Institutional Guide, supra, footnote 23, states at 6: "If the potential benefits are insubstantial, or are outweighed by risks, the committee may be justified in permitting the subjects to accept these risks in the interests of humanity." 49. Intramural Guidelines, supra, footnote 22, at 1. 50. The Intramural Guidelines, supra, footnote 22, at 1, state: The health and safety of persons other than the subject, if endangered by the research procedures, must be protected. DHEW policy neglects this problem. 51. Grants Administration manual, supra, footnote 22, 1-40-20 (A); see also Intramural Guidelines, supra, footnote 22, at 1, 4-5. 29 to intervene in their patients' behalf without full disclosure whenever it is supposed to be "in their patients' best interests." The doctrine of "informed consent" has had little impact on this longstanding professional practice. Since much medical research is carried out in the con text of "patient care" the right to make decisions for patients has more often than not unwittingly been carried over into the research domain. The confusion about patient-subjects' rights is bolstered by the scientist's felt obligation to advance knowledge for the good of society, although society has inadequately defined the extent of this obligation. To illustrate the confusion about subject's rights: Can the subject claim the right to be indemnified for any harm he suffers a s a result of the research, regardless of the investigator's fault and in spite on consent? If so, who is responsible for informing him that an injury has occurred which is not the result of the natural progression of his illness? Do Tuskegee Study subjects have a cause of action because they did not receive suitable medical treatment? If so, who may be liable-the individual investigators, the PHS, the Milbank Memorial Fund, the Tuskegee Institute? The intramural guidelines of the PHS and The Institutional Guide to DHEW Policy on Protection of Human Subjects also identify confidentiality as a right which must be protected.52 Does confidentiality extend only to the subject involved int eh study or does it also include the group of which he is a part? If the latter, what are the limits of group confidentiality? The Tuskegee Syphilis Study, in common wit many other studies, singled out one particular group and revealed much that was intimate and private about all its members. Where can review committees seek guidance in devising procedures which safeguard subjects' rights in general, and their rights to confidentiality, privacy and respect, in particular?53 (6) The jurisdiction of institutional review committees encompasses "any activity which goes beyond the application of those established and accepted methods necessary to meet..(the subject's) needs."54 How are "established and accepted" methods to be ascertained? Among "established" treatments should distinctions be made between those of "proven" and those of "dubious' value? What are the criteria for a "necessary" intervention? Since there is so much professional disagreement as to when a procedure becomes "therapeutic," the question must be posed: "accepted" by whom? Was the withholding of arsenic and heavy metal treatments at the beginning of the Tuskegee Study a "therapeutic"intervention since the effectiveness of such treatments was in doubt, particularly for late syphilis? When did penicillin treatment become an "established and accepted method"? What degree of certainty is required of investigators and review committees? Certainly no clear line can be drawn between experimental and routine treatment since, as has so frequently been asserted, "the therapy of disease is, and always will be, an experimental aspect of medicine."55 The vagueness and generality of the governing standards have disadvantaged all participants in the research decision-making process. For conscientious review committees, they have meant hard work and, insofar as the committees are overwhelmed by the enormity of their tasks, superficial examination of protocols. For subjects, the inevitable result has been to deprive them in some measure of the protection which review committees were supposed to provide. For investigators, the pervasive uncertainty about what kind of human studies are now permissible has impeded their research. And for society, fears about the protection of its citizens in the research enterprise have not been stilled. Especially because review committees work in isolation from one another and no mechanisms have been provided for disseminating the knowledge gained from their individual experiences, each committee is condemned to repeat the process of finding their own answers to all the questions we have raised. This is an overwhelming, unnecessary and unproductive task for which they are not prepared an which we doubt they are willing to assume. What is needed, is an overall official body authorized to formulate more detailed policies with respect to research on human beings. The need for such a policy making body has in point of fact already ben perceived, and other bodies, official and non-official, have partially and on an ad hoc basis attempted to fill the gap. For example, the FDA has promulgated comprehensive rules for the conduct of drug research, 56 although on many crucial issues of subject protection it has simply copied DHEW policy.57 Similarly, the wake of organ transplantation, an ad Hoc Committee of the Harvard __________ 52. Intramural Guidelines, supra, footnote 22, at 9; Institutional Guide, supra, footnote 23, at 6. 53. The Institutional Guide, ibid, does make an effort to suggest procedures for safeguarding confidentiality. 54. Grants Administration Manual, supra, footnote 23, 1-40-10 (B); see also Intramural Guidelines, supra, footnote 22, at 2-3, 7-8. 55. Ivy, "The History and Ethics of the Use of Human Subjects in Medical Experiments" 108 Science (July, 1948). Barber et al. have recently documented the prevalence of professional uncertainty over the definition of "research". See Barber et al., supra, footnote 3 at 150. 56. See 21 C.F.R. 130.3, 130.37. 57. Ibid.; see also 36 Fed. Reg. 5037 (1971). 30 Medical School redefined the criteria of "death" in order to facilitate the removal of needed organs.58 Moreover, the Division of Research Grants of NIH,59 which at present supervises the implementation of DHEW policy, has occasionally transmitted memoranda to review committees "concerning the interpretation and implementation of (its) policy."60 Recent memoranda focused on potential hazards of screening programs for sickle cell trait, the definition of "human subject," and guidelines for fetal studies. These policy making activities need to be consolidated, under the auspices of a broadly representative body, about which we shall have more to say below. Such a body would not only provide guidance to review committees but would also enable them to obtain advice whenever difficult problems arise. B. Invisibility The creation of institutional review committees could have led to increased visibility of decisions regarding the protection of subjects. But since neither publication nor free access to their findings was specifically planned for, increased visibility has not been realized. A low level of visibility hampers efforts to evaluate and learn from attempts to resolve the complex problems of human research. Especially so long as guidelines for human research remain so indefinite, high-visibility decision-making is an essential feature of a well-functioning regulatory framework. Moreover, since committee disapprovals can block research, with no recourse to higher level review, invisibility may impede the acquisition of valuable knowledge. The 1969 committee review of the Tuskegee Syphilis Study illustrates the problems which a low level of visibility creates. Our knowledge of that proceeding comes from an unofficial summary which constitutes the only available report on that committee's deliberations. From this summary it is impossible to determine the factors which the committee considered or the grounds on which the committee based its decision to approve a continuation of the study. This state of affairs is not atypical. Because institutional committee decisions are not published, committee decision-making operates at a primitive level, uninformed by pertinent prior decisions of other committees or by scholarly outside criticism. A mechanism for self-improvement over time is lacking. Professor Guido Calabresi has observed: The best way of broadening the inputs to the committee-lies in another device: publication of the cases decided by the committees. Such cases could well be anonymous (at least at first). They could be collected and published in much the same way that decisions of courts are collected. The reports on any case could include, first a factual part describing, among other things, the experience of the experimenter, the antecedent tests in non-human subjects, the major risks perceived, the scientific gains perceived possible, the availability of subsequent controls to limit the risks, the origin and life expectancy of the subjects, and the nature of the consent and the manner in which it was obtained; and, second, a jurisprudential section containing the decision of the committee (whether favorable or unfavorable), together with the principal arguments made for and against the decision reached. Such published cases would soon become the subject of intense study both inside and outside the medical profession. Analyses in learned journals by lawyers, doctors, and historians of science would inevitably follow. These would undoubtedly re-argue the more important or path-breaking cases. If law cases are any guide, the analyses would sometimes conclude that the cases were wrongly decided, but frequently that they were rightly decided, and perhaps more frequently that they were rightly decided but for the wrong reasons. To the extent that Law Reviews consider themselves courts of last appeal beyond the highest courts in the land, so would the learned journals in which this giurisprudenza would be dissected. From all this, a sense of what society at large deems proper in medical experiments might well arise. This sense would, in turn, guide the committees and make their decisions more sophisticated. The result would not only be better thought out decisions, but also a more complex system of controls, which, in effect, took into account much broader sources of information as to societal values....61 In the Recommendation section of our report we corporate Calabresi's suggestions in a comprehensive work for the regulation of human experimentation. ____________ 58. Ad Hoc Committee of the Harvard Medical School. "A Definition of Irreversible Coma," 205 J.A.M.A. 337 (1968). 59. Grants Administration Manual, supra. footnote 23, 1-40-50 (A). 60. Memorandum of January 24, 1972, from Stephen P. Hatchett, Director, Division of Research Grants, NIH, DHEW, to Officers Responsible for Institutional Implementation of DHEW Policy on Protection of Human Subjects. 61. Calabresi, "Reflections on Medical Experimentation in Humans," 98 Daedalus 387, 400-401 (1969). 31 C. Subject Consent 1. The Definition of "Informed Consent" Institutional review committees are expected to ascertain "that informed consent is obtained by... methods that are adequate and appropriate."62 The DHEW Grants Administration Manual, in contrast to its treatment of other important matters, defines "informed consent" in some detail: Informed consent is the agreement obtained from a subject, or from his authorized representative, to the subject's participation in an activity. The basic elements of informed consent are: 1. A fair explanation of the procedures to be followed, including an identification of those which are experimental; 2. A description of the attendant discomforts and risks; 3. A description of the benefits to be expected; 4. A disclosure of appropriate alternative procedures that would be advantageous for the subject; 5. An offer to answer any inquiries concerning the procedures; 6. An instruction that, the subject is free to withdraw his consent and to discontinue participation in the project or activity at any time.63 The PHS Intramural Guidelines also explicate informed consent in some detail: The individual must be free to choose whether or not to be a subject in research. His participation shall be accepted only after he has received a fair explanation of the procedures to be followed, benefits, and attendant hazards and discomforts, and, suited to his comprehension, the reasons for pursuing the study and its general objective. He must be informed of his right to withdraw from the study at any time.64 For no apparent reason, two "basic elements" of informed consent identified in DHEW policy are ignored by the DHEW intramural policy. Nothing is said in the intramural policy statement about disclosure of alternative procedures ("basic element" number four) or response to inquiries ("basic element" number five). Despite the commendably greater detail with which DHEW policy on obtaining informed consent is set forth, major gaps do remain. For instance, the DHEW directives permit consent to be obtained from the subject's "authorized representative" in lieu of the subject himself. But the circumstances in which third party consent may properly be substituted for the consent of subjects are undefined. Committees are not advised as to who can validly consent in place of the subject or whether consent can be obtained from mother person besides the subject only for certain investigations, such as those specifically designed to benefit the subjects themselves. Thus, committees are left to their own devices in fashioning rules about the participation in research of such subjects as the very young or the very old, the mentally incompetent or the emotionally disturbed, the imprisoned or those otherwise under duress, or, as in the Tuskegee Study, those who are ill-prepared as a consequence or cultural deprivation or inadequate education. In contrast to the DHEW extramural guidelines, the PHS intramural research rules do address the problems of substitute consent for special subjects in more detail: Studies involving children, the mentally ill or the mentally defective should be carried out only when there is no significant risk of physical or mental harm to the subject or when direct benefit to the subject is anticipated. ... In general, written informed consent of the parent or guardian shall be required for all medical or dental studies with such subjects, except in studies of an observational nature or in those conducted during the administration of accepted health care procedures that do not require specific informed consent in ordinary practice. Any exception shall be carefully considered and fully documented. Written informed consent of parent or guardian may be desirable in certain other studies with these groups and shall be required if conditions .... Studies of individuals with limited civil freedom shall also be subject to group consideration and approval. Informed consent of the responsible institutional authority shall be required in all cases. Written informed consent of the individual shall also be required except for studies of an observational nature conducted during the administration of accepted health care procedures that do not require specific informed consent in ordinary practice.65 The major difficulties with these provisions result from the exceptions to the general requirement of substitute consent. "Studies of an observational nature" and "accepted health care procedures that do not require specific informed consent in ordinary practice" are phrases too vague to be meaningful. For example, was the Tuskegee Syphilis Study "of an observational nature"? In what "other" kinds of studies may investigators dispense with the consent of parent or guardian unless unspecified "conditions warrant" it? ________ 62. Grants Administration Manual, supra, footnote 23, 1-40-20 (A). 63. Grants Administration Manual supra, footnote 23, 1-40-10 (C). 64. Intramural Guidelines, supra, footnote 22, at 1. 65. Intramural Guidelines, supra, footnote 22, at 10-11. 32 Moreover, the PHS instructions ignore the issue of the capacity of third parties to represent the interests of special subjects adequately, and the subtle inducements which may persuade prisoners to consent. Prisoners in particular are a group whose participation in research has long been controversial.66 Because prisoners are a captive group, the danger is great that their consent to participate in research will be obtained by duress. Jessica Mitford has recently documented some of the abuses to which, prisoner participants in experimentation have been subjected, and she comments: The (Institutional) Guide expresses a "particular concern" for "subjects in groups with limited civil freedom. These include prisoners...." Having uttered this praiseworthy sentiment, HEW has apparently let the matter drop. Dr. D.T. Chalkley, chief of the Institutional Relations Branch, Division of Research Grants, and signer of the Guide, tells me that HEW does not even maintain a list of prisons in which HEW financed research programs are in progress and has "no central source of information" on the scope of medical experiments on prisoners by drug companies. What efforts have been made by HEW to enforce its guidelines in HEW-financed medical research behind prison walls? "We do give some grants that involve prisoners. But there's no convenient way of recovering the information as to whether our guidelines are being followed," said Dr. Chalkley. "That responsibility lies with the principal investigator...." has HEW ever brought any action to enforce its regulations in any prisons anywhere? "None, to date."67 Most new drug testing is initially conducted on prisoners, and is subject to FDA regulations, but the FDA also has no list of persons in which such research is carried out.68 We regard the failure of the DHEW policies to include comprehensive guidelines for safeguarding prisoners, children, mental incompetents, and other special subjects in research, as a major shortcoming which must be rectified. Detailed policy must be formulated specifying the kinds of research which may be carried out with special subjects of different types, the inducements which are permissible, the circumstances in which third party consent is necessary, the identity of those who can validly consent for the subject, additional precautions which must be taken for such subjects, and other matters. 2. Exceptions to the Consent Requirement In its Institutional Guide to DHEW Policy on the Protection of Human Subjects, the Department sets forth the following additional exceptions to the requirement of informed consent: The review committee will determine if the consent required, whether to be secured before the fact, in writing or orally, or after the fact following debriefing, or whether implicit in voluntary participation in an adequately advertised activity, is appropriate in the light of the risks to the subject, and the circumstances of the project. Where an activity involves therapy, diagnosis, or management and a professional-patient relationship exists, it is necessary "to recognize that each patient's mental and emotional condition is important... and that in discussing the element of risk, a certain amount of discretion must be employed consistent with full disclosure of fact: necessary to any informed consent."'69 The first exception which permits obtaining consent, "after the fact," is so general in scope and so extensive in the discretion it accords review committees that it almost staggers the imagination. What are "the circumstances of the project" which could ever permit such an invasion of subjects' rights to self- determination and privacy? Is this exemption limited to investigations with normal subjects employing placebos or to deception studies so frequently employed by psychologists? In one sentence the requirement of prior70 informed consent is seriously undermined. Furthermore, another exception provides for a departure from informed consent in situations in which "a professional/patient relationship exists." Since most medical research is carried out in such settings, it can apply to almost all medical interventions. It is particularly in clinical settings that overreaching in obtaining consent, however unwItting, is a constant danger.71 Thus the unqualified provision that "a certain ____________ 66. See, e.g., Lasagna, "Special Subjects in Human Experimentation." 98 Daedalus 449 (1969); Katz, supra, note 12, pp. 1018-1052; Mitford, "Experiments Behind Bars," The Atlantic Monthly 64 (January, 1973). 67. Mitford, "Experiments Behind Bars," supra, footnote 67, at 67-68. 68. See Mitford, "Experiments Behind Bars." supra, footnote 67, at 68. 69. Institutional Guide, supra, footnote 23, at 8. 70. It is implicit that consent be obtained prior to the subject's participation in research, although DHEW policy nowhere so states. 71. See infra, pp. 40ff. 33 amount of discretion must be employed consistent with full disclosure of fact" is particularly unsatisfactory.72 PHS intramural policy also contains loopholes in its consent provisions. First, the guidelines state that An explanation so detailed as to bias his response or otherwise to invalidate findings is not necessary in those procedures that invoice no risk of physical harm to the subject.73 This qualification is apparently designed to minimize interference with behavioral and other studies common to the social sciences. This guidelines elsewhere state that a major class of procedures in the social and behavioral sciences does no more than observe or elicit information about the subject's status by means of tests, inventories, questionnaires or surveys of personality or background. In such instances, the ethical considerations of voluntary participation, confidentiality, and propriety in use of the findings are the most generally relevant ones. The procedures may in many instances not require the fully informed consent of the subject or even his knowledgeable participation.74 The lack of concern in the quoted passages for psychological-as opposed to physical-harm to subjects is striking. Despite acknowledged ethical problems, the guidelines suggest that in "many instances" the "knowledgeable participation" of the subject may be unnecessary. Here again, the regulations fail to provide meaningful guidance to review committees. 3. The Quality of "Informed Consent" Another difficulty which seriously undermines the implementation of informed consent has not been dealt with at all in the DHEW policies. It has long been recognized that consent is far too often obtained in form alone, and not in substance. As the Department itself admits in its Institutional Guide (quoting Doctor Hemy L Beecher of Harvard Medical School): "The informed consent of the subject, while often a Legal necessity is a goal toward which we must strive, but hardly ever achieve except in the simplest cases."75 For as Doctor Beecher has written elsewhere, Lay subjects, sick or well, are not likely to understand the full implications of complicated procedures, even after careful explanation.76 Even with the best of intentions, investigators may fail to "get through" to their subjects for a variety of reasons. The subjects themselves may have great difficulty in understanding or little interest in knowing the nuances of what the investigator tries to explain to them, as Senator Hubert Humphrey recently lamented in response to the Tuskegee Syphilis Study: Who are the people who have been the subject of medical experiment? The clear and shocking implications of the most recently revealed experiments indicate that the powerless, the poor, the least educated, and members of minority groups are the likeliest human guinea pigs. It is those who cannot understand what is being done to them that constitute by far the largest numbers among human experimentation subjects.77 Moreover, the circumstances in which consent is sought may foster or hinder an informed and voluntary decision. The subject may be under stress or distracted by other pressing concerns. For example, he may be a patient, desperately hoping for successful treatment of his condition, whose judgment is distorted by the natural tendency to grasp at any straw in reach. The likelihood of this result is magnified by the profound dependence which many patients develop on their attending physicians, who are often responsible for obtaining consent. Indeed, however wrongly, the patient may well fear that his refusal to consent to ____________ 72. Compare the more satisfactory provisions on informed consent adopted by the FDA, 21 CFR a 130.37, which require that consent be obtained "in all but exceptional cases." This is defined as follows: (d) "Exceptional cases," as used in paragraph (b) of this section, which exceptions are to be strictly applied, are cases where it is not feasible to obtain the patient a consent or the consent of his representative, or where, as a matter of professional judgment exercised in the best interest of a particular patient under the investigator's care. It would be contrary to that patient's welfare to obtain his consent. (f) "Not feasible" is limited to cases where the investigator is not capable of obtaining consent because of inability to communicate with the patient or his representative; for example, where the patient is in a coma or is otherwise incapable of giving informed consent, his representative cannot be reached, and it is imperative to administer the drug without delay. (g) "Contrary to the best interests of such human beings" applies when the communication of information to obtain consent would seriously affect the patient's disease status and the physician has exercised a professional judgment that under the particular circumstances of this patient's case, the patient's best interests would suffer if consent were sought. 73. Intramural Guidelines, supra, footnote 22, at 1-2. 74. Intramural Guidelines, supra, footnote 22, at 9. 75. Institutional Guide, supra, footnote 23, at 7. 76. Beecher, Research and the Individual (Little, Brown and Co, 1970). 77. 118 Cong. Rec. S 14041 (Sept. 5, 1972). Senator Humphrey's assertion is corroborated by the recent study of research practices conducted by Barber et al. In the two institutions they analyzed, they found that studies in which the subjects were relatively high in proportion to therapeutic benefits to the subjects were "almost twice as likely as more favorable studies to be done using subjects more than three-fourths of whom (were) ward and/or clinical patients," as opposed to private and/or semi-private patients. Moreover, this proportion is not significantly altered when studies in which the risk exceeds all possible benefits, to the subjects or to medicine generally are examined: "the least favorable studies (were) still almost twice as likely as the more favorable to be done using three-fourths or more ward or clinical patients." Barber et al, supra, footnote 3 at 55, 56. 34 experimental treatment will anger his physician and deprive him of adequate medical care. Lastly, the investigator himself may fail to describe his own research objectively, or unwittingly create subtle pressures on a subject to consent. To suggest this is not to deny the integrity of the researcher, but only to acknowledge the reality of investigators' bias toward their work. Their scientific curiosity and excitement make it difficult for them to take, a detached view of the research they wish to conduct with their subjects. D. Continuing Review Although extramural research projects supported by DHEW grants or contracts must be reviewed on a continuing basis, intramural research activities of the Public Health Service need not be reviewed again after initial committee approval. This omission for intramural programs of what the Department itself calls "an essential part of the review process"78 explains the long neglect of the Tuskegee Study. Begun long before committee review became a reality, the Study was not reviewed by any committee until 1969, three years after Surgeon General Stewart had inaugurated the policy of committee review. Moreover, the 1969 review was undertaken at the behest of the principal investigators themselves, and not as the result of the Public Health Service review policy. The Tuskegee Study was not reviewed again until this Panel was appended. We have been unable to ascertain why intramural research programs are exempt from the continuing review requirement. Although DHEW extramural policy does require "continuing review," a better definition of the nature and extent of this obligation is needed. The present indefinite regulations invite a perfunctory performance of the continuing review function. Essentially the Department expects that the committees will ...adopt a variety of continuing review mechams. They may involve systematic review of projects at fixed intervals, or at intervals set by the committee commensurate with the project's risk. Thus, a project involving an untried procedure may initially require reconsideration as each subject completes his involvement. A highly routine project may need no more than annual review. Routine diagnostic service procedures, such as biopsy and autopsy, which contribute to research and demonstration activities generally require no more than annual review. Spot checks may be used to supplement scheduled reviews. Actual review may involve interviews with the responsible staff, or review of written reports and supporting documents and forms...79 Institutional review committees, already over burdened by the task of examining all new research projects, are thus also responsible for re-examining from time to time all ongoing research. If something has to give first, it tends to be this assignment. Pressed for time, the review committees assume that the initial review has satisfactorily resolved all existing problems and that a cursory review is sufficient. E. Structure and Composition of Institutional Committees Institutional review committees are charged with carrying out a number of distinct functions. They are required to formulate policies and regulations to guide the conduct of research at their institutions,80 often under the rubric of protocol review; to communicate these policies to investigators; to administer the policies they have promulgated through the prior appraisal of research proposals, the supervision of the attempt to obtain consent and the continuing review of approved research activities; to review the consequences of their decisions; and to keep informed of DHEW policy changes and suggestions in order to reformulate institutional policies and rules when necessary. In recognition of the variety of tasks which have been delegated to committees, DHEW policy stresses the composition of committee membership. ... In addition to possessing the professional competence to review specific activities, the committee should be able to determine acceptability of the proposal in terms of institutional commitments and regulations, applicable law, standards of professional conduct and practice, and community attitudes. The committee may therefore need to include persons whose primary concerns lie in these areas rather than in the conduct of research, development, and service programs of the types supported by DHEW (emphasis supplied).81 ___________ 78. Institutional Guide, supra, footnote 23, at 8. 79. Institutional Guide, supra, footnote 23. at 8-9. 80. Although the parent institutions are charged by DHEW with the responsibility of formulating policies to guide institutional review committees. Grants Administration Manual, supra, footnote 23, 1-40-40, to our knowledge this task is generally delegated to those committees. As we have previously described, the burden of formulating policy weighs heavily on local institutions because the DHEW policy is vague and incomplete. 81. Grants Administration Manual, supra. footnote 23, 1-40-40 (C) (2) (b). 35 In carrying out their functions, the institutional review committees are thus also asked: "to determine acceptability of the proposal in terms of... applicable law, standards of professional conduct and practice, and community attitude." By assigning these tasks to a broadened committee membership, DHEW recognizes that decision-making in the human experimentation process cannot be left solely to professionals, but requires the participation of informed and concerned non-scientists, who may be laymen, lawyers, clergymen, and appropriate others. However, the functions of these non-professional participants are not spelled out. And the assumption that they can make their most effective contribution at the administrative stage, when individual protocols are reviewed, rather than at other stages of the process remains unexamined. The DHEW policies attempt to consolidate all phases of research regulation-formulation of detailed policies, administration of research, and review of decisions and consequences-in one committee structure. Asking each review committee to determine far-reaching policies by itself overburdens the review committee structure. The policy issues which must be resolved with the assistance of lay members are so complex than to require each committee to work them out by itself is at best inefficient and at worst self-defeating. It would be more functional and efficient to leave the administration of research, like the administration of therapeutic interactions between physicians and patients, primarily in the hands of the professionals. If review committees were guided by comprehensive policies formulated by a broadly representative body, the review of individual protocols could focus on technical matters, such as degree of risk, likely benefits, research design, competence of investigators, safety precautions, and the like. This allocation of authority would help to reduce the widespread concern among physician investigators about "meddlesome outsiders." F. Enforcement The DHEW guidelines on enforcement are written in permissive and general language: The Division of Research Grants (DRG), NIH, will follow up reports by reviewers, evaluators, consultants, and staff of the DHEW indicating concern for the welfare of subjects involved in approved and funded grants or contracts, and of subjects potentially involved in activities approved but not funded, and in disapproved proposals. On the basis of these reports and of other sources of information, the DRG, NIH, may in collaboration with the operating agency concerned, correspond with or visit institutions to discuss correction of any apparent deficiencies in its implementation of the procedures described in its institutional assurance. If, in the judgment of the Secretary, an institution has failed in a material manner to comply with the terms of this policy with respect to a particular DHEW grant or contract, he may require that it be terminated in the manner provided for in applicable grant or procurement regulations. The institution shall be promptly notified of such finding and of the reason therefor. If, in the judgement of the Secretary, an institution fails to discharge its responsibilities for the protection of the rights and welfare of the individuals in its care, whether or not DHEW funds are involved, he may question whether the institution and the individuals concerned should remain eligible to receive future DHEW funds for activities involving human subjects. The institution and individuals concerned shall be promptly notified of this finding and of the reasons therefor.82 These enforcement guidelines delegate sole responsibility for the detection of failures to comply to the Division of Research Grants. But staff members of the DRG are probably the last persons to hear of any infractions once they have occurred, and then only when, as in the Tuskegee Study, they are of major proportions. Indeed, no procedures have been established to require institutional review committees to report to DHEW any evidence on noncompliance. Moreover, DHEW has made no efforts to define categories of noncompliance83 which should lead to the imposition of sanctions or to specify different kinds of sanctions which should be imposed in particular cases. Finally, institutional review committees and DHEW are not authorized to take disciplinary action. except for the Secretary's prerogative to terminate grants or make the investigator or his institution ineligible to receive future funds. G. Compensation of Subjects Existing DHEW policy provides no mechanism for the compensation of subjects harmed as a consequence of their participation in research, in spite of the growing recognition that no matter how careful investigators may be, harm still will befall some subjects.84 Unavoidable injury, to a few is the "cost" of engaging in research which ultimately benefits the many. But unless the injured individuals can prove carelessness, failure to _________rveyed some clinical research was not reviewed by an institutional committee. Moreover, 35% of these institutions were medical schools, the type of institutional setting most productive of biomedical investigations using human subjects." They concluded that "a perhaps significant volume of human research is still not subject to review by peer, review committees." Barber et al, supra, footnote 3, at 149. 88. Grants Administration Manual, supra, footnote 23, 1-40-50 (E). 37 V. RECOMMENDATIONS A. Preface Before turning to our specific recommendations we would like to anticipate three possible criticisms of our proposals. First, the argument may be advanced that any regulation of human research is an unwarranted infringement of the "freedom of inquiry." But freedom of inquiry is only one facet of freedom in general. When scientists use other human beings as subjects of experimentation and in so doing jeopardize their rights and welfare, the scientists' freedom of inquiry clashes head-on with the right of every individual in our society to personal autonomy. Therefore, society must retain the right to define and Limit the human costs it is willing to Bear in order to benefit from advances of knowledge. Second, whenever it is suggested that representatives society at large participate in decision-making of significance to both science and society, concerns about the intrusion of "outsiders" in the domain of professionals are voiced. This position was forcefully expressed by Dr. Owen W. Wangensteen in a letter to Senator Walter F. Mondale prior to congressional hearings. In 1968 on a proposed Commission to study the social and ethical problems raised by biomedical advances. Senator, I would urge you with all the strength I can muster to leave this subject to the conscionable people in the profession who are struggling valiantly to advance medicine. We are living through an era in which the innovator is often under suspicion, being second-guessed by self-appointed arbiters more versed in the art of criticism than in the subject under scrutiny. We need to take great care lest the wells of creativity and the spring of the mind of those who break with tradition are not manacled by well- intentioned but meddlesome intruders. I would urge you to leave these matters in the hand of their proponents, the persons who are actually doing the work. They know more about all this than any of us possibly could. They have wrestled with the problem day and night, almost invariably over many years. Theirs are not overnight judgments or convictions. In the academic community in which I have worked and spent my entire professional life of almost 50 years, you will find as warm, sympathetic human beings as are to be found on this earth. It is important that we look back as well as forward. To have no concern for history is tantamount to having a physician with total amnesia. If we leave this matter alone, it will simmer down. Discussion should not be restrained, but legislative action, never.89 We appreciate Dr. Wangensteen's fears, which have been echoed by others. But not all intrusions by "outsiders" into medical decision-making are viewed by the profession as unwarranted interferences with the practice of medicine. Authorized representatives of society have the right to circumscribe some activities of professionals and this has been accepted; for example, the discretion of physicians to commit patients against their will or to prescribe addictive drugs is limited. Thus, the pertinent questions are: under what circumstances, to what extent, and by what means should the activities of the medical professional be controlled? We have already mentioned that the human research decision- making process can be divided into three functionally distinct stages: the formulation of research policies, the administration of research, and the review of research decisions and their consequences. The participation of "outsiders"-which is to say, of persons deemed capable of representing the interests of society in the proper conduct of research-is highly desirable in the formulation and review stages. Such decisions as the allocation of resources for research, the extent of hazardous experimentation, the degree of respect to be shown for the autonomy of research subjects, and the extent of the participation of children, prisoners, members of minority groups. and other captive or disadvantaged persons in research, are of momentous consequence t society as well as to science. These decisions implicate general social policies and must not be left to the sole discretion of scientists. Nonetheless, we agree that the often expressed fear of interference by laymen with the immediate clinical research decisions which physician-investigators must make has merit. However, we believe that the two positions can be reconciled. Once satisfactory rules and procedures for the protection of human subjects have been formulated and research practices are adequately reviewed by "insiders" and "outsiders," society should feel safe in leaving the actual administration of research and therapy to physician-investigators within the restraints imposed by peer review (through the already established institutional review committees.) Current DHEW policies fail to identify the different stages in the regulation of research. Instead, institutional review committees are charged with formulating policies, administering policies, and evaluating the consequences of their decisions. Taken together these tasks are too burdensome for such committees. ___________ 89 Hearings on S.J. Res. 145 before the Subcommittee on Government Research of the Senate Committee on Government Operations, 90th Cong., 2d Sess. 98-99 (1968). 38 Moreover, because these committees must formulate policy and evaluate decisions, the demand for outsiders to sit on them has intensified, justifying the fear of interference in professional day-to-day decision-making by persons not qualified to do so. Our recommendations seek to reverse this development by confining the role of the institutional committees largely to the implementation of policies already adequately formulated by others. A third criticism may be leveled against our recommendation that a National Human Investigation Board be established to oversee human experimentation. Some may fear that this Board will promulgate such detailed rules and impose so many legal duties that progress in research and innovation in treatment will be seriously impaired. The danger of cumbersome bureaucracy cannot be lightly dismissed and every effort must be made to avert it.90 At the same time we doubt that society, if properly informed, would tolerate any serious impediments to the acquisition of knowLedge, for the pervasive and compelling desire to benefit from advances in medicine should counteract any tendency to stifle research. A national Board to regulate human research is needed for many reasons. One central group should be responsible for formulating policy, instead of the many different Federal agencies and the hundreds of individual review committees which, as we have argued, cannot be expected to assume this complex task. Moreover, "outsiders" who could represent and protect individual and societal values and interests could then be included in policy formulation and review, where they are most needed, without thereby hindering physician-investigators in their professional decision-making. The national Board would provide a forum in which the competing interests of science and society could be debated openly before authoritative decisions are made. B. National Human Investigation Board A permanent Governmental agency, to be called the National Human Investigation Board (NHIB), should be established to oversee at a minimum all Federally-supported research involving human subjects. The jurisdiction of this Board should extend to all extramural and intramural research sponsored by DHEW (including human research currently governed by FDA regulations) as well as to research supported by Government agencies other than DHEW, such as the Department of Defense. Ideally, the authority of this Board should also extend to all human research activities, even if not Federally supported. However, despite its apparent merits, such a sweeping proposal may raise insurmountable jurisdictional problems. We leave it to others to determine whether Congressional authority to regulate research may encompass investigations not conducted or financed by the Federal Government.91 The primary function of the NHIB would be to formulate policies and procedures to govern research with human beings. For this reason the Board must include, in addition to eminent medical and other professional researchers, lay members who can represent the interests of society in the ethical conduct of research with human subjects. Such lay members should be selected for their ability to make disinterested judgments about research issues of societal concern. Because medical and other research professionals have been trained to pursue other goals, they should not be expected to shoulder the added burden of speaking for the concerns of society. Senator Hubert Humphrey has called for the establishment of a National Human Experimentation Standards Board which in some respects resembles the Board we propose. His bill92 provides as follows: Sec. 2. (a) There is hereby established, as an independent agency in the executive branch, a National Human Experimentation Standards Board (hereinafter referred to as the "Board"). (b) The Board shall be composed of 5 members to be appointed by the President by and with the advice and consent of the Senate from among individuals who by virtue of their service, experience, or education are especially qualified to serve on the Board... (3d) Members should be chosen from persons who are representative of the fields associated and concerned with clinical investigations. Sec. 5. (a) It shall be the function of the Board to (1) establish guidelines for the involvement of human beings in medical experiments which are funded in whole or in part with Federal funds; (2) review all planned medical experiments that involve human beings which are funded in whole _____________ 90. Another commonly expressed fear is that detailed regulations may adversely affect the well-being of patient-subjects because the physician-investigator's authority to intervene quickly, whenever his professional judgment dictates it, is unduly restricted. But discretionary authority must of course be delegated to physician-investigators in the exercise of purely professional judgments regarding their patient's health. 91. Senator Jacob Javits has also recently introduced a bill in response to the Tuskegee Study, for the protection of research subjects. S. 3935, 92d Cong., 2d Sess. However, this proposed amendment to the Public Health Service Act is in essence simply a statutory enactment of current DHEW regulations. As we have argued, more than this is needed for the protection of research subjects. 92. S. 3951, 92d Cong., 2d Sess. 39 or in part with Federal finds to determine if the guidelines established under paragraph (1) are being complied with; (3) obtain an injunction to prevent such experimentation in a case where such experiments are found not to comply with established guidelines; and (4) prepare and submit an annual report to the President, for transmittal to the Congress recommending legislation, if required, and detailing the performance of the Board during the preceding year. Senator Humphrey's bill assigns to his Board policy making, administrative and review powers. We believe that some of these functions should not be delegated entirely to the NHIB and that those functions which the NHIB should be given must be spelled out in greater detail. Senator Humphrey's bill also does not provide for he continuation of the institutional review committee system. We believe that institutional review committees should be maintained, although in modified form. We now turn to a discussion of the functions of the NHIB and institutional committees in the formulation, administration and review of policies for human research. 1. Formulation of Policy The National Human Investigation Board must establish guidelines for the conduct of research with human beings with respect to such matters as: a. Selection of Subjects-The Board must formulate criteria for the selection of subjects. It will have to examine the contemporary research practice of choosing subjects from the less educated, disadvantaged, or captive groups within society. In doing so, the Board will have to confront many questions. For example, should every effort be made, consistent with research objects, to obtain a subject sample which represents a cross- section of the population at large? Or should subjects first be selected from among the best educated before turning to the less educated, since the former are more capable of giving "informed consent"? How should the recruitment of subjects be effectuated to implement whatever rules for their selection are adopted? Under what circumstances should non-comprehending subjects such as children or severely mentally disturbed individuals, or captive subjects such as prisoners or other institutionalized persons, be barred from participating in research? b. Ambit of Informed Consent-The Board must not only formulate the overall criteria of informed consent but must also specify the circumstances in which the consent requirement can be modified, and to what extent, in order to accomplish important research adjectives. In doing so, the Board will have to find answers to such policy questions as: Under what circumstances can what benefits to individuals or society justify modifications in the informed consent requirement? Should certain groups or potential subjects be excluded from participating in research or high-risk investigations be proscribed unless informed consent can be obtained? When is third party consent permissible, and what safeguards should be introduced whenever the onset of a third party is invoked? The Board may have to promulgate separate guidelines for the conduct of investigations which are predicated on the absence of informed consent, such as placebo, double blind, deception and secret observation studies. The latter two procedures are employed by sociologists and psychologists on such an extensive and repetitive scale, and constitute such a significant exception to the general requirement of informed consent, that serious consideration should be given to restricting their use. This may be an appropriate place to introduce a note of caution. The policies we have in mind cannot be formulated overnight or without serious study of the problems inherent in this field. An example from the literature on informed consent illustrates this point. It has traditionally been assumed that the consent requirements should be more stringent in research with "healthy" volunteers than with patients. This assumption ought to be reexamined. Perhaps as Alexander Capron has written: ... higher requirements for informed consent should be imposed in therapy than in investigation, particularly when an element of honest experimentation is joined with the therapy. The "normal volunteer" solicited for an experiment is in a good position to consider the physical, psychological and monetary risks and benefits to him in consenting to participate. How much harder that is for the patient to whom an experimental technique is offered during a course of treatment. The man proposing the experiment is one to whom the patient may be deeply indebted (emotionally as well as financially) for past care and on whom he is probably dependent for his future well-being; the procedure may be offered, despite its unknown qualities, because more conventional modalities have proved ineffective.93 ___________ 93. Cipron, "The Law of Genetic Therapy." in The New Genetics and the Future of Man, M. Hamilton, ed. (Eerdmans Pub. Co., 1972). 40 Finally, more attention must be given to the nature and quality of the interactions between investigator and subject if the ensuing consent is to be truly informed and voluntary. In this connection, consideration should also be given to make an adviser available to a subject whenever he thinks that his decision to participate or not might benefit from disinterested advice.94 The authority and obligations of such advisers must be carefully defined and, as we have said repeatedly, with regard to policy formulation, cannot be left to each individual research committee to work out. Definition of "Research "-To clarify the jurisubjects first be selected from among the best educated before turning to the less educated, since the former are more capable of giving "informed consent"? How should the recruitment of subjects be effectuated to implement whatever rules for their selection are adopted? Under what circumstances should non-comprehending subjects such as children or severely mentally disturbed individuals, or captive subjects such as prisoners or other institutionalized persons, be barred from participating in research? b. Ambit of Informed Consent-The Board must not only formulate the overall criteria of informed consent but must also specify the circumstances in which the consent requirement can be modified, and to what extent, in order to accomplish important research adjectives. In doing so, the Board will have to find answers to such policy questions as: Under what circumstances can what benefits to individuals or society justify modifications in the informed consent requirement? Should certain groups or potential subjects be excluded from participating in research or high-risk investigations be proscribed unless informed consent can be obtained? When is third party consent permissible, and what safeguards should be introduced whenever the onset of a third party is invoked? The Board may have to promulgate separate guidelines for the conduct of investigations which are predicated on the absence of informed consent, such as placebo, double blind, deception and secret observation studies. The latter two procedures are employed by sociologists and psychologists on such an extensive and repetitive scale, and constitute such a significant exception to the general requirement of informed consent, that serious consideration should be given to restricting their use. This may be an appropriate place to introduce a note of caution. The policies we have in mind cannot be formulated overnight or without serious study of the problems inherent in this field. An example from the literature on informed consent illustrates this point. It has traditionally been assumed that the consent requirements should be more stringent in research with "healthy" volunteers than with patients. This assumption ought to be reexamined. Perhaps as Alexander Capron has written: ... higher requirements for informed consent should be imposed in therapy than in investigation, particularly when an element of honest experimentation is joined with the therapy. The "normal volunteer" solicited for an experiment is in a good position to consider the physical, psychological and monetary risks and benefits to him in consenting to participate. How much harder that is for the patient to whom an experimental technique is offered during a course of treatment. The man proposing the experiment is one to whom the patient may be deeply indebted (emotionally as well as financially) for past care and on whom he is probably dependent for his future well-being; the procedure may be offered, despite its unknown qualities, because more conventional modalities have proved ineffective.93 ___________ 93. Cipron, "The Law of Genetic Therapy." in The New Genetics and the Future of Man, M. Hamilton, ed. (Eerdmans Pub. Co., 1972). 40 Finally, more attention must be given to the nature and quality of the interactions between investigator and subject if the ensuing consent is to be truly informed and voluntary. In this connection, consideration should also be given to make an adviser available to a subject whenever he thinks that his decision to participate or not might benefit from disinterested advice.94 The authority and obligations of such advisers must be carefully defined and, as we have said repeatedly, with regard to policy formulation, cannot be left to each individual research committee to work out. Definition of "Research "-To clarify the jurisdiction of the Board and of the institutional review committees, distinctions must be made between "research" activities and" accepted and established procedure." We have pointed out already that the borderline between research and therapy is difficult to draw. Physician investigators have often wittingly or unwittingly added to the obfuscation by calling some investigations "therapy" in order to escape the obligations which the research designation entails. Such practices diminish the protection afforded subjects, and also undermine the scientific validity of the results of such investigations, because they were not established in carefully controlled clinical trials. d. Application of Risk-Benefit Criteria-We have already suggested that the risk benefit equation is one of the most difficult guidelines to implement. To evaluate risk taking, distinctions must be made between research designed to benefit its participants and those which may benefit society at large. With respect to societal benefits, answers will have to be found to such crucial questions as: Do even minimal risks from participation require an intensive scrutiny of the benefits to be derived from the study or should "minimal" risks, however defined, be exempted from this burdensome requirement? How often can risky experiments be repeated for the sake of verification, if results have already been reported in the literature? Must certain groups, such as children and mentally defective subjects, be excluded from all risky studies that are not designed to benefit them? When the risks and benefits of therapeutic measures are unknown, as in all first clinical trials of a new drug. Should the tests be randomized with a limited number of patients in order to ascertain a scientifically valid estimate of effectiveness? In research with so-called normal volunteers or other subjects who are able to give a satisfactory consent. Can greater risks to be taken than a weighing of risks against benefits would in general permit. Should dying patients who are willing to participate in risky experiments be exempted from the rule that no experiments are to be conducted which might hasten death? e. Promulgation of a Compensation Scheme-An insurance plan should be devised and implemented for the compensation of subjects harmed as a consequence of their participation in research activities. Though many schemes for compensating subject deserve consideration, we mention one which we believe has substantial merit: "no fault" clinical research insurance paid for by each institution sponsoring research. Subjects would be compensated for any injurious consequences of their participation in research whether or not caused by the fault of the investigator. This plan would provide full protection for subjects and relieve investigators of the threat of liability. As to cost, one of the principal promoters of research insurance, Irving Ladimer, has asserted that: ... it is unlikely that the costs will be great, probably a small fraction of customary malpractice premiums. First, there are few compensable occurrences within responsible research institutions, where most of the studies are conducted. Second, the assumption of medical care, most likely at the sponsor's premises, will reduce such costs. Third, the adoption of such a system should tend to improve prior protection, controls, and research design; this is especially true for studies approved by research review committees. Fourth, the spirit and philosophy of this form which should be fully explained in advance in discussions with participants, should serve to diminish rather than induce any questionable clams.95 The cost of the insurance would probably vary directly with institutional safety records and thus might provide an additional impetus to careful consideration to research proposals. Guido Calabresi has called attention to this possibility: ... Requiring compensation of injured subjects causes the full cost of research in humans to be placed on the research center. Accordingly, approval by the center of a particular experiment will require conscious consideration not only of the possible payoff (either in market or scientific terms), but also of the risks, converted to money, that the project entails. This may not deter many experiments, but it may cause those involved in the most risky or least useful ones to consider carefully whether the experiment is worth it, whether it is best done by those who propose to do it, and whether there is an alternative and safer, way of obtaining approximately the same results. It may well be that all these considerations are already firmly in the minds of the experimenters. _____________ 94. We elaborate upon this recommendation infra. pp. 44 ff. 95. Ladimer, supra. footnote 84, at 259. 41 If so, nothing is changed by requiring compensation. But if researchers-like auto makers, coal mine owners and the rest of mankind-tend to consider costs and benefits a bit more carefully when money is involved, a useful added control device will have been imposed.96 If "no fault" research insurance, or any other mechanism, is adopted as a device for compensating subjects, regulations will have to be established for adjudicating disputes over such matters as causation- whether the worsened condition of the subject was caused by the research in which he participated or whether it was merely the inevitable outcome of the subject's particular illness-or the amount of compensation. Similarly, the NHIB will have to work out procedures for implementing whatever compensation scheme is adopted. f. Promulgation of Sanctions-Senator Humphrey's bill, authorized his Board "to obtain an injunction to prevent experimentation in a case where experiments are found not to comply with established guidelines." Though the promulgation of sanctions raises many sensitive issues, more is needed than has been provided in Senator Humphrey's bill. Other sanctions tailored to specifIc violations of the policies governing research are required. For example, an investigator's failure to submit a protocol for review, his departure from an approved research protocol or a review committee's failure to follow its established procedures might in some circumstances justify suspension of further Federal funding of the investigator or the sponsoring institution. It is beyond the scope of this report to detail the offenses which should lead to the invocation of sanctions, the particular penalties which should be imposed, or the procedures which must be followed to satisfy due process requirements. We also leave open the question of who-the National Human Investigation Board or Congress-should promulgate the regulations which will govern the imposition of sanctions. g. Delegation of Authority to Administer and Review the Research Process-The National Human Investigation Board must also promulgate rules and procedures for the administration and review of the human research process. We now turn to these issues under their appropriate headings. 2. Administration of Research a. Institutional Human Investigation Committees Once adequate research policies have been formulated by a broadly representative body, "outsiders" should intervene as little as possible in the administration of those policies. For when research policies are put into effect, limitations imposed by colleagues are better tolerated by investigators than restrictions imposed by outsiders. The administration of research should therefore be performed principally by researchers' professional peers sitting on institutional review committees. Thus we seek to reverse the trend97 toward outsider membership on institutional review committees and outsider interference with day-to-day professional decision-making. In our proposed restructuring of institutional review committees, we have sought to restrict the participation or outsiders to those areas where they have the most to contribute. Senator Humphrey's bill does not specify the status of the institutional review committees which are now required by DHEW. The advantages of institutional committees are numerous, and we propose that they be retained, though with redefined functions. Among other things, administration at the institutional level simplify the task of prior review of research protocols; permits closer scrutiny of research activities; encourages investigator involvement in and respect for the problems of ethical research; enables different institutions to deal with complex new problems from different vantage points, and facilitates responsiveness to difficulties in the research process as they arise. Instead of emanating institutional committees, they should be restructured to enable them to perform their functions better than they now do. We recommend the creation of structured institutional body, to be called the Institutional Human Investigation Committee (IHIC), in place of the existing unspecialized institutional review committee. Each institution which is subject to the jurisdiction of the NHIB would be required to provide written assurance to the NHIB that it had appointed an IHIC. This would be similar to current practice which requires institutions to negotiate assurances with the NIH's Division of Research Grants.98 As outlined below, each IHIC would be responsible for the conduct of research in its institution, and would be required to file with the NHIB its plans for carrying out the responsibility. Thus the NHIB would pass on the suitability of the IHIC membership, local policies, and administrative _______________ 96. Calabresi, "Reflections on Medical Experimentation in Humans," 98 Daedalus 387, 398 (1969). 97. Current DHEW regulations suggest, and FDA regulations require that outsiders be members of institutional review committees. See Grants Administration Manual, supra, footnote 23,1-40-40 (C)(2) (b); 21 CFR 130.3; 36 Fed. Reg. 5037, 5038 (March 17, 1971). 98. See Grants Administration Manual supra, footnote 23, 1-40-40 (A): The assurance shall embody a statement of compliance with DHEW requirements for initial and continuing committee review of the supported activities; a set of implementing guidelines, including identification of the committee; and a description of its review procedures. 42 procedures, and NHIB approval would be required before Federally funded research99 could be conducted at the institution.100 IHIC members should be appointed by their institutions to serve for a period of years, so as to accumulate expertise in the problems of human experimentation. The membership should represent a cross-section of the disciplines involved in research at the institution. It ought also to include a few "outsiders" who can make a valuable contribution to the supervision of the consent process, as described below. The main functions of each IHIC would be: to establish local policies, consistent with the uniform national guidelines promulgated by the NHIB, which are responsive to the individualized needs of the institution, to bring to the attention of the NHIB any procedural modifications deemed necessary for effective functioning; to inform local participants in the research enterprise of their rights and obligations; and to establish two subcommittees to carry out its administrative functions-a Protocol Review Group and a Subject Advisory Group. Although the membership of the sub-committees should be drawn largely from the IHIC, these subcommittees could also include others associated with the institution. Our recommendations regarding the two subcommittees are modeled on a similar proposal recently advanced by Jay Katz and Alexander Capron in a somewhat different context, and in what follows we quote from the draft document they have prepared. b. Protocol Review Groups The heart of IHIC's will be their Protocol Review Groups (PRG) which will be responsible for approving, disapproving or offering suggestions for modification in protocols for experimental and therapeutic interventions which come within the policies on risk and consent formulated earlier in the process. The PRG's task is to apply the rules and policies already set down, but this should not be a matter of "clockwork" or mere routine. Realistically, it is unlikely that even if policy formulation proceeded with much more rigor (as we urge) it will result in directive that settle all issues faced by the PRG's. This does not suggest, however, that Protocol Review Groups set policies themselves, though these rules may give them some discretion in light of local institutional conditions and so as to permit experimentation with a variety of alternative policies which are still consistent with the general directives. This sort of flexibility is vital if the PRG's are to operate effectively and secure the services of thoughtful, devoted members. Membership in the Protocol Review Group should consist primarily of professionals with competence in biomedicine. This reflects the committee's function, which is to scrutinize protocols in light of the policy guidelines and directives, to evaluate whether the procedure should be undertaken, and to give advice to the physicians and scientists involved. In most instances these group members will be members of the university or research center's staff and faculty, but when the presence of more than one institution in a locality permits it, the cross-fertilization of having some people from one center serve on another's PRG would probably be advisable. Such an arrangement would provide "outsiders" in the sense of people's free of the personal ties and biases of the institution's own employees, while maintaining the biomedical expertise that should characterize "insiders."101 c. Subject Advisory Groups Katz and Capron also propose "the establishment of Subject Advisory Groups (SAG) to aid patient-subjects in decision- making."102 We do not lightly suggest the creation of another subgroup within the IHIC, since we have no desire to overburden the process with excessive bureaucracy. But, as we have emphasized, present procedures for obtaining consent are concerned with form to the neglect of substance. If informed and voluntary subject consent is to become a reality in human experimentation, efforts must focus on improving the quality of the communications between investigator and subject. We therefore endorse the Katz and Capron proposal that an advisor be made available to counsel any prospective subject who thinks his decision to participate or not might benefit from disinterested advice. Not all patient-subjects may wish to seek out representatives of the Subject Advisory Group, for some may be satisfied with the information obtained from physician-investigators. But patient-subjects should be well apprised of the availability of these representatives prior to their participation in projects which have to be submitted to the PRG because of the _____________ 99. Or any research - see supra. p. 39. 100. It should be noted that, as in present DHEW policy, different requirements might be established for institutions "having a significant number of concurrent" research projects and for institutions sponsoring only one, or a limited number, of such projects. See Grants Administration Manual, supra, footnote 23, 1- 40-40 (B), (C), and (D). The description of the IHIC presented in our report hereinafter is for an institution with a number of research activities. 101. Katz and Capron, supra, footnote 18. 102. Ibid. 43 risk involved or because of the problems anticipated with obtaining valid consent. Patient-subjects may also wish to avail themselves of the SAG's services when they begin to wonder whether continuation of the intervention is worth the pain and suffering they have to endure. At such times the Subject Advisory Group assumes the important function of administering the procedures formulated for the termination of experimental treatments.103 The SAG should also aid investigators in developing fair methods of obtaining consent, and in avoiding advertent bias or coercion when seeking consent. It ought to go without saying that ... (c)reating an opportunity for someone in addition to physician-investigators to talk with patient-subjects does not suggest a lack of trust in the investigators' integrity, rather it recognizes the reality that investigators cannot help but plead, however unconsciously, their interests in the research and therefore must find it difficult fully to safeguard the interests of their subjects.104 Because the work of the SAG would be restricted to sues relating to consent, laymen could make a significant contribution in this subcommittee. They, more than professionals, would appreciate the difficulties prospective subjects might have when faced with an invitation to participate in research. And potential subjects might be less overawed in interactions with their peers, than in interactions with physicians. d. Appeals From time to time disagreements will arise between investigators and the Protocol Review Groups. No opportunity for appeal from an adverse institutional review committee ruling exists at present, and committees can cut investigators off from Federal funding without possibility of reconsideration. This may not only hinder the acquisition of knowledge; it may also undermine the legitimacy of peer review. Barber et al. have written: We have heard researchers object to peer review as they know or understand it because they believe that research proposals having real potential for medical scientific advances, or even "pioneering breakthroughs," frequently either are not or will not be approved by those who sit on institutional review committees. The reasons for these rejections they are especially concerned about do not involve the ethical defectiveness of the proposals. Rather they include local institutional politics and conflicts as well as resistance to innovations just because they depart from accustomed ways of scientific thinking and proceeding... (T)o forestall rejections of this kind, the biomedical community may have to go beyond the establishment of local appeal procedures by institutions. Perhaps what is necessary is the establishment of a hierarchy of "courts of appeal" throughout the nation, culminating, as a final resort, in a "supreme court" composed of eminent peers including both "insiders" and "outsiders" with respect to any field. Such a system might be the best safeguard available against the object of these concerns- unjustified hindrance of medical progress by the peer review process.105 Procedures should be established for appeals to the [National Human Investigation Board.106 After a hearing of the controversy, the NHIB should be empowered to sustain or overrule the judgement of the Protocol Review Group. Since the NHIB has a role to play in the administration of research, it must employ expert staff to evaluate research protocols and to prepare detailed findings. This staff would take over the reviewing function currently handled by DHEW study groups. However, it is beyond he scope of this report to set forth all the specific functions which the NHIB should assume. In particular, we have refrained from deciding how many of the protocols approved by the PRG's should be reviewed again by the NHIB. Though a certain number will have to be examined in order to provide the NHIB with sufficient information to carry out its most important function- policy formulation, -it may not be necessary to review all protocols a second time. This would be a time-consuming task. 3. Review of Decisions and Consequences The NHIB must create mechanisms for the overall review of the human experimentation process in order to assess the continuing efficacy of its own policies and of the institutional peer group review. Thus, the Board has to keep itself informed about ongoing research practices, and a number of already existing resources would facilities this task: scientific journals which publish research studies, legal cases in which conflicting claims about research have been brought before courts, news paper accounts _____________ 103. Ibid. 104. Ibid. 105. Barber et al. supra, footnote 3, at 156-157. (footnote omitted). 106. IHIC's might also find it appropriate to establish an internal appeals procedure. This would be more convenient than, and would sometimes obviate the need for, appeals to the national level. 44 (such as the initial reports of the Tuskegee Syphilis Study), reports from Institutional Human Investigation Committees, etc-107 The NHIB must also establish rules and procedures for the direct review by IHIC's and by NHIB staff members of ongoing previously approved research projects. The current requirement of systematic review of all projects at fixed intervals is burdensome and inefficient and encourages perfunctory review. Instead of requiring continuing review of all research projects on a routine basis, it would reduce the' burden on IHIC's and maximize the effectiveness of continuing review if investigators were asked to report immediately any contemplated or necessary deviations from approved research protocols, all inconveniences and injuries suffered by any subjects which has not been anticipated in the original protocol, or any medical advances which might benefit subjects and which has not been anticipated in the original protocol.. Moreover, periodic "spot checks" of selected interventions which are now discretionary should be made a requirement. It is apparent that some approved research projects are carried out improperly. For example, in a recent study involving subjects subsequent to their participation in a medical research projects which had been approved by an institutional review committee, an interviewer found that, (m)ost of these subjects learned of the existence of the study during the interviews done for my research. Second, many more subjects (the exact number awaits further analysis), while aware of the research, has significant gaps in their under-standing of the project and consented on a more or less uninformed basis. These included women who had no knowledge of whether there were alternatives to participation, women who did not know of the double-blind nature of the study (it was not part of the research design to withhold this information), and women who were not aware of the fetal monitoring procedures and extra blood samples required by the research. Others were not aware beforehand that their consent to have the baby observed would be sought by a separate researcher.108 Spot checks would determine the extent of noncompliance with existing procedures. Should the checks reveal widespread noncompliance, then remedial steps could be taken, such as better education of physician-investigators about their responsibilities, more careful evaluation of protocols, or routine monitoring of all research activities for a period of time. The NHIB should also invite the IHIC's to submit their most difficult decisions for an evaluation. Significant cases, including the original PRG rulings and the subsequent NHIB opinions, should be published to give direction to the deliberation of local committees, to provide material for scholarly analysis, and to foster and sustain public awareness of the issues raised by human experimentation. Indeed, all important decisions rendered at the local or national level should be published and preserved in easily accessible form. These cases would serve as precedents for future opinions. Thus publication would be a first step toward the case-by-case development of sound policies for human experimentation. No regard such a development, analogous to the growth of the common law, as the best hope for ultimately providing workable standards for the regulation of the human experimentation process. Finally, we emphasize again that the review of research decisions and their consequences requires the participation of persons representing a wide variety of societal interest and should not be limited to members of the biomedical professions. It is at the policy-formulation and review stages of the human experimentation process that "outsiders" have an important role to play by championing individual and societal rights and interests. Professionals have been trained to pursue other goals and should not be expected, even if they could, to shoulder the added burden of speaking for the concerns of society. C. Education Our last recommendation pertains to the education of investigators, particularly when they are still students, for the responsible practice of human research in a democratic society. Recently, Senator Jacob Javits introduced a bill109 in the Senate which addresses itself to this problem. The bill would authorize special project grants for medical schools to develop and operate programs which provide increased emphasis on the ethical, social, moral, and legal implications of advanced in biomedical research and technology. _____________ 107. The NHIB might consider inviting others - for example, editors of scientific journals - to submit for review studies which raise ethical questions. Editorial boards should welcome such an opportunity. particularly in the light of the recent debate about the publication of articles based on "unethical" research. Some commentators have favored non-publication. While others have felt that "(s)uch an editorial policy would maintain the low-visibility of unethical experimentation and preclude not only review but also careful and constant appraisal of the conflicting values inherent in experimentation." (Katz. "Human Experimentation." 275 New Eng. J. of Med. 790 (1966)). Journal censorship creates difficult problems. If editorial boards could be assured that violations of "ethical" practice would be dealt with by an authorized body, they might prefer to call them to the attention of the NHIB and judge acceptability of articles on the basis of scientific merits. 108. Gray. "Some Vagaries of Consent," a preliminary report (1971) on data collected for the author's doctoral thesis. reproduced in Katz, supra. footnote 12. at 660. 109. S. 974, 93d Cong., 1st Sess. 45 The bill... provides the opportunity for our Nation's medical schools to develop the appropriate program curriculums regarding ethical, moral, and social issues to meet the need the protection of human subjects at risk in medical research and improved understanding of the con-sequences and implications for the individual and society of the advances in biomedical science- and through their own initiative and leadership construct and appropriate continuing professional institutional activity to safeguard human subjects in research.110 Senator Javits referred to the findings of Professor Bernard Barber et al, and to document further the need for such an educational effort, we quote briefly another passage from their study: It is clear from our date that medical schools are presently giving very little serious attention to these matters in their curriculum. Of the 307 physicians interviewed, only 13% reported that they had a seminar, a lecture or part of a course devoted to the issues involved in the use of human subjects in biomedical research, and only one researcher said that he had had a complete course dealing with these issues. Thirteen per cent of the respondents said that the issues of research ethics came up when as students they did practice procedures on one another, and 24% said that they became aware of the issues of balancing risk or suffering against potential benefits when doing experimental work with animals. Thirty-four per cent remembered discussions with instructors or other students of the ethical issues involved in specific research project which they had read about or learned of in class. But 57% of the physicians interviewed reported none of these experiences, even those peripheral to work with humans, such as those involving animal experimentation. 111 It has sometimes been asserted that the human subject in experimentation is best safeguarded by the presence of an intelligent, informed, conscientious, compassionate, responsible investigator."112 Whatever merit underlies such a contention, sufficient attention has not been paid by educators in all professional schools to exploring the responsIbilities of the professional toward his patients, clients, or research subjects. Without training, even a "conscientIous investigator is poorly prepared to deal knowledgeably or systematically with these problems. Though in recent years there has been an upsurge in efforts to expose students to the issues raised by professional responsibility, considerably more thought and support must be given to this work. Professional schools must recruit faculty members who are interested in pursuing the complex problems created by human research in particular and contemporary professional practices in general. The task is not limited to educating students but must ultimately include a re-examination of the entire scope of professional decision-making. 110. 110 Cong. Rec. s 3114 (Feb. 22, 1973) 111. Barber et al. supra, footnote 3, at 101; 112. Beecher. "Ethics and Clinical Research," 274 New Eng. J Med. 1354, 1360 (1966). 46 VI. CONCLUSION Human experimentation reflects the recurrent societal dilemma of reconciling respect for human rights and individual dignity with the felt needs of society to overrule individual autonomy for the common good. Throughout this report we have expressed our concern for the lack of attention which has been given to the protection of the rights and welfare of human subjects in research. Society can no longer afford to leave the balancing of individual rights against scientific progress to the scientific community alone. The revelations of the Tuskegee Syphilis Study once again dramatically confirmed this conclusion. We offer our far-reaching proposals in the hope that the decision-making process for human research will become more open and more effectively regulated. We have amply documented the need for implementing this most basic recommendation. Precise rules and efficient procedures. However, are not by themselves proof against a repetition of Tuskegee. For, however well designed the system of regulation the danger of token adherence to ethical standards and evasion in the guise of flexibility will persist. Ultimately, the spirit in which an aware Society undertakes to use human beings for research ends will determine the protection which those human beings will receive. Therefore, we have urged throughout a greater participation by society in the decisions which affect so many human lives. Respectfully submitted, Ronald H. Brown Vernal Cave, M.D. Jean L. Harris, M.D. Seward Hiltner, Ph.D., D.D. Jay Katz, M.D. Jeanne C. Sinkford, D.D.S.,Ph.D. Fred Speaker Barney H. Weeks Abstention: Broadus N. Butler. Ph.D. 47 TAB 4 Research Ethics: The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guideline for the Protection of Human Subjects of Research (April 18, 1979) OPRR REPORTS NIH PHS HHS THE BELMONT REPORT Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research April 18, 1979 Page 2 THE BELMONT REPORT DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Office of the Secretary Protection of Human Subjects Belmont Report: Ethical Principles And Guidelines for the Protection of Human Subjects of Research, Report the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research AGENCY: Department of Health, Education, and Welfare. ACTION: Notice of Report for Public Comment. SUMMARY: On July 12, 1974, the national Research Act (Pub. L. 93- 148) was signed into law, there-by creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral research. One of the charges to the commission was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which could be followed to assure that such research is conducted in accordance with those principles. In carrying out the above, the Commission was directed to consider: (i) the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine, (ii) the role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects, (iii) appropriate guidelines for the selection of human subjects for participation in such research and (iv) the nature and definition of informed consent in various research settings. The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations. It is the outgrowth of an intensive four-day period of discussions that were held in February 1976 at the Smithsonian Institution's Belmont Conference Center supplemented by the monthly deliberations of the Commission that were held over a period of nearly four years. it is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. By publishing the Report in the Federal Register, and providing reprints upon request, the Secretary intends that it may be made readily available to scientists, members of institutional Review Boards, and Federal employees. The two- volume Appendix, containing the lengthy reports of experts and specialists who assisted the Commission in fulfilling this part of its charge, is available as DHEW Publication No. (OS) 78- 0013 and No. (05) 784)014, for sale by the Superintendent of Documents U.S. Government Printing Office, Washington, D.C. 20402. Unlike most other reports of the Commission, the Belmont Report does not make specific recommendations for administrative action by the Secretary of Health, Education, and Welfare. Rather, the Commission recommended that the Belmont Report be adopted in its entirety, as a statement of the Department's policy. The Department requests public comment on this recommendation. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research Members of the Commission Kenneth John Ryan, M.D., Chair-man, Chief of Staff, Boston Hospital for Women. Joseph V. Brady, Ph.D., Professor of Behavioral Biology. Johns Hopkins University. Robert E. Cooke, M.D., President, Medical College of Pennsylvania. Dorothy l. Height, President, National Council of Negro Women, Inc. Albert R. Jonsen, Ph.D., Associate Professor of Bioethics, University of California at San Francisco. Patricia King, J.D., Associate Professor of Law, Georgetown University Law Center. Karen Lebacqz, Ph.D., Associate Professor of Christian Ethics, Pacific School of Religion. *David W. Louisell,J.D., Professor of Law, University of California at Berkeley. Donald W. Seldin, M.D., Professor and Chairman, Department of internal Medicine, University of Texas at Dallas. Elliot Stellar, Ph.D., Provost of the University and Professor of Physiological Psychology, University of Pennsylvania. *Robert H. Turtle, LL.B., Attorney, VomBaur, Coburn, Simmons & Turtle, Washington, D.C. * Deceased. Table of Contents A. Boundaries Between Practice and Research B. Basic Ethical Principles 1. Respect for Persons 2. Beneficence 3. Justice C. Applications 1. Informed Consent 2. Assessment of Risk and Benefits 3. Selection of Subjects THE BELMONT REPORT Page 3 Belmont Report Principles and Guidelines for Research Involving Human Subjects Scientific research has produced substantial social benefits. It has also posed some troubling ethical questions. public attention was drawn to these questions by reported abuses of human subjects in biomedical experiments, especially during the Second World War. During the Nuremberg War Crime Trials, the Nuremberg code is drafted as a set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp prisoners. This code became the prototype of many later codes1 intended to assure bat research involving human subjects would be carried out in an ethical manner. The codes consist of rules, some general, others specific, that guide the investigators or the reviewersbeen given to the protection of the rights and welfare of human subjects in research. Society can no longer afford to leave the balancing of individual rights against scientific progress to the scientific community alone. The revelations of the Tuskegee Syphilis Study once again dramatically confirmed this conclusion. We offer our far-reaching proposals in the hope that the decision-making process for human research will become more open and more effectively regulated. We have amply documented the need for implementing this most basic recommendation. Precise rules and efficient procedures. However, are not by themselves proof against a repetition of Tuskegee. For, however well designed the system of regulation the danger of token adherence to ethical standards and evasion in the guise of flexibility will persist. Ultimately, the spirit in which an aware Society undertakes to use human beings for research ends will determine the protection which those human beings will receive. Therefore, we have urged throughout a greater participation by society in the decisions which affect so many human lives. Respectfully submitted, Ronald H. Brown Vernal Cave, M.D. Jean L. Harris, M.D. Seward Hiltner, Ph.D., D.D. Jay Katz, M.D. Jeanne C. Sinkford, D.D.S.,Ph.D. Fred Speaker Barney H. Weeks Abstention: Broadus N. Butler. Ph.D. 47 TAB 4 Research Ethics: The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guideline for the Protection of Human Subjects of Research (April 18, 1979) OPRR REPORTS NIH PHS HHS THE BELMONT REPORT Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research April 18, 1979 Page 2 THE BELMONT REPORT DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Office of the Secretary Protection of Human Subjects Belmont Report: Ethical Principles And Guidelines for the Protection of Human Subjects of Research, Report the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research AGENCY: Department of Health, Education, and Welfare. ACTION: Notice of Report for Public Comment. SUMMARY: On July 12, 1974, the national Research Act (Pub. L. 93- 148) was signed into law, there-by creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral research. One of the charges to the commission was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which could be followed to assure that such research is conducted in accordance with those principles. In carrying out the above, the Commission was directed to consider: (i) the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine, (ii) the role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects, (iii) appropriate guidelines for the selection of human subjects for participation in such research and (iv) the nature and definition of informed consent in various research settings. The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations. It is the outgrowth of an intensive four-day period of discussions that were held in February 1976 at the Smithsonian Institution's Belmont Conference Center supplemented by the monthly deliberations of the Commission that were held over a period of nearly four years. it is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. By publishing the Report in the Federal Register, and providing reprints upon request, the Secretary intends that it may be made readily available to scientists, members of institutional Review Boards, and Federal employees. The two- volume Appendix, containing the lengthy reports of experts and specialists who assisted the Commission in fulfilling this part of its charge, is available as DHEW Publication No. (OS) 78- 0013 and No. (05) 784)014, for sale by the Superintendent of Documents U.S. Government Printing Office, Washington, D.C. 20402. Unlike most other reports of the Commission, the Belmont Report does not make specific recommendations for administrative action by the Secretary of Health, Education, and Welfare. Rather, the Commission recommended that the Belmont Report be adopted in its entirety, as a statement of the Department's policy. The Department requests public comment on this recommendation. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research Members of the Commission Kenneth John Ryan, M.D., Chair-man, Chief of Staff, Boston Hospital for Women. Joseph V. Brady, Ph.D., Professor of Behavioral Biology. Johns Hopkins University. Robert E. Cooke, M.D., President, Medical College of Pennsylvania. Dorothy l. Height, President, National Council of Negro Women, Inc. Albert R. Jonsen, Ph.D., Associate Professor of Bioethics, University of California at San Francisco. Patricia King, J.D., Associate Professor of Law, Georgetown University Law Center. Karen Lebacqz, Ph.D., Associate Professor of Christian Ethics, Pacific School of Religion. *David W. Louisell,J.D., Professor of Law, University of California at Berkeley. Donald W. Seldin, M.D., Professor and Chairman, Department of internal Medicine, University of Texas at Dallas. Elliot Stellar, Ph.D., Provost of the University and Professor of Physiological Psychology, University of Pennsylvania. *Robert H. Turtle, LL.B., Attorney, VomBaur, Coburn, Simmons & Turtle, Washington, D.C. * Deceased. Table of Contents A. Boundaries Between Practice and Research B. Basic Ethical Principles 1. Respect for Persons 2. Beneficence 3. Justice C. Applications 1. Informed Consent 2. Assessment of Risk and Benefits 3. Selection of Subjects THE BELMONT REPORT Page 3 Belmont Report Principles and Guidelines for Research Involving Human Subjects Scientific research has produced substantial social benefits. It has also posed some troubling ethical questions. public attention was drawn to these questions by reported abuses of human subjects in biomedical experiments, especially during the Second World War. During the Nuremberg War Crime Trials, the Nuremberg code is drafted as a set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp prisoners. This code became the prototype of many later codes1 intended to assure bat research involving human subjects would be carried out in an ethical manner. The codes consist of rules, some general, others specific, that guide the investigators or the reviewers of in their work. Such rules are inadequate to cover common situations; at times they come into conflict, and they are frequently difficult to interpret or apply. Broader ethical principles will provide a basis on which specific rules may be formulated, criticized and interpreted. Three principles, or general prescriptive judgments, that are relevant to research involving human subjects are identified in this statement. Other principles may also be relevant. These three are comprehensive, however, and are stated at a level of generalization that should assist scientists, subjects, reviewers and interested citizens to understand the ethical issues inherent in research involving human subjects. These principles cannot always be applied so as to resolve beyond dispute particular ethical problems. The objective is to provide an analytical framework that will guide the resolution of ethical problems arising from research involving human subjects. This statement consists of a distinction between research and practice, a discussion of the three basic ethical principles and remarks about the application of these principles. A. Boundaries Between Practice and Research It is important to distinguish between biomedical and behavioral research, on the one hand, and the practice of accepted therapy on the other, in order to know what activities ought to undergo review for the protection of human subjects of research. The distinction between research and practice is blurred partly because both often occur together (as in research designed to evaluate a therapy) and partly because notable departures from standard practice are often called "experimental" when the terms "experimental" and "research" are not carefully defined. For the most part, the term "practice" refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment or therapy to particular individuals.2 By contrast, the term "research" designates an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective. When a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is "experimental," in the sense of new, untested or different, does not automatically place it in the category of research. Radically new procedures of this description should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Thus, it is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research project.3 Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy. This need not cause any confusion regarding whether or not the activity requires review; the general rule is that if there is any element of research in a activity, that activity should undergo review for the protection of human subjects. B. Basic Ethical Principles The expression "basic ethical principles" refers to those general judgments that serve as a basic justification for the many particular ethical prescriptions and evaluations of ______________ 1 Since 1945. various codes for the proper and responsible conduct of human experimentation in medical research have been adopted by different organizations. The best known of of these codes are the Nuremberg Code of 1947, Helsinki Declaration of 1964 (revised in and the 1971 Guidelines (codified into Federal Regulations in 1974) issued by the U.S. Department of Health, Education, and Welfare Codes for the conduct of social and behavioral research have also been adopted. The best known being that of the American Psychological Association, published in 1973. 2 Although practice usually involves interventions designed solely to enhance the well-being of a particular individual, interventions are sometimes applied to one individual for the enhancement of the well-being of another (e.g., blood donation, skin grafts, organ transplants) or an intervention may have the dual purpose of enhancing the well-being of a particular individual, and, at the same time, providing some benefit to others (e.g., vaccination. which protects both the person who is vaccinated and society generally). The fact that some forms of practice have elements other than immediate benefit to the individual receiving an intervention, however, should not confuse the general distinction between research and practice. Even when a procedure applied in practice may benefit some other person. it remains an intervention designed to enhance the well-being of a particular individual or groups of individuals; thus, it is practice and need not be reviewed as research. 3 Because the problems related to social experimentation may differ substantially from those of biomedical and behavioral research. The Commission specifically declines to make any policy determination regarding such research at this time. Rather, the Commission believes that the problem ought to be addressed by one of its successor bodies. Page 4 THE BELMONT REPORT human actions. Three basic principles, among those generally accepted in our cultural tradition, are particularly relevant to the ethics of research involving human subjects: the principles of respect for persons, beneficence and justice. 1. Respect for Persons. Respect for persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy. An autonomous person is an individual capable of deliberation about personal goals and of acting under the direction of such deliberation. To respect autonomy is to give weight to autonomous persons' considered opinions and choices while refraining from obstructing their actions unless they are clearly detrimental to others. To show lack of respect for an autonomous agent is to repudiate that person's considered judgments, to deny an individual the freedom to act on those considered judgments, or to withhold information necessary to make a considered judgment, when there are no compelling reasons to do so. However, not every human being is capable of self- determination. The capacity for self-determination matures during an individual's life, and some individuals lose this capacity wholly or in part because of illness, mental disability, or circumstances that severely restrict liberty. Respect for the immature and the incapacitated may require protecting them as they mature or while they are incapacitated. Some persons are in need of extensive protection, even to the point of excluding them from activities which may harm them; other persons require little protection beyond snaking sure they undertake activities freely and with awareness of adverse consequences. The extent of protection afforded should depend upon the risk of harm and the likelihood of benefit. The judgment that any individual lacks autonomy should be periodically reevaluated and will vary in different situations. In most cases of research involving human subjects, respect for persons demands that subjects enter into the research voluntarily and with adequate information. In some situations, however, application of the principle is not obvious. The involvement of prisoners as subjects of research provides an instructive example. On the one hand, it would seem that the principle of respect for persons requires that prisoners not be deprived of the opportunity to volunteer for research. On the other hand, under prison conditions they may be subtly coerced or unduly influenced to engage in research activities for which they would not otherwise volunteer. Respect for persons would then dictate that prisoners be protected. Whether to allow prisoners to "volunteer' or to "protect" them presents a dilemma. Respecting persons, in most hard cases, is often a matter of balancing competing claims urged by the principle of respect itself. 2. Beneficence.-Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being. Such treatment falls under the principle of beneficence. The term "beneficence" is often understood to cover acts of kindness or charity that go beyond strict obligation. In this document, beneficence is understood in a stronger sense, as an obligation. Two general rules have been formulated as complementary expressions of beneficent actions in this sense: do not harm and (2) maximize possible benefits and minimize possible harms. The Hippocratic maxim "do no harm" has long been a fundamental principle of medical ethics. Claude Bernard extended it to the realm of research saying that one should not injure one person regardless of the benefits that might come to others. However, even avoiding harm requires learning what is harmful; and, in the process of obtaining this information, persons may be exposed to risk of harm. Further, the Hippocratic Oath requires physicians to benefit their patients "according to their best judgment." Learning what will in fact benefit may require exposing persons to risk. The problem posed by A special problem of consent arises there informing subjects of some pertinent aspect of the research is likely to impair the validity of the research. In many cases, it is sufficient to indicate to subjects that they are being invited to participate in research of which some features will not be revealed until the research is concluded. In all cases of research involving incomplete disclosure, such research is justified only if it is clear that (1) incomplete disclosure is truly necessary to accomplish the goals of the research, (2) there are no undisclosed risks to subjects that are more than minimal, and (3) there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them. Information about risks should never be withheld for the purpose of eliciting the cooperation of subjects, and truthful answers should always be given to direct questions about the research. Care should be taken to distinguish cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply inconvenience the investigator. Comprehension. The manner and context in which information is conveyed is as important as the information itself. For example, presenting information in a disorganized and rapid fashion, allowing too little time for consideration or curtailing opportunities for questioning, all may adversely affect a subject's ability to make an informed choice. Because the subject's ability to understand is a function of intelligence, rationality, maturity and presentation of the information to the subject's capacities. Investigators are responsible for ascertaining that the subject has comprehended the information. While there is always an obligation to ascertain that the information about risk to subjects is complete and adequately comprehended, when the risks are more serious, that obligation increases. On occasion, it may be suitable to give some oral or written tests of comprehension. Special provision may need to be made,when comprehension is severely limited-for example, by conditions of immaturity or mental disability. Each class of subjects that one might consider as incompetent (e.g., infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered on its own terms. Even for these-persons however, respect requires giving them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections of these subjects to involvement should be honored, unless the research entails providing them a therapy unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes and by the use of third parties to protect them from harm. The third parties chosen should be those who are most likely to understand the incompetent subject's situation and to act in that person's best interest. The person authorized to act on behalf of the subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the subject from the research, if such action appears in the subject's best interest. Voluntariness. An agreement to participate in research constitutes a valid consent only if voluntarily given. This element of informed consent requires conditions free of coercion and undue influence. Coercion occurs when an overt threat of harm is intentionally presented by one person to another in order to obtain compliance. Undue influence, by contrast, occurs through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance. Also, inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable. Unjustifiable pressures usually occur when persons in positions of authority or commanding influence especially where possible sanctions are involved-urge a course of action for a subject. A continuum of such influencing factors exists, however, and it is impossible to state precisely where justifiable persuasion ends and undue influence begins. But undue influence would include actions such as manipulating a person s choice through the controlling.influence of a close relative and threatening to withdraw health services to which an individual would otherwise be entitled. 2. Assessment of Risks and Benefits. The assessment of risks and benefits requires a careful arrayal of relevant data, including, in some cases, alternative ways of obtaining the benefits sought in the research. Thus, the assessment presents both an opportunity and a responsibility to gather systematic and comprehensive information about proposed research. For the investigator, it is a means to examine whether the proposed research is properly designed. For a review committee, it is a method for determining whether the risks that will be presented to subjects are justified. For prospective subjects, the assessment will assist the determination whether or not to participate. The Nature and Scope of Risks and Benefits. The requirement that research be justified on the basis of a favorable risk/benefit assessment bears a close relation to the principle of beneficence, just as the moral requirement that informed consent be obtained is derived primarily from the principle of respect for persons. THE BELMONT REPORT Page 7 The term "risk" refers to a possibility harm may occur. However, expressions such as "small risk" or "high risk" are used, they usually refer (often ambiguously) both to the chance (probability) of experiencing a harm and the severity (magnitude) of the envisioned harm. The term "benefit" is used in the research context to refer to something of positive value related to health or welfare. Unlike "risk," "benefit" is not a term that expresses probabilities. Risk is properly contrasted to probability of benefits, and benefits are properly contrasted with harms rather than risks of harm. Accordingly, so-called risk/benefit assessments are concerned with the probabilities and magnitudes of possible harms and anticipated benefits. Many kinds of possible harms and benefits need to be taken into account. There are, for example, risks of psychological harm, physical harm, legal harm, social harm and economic harm and corresponding benefits. While the most likely types of harms to research subjects are those of psychological or physical pain or injury, other possible kinds should not be overlooked. Risks and benefits of research may affect the individual subjects, the families of the individual subjects, and society at large (or special groups of subjects in society). Previous codes and Federal regulations have required that risks to subjects be outweighed by the sum of both the anticipated benefit to the subject, if any, and the anticipated benefit to society in the form of knowledge to be gained from the research. In balancing these different elements, the risks and benefits affecting the immediate research subject will normally carry special weight. On the other hand, interests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research so long as the subjects' rights have been protected. Beneficence thus requires that we protect against risk of harm to subjects and also that we be concerned about the loss of the substantial benefits that might be gained from research. The Systematic Assessment of Risks and Benefits. It is commonly said that benefits and risks must be "balanced" and shown to be "in a favorable ratio." The metaphorical character of these terms draws attention to the difficulty of making precise judgments. Only on rare occasions will quantitative techniques be available for the scrutiny of research protocols. However, the idea of systematic, non-arbitrary analysis of risks and benefits should be emulated insofar as possible. This ideal requires those making decisions about the justiciability of research to be thorough in the accumulation and assessment of information about all aspects of the research, and to consider alternatives systematically. This procedure renders thc assessment of research more rigorous and precise, while making communication between review board members and investigators less subject to misinterpretation, misinformation and conflicting judgments. Thus, there should first be a determination of the validity of the presuppositions of the research; then the nature, probability and magnitude of risk should be distinguished with as much clarity as possible. The method of ascertaining risks should be explicit, especially where there is no alternative to the use of such vague categories as small or slight risk. It should also be determined whether an investigator's estimates of the probability of harm or benefits are reasonable, as judged by known facts or other available studies. Finally, assessment of the justiciability of research should reflect at least the following considerations: (i) Brutal or inhumane treatment of human subjects is never morally justified. (ii) Risks should be reduced to those necessary to achieve the research objective. It should be determined whether it is in fact necessary to use human subjects at all. Risk can perhaps never be entirely eliminated, but it can often be reduced by careful attention to alternative procedures. (iii) When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk (looking usually to the likelihood of benefit to the subject or, in some rare cases, to the manifest voluntariness of the participation). (iv) When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. A number of variables go into such judgments, including the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits. (v) Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process. 3. Selection of Subjects. Just as the principle of respect for persons finds.expression in the requirements for consent, and the principle of beneficence in risk/benefit assessment, the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the selection of research subjects. Justice is relevant to the selection of subjects of research at two levels: the social and the individual. Individual justice in the selection of subjects would require that researchers exhibit fairness: thus, they should not offer potentially beneficial research only to some patients who are in their favor or select only "undesirable" persons for risky research. Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens and on the appropriateness of placing fun her burdens on already burdened persons. Thus, it can be considered a matter of social justice that there is an order of preference in the selection of classes of subjects (e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalized mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions. Page 8 THE BELMONT REPORT Injustice may appear in the selection of subjects, even if individual subjects are selected fairly by investigators and treated fairly in the course of research. Thus injustice arises from social, racial, sexual and cultural biases institutionalized in society. Thus, even if individual researchers are treating their research subjects fairly, and even if IRBs are taking care to assure that subjects are selected fairly within a particular institution, unjust social patterns may nevertheless appear in the overall distribution of the burdens and benefits of research. Although individual institutions or investigators may not be able to resolve a problem that is pervasive in their social setting, they can consider distributive justice in selecting research subjects. Some populations, especially institutionalized ones, are already burdened in many ways by their infirmities and environments. When research is proposed that involves risks and does not include a therapeutic component, other less burdened classes of persons should be called upon first to accept these risks of research, except where the research is directly related to the specific conditions of the class involved. Also, even though public funds for research may often flow in the same directions as public funds for health care, it seems unfair that populations dependent on public health care constitute a pool of preferred research subjects if more advantaged populations are likely to be the recipients of the benefits. One special instance of injustice results from the involvement of vulnerable subjects. Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition. (FR Doc. 79.12065 Filed 4-17-79, 8:45 am) TAB 4 Research Ethics: Federal Policy for the Protection of Human Subjects FEDERAL REGISTER Tuesday June 18, 1991 Part II Federal Policy for the Protection of Human Subjects; Notices and Rules Office of Science and Technology Policy Department of Agriculture Department of Energy National Aeronautics and Space Administration Department of Commerce Consumer Product Safety Commission International Development Cooperation Agency Agency for International Development Department of Housing and Urban Development Department of Justice Department of Defense Department of Education Department of Veterans Affairs Environmental Protection Agency Department of Health and Human Services Office of the Secretary Food and Drug Administration National Science Foundation Department of Transportation 28002 Federal Register / Vol. 56. No. 117 / Tuesday, June 18, 1991 /Notices Editorial Note: This reprint incorporates a correction document published in the Federal Register of June 28, 1991. OFFICE OF SCIENCE AND TECHNOLOGY POLICY Federal Policy for the Protection of Human Subjects AGENCY: Office of Science and Technology Policy, Executive Office of the President. ACTIoN: Notice of Federal Policy for Protection of Human Subjects. SUMMARY: The Office of Science and Technology Policy has accepted the Final Federal Policy for the Protection of Human Subjects in the form of the common rule promulgated in this issue of the Federal Register. The common rule was developed by the Interagency Human Subjects Coordinating Committee of the Federal Coordinating Council for Science, Engineering and Technology, in response to public comment on the notice of proposed policy for Department and Agency implementation published in the Federal Register on November 10, 1988 (53 F)t 45660). Note that the Central intelligence Agency is required by Executive Order 1233 to conform to the guidelines issued by the Department of Health and Human Service. (HHS). ADDRESSES: Requests for additional information should be addressed to Dr. Joan P. Porter. Interagency Human Subjects Coordinating Committee. Building 31. room 5B59. Bethesda. Maryland 20892. Telephone: (301) 496 7005. D. Allan Bromley. Director. Office of Science and Technology Policy. Executive Office of the President. (FR Doc. 91-14257 Filed 6-17-91: 8:45 am BILLING CODE 3170-01-M DEPARTMENT OF AGRICULTURE 7CFR Part Ic DEPARTMENT OF ENERGY 10 CFR Part 745 NATIONAL AERONAUTICS AND SPACE ADMINISTRATION 14 CFR Part 1230 DEPARTMENT OF COMMERCE 15 CFR Part 27 CONSUMER PRODUCT SAFETY COMMISSION 16 CFR Part 1028 INTERNATIONAL DEVELOPMENT COOPERATION AGENCY Agency for International Development 22 CFR Part 225 DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT 24 CFR Part 60 DEPARTMENT OF JUSTICE 28 CFR Part 46 DEPARTMENT OF DEFENSE 32 CFR Part 219 DEPARTMENT OF EDUCATION 34 CFR Part 97 DEPARTMENT OF VETERANS AFFAIRS 38 CFR Part 16 ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 26 DEPARTMENT OF HEALTH AND HUMAN SERVICES 45 CFR Part 46 NATIONAL SCIENCE FOUNDATION 45 CFR Part 690 DEPARTMENT OF TRANSPORTATION 49 CFR Part II Federal Policy for the Protection of Human Subjects AGENCIES: United States Department of Agriculture; Department of Energy; National Aeronautics and Space Administration: Department of Commerce; Consumer Product Safety Commission; International Development Cooperation Agency, Agency for International Development; Department of Housing and Urban Development; Department of justice; Department of Defense; Department of Education; Department of Veterans Affairs; Environmental Protection Agency; Department of Health and Human Services; National Science Foundation; Department of Transportation. ACTION: Final rule. SUMMARY: This document sets forth a common Federal Policy for the Protection of Human Subjects (Model Policy) accepted by the Office of Science and Technology Policy and promulgated in regulation by each of the listed Departments and Agencies. A Proposed Federal Policy for the Protection of Human Subjects published November 10, 1988 (53 FR 45661) has been revised in response to public comments. The Policy as revised is now set forth as a common final rule. For related documents, see other sections of this Federal Register part. EFFECTIVE DATE: These regulations shall become effective on August 19, 1991. The Department of Education regulations (34 CFR part 97) take effect either August 19, 1991, or later if Congress takes certain adjournments. If you want to know the effective date of the Department of Education regulations in 34 CFR part 97, call or write Mr. Edward Glassman, Office of Planning, Budget and Evaluation. U.S. Department of Education, room 3127, 400 Maryland Avenue SW., Washington. DC 20202-4132. A document announcing the effective date of the Department of Education regulations will be published in the Federal Register. Institutions currently conducting or supporting research in accord with Multiple Project Assurances of Compliance (MPAs) approved by and on file in the Office for Protection from Research Risks (OPRR) in the Department of Health and Human Services may continue to do so in accord with the terms and conditions of their MPAs. See Supplementary Information for further details. FOR FURTHER INFORMATION CONTACT: Dr. Joan P. Porter, (301) 496- 7005. Office for Protection from Research Risks, National Institutes of Health, Building 31. room 5B59, Bethesda. MD 20892. SUPPLEMENTARY INFORMATION: Paperwork Reduction Act Requirements: Sections 103(a): .103(b); .103(b)(4)(i); .103(b)(4)(iii); .103(b)(5); .103(f); .109(d); .113; .115(a); .116: and 117 contain information collection requirements subject to approval by the Office of Management and Budget (OMB) under the Paperwork Reduction Act. HHS has submitted the request for approval to OMB on behalf of all Departments and Agencies governed by this final rule and has published elsewhere in this issue of the Federal Register a request for OMB expedited review and approval of the information collection requirements: OMB has assigned OMB control number 9999-0O20; however. the information collection requirements will not become effective until OMB has approved them. Unless a notice is published to the contrary, the public may assume that OMB has approved the information collection requirements during the 60 day period before the final rule becomes effective. For further information regarding OMB approval of the information collection, contact Ms. Shannah Koss McCallum, OMB, (202) 395-7316. Compliance Dates: Institutions that hold MPAs are permitted and encouraged to apply all provisions of this final rule as soon as it is feasible to do so. They are urged not to wait for the negotiation and approval of a revised MPA to begin to function in accord with this rule. The OPRR, acting on behalf of the Secretary, Department of Health and Human Services (HHS), will continue to renegotiate and approve MPAs in the normal periodic cycle of renewal. Institutions that are not operating under an MPA approved by OPRR will be required to negotiate an Assurance of Compliance with the supporting Department or Agency. prior to initiating research involving human subjects. Institutions with MPAs approved by and on file with HHS will be allowed a "grace period" of sixty days after the 28004 Federal Register / Vol. 56, No. 117 / Tuesday, June 18, 1991 / Rules and Regulations submission date for an application seeking HHS support, to provide certification of Institutional Review Board (IRB) review and approval. Exceptions may occur for reasons of Congressional mandate or special program or review requirements. In such cases, institutions will be advised that certification must be sent at an earlier time. Background The notice sets forth as a common rule requirement for the protection of human subjects involved in research conducted or funded by the following Federal Departments and Agencies: United States Department of Agriculture; Department of Energy; National Aeronautics and Space Administration; Department of Commerce; Consumer Product Safety Commission; International Development Cooperation Agency, Agency for International Development; Department of Housing and Urban Development; Department of Justice; Department of Defense; Department of Education; Department of Veterans Affairs; Environmental Protection Agency;National Science Foundation; Department of Health and Human Services and the Department of Transportation. Each of these Departments and Agencies have adopted the common rule as regulations to the codified as listed above. The Food and Drug Administration (FDA) Final Rule to modify current regulations to conform to the Federal Policy are presented elsewhere in this issue of the Federal Register. Existing FDA regulations governing the protection of human subjects share a common core with the Federal Policy and implement the fundamental principles embodied in the policy. The agency is committed to being as consistent with the final Federal Policy as it can be, given the unique requirements of the Federal Food, Drug, and Cosmetic Act under which FDA operates; and the fact that FDA is a regulatory agency that rarely supports or conducts research under its regulations. Adoption of the common policy by Federal Departments and Agencies in regulatory form will implement a recommendation of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research which was established on November 9, 1978, by Public Law 95-622. One of the charges to the President's Commission was to support biannually to the President, the Congress, and appropriate Federal Departments and Agencies on the protection of human subjects of biomedical and behavioral research. In carrying out the charge, the President's Commission was directed to conduct a review of the adequacy and uniformity (1) of the rules, policies, guidelines and regulations of all Federal Departments and Agencies regarding the protection of human subjects of biomedical or behavioral research which such department and agencies conduct or support, and(2) of the implementation of such rules, policies, guidelines, and regulations by such Departments and Agencies, such review to include appropriate recommendations for legislation and administrative action. In December 1981 the President's Commission issued its First Biennial Report on the Adequacy and Uniformity of Federal Rules and Policies, and their Implementation, for the Protection of Human Subjects in Biomedical and Behavioral Research, Protecting Human Subjects. In accord with Pubic Law 95-622, each Federal Department or Agency which receives recommendations from the President's Commission with respect to its rules, policies guidelines or regulations, must publish the recommendations in the Federal Register and provide an opportunity for interested persons to submit written data, views and arguments with respect to adoption of the recommendations. On March 29, 1982 (47 FR 13262-13305), the Secretary, HHS published the recommendation on behalf of all affected Departments and Agencies. In May 1982 the Chairman of the Federal Coordinating Council for Science, Engineering, and Technology (FCCSET) appointed an Ad Hoc Committee for the Protection of Human Research Subjects under the auspices of the FCCSET. The Committee, chaired by Dr. Edward N. Brandt, Jr., Assistant Secretary for Health, Health and Human Services (HHS), was composed of representatives and ex- officio members of the affected Departments and Agencies. In consultation with the Office of Science and Technology Policy (OSTP) and the Office of Management and Budget, the Ad Hoc Committee, after considering all public comments developed responses to the recommendations of the President's Commission. After further review and refinement, OSTP responded on behalf of all the affected Department and Agency Heads to the recommendations of the President's Commission, including the recommendation that: The President should, through appropriate action, require that all federal departments and agencies adopt as a common core the regulations governing research with human subjects issued by the Department of Health and Human Services (codified at 45 CFR Part 46), as periodically amended or revised, while permitting additions needed by any department or agency that are not inconsistent with these core provisions. The Ad Hoc Committee agreed that uniformity is desirable among Departments and Agencies to eliminate unnecessary regulation and to promote increased understanding and ease of compliance by institutions that conduct federally supported or regulated research involving human subjects. Therefore, the Ad Hoc Committee developed a Model Federal Policy which applies to research involving human subjects conducted, supported or regulated by Federal Departments and Agencies. In accordance with the Commission's recommendation, the Model Federal Policy is based on subpart A of the regulations of HHS for the protection of human research subject (45 CFR part 46). The proposed Model Federal Policy developed by the Ad Hoc Committee was modified by OSTP to enhance uniformity of implementation among the affected Federal Departments and Agencies to provide consistency with other related policies. The revised Model Federal Policy was concurred in by all affected Federal Departments and Agencies in March 1985. An Interagency Human Subjects Coordinating Committee was charted on October 1983 under the auspices of FCCSET to provide continued interagency cooperation in human subject research once the AD Hoc Committee had completed its assignment. It is charged by the Director of the Office for Protection from Research Risks, HHS, and composed of representatives of all Federal Departments and Agencies that conduct, support or regulate research involving human subjects. The Committee is advisory to Department and Agency Heads and among other responsibilities, will evaluate the implementation of the Federal Policy and recommend modification as necessary. On June 3, 1986, OSTP published for public comment in the Federal Register (51 FR 20204) a Proposed Model Federal Policy for Protection of Human Subjects and Response to the First Biennial Report of the President's Commission. Over 200 written comments were received concerning the publication. The Interagency Human Subjects Coordinating Committee considered these comments in the revision of a common Federal Policy proposed as a common rule on November 10, 1988, for Federal Register/ Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations adoption by each of the Departments and Agencies listed. Response to the more than 60 public comments, discussion of revisions made to that publication and the final common rule follow. Summary of Public Comments Received in Response to the November 10, 1988, Federal Register publication (53 FR 45661) of the Notice of Proposed Common Rulemaking. Federal Policy for the Protection of Human Subjects for 16 Federal Departments and Agencies. In response to the November 10 1988 publication, 66 commentators responded within the comment period. which was extended to February 8, 1989. The source of comments included institutional offices of sponsored research, departmental deans and chairs and other staff of academic institutions, institutional review board members and staff, principal investigators, and drug company representatives. Although there were 66 separate commentators, several responses were prepared by organizations each representing a consortium of institutions which had been polled concerning the notice of proposed common rulemaking. For example. the Council on Governmental Relations, the Association of American Medical Colleges, Public Responsibility for Medicine and Research, Association of American Universities, the American Medical Association and the Consortium of Social Science Associations offered comment on behalf of their member institutions. In general, commentators endorsed the efforts of the Office of Science and Technology Policy and the Federal Departments and Agencies to develop a Common Rule for the protection of human subjects. The majority of the comments dealt with three points in the proposed common rule, as follows: Section_________103(b)(5) concerns those procedures set forth in Assurances of Compliance for research conducted or supported by a federal Department or Agency. As proposed, this section required that an Assurance should include: Written procedures for ensuring prompt reporting to the IRB. appropriate institutional officials. and the department or agency head (i) any unanticipated problems or scientific misconduct involving risks to human subjects or others (ii) any instance of serious or continuous noncompliance with this policy or the requirements of the terminations of the IRB and (iii) any suspension or termination of IRB approval. Some commentators indicated that they believed the proposed policy would inappropriately require IRBs to notify Department and Agency heads of scientific misconduct involving risks to human subjects and others and that the scientific fraud and misconduct regulations (September 19, 1983, Responsibilities of PHS Awardee and Applicant Institutions for Dealing with and Reporting Possible Misconduct in Science (53 FR 36344)] create duplicate and potentially conflicting requirements. Several suggested that the proposed rules on misconduct should leave undisturbed other existing regulatory schemes such as human subjects regulations of the Department of Health and Human Services at 45 CFR part 46. Other commentators indicated that the IRB should not have a "police" role and that its members are potentially legally liable if they did or did not report certain misconduct activities. Concern was also noted about additional responsibility and work placed on the IRB. Several commentators requested clarification of 103(b)(5)(i) in the terms "misconduct" and "unanticipated" problems. Respondents suggested that scientific misconduct implies falsification of data, plagiarism abuse of confidentiality, dishonesty in presenting publications, legal violations and a range of other activities which should be addressed in a separate policy involving broader institutional considerations than those appropriate for an IRB. In addition, some respondents suggested that actual "harm" rather than "possible risk" to human subjects be reported to Departments and Agencies. Concerning ____.103(b)(5)(iii) two commentators suggested that IRBs would be reluctant to suspend IRB approved research for administrative infractions (such as tardiness of response to an IRB) if such suspension must be reported to an Agency. One commentator requested that revisions be made so that only suspensions or terminations for serious or continuing noncompliance with the policy or determination of the IRB need be reported to the Department or Agency head. In that way, IRBs would use suspension or termination as an administrative tool and continue to keep Departments and Agencies informed of serious problems. One specific set of comments addressed all aspects of this section by suggesting deletion of reporting requirements to Department and Agency Heads altogether. Rather, reports to IRBs and institutional officials would be required concerning unanticipated problems involving risks to human subjects which are substantial; proven scientific fraud; instances of substantial or continuing noncompliance with the policy or the requirements or determination of the IRB; or any suspension or termination which is more than minor or temporary. Response In view of the comments and the policy concerning fraud and misconduct that is now under deliberation, the Interagency Human Subjects Coordinating Committee revised ________ 103(b)(5) as follows: Written procedures for ensuring prompt reporting to the IRB. appropriate institutional officials. and the department or agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or the terminations of the IRB and (ii) any suspension or termination of IRB approval. The President's Commission recommended in its 1981 First Biennial Report that institutional assurances should specify how "misconduct" should be reported and investigated (pp. 7782, Recommendations 7 and 8). Since the time of the publication of the 1981 report, however, the issue of identification and reporting of misconduct has been deliberated in many other contexts and has included consideration of more than misconduct involving risks to human subjects. In August 1989 the Department of Health and Human Services published a final rule announcing responsibilities of awardee and applicant institutions for dealing with and reporting possible misconduct in science (53 CKR 32446). The Committee agrees that in the current context the inclusion of the term "misconduct" in the Federal Policy is confusing and misleading because other policy development efforts giving specific meaning to scientific misconduct are ongoing. Therefore the term is deleted from this document. The revised language is closer to that of the original provision in the Department of Health and Human Services regulations. The interagency Committee wishes to clarify that it was never the intention of the Policy to require IRBs to report directly to Department and Agency Heads. Assurances of Compliance are negotiated between Departments or Agencies and awardee institutions. Assurances allow institutions to specify how reporting to Department and Agency Heads will take place. Reporting is the responsibility of the institutional official identified in each Assurance. Further, the Committee wishes to clarify that "unanticipated problems in this context includes serious and unexpected reactions to biologicals, 28006 Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations drugs, or medical devices. Institutions have flexibility to establish channels of reporting to meet reporting requirements of Departments and Agencies. In addition, the Committee believes it is important that suspension or termination for whatever reason, be reported to the Department and Agency Heads. The Sixty Day "Grace" Period Comment The section of the proposed Policy and Final Rule eliciting the most comments was 103(f) regarding submission of certification. That section is as follows: Certification is required when the research is supported by a federal department or agency and not otherwise exempted or waived under ______.101(b) or (i). An institution with an approved assurance shall certify research covered by the assurance and by  .103 of this policy has been reviewed and approved by the IRB. Such certification must be submitted with the application or proposal or by such later date as may be prescribed by the department or agency to which the application or proposal is submitted. Under no condition shall research covered by  .103 of the policy be supported prior to receipt of the certification that the research has been reviewed and approved by the IRB. institutions without an approved assurance covering the research shall certify within 30 days after receipt of a request for such a certification from the department or agency. that the application or proposal has been approved by the IRB. If the certification is not submitted within these time limits. the application or proposal may be returned to the institution. Most of the commentators (50) addressed the need for a grace period between the time of submission of an application for support to a Department and Agency and submission of certification by the IRB of review and approval of the proposal. A 60-day grace period was allowed in the previous Department of Health and Human Services Regulations for the Protection of Human Subjects. Under this provision, institutions with Multiple Project Assurances on file with HHS had sixty days to complete IRB review and approval and to notify HHS. This period of time roughly corresponded to the time between receipt of the application and initial scientific merit review. The groups evaluating the application for scientific merit need certification of the fact that an appropriate IRB has determined that human subject protections are adequate. The commentators cited many reasons why a grace period is important for orderly institutional review and for protection of human subjects. Many of the comments on this sectIon requested that the grace period be reinstated in the regulations. In brief, respondents noted that if the grace period is not allowed, investigators would be required to submit proposals to IRBs about two months earlier than at present. IRBs would be convened into emergency sessions or required to meet more frequently. Pressure to grant approval would increase. Some commentators noted that institutions that have no Multiple Project Assurance on file with HHS are given 30 days to review and certify upon HHS request. If Multiple Project Assurance holders have no grace period. they may be at a.disadvantage in time permitted for preparation and institutional review of their applications as compared to the time permitted institutions without a Multiple Project Assurance. Also, data for competitive renewals is often added just before submission to HHS so that the most current progress under the original award can be reported. If a grace period is not offered, applications may not contain information vital for appropriate peer review. Another concern raised was that some researchers are required to modify their proposals several times before submission. The current 60-day period allows the IRB to review the final submission carefully. One commentator indicated that the proposed provision was acceptable to the institution. Response Many Federal Departments and Agencies do not have application review schedules that correspond to those of HHS. A 60-day grace period is without relevance to their review systems. At the time of publication of the proposed common rule, the Interagency Committee noted that HHS intended to retain a "grace period" for institutions that have Multiple Project Assurances and announce the period through advisories that are routinely received by institutions. HHS has carefully considered the public comments and will ordinarily retain the 60-day grace period in its administrative procedures. In some programs, such as AIDS- related research. HHS has modified the receipt and review schedules in accordance with a Congressional mandate. The Departments and Agencies other than HHS, adopting the common rule are aware of the concerns of the institutions and will provide as much flexibility to IRBs as possible if the orderly processing of applications for support. To require a 60- day grace period or any standard grace period for all Departments and Agencies would require far-reaching changes in the review and processing systems of these organizations. Institutions will be advised of Department and Agency procedures through routine publications. Consequently, the language in the final rule remains unchanged. Composition of the IRB Comments Section_______ .107 of the Policy deals with composition of the IRB. Several points made by commentators are as follows: In ________. 107(a) there is the requirement that if an IRB regularly reviews research that involves a vulnerable category of subjects. such as children, prisoners. pregnant women or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects. The HHS regulations at 45 CFR part 46 promulgated in 1981 utilized a different standard, i.e., "if an IRB regularly reviews research that involves a vulnerable category of subjects, including but not limited to subjects covered by other subparts of (45 CFR part 46), the IRB shall include one or more individuals who are primarily concerned with the welfare of these subjects." The commentator indicated that his institution would retain previous standards, because advocates for special populations have been of great benefit in the IRB's decision-making process. Another commentator wrote that in her institution, full committee review is required when a vulnerable population is involved; all committee members are advocates for subjects whether or not they themselves are involved in a vulnerable population. Adding new members would make the committee too large to be workable, she wrote. The majority of the comments on this section were directed to the departure proposed by the Department of Education at 34 CFR part 97.107(a). The proposed departure was based on a concern for protection of mentally disabled persons and handicapped children. The departure would have provided that, for research conducted OLD supported by the Department of Education, "when an IRB reviews research that deals with handicapped children or mentally disabled persons, the IRB shall include at least one person primarily concerned with the welfare of the research subject." The remainder of the departure reiterated the common Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations 28007 rule's provision which required institutions to consider representation on the IRB of persons who are knowledgeable about and experienced in working with certain vulnerable subjects if the IRB regularly reviews research involving those vulnerable subjects. Twenty-one institutions commented on this proposed departure. The majority of these comments were opposed to the proposed departure. Some commentators, while supporting the proposed language in _____ .107, stated their belief that the departure was not necessary because the policy in ________.107 already addresses representation of the special concerns of vulnerable subjects on the IRB. Thus, the rights of handicapped children and mentally disabled persons should be represented on any IRB that regularly reviews proposals involving those individuals, and there is no constructive advantage to emphasizing these two categories of subjects. Such an emphasis was seen as a precedent with the potential for discrimination against other categories of vulnerable subjects. When special expertise is required. IRBs already have the option and the obligation to seek informed consultants, respondents noted. One commentator stated, however, "If in future staffing of our IRB. someone with expertise in this area is available and willing to serve, we would be happy to encourage such participation." Some commentators objected to the lack of consistency among Federal Departments and Agencies and cited the Department of Education's proposed departure as being inconsistent with the purpose of the common rule. One commentator suggested that only when the IRB regularly reviews research that deals with handicapped children or mentally disabled persons should the IRB include at least one person primarily concerned with the welfare of the research subjects. Otherwise, consultation should take place when appropriate. Another suggestion was that handicapped children and mentally disabled persons be added to the list of examples of vulnerable subjects for which an IRB that regularly reviews research might want to consider inclusion of one or more members who are knowledgeable about and experienced in working with these subjects. Response The Department of Education has considered these comments carefully and has decided to withdraw the departure to the common rule and to adopt the common rule as promulgated in this document. The Secretary. however, continues to believe that there is a special need to protect handicapped children and mentally disabled persons. Thus, the Secretary strongly urges institutions to included at least one person who is primarily concerned with the welfare of the research subjects whenever the research involved handicapped children or mentally disabled persons. While the Secretary agrees to the common rule provision regarding IRB representation as a general matter, the Secretary has decided to address the concerns underlined by the proposed departure on a programmatic basis under the Department of Education's programs of the National Institute on Disability and Rehabilitation Research (34 CFR parts 350 and 356). Accordingly, the Secretary ameds the program regulations for these programs in a document published in another section of this Federal Register part. In light of the concern of the Department of Education that these groups were not clearly identified as vulnerable populations. "handicapped" has been added to the illustrative list in  .107. Comments on Other Sections Section________.101 explains the application of the Policy. Section .101(b) describes categories of research that are exempt from the Policy. Comment Several commentators indicated that the language and intent of this section was helpful. One commentator indicated that he believes the section was written primarily for medical and health research and should not apply to involvement of human subjects for general business interviews or surveys. The commentators recommended the exemption of information gathering related to business. Further comment suggested that all minimal risk research be exempt from the regulations. Response The Committee believes that the exemptions are sufficiently clear so that all types of research. not just biomedical or health research. may be reviewed using the specified criteria. In addition the Committee has indicated that the exemptions of  .101(b) of the Policy provides for the exemption of certain research including much of the research used by business (e.g., survey research) in which there is little or no risk. Section__________101[b)(2] Comment Section_________101(b)(2) is an exemption for research involving the use of educational tests, survey procedures or observation of public behavior. To paraphrase. this type of research is exempt unless information is recorded in a manner such that subjects can be identified and disclosure of the responses outside the research could place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation. Three commentators expressed concern that the additional subparts B, C, and D of the HHS regulations for the protection of human subjects are not part of the Federal policy. They noted that institutions with assurances with HHS will be required to apply provisions of those subparts in research they support or conduct, while other Federally-supported research would not be subject to the subpart requirements. Others commenting on _________.101(b)(2) indicated that research that could involve sensitive data could place the subjects at risk, even if information is not recorded in such a manner that human subjects can be identified and should not be exempt from provisions of the Policy. One respondent noted that one IRB reviews this type of research even f an exemption is permitted by the regulations. Another indicated that this section will exclude from normally exempt educational, survey, interview or observational research any instance wherein disclosure of subjects responses could be damaging to the subject's reputation. Because reputation is a subjective term that is difficult to define operationally. the commentator suggested that the wording be changed to limit exceptions to specific risks of "professional and sociological damage." Response The Interagency Committee may at a later date wish to consider incorporation or provisions of the other subparts of the HHS regulations into federal policy. However, such considerations should not delay publication of basic protections for all human subjects. At this time, institutions sponsoring research under HHS-approved assurances will adhere to provisions of all the subparts of 45 CFR part 46. A footnote has been added to .101(b) indicating that Institutions with HHS-approved assurances on file will abide by provisions of 45 CFR 46 subparts A-D. Some of the other 28008 Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations Departments and Agencies have incorporated all provisions of 45 CFR 101(b) into their policies and procedures as well. However, the exemptions at 45 CFR.101(b) do not apply to research involving prisoners, fetuses, pregnant women, or human in vitro fertilization. subparts B and The exemption at 45 CFR 46. 101(b)(2) for research involving survey or interview procedures or observation of public behavior, does not apply to research with children, subpart D, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed. A Notice to amend subpart D. 45 CFR 3.401(a)(2)(b) to renumber exemptions permitted and not permitted to inform the subpart D reference to the numbered exemptions in the Common rule is published elsewhere in this issue if the Federal Register. Under this footnote, for research involving children, institutions that have Multiple Project Assurances on file with OPRR will not be able to use all provisions in the exemption in __________.101(b)(2). However, the educational tests basis for the exemption contained in _________101(b)(2) will still be available to institutions conducting search involving children. In developing the common rule, a number of HHS exemptions were consolidated, including the HHS educational tests exemption. The educational tests exemption has been available for use under subpart D of the HHS regulations, Additional Protections Involving Children. Thus, the footnote to the common rule continues the provision that existed under the previous regulations. Some institutions do not choose to permit exemptions even if they are permitted by the policy. This is their prerogative, and assurances of compliance incorporate provisions for utilizing exemptions. Section_______ 101(b)(3] Comment Section________.101(b)(3) described an exemption for research involving the use of educational tests. survey procedures, interview procedures, or observation of public behavior that is not exempt under the exemption in _______.101(b)(2) if human subjects are elected or appointed public officials or candidates for public office or if Federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will e maintained throughout the research and thereafter. Two commentators commended deletion of this exemption because confidentiality considerations are not the only purpose of IRB review. Other human subjects protections issues might need to be considered in research that is not exempt by the criteria described in 101(b)(2). Furthermore, the commentators explained that IRBs and institutions will not know that Federal statutes afford these protections, and inconsistency and confusion is likely. Response At present the only statutes that meet the criteria in .101(b)(3)(ii) of which the Committee is aware are those for research conducted or supported by the Department of Justice under 42 U.S.C. 3789g. and certain research conducted or supported by the National Center for Education Statistics of the Department of Education under 20 U.S.C. 1221e-1. The Department of Justice's Office of Justice Programs (OJP) has several constituent offices that conduct research that would fall under ________ .101(b)(3). The law governing OJP research activities, 42 U.S.C. 3789g(a), provides that Except as provided by Federal law other than this chapter, no officer or employee of the Federal Government, and no recipient of assistance tinder the provisions of this chapter shall use or reveal any research or statistical information furnished under this chapter by any person and identifiable to any specific private person for any purpose other than the purpose for which it was obtained in accordance with this chapter. Such information and copies thereof shall be immune from legal process, and shall not, without the consent of the person furnishing such information, be admitted as evidence or used for any purpose in any action, suit, or other judicial, legislative, or administrative proceedings. The law governing research conducted by the National Center for Education Statistics under 20 U.S.C. 12211 provides that data collected by the National Center for Education Statistics may not be used for any purpose other than the statistical purpose for which the data were collected and establishes further protections regarding that data, including a provision that they shall be immune from legal process, and shall not, without the consent of the individual concerned, be admitted as evidence or used for any purpose in any action, suit, or other judicial or administrative proceeding. 20 U.S.C. 1221e-1(d)(4)(B). It is the responsibility of a Federal Department or Agency to assist the institutions proposing to conduct a research project which it supports in determining if the research is subject to the provisions of the Federal statutes meeting the 101(b)(3)(ii). Section101(h) Comment Section________.101(h) discusses research that takes place in foreign countries covered by the policy. One respondent endorsed this section. Another found the provision somewhat ambiguous and suggested that it be made clear that a researcher may either comply with the policy provision or may substitute the foreign procedure in lieu of the policy only following a determination by the Department or Agency Head that the foreign procedures are at least equivalent to those required in the policy. Another comment reflected that it may be difficult at the time of submitting a research proposal to a supporting Department or Agency to know if a foreign country's guidelines provide protections which are at least equivalent to the policy; the Interagency Committee or Department or Agency Heads should publish regulations or advisories indicating which are considered "equivalent." Response The Interagency Committee concurs that evaluation of other country's protection requirements in comparison with the policy will be an important Committee initiative and it will consider publication of notices that reflect the decisions of Department and Agency Heads. Also in ______.101(h),reference to Helsinki as amended in 1983 is now changed to Helsinki as amended in 1989. Section_________102 Definitions Comment Section________.102 includes the definition section in the Federal Policy. In this section, one commentator asked for a definition of "principal investigator", since that individual bears responsibility for human subject protection. Another commentator suggested adding a definition of "scientific fraud." Another suggestion was to take into account First Amendment concerns involving freedom of speech in situations where social scientists interview foreign and domestic government and private individuals to obtain information. Another commentator suggested that the definition of human subject in ________.102(f) should make clear that with, respect to interview research, a distinction should be made between Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations 28009 information provided by a person which relates to past or present events or the actions of others, as opposed to the attitudes or actions of the interviewees themselves; only in the latter case should the interviewee constitute a human subject. Also, another letter explained that in some cultures, ancestral research would not come under the definition of "human subject" because individuals were deceased. However, this type of research might be distressing to living family members. Section .102(b) includes the definition of "institution." One commentator proposed that the definition of "private entity" should also be included. Section .102(h) includes the definition of "IRB approval." Three commentators suggested that the term "at the institution" was not appropriate in the definition of approval as"* * * determination of the IRB that the research has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and federal requirements." Much of the research of an institution is off-site and thus seemed to be in technical violation under the proposed language. Response The Interagency Committee agrees that the principal investigator is a key person for protection of human subjects and bears a broad responsibility for implementation of the requirements. The term "investigator" is used in the policy, but not "principal investigator" and no definition is provided because the responsibility for protecting human subjects is shared by the entire research team. No definition of scientific fraud has been included, and the term has been deleted from  .103(b)(5), as described previously. The Committee believes that the comment on 102(f), definition of "human subject," about interview content is addressed through application of exemption criteria in 101(b)(2) as well as in the precise wording of the definition itself. In response to the comments about the phrase "at the institution" in the definition of IRB approval in .102(h), the Interagency Committee responds that there are instances in which the IRB has approval authority where the research is not conducted at the institutional site. The policy at .114, Cooperative Research, is an important cross-reference. Establishment and approval of other off-site IRBs may be required in some circumstances in which another institution is involved in research. The Department or Agency Heads reserve the authority to approve cooperative arrangements. The phrase "at the institution" in the definition of IRB approval should be interpreted to mean field sites and other off-site facilities over which an institution has jurisdiction. Section_________103 Assurances Comment Section________.103 explains how compliance is assured under this Policy in research conducted or supported by federal Department or Agency. Most of the comments on this section concerned reporting and misconduct issues in ________103(b)(5) or the "grace period" or timing of certification in .103(f). discussed previously. Several other comments are as follows: Three respondents asked for clarification of the rationale for reporting requirements in ________.103(a). This section requires that when the existence of an HHS approved assurance is accepted in lieu of requiring submission of a new assurance, reports required by the Policy are to be made to the Department and Agency Heads. Reports (with the exception of certification) are also to be made to OPRR. Another comment was prompted by review of _______.103(b)(1) which requires inclusion in the assurance of principles governing the institution in protection of human subjects, such as a statement of ethical principles or existing codes. The commentator suggested that a statement as to the purpose of having regulations which create an IRB structure should be explicitly included in the regulations. A comment concerning .103(f) requests clarification on what type of certification documentation will be acceptable. Response In consideration of these comments, the Interagency Committee offers the following information. In ____.103(a) the only reports required to be made to both the head of the Department or Agency supporting the research and the OPRR when the HHS assurance is utilized are those required under .103(b)(5), The head of the Department or Agency supporting a research project must have information concerning conduct of that research including instances of unanticipated problems or serious or continuing noncompliance with the Policy or the requirements or determinations of the IRB and any suspension or termination of IRB approval. OPRR requires this information to ensure that human subjects protections under the Policy and under the HHS-approved Assurance are being properly implemented and that institutions have fulfilled their requirements in an appropriate and timely manner. With regard to the comment concerning certification requirements in 103(f), standardized language for the certification will be developed. Certification now used by HHS has been suggested as a basis for development of the language. Section_________107 IRB Membership Comment Most of the commentators on  .107 address the proposed departure on IRB membership for the Department of Education that has been discussed above ( .107(a)]. Other comments received were as follows: Reference is made in the Policy in several places to vulnerable subject populations. One commentator indicated that all subject populations are vulnerable and that the term "exceptionally vulnerable" would be better phraseology for those instances for which additional safeguards are urged or required. Section 107(b) requires that every reasonable nondiscriminatory effort be made to ensure that no IRB consists entirely of men or entirely of women, including the institution's consideration of qualified persons of both sexes. One respondent indicated that the HHS standard in the regulations published in 1981 requiring that no IRB shall be constituted entirely of men or entirely of women should be retained. A further requirement of  .107(b) is that no IRB may consist entirely of members of one profession. Another respondent suggested that the word "discipline" be substituted for "profession." Response The Committee did not believe that the suggested language changes would significantly improve the understanding or implementation of the sections. It expects that institutions will use good judgment and diligence in selecting persons as IRB members who can fulfill the requirements of  107 (a) and (b) so that persons of both genders and persons with varying backgrounds will promote responsible review of the research activities. In approving Assurances, the Federal Departments and Agencies that conduct, support or regulate research will review IRB 28010 Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations composition to ensure that the membership is appropriate for the research, and may request that membership be supplemented if complete and adequate review of the research does not appear possible. As regards the gender consideration in IRB composition the Committee notes that in seeking diverse membership on the IRB the IRB the institution must consider both men and women who can contribute to the role of the IRB. Section ________ 110 Expedited Review Procedures Comment This section sets forth expedited review procedures for certain kinds of research involving no more than minimal risk and for minor changes in, approved research. Section ___.110(b) indicates that an IRB may use the expedited review procedure under certain specified circumstances with the approval of Department or Agency heads. Four respondents noted that confusion may result in institutions if Departments or Agencies have different requirements. Furthermore, it may be burdensome to IRBs and institutions to seek Department and Agency approval for use of expedited review. One respondent recommended that the phrase "with the approval of department or agency heads" in _________.110(b) be deleted because it will result in bureaucratic delays in approval to use the authority. Furthermore, the authority to restrict use of expedited review is found in _______.110(d) whereby the Department or Agency head may restrict, suspend, terminate or choose not to authorize the use of the expedited review procedure. Response The Committee agreed that the phrase in _______.110(b) "with the approval of department or agency heads," should be deleted because  .110(d) accomplished the intention of the Committee. As an example of Department and Agency use of this authority, note that HHS does not permit expedited review for institutions that do not hold Multiple Project Assurances of Compliance. Note also that some institutions which have authority to use expedited procedures choose to use full IRB review instead. Note that parentheses have been added to the word "reviewer(s)" in .110(b)(1) to clarify that one or more reviewers may carry out the expedited review procedures in accordance with  .110(b). Section_________111 Criteria for IRB Approval of Research Comment Three commentators requested deletion of the term "economically or educationally disadvantaged" in the examples of those who are vulnerable subjects because of lack of clarity of the term, difficulty in determining if some subjects were in this category and possible exclusion from beneficial research protocols of those deemed to be included in this category. Response The Committee believes that the criteria for participation and the potential vulnerability of some research subjects are still a very important consideration for IRBs. In exercising their responsibilities, IRBs are charged with evaluating the benefits and the burdens of the research so that unjust social patterns do not appear in the overall distribution of the burdens and benefits of research. The 1979 Belmont Report outlining ethical principles and guidelines for the protection of human subjects of research written by the national Commission for the Protection of Human Subjects of Biomedical and Behavioral Research makes special note that some populations are burdened in many ways by their social circumstances and environments. ***when research is proposed that involves risks and does not include a therapeutic component, other less burdened classes of persons should be called on first to accept these risks of research except where research is directly related to the specific conditions of the class involved. ***certain groups. such as racial minorities, the economically disadvantaged, be very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings there research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience. or because they are easy to manipulate as a result of their illness or socioeconomic condition. The Committee expects that in its review of equitable treatment and review of benefits and burdens, the educationally or economically disadvantaged will not be excluded from potentially beneficial research to individuals or to those persons as a class Section_________113 Suspension or Termination of IRB Approval of Research Comment One comment was offered suggesting that institutions, not IRBs, should report to Department and Agency Heads. Another response recommended that OPRR be designated as the central coordinating office to which such notification should be sent. Designation of OPRR as the single reporting channel would ensure prompt requisite reporting to the Government, the commentator noted. Response This section does not require that the IRB report to the Department or Agency head. The responsibility for reporting is specified in the institution's assurance. OPRR will receive reports if institutions have an assurance on file with the HHS which covers the research in question and will be notified in accordance with  .103(b)(3). OPRR cannot act as a central information office for other Departments and Agencies in receiving reports of this nature because of insufficient resources and regulatory jurisdictional considerations. Section _______ 114 Cooperative Research Comment Confusion may result for institutions of Departments and Agencies have differing requirements. Response The Committee will attempt to advise Departments and Agencies so that procedural requirements will be consistent. Section ______115 IRB Records Comment Modified language for this section was suggested to assure that confidentiality will be maintained to the greatest extent possible. Response The Committee agreed that confidentiality considerations are most important for IRB records. While it rejected the detailed language suggested by the commentator, it acknowledged the importance of maintaining confidentiality. It believes that the proposed language is adequate, Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations 28011 Section_________ 116 General Requirements for Informed Consent; and Section_______117 Documentation of Informed Consent Comment One respondent wrote that the differences between  .116(c) and (d) and _______.117(c) were confusing. Response Section________116(c) specifies that an 1RB may approve a consent procedure which alters some or all of the required elements of informed consent or waives the requirement to obtain informed consent in research or demonstration projects which are subject to approval of state and local authorities and which meet certain other requirements. Section______ .116(d) specifies that an IRB may, under limited circumstances (other than those of .116(c)) approve a consent procedure which alters some or all of the elements of informed consent or waive the requirements to obtain informed consent for certain types of research. Section, 117(c) specifies conditions under which an IRB may waive the requirement for the investigator to obtain a signed consent document for some or all subjects in the research. Section________123 Early Terminator of Research Comment Two commentators expressed concern the establishment of this section implies that a "blacklist" composed of individuals and institutions that, in the judgment of Department and Agency Heads, have failed to discharge properly their responsibilities for the protection of human subjects. Serious breaches of confidentiality and due process could be implied. The inclusion of the parenthetical phrase" (whether or not the research was subject to federal regulations)" was also of concern because it implies that information gathering may lead to violations of confidentiality. Response The Committee is aware of concerns about the need for confidentiality and due process considerations. The Committee notes that other federal regulations deal with the suspension and termination of funding. These regulations provide the requisite due process. Sources of information and criteria to be used by Department and Agency Heads for making decisions are addressed with more specificity in those regulations. The federal government does maintain information that is pertinent to the exercise of the discretionary authority to award funding. Appropriate confidentiality protections apply to that information. Section_________124 Conditions Comment A suggestion was made that additional considerations of the Department or Agency head noted in this section should be limited to those required by statute. Response The Committee, in its ongoing deliberations, will attempt to maintain consistency and minimize burdens to institutions. Department and Agency-Specific Comments Department of Education The 34 CFR 97.107(a) departure on composition of the IRB was discussed earlier in this preamble. The Department of Education proposed to amend  .101(b)(3), To what does this policy apply. by revising paragraph (b)(3)(ii) to exempt educational tests and surveys, interviews, or certain observations from coverage of the regulations if the research is conducted under a program subject to the protections of the General -Education Provisions Act (GEPA). This departure would have expanded upon an exception contained in the common rule that exempted research conducted under a statute that requires that the confidentiality of the personally identifiable information be maintained, without exception, throughout the research and thereafter. Much of the research that would have been covered by the GEPA exception i conducted by the National Center for Education Statistics (NCES). Since publication of the NPRM for the common rule, the Department has developed procedures implementing new authority under GEPA that establish absolute confidentiality for individuals who are the subjects of the NCES research which is subject to the confidentiality requirements of section 406(d) (4) of GEPA. Thus, NCES research covered by the GEPA confidentiality requirements now falls within the exception in the common rule that excludes from coverage of the regulations research under a statute that provides for absolute confidentiality ________.101(b)(3)(ii)] and an expanded exception for that research is unnecessary. The Secretary has decided to withdraw the GEPA departure as being inconsistent with the Department's overall objective of ensuring that research conducted or sponsored by the Department contain the greatest possible protections consistent with the common rule. Research of the Department other than that conducted under the NCES statute will be covered by the common rule. Comment Four comments were received regarding the exception from the common rule requirements for programs covered by GEPA. Three of the commentators were concerned that the proposed departure removed safeguards or did not provide additional safeguards for the protection of research subjects, while possibly increasing administrative burden on IRBs. One of these three commentators was concerned that the proposed departure might prohibit certain research procedures as applied to educational practices or programs. One commentator indicated that the proposed departure would not pose any problems. Response The departure to ______.101(b)(3)(ii) was based on statutes applicable to the Department that provide protection for subject: of the Department's education-related tests and surveys, interview procedures, and observation of public behavior. The protections are found in the GEPA section 400A (control of paperwork) (20 U.S.C. 1221-3); section 406(d) (4) (confidentiality of National Center for Education Statistics data) (20 U.S.C. 12211); section 438 (Family Educational Rights and Privacy Act) (20 U.S.C. 1232g); and section 439 (Protection of Pupil Rights Amendment) (20 U.S.C. 1232h). The departure was not intended to create additional burdens for IRBs but to eliminate the need for IRB approval of research in those cases where the research was subject to the GEPA. The Secretary has withdrawn the proposed departure because it is inconsistent with ensuring the greatest protection under the programs administered by the Department. Because the departure is being withdrawn, there is no need to explain how the proposed departure would have affected research practices. Department of Veterans Affairs (VA) Concern was expressed that______.111(a)(4) and .116 28012 Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations of the Federal Policy would supersede the Veterans Administration Department of Medicine and Surgery (VA DM&S) Circular 10-88-50 which allows next of kin to grant consent for incompetent relatives under specific conditions. The VA responded, however, that Federal Policy mandates informed consent by the subject, or the subject's "legally authorized representative." "Legally authorized representative" is defined to include "individual(s) *authorized under applicable law * *to consent on behalf of a prospective subject * ." Thus, the proposed consent does not preclude next of kin consent so long as such consent is "authorized under applicable law." 38 U.S.C. 4131, and VA policies promulgated thereunder, do authorize next of kin consent. Accordingly, the Common Federal Policy and current VA policies are consistent. Department of Justice The Department of Justice intends to retain special protections for prison populations in research it supports or conducts in accordance with 28 CFR parts 22 and 512. Department of Defense Comment One response requested clarification of how the Federal Policy will extend to DOD research. Numerous questions concerning applicability to military and non-military personnel, voluntary versus mandated participation situations, identifiable data and the broad range of DOD-sponsored research were posed. The respondent indicated that formulating guidelines for informed consent is particularly important in the military context. Response Questions raised regarding application of the proposed regulations to DOD-supported research are reasonable and appropriate but are regarded as agency specific. DOD plans to address these particular issues through revision of DOD Directive 32- 16.2, Protection of Human Subjects in DOD-supported Research. The text of the common rule is adopted by the following Department and Agencies as set forth below: Text of the Common Rule The text of the Common Rule as opted by the Department and Agencies in this document appears below: CFR Part _____ Protection of Human Subjects Sec. .101 To what does this policy apply? .102 Definitions. .103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. .104_106 (Reserved) .107 IRB Membership. .108 IRB functions and operations. .109 IRB review of research. .110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. .111 Criteria for IRB approval of research. .112 Review by institution. .113 Suspension or termination of IRB approval of research. .114 Cooperative research. .115 IRB records. .116 General requirements for informed consent. .117 Documentation of informed consent. .118 Applications and proposals lacking definite plans for involvement of human subjects. .119 Research undertaken without the intention of involving human subjects. .120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. .121 (Reserved) .122 Use of Federal funds. .123 Early termination of research. support: Evaluation of applications and proposals. .124 Conditions. .101 To what does this policy apply? (a) Except as provided in paragraph (b) of this section, this policy applies to all research involving human subjects conducted, supported or otherwise subject to regulation by any federal department or agency which takes appropriate administrative action to make the policy applicable to such research. This includes research conducted by federal civilian employees or military personnel, except that each department or agency head may adopt such procedural modifications as may be appropriate from an administrative standpoint. It also includes research conducted, supported, or otherwise subject to regulation by the federal government outside the United States. (1) Research that is conducted or supported by a federal department or agency, whether or not it is regulated as defined in .102(e). must comply with all sections of this policy. (2) Research that is neither conducted nor supported by a federal department or agency but is subject to regulation as defined in  .102(e) must be reviewed and approved, in compliance with 101, .102, and 107 through 117 of this policy, by an institutional review board (IRB) that operates in accordance with the pertinent requirements of this policy. (b) Unless otherwise required by department or agency heads, research activities in which the only involvement of human subjects will be in one or more of the following categories are exempt from this policy: (1) Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as (i) research on regular and special education instructional strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods. (2) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless: (i) Information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing employability. or reputation. (3) Research involving the use of educational tests (cognitive, diagnostic aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (b)(2) of this section, if: (i) The human subjects are elected or appointed public officials or candidates for public office; or (ii) federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter. (4) Research, involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens. If these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly through identifiers linked to the subjects. (5) Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine: Federal Register/Vol 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations 28013 (i) Public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs: (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs. (6) Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture. (c) Department or agency heads retain final judgment as to whether a particular activity is covered by this policy. (d) Department or agency heads may require that specific research activities or classes of research activities conducted, supported, or otherwise subject to regulation by the department or agency but not otherwise covered by this policy, comply with some or all of the requirements of this policy. (e) Compliance with this policy requires compliance with pertinent federal laws or regulations which provide additional protections for human subjects. (f) This policy does not affect any state or local laws or regulations which may otherwise be applicable and which provide additional protections for human subjects. (g) This policy does not affect any foreign laws or regulations which may otherwise be applicable and which provide additional protections to human subjects of research. (h) When research covered by this policy takes place in foreign countries, procedures normally followed in the foreign countries to protect human subjects may differ from those set forth in this policy. (An example is a foreign institution which complies with guidelines consistent with the World Medical Assembly Declaration (Declaration of Helsinki amended 1989) issued either by sovereign states or by an organization whose function for the protection of human research subjects is internationally recognized.] In these circumstances, if a department or agency head determines that the procedures' prescribed by the institution afford protections that are at least equivalent to those provided in this policy, the department or agency head may approve the substitution of the foreign procedures in lieu of the procedural requirements provided in this policy. Except when otherwise required by statute, Executive Order, or the department or agency head notices of these actions as they occur will be published in the Federal Register or will be otherwise published as provided in department or agency procedures. (i) Unless otherwise required by law, department or agency heads may waive the applicability of some or all of the provisions of this policy to specific research activities or classes of research activities otherwise covered by this policy. Except when otherwise required by statute or Executive Order, the department or agency head shall forward advance notices of these actions to the Office for Protection from Research Risks, Department of Health and Human Services (HHS), and shall also publish them in the Federal Register or in such other manner as provided in department or agency procedures.1  102 Definitions. (a) Department or agency head means the head of any federal department or agency and any other officer or employee of any department or agency to whom authority has been delegated. (b) Institution means any public or private entity or agency (including federal, state, and other agencies). (c) Legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research. (d) Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities. (e) Research subject to regulation, and similar terms are intended to encompass those research activities for which a federal department or agency has specific responsibility for regulating as a research activity, (for example, investigational New Drug requirements administered by the Food and Drug administration). It does not include research activities which are incidentally regulated by a federal department or agency solely as part of the department's or agency's broader responsibility to regulate certain types of activities whether research or non-research in nature (for example, Wage and Hour requirements administered by she Department of Labor). (f) Human subject means a living individual about whom an investigator whether professional or student), conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulation of the subject or the subject's environment that are performed for research purposes. Interaction includes communication or interpersonal contact between investigator and subject. "Private information" includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects. (g) IRB means an institutional review board established in accord with and for the purposes expressed in this policy. (h) IRB approval means the determination of the IRB that the research has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and federal requirements. (i) Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. ____________ 1. Institutions with HHS-approved assurances on file will abide by provisions of title 45 CFR part 46 subparts A-D. Some of the other Departments and Agencies have incorporated all provisions of title 45 CFR part 46 into their policies and procedures as well. However, the exemptions at 45 CFR part 46.101(b) do not apply to research involving prisoners, fetuses, pregnant women. or human in vitro fertilization. subparts 8 and C. The exemption at 45 CFR part 46.101(b)(2). for research involving survey or interview procedures or observation of public behavior, does not apply to research with children. subpart D. except for research involving observations of public behavior when the investigators) do not participate in the activities being observed. 28014 Federal Register/Vol. 56, No., 117/Tuesday, June 18, 1991/Rules and Regulations (j) Certification means the official notification by the institution to the supporting department or agency, in accordance with the requirements of this policy, that a research project or activity involving human subjects has been reviewed and approved by an IRB in accordance with an approved assurance.  103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. (a) Each institution engaged in research which is covered by this policy and which is conducted or supported by a federal department or agency shall provide written assurance satisfactory to the department or agency head that it will comply with the requirements set forth in this policy. In lieu of requiring submission of an assurance, individual department or agency heads shall accept the existence of a current assurance, appropriate for the research in question, on file with the Office for Protection from Research Risks, HHS, and approved for federal- wide use by that office. When the existence of an HHS-approved assurance is accepted in lieu of requiring submission of an assurance, reports (except certification) required by this policy to be made to department and agency heads shall also be made to the Office for Protection from Research Risks, HHS. (b) Departments and agencies will conduct or support research covered by this policy only if the institution has an assurance approved as provided in this section, and only if the institution has certified to the department or agency head that the research has been reviewed and approved by an IRB provided for in the assurance, and will be subject to continuing review by the IRB. Assurances applicable to federally supported or conducted research shall at a minimum include: (1) A statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects of research conducted at or sponsored by the institution, regardless of whether the research is subject to federal regulation. This may include an appropriate existing code. declaration. or statement of ethical principles, or a statement formulated by the institution itself. This requirement does not preempt provisions of this policy applicable to department- or agency-supported or regulated research and need not be applicable to any research exempted or waived under ______101(b) or (i). (2) Designation of one or more IRBs established in accordance with the requirements of this policy, and for which provisions are made for meeting space and sufficient staff to support the IRB's review and record keeping duties. (3) A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions to IRB deliberations; and any employment or other relationship between each member and the institution; for example: full-time employee, part-time employee. member of governing panel or board, stockholder, paid or unpaid consultant. Changes in IRB membership shall be reported to the department or agency head, unless in accord with  .103(a) of this policy. the existence of an HHS approved assurance is accepted. In this case, change in IRE membership shall be reported to the Office for Protection from Research Risk, HHS. (4) Written procedures which the IRE will follow (i) for conducting its initial and continuing review of research and for reporting its findings and actions to th. investigator and the institution; (ii) for determining which projects require review more often than annually and which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review; and (iii) for ensuring prompt reporting to the IRB of proposed changes in a research activity. and for ensuring that such changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject. (5) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB and (ii) any suspension or termination of IRB approval. (c) The assurance shall be executed by an individual authorized to act for the institution and to assume on behalf of the institution the obligations imposed by this policy and shall be filed in such form and manner as the department or agency head prescribes. (d) The department or agency head will evaluate all assurances submitted in accordance with this policy through such officers and employees of the department or agency and such experts or consultants engaged for this purpose is the department or agency head determines to be appropriate. The department or agency head's evaluation will take into consideration the adequacy of the proposed IRB in light of the anticipated scope of the institution's research activities and the types of subject populations likely to be involved, the appropriateness of the proposed initial and continuing review procedures in light of the probable risks, and the size and complexity of the institution. (e) On the basis of this evaluation, the department or agency head may approve or disapprove the assurance, or enter into negotiations to develop an approvable one. The department agency head may limit the period during which any particular approved assurance or class of approved assurances shall remain effective or otherwise condition or restrict approval. (f) Certification is required when the research is supported by a federal department or agency and not otherwise exempted or waived under  .101 (b) or (i). An institution with an approved assurance shall certify that each application or proposal for research covered by the assurance and by  .103 of this Policy has been reviewed and approved by the IRB. Such certification must be submitted with the application or proposal or by such date as may be prescribed by the department or agency to which the application or proposal is submitted. Under no condition shall research covered by  .103 of the Policy be supported prior to receipt of the certification that the research has been reviewed and approved by the IRB. Institutions without an approved assurance covering the research shall certify within 30 days after receipt of a request for such a certification from the department or agency. that the application or proposal has been approved by the IRB. If the certification is not submitted within these time limits, the application or proposal may be returned to the institution. (Approved by the Office of Management and Budget under Control Number 9999-0020.)  104 [Reserved]  105 (Reserved]  106 (Reserved]  107 IRB Membership. (a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. The IRB shall Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations 28015 be sufficiently qualified through the experience and expertise of its members, and the diversity of the members, including consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects. (b) Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the institution's consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of gender. No IRB may consist entirely of members of one profession. (c) Each IRB shall include at least one member whose primary concerns are in scientific areas and at least one member whose primary concerns are in nonscientific areas. (d) Each IRB shall include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution. (e) No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB. (f) An IRB may. in its discretion, invite individuals with competence in special areas to assist in the review of issues which require expertise beyond or in addition to that available on the IRB. These individuals may not vote with the IRB. Sec ___108 IRB functions and operations. In order to fulfill the requirements of this policy each IRB shall: (a) Follow written procedures in the same detail as described in  103(b)(4) and, to the extent required by  103(b)(5). (b) Except when an expedited review procedure is used (see  110) review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are in nonscientific areas. In order for the research to be approved, it shall receive the approval of a majority of those members present at the meeting. 109 IRB Review of Research. (a) An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by this policy. (b) An IRB shall require that information given to subjects as part of informed consent is in accordance with  .116. The IRB may require that information, in addition to that specifically mentioned in  .116, be given to the subjects when in the IRB's judgment the information would meaningfully add to the protection of the rights and welfare of subjects. (c) An IRB shall require documentation of informed consent or may waive documentation in accordance with  .117. (d) An IRB shall notify investigators and the institution in writing of its decision to approve or disapprove the proposed research activity, or of modifications required to secure IRB approval of the research activity. If the IRB decides to disapprove a research activity. It shall include in its written notification a statement of the reasons for its decision and give the investigator an opportunity to respond in person or in writing. (e) An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research. (Approved by the Office of Management and Budget under Control Number 9999-0020.) .110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. (a) The Secretary, HHS, has established, and published as a Notice in the Federal Register, a list of categories of research that may be reviewed by the IRB through an expedited review procedure. The list will be amended, as appropriate after consultation with other departments and agencies, through periodic republication by the Secretary. HHS, in the Federal Register. A copy of the list is available from the Office for Protection from Research Risks, National Institutes of Health, HHS, Bethesda, Maryland 20892. (b) An IRB may use the expedited review procedure to review either or both of the following: (1) Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk. (2) Minor changes in previously approved research during the period (of one year or less) for which approval is authorized. Under an expedited review procedure, the review may be carried out by the IRB chairperson or by one or more experienced reviewers designated by the chairperson from among members of the IRB. In reviewing the research, the reviewers may exercise all of the authorities of the IRB except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the non-expedited procedure set forth in .108(b). (c) Each IRB which uses an expedited review procedure shall adopt a method for keeping all members advised of research proposals which have been approved under the procedure. (d) The department or agency head may restrict, suspend, terminate, or choose not to authorize an institution's or IRB's use of the expedited review procedure. .111 Criteria for IRB approval of research. (a) In order to approve research covered by this policy the IRB shall determine that all of the following requirements are satisfied: (1) Risks to subjects are minimized: (i) By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. (2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefit of therapies subjects would receive even if not participating in the research). The IRB should not consider possible longrange effects of applying knowledge gained in the research (for example the 28016 Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/Rules and Regulations possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility. (3) Selection of subjects is equitable in making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons. (4) Informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with, and to the extent required by  116. (5) Informed consent will be appropriately documented, in accordance with, and to the extent required by  117. (6) When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure he safety of subjects. (7) When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. (b) When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects. ___.112 Review by Institution. Research covered by this policy that as been approved by an IRB may be subject to further appropriate review and approval or disapproval by officials of the institution. However, those officials may not approve the research if it has not been approved by an IRB. ___.113 Suspension or termination of RB approval of research. An IRB shall have authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected serious harm to subjects, any suspension or termination of approval shall include a statement of the reasons for the IRB's action and shall be reported promptly to the investigator, appropriate institutional officials, and the department or agency head. (Approved by the Office of Management and Budget under Control Number 9999-0020.) ___.114 Cooperative research. Cooperative research projects are those projects covered by this policy which involve more than one institution. In the conduct of cooperative research projects, each institution is responsible (or safeguarding the rights and welfare of human subjects and for complying with this policy. With the approval of the department or agency head, an institution participating in a cooperative project may enter into a joint review arrangement. rely upon the review of another qualified IRB, or make similar arrangements for avoiding duplication of effort. Sec. 115 IRB records. (a) An institution, or when appropriate an IRB, shall prepare and maintain adequate documentation of IRB activities. including the following: (1) Copies of all research proposals reviewed. scientific evaluations. if any, that accompany the proposals, approved sample consent documents, progress reports submitted by investigators, and reports of injuries to subjects. (2) Minutes of IRB meetings which shall be in sufficient detail to show attendance at the meetings; actions taken by the IRB; the vote on these actions including the number of members voting for, against. and abstaining; the basis for requiring changes in or disapproving research; and a written summary of the discussion of controverted issues and their resolution. (3) Records of continuing review activities. (4) Copies of all correspondence between the IRB and the investigators. (5) A list of IRB members in the same detail as described is  .103(b)(3). (6) Written procedures for the IRB in the same detail as described in  .103(b)(4) and  .103(b) (5). (7) Statements of significant new findings provided to subjects, as required by  .116(b)(5). (b) The records required by this policy shall be retained for at least 3 years, and records relating to research which is conducted shall be retained for at least 3 years after completion of the research. All records shall be accessible for inspection and copying by authorized representatives of the department or agency at reasonable times and in a reasonable manner. (Approved by the Office of Management and Budget under Control Number 9999- 0020.)  116 General requirements for Informed consent Except as provided elsewhere in this policy, no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights. or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence. (a) Basic elements of informed consent. Except as provided in paragraph (c) or (d) of this section, in seeking informed consent the following information shall be provided to each subject: (1) A statement that the study involves research. an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental; (2) A description of any reasonably foreseeable risks or discomforts to the subject; (3) A description of any benefits to the subject or to others which may reasonably be expected from the research; (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject; (5) A statement describing the extent. if any, to which confidentiality of records identifying the subject will be maintained; (6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained; (7) An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject; and (8) A statement that participation is voluntary, refusal to participate will Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/ Rules and Regulations 28017 involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. (b) Additional elements of informed consent. When appropriate, one or more of the following elements of information shall also be provided to each subject: (1) A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable; (2) Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent; (3) Any additional costs to the subject that may result from participation in the research; (4) The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject; (5) A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject; and (6) The approximate number of subjects involved in the study. An IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth above, or waive the requirement to obtain informed consent provided the IRB finds and documents that: (1) The research or demonstration project is to be conducted by or subject to the approval of state or local government officials and is designed to study, evaluate, or otherwise examine: (i) Public benefit of service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs; and (2) The research could not practicably be carried out without the waiver or alteration. (d) An IRB may-approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth in this section, or waive the requirements to obtain informed consent provided the IRB finds and documents that: (1) The research involves no more than minimal risk to the subjects; (2) The waiver or alteration will not adversely affect the rights and welfare of the subjects; (3) The research could not practicably be carried out without the waiver or alteration; and (4) Whenever appropriate, she subjects will be provided with additional pertinent information after participation. (e) The informed consent requirements in this policy are not intended to preempt any applicable federal, state, or local laws which require additional information to be disclosed in order for informed consent to be legally effective. (f) Nothing in this policy is intended to limit the authority of a physician to provide emergency medical care, to the extent the physician is permitted to do so under applicable federal, state, or local law. (Approved by the Office of Management and Budget under Control Number 9999-0020.) ____.117 Documentation of Informed consent (a) Except as provided in paragraph (c) of this section, informed consent shall be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject's legally authorized representative. A copy shall be given to the person signing the form. (b) Except as provided in paragraph (c) of this section. the consent form may be either of the following: (1) A written consent document that embodies the elements of informed consent required by  116. This form may be read to the subject or the subject's legally authorized representative, but in any event, the investigator shall give either the subject or the representative adequate opportunity to read it before it is signed; or (2) A short form written consent document stating that the elements of informed consent required by 116 have been presented orally to the subject or the subject's legally authorized representative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subject or the representative. Only the short form itself is to be signed by the subject or the representative. However, the witness shall sign both the short form and a cope of the summary. and the person actually obtaining consent shall sign a copy of the summary. A copy of the summary shall be given to the subject or the representative, in addition to a copy of the short form. (c) An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds either: (1) That the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern; or (2) That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context. In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research. (Approved by the Office of Management and Budget under Control Number 9999-0020.)  118 Applications and proposals lacking definite plans for Involvement of human subjects. Certain types of applications for grants, cooperative agreements, or contracts are submitted to department or agencies with the knowledge that subjects may be involved within the period of support, but definite plans would not normally be set forth in the application or proposal. These include activities such as institutional type grants when selection of specific projects is the institution's responsibility; research training grants in which the activities involving subjects remain to be selected; and projects in which human subjects' involvement will depend upon completion of instruments, prior animal studies, or purification of compounds. These applications need not be reviewed by an IRB before an award may be made. However, except for research exempted or waived under  101(b) or (i), no human subjects may be involved in any project supported by these awards until the project has been reviewed and approved by the IRB, as provided in this policy, and certification submitted, by the institution, to the department or agency. ___.119 Research undertaken without the intention-of Involving human subjects. In the event research is undertaken without the intention of involving human subjects, but it is later proposed to involve human subjects in the research, the research shall first be reviewed and approved by an IRB, as provided in this policy, a certification submitted, by the institution, to the department or agency, 28018 Federal Register/ Vol. 56, No. 117/ Tuesday, June 18, 1991 /Rules and Regulations and final approval given to the proposed change by the department or agency. ______.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. The department or agency head will evaluate all applications and proposals involving human subjects submitted to the department or agency through such officers and employees of the department or agency and such experts and consultants as the department or agency head determines to be appropriate. This evaluation will take into consideration the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the and others, and the importance of the knowledge gained or to be gained. (b) On the basis of this evaluation, the department or agency head may approve or disapprove the application or proposal, or enter into negotiations to develop an approvable one. ____.121 (Reserved) ___.122 Use of Federal funds. Federal funds administered by a department or agency may not be expended for research involving human subjects unless the requirements of this policy have been satisfied. ____.123 Early termination of research support: Evaluation of applications and proposals. (a) The department or agency head may require that department or agency support for any project be terminated or suspended in the manner prescribed in applicable program requirements, when the department or agency head finds an institution have materially failed to comply with the terms of this policy. (b) In making decisions about supporting or approving applications or proposals covered by this policy the department or agency head may take into account, in addition to all other eligibility requirements and program criteria, factors such as whether the applicant has been subject to a termination or suspension under paragraph (a) of this section and whether the applicant or the person or persons who would direct or has have directed the scientific and technical aspects of an activity has have, in the judgment of the department or agency head materially failed to discharge responsibility for the protection of the rights and welfare of human subjects (whether or not the research was subject to federal regulations). ____.124 Conditions. With respect to any research project or any class of research projects the department or agency head may impose additional conditions prior to or at the time of approval when in the judgment of the department or agency head additional conditions are necessary for the protection of human subjects. DEPARTMENT OF AGRICULTURE 7 CFR Part 1c RIN 0518-AA00 List of Subjects in 7 CFT Part 1c Human subjects, Research, Reporting and record keeping requirements. Title 7 of the Code of Federal Regulations is amended by adding part 1c as set forth at the end of this document.1 PART 1c PROTECTION OF HUMAN SUBJECTS Sec 1c.101 To what does this policy apply? 1c.102 Definitions 1c.102 Assuring compliance with this policy--research conducted or supported by any Federal Department or Agency. 1c.104 (Reserved) 1c.105 (Reserved) 1c.106 (Reserved) 1c.107 IRB Membership 1c.108 IRB review of research. 1c.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 1c.111 Criteria for IRB approval of research. 1c.112 Review by institution. 1c.113 Suspension or termination of IRB approval of research. 1c.114 Cooperative research. 1c.115 IRB records. 1c.116 General requirements for informed consent. 1c.117 Documentation of informed consent. 1c.118 Applications and proposals lacking definite plans for involvement of human subjects. 1c.119 Research undertaken without the intention of involving human subjects. 1c.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 1c.121 (Reserved) 1c.122 Use of Federal funds. 1c.123 Early termination of research support: Evaluation of applications and proposals. 1c.124 Conditions. Authority: 5 U.S.C. 301; 42 U.S.C. 300v-1(b) Dated: December 13, 1990 Charles E. Hess, Assistant Secretary, Science and Education DEPARTMENT OF ENERGY 10 CFR Part 745 RIM 1901-AA13 List of Subjects in 10 CFR Part 745 Human subjects, Research, reporting, and Record-keeping requirements. Title 10 of the Code of Federal Regulations is amended by revising part 745 as set forth at the end of this document.1 PART 745 PROTECTION OF HUMAN SUBJECTS Sec. 745.101 To what does this policy apply? 745.102 Definitions 745.103 Assuring compliance with this policy--research conducted or supported by any Federal Department or Agency. 745.104 (Reserved) 745.105 (Reserved) 745.106 (Reserved) 745.107 IRB Membership 745.108 IRB functions and operations. 745.109 IRB review of research. 745.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 745.111 Criteria for IRB approval of research. 745.112 Review by institution. 745.113 Suspension or termination of IRB approval of research. 745.114 Cooperating research. 745-115 IRB Records.. 745.116 General requirements for informed consent. 745.117 Documentation of informed consent. 745.118 Applications and proposals lacking definite plans for involvement of human subjects. 745.119 Research undertaken without the intention of involving human subjects. 745.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 745.121 (Reserved) 745.122 Use of Federal funds 745.123 Early termination of research support: Evaluation of applications and proposals. 745.124 Conditions. Authority: 5 U.S.C. 301;42 U.S.C. 7254;42 U.S.C. 300v-1(b) __________ 1 See Footnote 1 on page 28023 Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/ Rules and Regulations 28019 Dated: December 21, 1990 James D. Watkins, Secretary of Energy. NATIONAL AERONAUTICS AND SPACE ADMINISTRATION 14 CFR Part 1230 RIN 2700-AA76 List of Subjects in 14 CFR Part 1230 Human subjects. Research, Reporting and Record-keeping requirements. Title 14 of the Code of Federal Regulations is amended by adding part 1230 as set forth at the end of this document.1 PART 1230 PROTECTION OF HUMAN SUBJECTS Sec. 1230.101 To what does this policy apply?. 1230.102 Definitions. 1230.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 1230.104 [Reserved] 1230.105 [Reserved] 1230.106 [Reserved] 1230.107 IRB Membership. 1230.108 IRB functions and operations. 1230.109 IRB review of research. 1230.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 1230.111 Criteria for IRB approval of research. 1230.112 Review by institution. 1230.113 Suspension or termination of IRB approval of research. 1230.114 Cooperative research. 1230.115 IRB records. 1230.116 General requirements for informed consent. 1230.117 Documentation of informed consent. 1230.118 Applications and proposals lacking definite plans for involvement of human subjects. 1230.119 Research undertaken without the intention of involving human subjects. 1230.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 1230.121 [Reserved] 1230.122 Use of Federal funds. 1230.123 Early termination of research support: Evaluation of applications and proposals. 1230.124 Conditions. Authority: 5 U.S.C. 301; 42 U.S.C. 3O0v-1(b). Dated: December 20. 1990. Richard H. Truly Administrator. DEPARTMENT OF COMMERCE 15 CFR Part 27 RIN 0690-AA17 List of Subjects in 15 CFR Part 27 Human subjects. Research. Reporting and record-keeping requirements. Title 15 of the Code of Federal Regulations is amended by adding part 27 as set forth at the end of this document. 1 PART 27 PROTECTION OF HUMAN SUBJECTS Sec. 27.101 To what does this policy apply? 27.102 Definitions. 27.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 27.104 [Reserved] 27.105 [Reserved] 27.106 [Reserved] 27.107 IRB Membership. 27.108 IRB functions and operations. 27.109 IRB review of research. 27.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 27.111 Criteria for IRB approval of research. 27.112 Review by institution. 27.113 Suspension or termination of IRB approval of research. 27.114 Cooperative research. 27.115 IRB records. 27.116 General requirements for informed consent. 7.117 Documentation of informed consent. 27.118 Applications and proposals lacking definite plans for involvement of human subjects. 27.119 Research undertaken without the intention of involving human subjects. 27.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 27.121 [Reserved] 27.122 Use of Federal funds. 27.123 Early termination of research support: Evaluation of applications and proposals. 27.124 Conditions. Authority: 5 U.S.C. 301; 42 U.S.C. 300v-1(b). Dated: December 21. 1990. Robert Mosbacher, Secretary of Commerce. CONSUMER PRODUCT SAFETY COMMISSION 16 CFR Part 1028 RIN 3041-AAgs List of Subjects in 16 CFR Part 1028 Human subjects, Research, Reporting and record-keeping requirements. Title 16 of the Code of Federal Regulations is amended by revising part 1028 as set forth at the end of this document. 1 PART 1028 PROTECTION OF HUMAN SUBJECTS Sec. 1028.101 To what does this policy apply? 1028.102 Definitions. 1028.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 1028.104 [Reserved] 1028.105 [Reserved] 1028.105 [Reserved] 1028.107 IRB Membership. 1028.108 IRB functions and operations. 1023.109 IRB review of research. 1028.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 1028.111 Criteria for IRB approval of research. 1028.112 Review by institution. 1028.113 Suspension or termination of IRB approval of research. 1028.114 Cooperative research. 1028.115 IRB records. 1028.116 General requirements for informed consent. 1028.117 Documentation of informed consent. 1028.118 Applications and proposals lacking definite plans for involvement of human subjects. 1028.119 Research undertaken without the intention of involving human subjects. 1028.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency 1028.121 Reserved 1028.122 Use of Federal funds. 1028.123 Early termination of research support: Evaluation of applications and proposals. 1028.124 Conditions. Authority: 5 U.S.C. 301; 42 U.S.C. 300v-1(b). ______________ 1 See Footnote 1 on page 28023. Federal Register/Vol. 56, No. 117/Tuesday, June 18, 1991/ Rules and Regulations 28020 Dated: January 11. 1991. Sheldon D. Butts, Acting Secretary. INTERNATIONAL DEVELOPMENT COOPERATION AGENCY, AGENCY FOR INTERNATIONAL DEVELOPMENT 22 CFR Part 225 RIN 0412-AA17 List of Subjects in 22 CFR Part 225 Human subjects. Research, Reporting and record-keeping requirements. Title 22 of the Code of Federal Regulations is amended by adding part 225 as set forth at the end of this document.1 PART 225 PROTECTION OF HUMAN SUBJECTS Sec. 225.101 To what does this policy apply? 225.102 Definitions. 225.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 225.104 [Reserved] 225.105 [Reserved] 225.105 [Reserved] 225.107 IRE Membership. 225.108 IRE functions and operations. 225.109 IRE review of research. 225.110 Expedited review procedures for certain kinds of research involving no more than minimal risk. and for minor changes in approved research. 225.111 Criteria for IRB approval of research. 225.112 Review by institution. 225.113 Suspension or termination of IRB approval of research. 225.114 Cooperative research. 225.115 IRB records. 225.116 General requirements for informed consent. 225.117 Documentation of informed consent. 225.118 Applications and proposals lacking definite plans for involvement of human subjects. 225.119 Research undertaken without the intention of involving human subjects. 225.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 225.121 [Reserved] 225.122 Use of Federal funds. 225.123 Early termination of research support: Evaluation of applications and proposals. 225.124 Conditions. Authority: 5 U.S.C. 301; 42 U.S.C. 300v-1[b 56. No. 117 / Tuesday. June 18. 1991 Dated: December 13, 1990. Richard E. Bissell. Assistant Administrator for Science and Technology. DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT 24 CFR Part 60 RIN 2501-AAIS List of Subjects in 24 CFR Part 60 Human subjects, Research, Reporting and record-keeling requirements. Title 24 of the Code of Federal Regulations is amended by adding part 60 as set forth at the end of this document.1 PART 60 PROTECTION OF HUMAN SUBJECTS Sec. 80.101 To what does this policy apply? 60.102 Definitions. 60.103 Assuring compliance with this policy-research conductor supported by any Federal Department or Agency. 60.104 [Reservedl 60.105 [Reserved] 60.106 [Reserved] 60.107 IRB Membership. 60.108 IRB functions and-operations. 60.109 IRB review of research. 60.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 60.111 Criteria for IRB approval of research. 60.112 Review by institution. 60.113 Suspension or termination of IRB approval of research. 60.114 Cooperative research. 60.115 IRB records. 60.116 General requirements for informed consent. 60.117 Documentation of informed consent. 60.118 Applications and proposals lacking definite plans for involvement of human subjects. 60.119 Research undertaken without the intention of involving human subjects. 60.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 60.121 [Reserved] 60.122 Use of Federal funds. 60.123 Early termination of research support: Evaluation of applications and proposals. 60.124 Conditions. Authority: 5 U.S.C. 301; 42 U.S.C. 509-510. 42 U.S.C. 300v-1(b). Dated: January 16, 1991. Jack Kemp. Secretary, US Department of Housing and Urban Development DEPARTMENT OF JUSTICE 28 CFR Part 46 RIN 11O5-AA13 List of Subjects in 28 CFR Part 4(3 Human subjects. Research, Reporting and record-keeping requirements. Title 28 of the Code of Federal Regulations is amended by adding part 46 as set forth at the end of this document. 1 PART 46-PROTECTION OF HUMAN SUBJECTS Sec. 46.101 To what does this policy apply? 46.102 Definitions. 46.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 46.104 [Reserved] 46.105 [Reserved] 46.105 [Reserved] 46.107 IRB Membership. 46.108 IRB functions and operations. 46.109 IRB review of research. 46.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 46.111 Criteria for IRB approval of research. 46.112 Review by institution. 46.113 Suspension or termination of IRE approval of research. 46.114 Cooperative research. 46.115 IRB records. 46.116 General requirements for informed consent. 46.117 Documentation of informed consent. 46.118 Applications and proposals lacking definite plans for involvement of human subjects. 46.119 Research undertaken without the intention of involving human subjects. 46.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 46.121 [Reserved 46.122 Use of Federal funds. 46.123 Early termination of research support: Evaluation of applications and proposals. 46.124 Conditions. Authority: 5 U.S.C. 301; 28 U.S.C. 509-51O; 42 U.S.C. 300v- 1(b). 1 See Footnote 1 on page 28023. Dated: December 24. 1990. Dick Thornburgh. Attorney General. DEPARTMENT OF DEFENSE 32 CFR Part 219 RIN 0790-AC80 List of Subjects in 32 CFR Part 219 Human subjects, Research, Reporting and record-keeping requirements. Title 32 of the Code of Federal Regulations is amended by revising part 219 as set forth at the end of this document.1 PART 219-PROTECTION OF HUMAN SUBJECTS Sec. 219.101 To what does this policy apply? 219.102 Definitions. 219.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 219.104 (Reserved) 219.105 (Reserved) 219.105 (Reserved) 219.107 IRB Membership. 219.108 IRB functions and operations. 219.109 IRB review of research. 219.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 219.111 Criteria for IRB approval of research 219.112 Review by institution. 219.113 Suspension or termination of IRB approval of research. 219.114 Cooperative research. 219.115 IRB records. 219.116 General requirements for informed consent. 219.117 Documentation of informed consent. 219.118 Applications and proposals lacking definite plans for involvement of human subjects. 219.119 Research undertaken without the intention of involving human subjects. 219.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 219.121 [Reserved] 219.122 Use of Federal funds. 219.123 Early termination of research support: Evaluation of applications and proposals. 219.124 Conditions. Authority:5 U.S.C. 301; 42 U.S.C. Dated: January 9. 1991. Linda M. Bynum, Alternate OSD Federal Register Liaison Officer Department of Defense. DEPARTMENT OF EDUCATION 34 CFR Part 97 RIN 1875-AAO7 List of Subjects in 34 CFR Part 97 Human subjects, Research. Reporting and record-keeping requirements. Title 34 of the Code of Federal Regulations is amended by adding part 97 as set forth at the end of this document.1 PART 97-PROTECTION OF HUMAN SUBJECTS Sec. 97.101 To what does this policy apply? 97.102 Definitions. 97.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 97.104 (Reserved) 97.105 (Reserved) 97.105 [Reserved) 97.107 IRB Membership. 97.108 IRB functions and operations. 97.109 IRB review of research. 97.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 97.111 Criteria for IRB approval of research. 97.112 Review by institution. 97.113 Suspension or termination of IRB approval of research. 97.114 Cooperative research. 97.115 IRB records. 97.116 General requirements for informed consent. 97.117 Documentation of informed consent. 97.118 Applications and proposals lacking definite plans for involvement of human subjects. 97.119 Research undertaken without the intention of involving human subjects. 97.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 97.121 (Reserved) 97.122 Use of Federal funds. 97.123 Early termination of research support: Evaluation of applications and proposals. 97.124 Conditions. Authority: 5 U.S.C. 301; 42 U.S.C. 300v-1(b). Dated: June 6. 1991 Lamar Alexander, US. Secretary of Education. DEPARTMENT OF VETERANS AFFAIRS 38 CFR Part 16 RIN 290O-AE29 List of Subjects in 38 CFR Part 16 Human subjects, Research, Reporting and record-keeping requirements. Title 38 of the Code of Federal Regulations is amended by adding part 16 as set forth at the end of this document.1 PART 16-PROTECTION OF HUMAN SUBJECTS Sec. 16.101 To what does this policy apply? 16.102 Definitions. 16.103 Assuring compliance with this policy- research conducted or supported by any Federal Department or Agency. 16.104 (Reserved] 16.105 (Reserved] 16.105 [Reserved] 16.107 IRB Membership. 16.108 IRB functions and operations. 16.109 IRB review of research. 16.110 Expedited review procedures for certain kinds of research involving no more than minimal risk. and for minor changes in approved research. 16.111 Criteria for IRB approval of research. 16.112 Review by institution. 16.113 Suspension or termination of IRB approval of research. 16.114 Cooperative research. 16.115 IRB records. 16.116 General requirements for informed consent. 16.117 Documentation of informed consent. 16.118 Applications and proposals lacking definite plans for involvement of human subjects. 16.119 Research undertaken without the intention of involving human subjects. 16.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 16.121 (Reserved] 16.122 Use of Federal funds. 16.123 Early termination of research support: Evaluation of applications and proposals. 16.124 Conditions. ____________ 1 See Footnote 1 on page 28023. 28022 Federal Register I Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations Authority: 5 U.S.C. 301; 38 U.S.C. 210(c)(1). 4131, 4134: 42 U.S.C. 300v-1(b). Dated: February 19, 1991. Edward J. Derwinski Secretary of Veterans Affairs. ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 26 RIN 2080-AA04 List of Subjects in 40 CFR Part 26 Human subjects, Research, Reporting and record-keeping requirements. Title 40 of the Code of Federal Regulations is amended by adding part 26 as set forth at the end of this document.1 PART 26-PROTECTiON OF HUMAN SUBJECTS Sec. 26.101 To what does this policy apply? 26.102 Definitions. 26.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 26.104 [Reserved] 26.105 [Reserved] 26.106 [Reserved] 26.107 IRB Membership. 26.108 IRB functions and operations. 26.109 IRB review of research. 26.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 26.111 Criteria for IRB approval of research. 26.112 Review by institution. 26.113 Suspension or termination of IRB approval of research. 26.114 Cooperative research. 26.115 IRB records. 26.116 General requirements for informed consent. 26.117 Documentation of informed consent. 26.118 Applications and proposals lacking definite plans for involvement of human subjects. 26.119 Research undertaken without the intention of involving human subjects. 26.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 26.121 (Reserved). 26.122 Use of Federal funds. 26.123 Early termination of research support: Evaluation of applications and proposals. 26.124 Conditions. Authority: 5 U.S.C. 301; 42 U.S.C. 300v-1(b). Tuesday, June 18, 1991 Dated: January 28, 1991. William K. Reilly, Administrator. DEPARTMENT OF HEALTH AND HUMAN SERVICES 45 CFR Part 46 BIN O991-AA71 List of Subjects in 45 CFR Part 46 Human subjects, Research, Reporting, and record-keeping requirements. Title 45 of the Code of Federal Regulations part 46 is amended, as follows: 1. An authority citation for subpart A is added to read as follows: Authority: 5 U.S.C. 301;42 U.S.C. 289,42 U.S.C. 300v-1(b). 2. Subpart A is revised to read as set forth at the end of this document.1 PART 46-PROTECTION OF HUMAN SUBJECTS Subpart A-Basic HHS Policy for Protection of Human Research Subjects Sec. 46.101 To what does this policy apply? 46.102 Definitions. 46.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 46.104 [Reserved] 46.105 [Reserved] 46.105 [Reserved] 46.107 IRB Membership. 46.108 IRB functions and operations. 46.109 IRB review of research. 46.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 46.111 Criteria for IRE approval of research. 46.112 Review by institution. 46.113 Suspension or termination of IRB approval of research. 46.114 Cooperative research. 46.115 IRB records. 46.116 General requirements for informed consent. 46.117 Documentation of informed consent. 46.118 Applications and proposals lacking definite plans for involvement of human subjects. 46.119 Research undertaken without the intention of involving human subjects. 46.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 46.121 [Reserved] 46.122 Use of Federal funds. 46.123 Early termination of research support: Evaluation of applications and proposals. 46.124 Conditions. Dated: March 29. 1991. Louis W. Sullivan, Secretary of Health and Human Services. NATIONAL SCIENCE FOUNDATION 45 CFR Part 690 RIN 3145-AA18 List of Subjects in 45 CFR Part 690 Human subjects, Research. Reporting and record-keeping requirements. Title 45 of the Code of Federal Regulations is amended by adding part 690 as set forth at the end of this document.1 PART 690-PROTECTION OF HUMAN SUBJECTS Sec. 690.101 To what does this policy apply? 690.102 Definitions. 690.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency 690.104 [Reserved] 690.105 [Reserved] 690.105 [Reserved] 690.107 IRB Membership. 690.108 IRB functions and operations. 690.109 IRB review of research. 690.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 690.111 Criteria for IRE approval of research. 690.112 Review by institution. 690.113 Suspension or termination of 1119 approval of research. 690.114 Cooperative research. 690.115 IRB records. 690.116 General requirements for informed consent. 690.117 Documentation of informed consent. 690.118 Applications and proposals lacking definite plans for involvement of human subjects. 690.119 Research undertaken without the intention of involving human subjects. 690.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 690.121 (Reserved] 690.122 Use of Federal funds. 690.123 Early termination of research support: Evaluation of applications and proposals 690.124 Conditions. Dated: December 17, 1990. __________ 1 See Footnote 1 on page 28023. Federal Register I Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations 28023 Authority: 5 U.S.C. 301; 42 U.S.C. 360v-1(b). Frederick M. Bernthal, Acting Director. DEPARTMENT OF TRANSPORTATION 49 CFR Part 11 RlN 21OAB74 List of Subjects in 49 CFR Part 11 Human subjects, Research, Reporting and record-keeping requirements. Title 49 of the Code of Federal Regulations is amended by adding part 11 as set forth at the end of this document.1 PART 11-PROTECTION OF HUMAN SUBJECTS Sec. 11.101 To what does this policy apply? 11.102 Definitions. 11.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 11.104 (Reserved) 11.105 (Reserved) 11.106 (Reserved) 11.107 IRB Membership. 11.108 IRB functions and operations. 11.109 IRB review of research. 11.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 11.111 Criteria for IRB approval of research. 11.112 Review by institution. 11.113 Suspension or termination of IRB approval of research. 11.114 Cooperative research. 11.115 IRB records. 11.116 General requirements for informed consent. 11.117 Documentation of informed consent. 11.118 Applications and proposals lacking definite plans for involvement of human subjects. 11.119 Research undertaken without the intention of involving human subjects. 11.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 11.121 (Reserved] 11.122 Use of Federal funds. 11.123 Early termination of research support: Evaluation of applications and proposals. 11.124 Conditions. Authority: 5 U.S.C. 301; 42 U.S.C. 300v-1(b]. Dated: February 4. 1991. Samuel K. Skinner, Secretary of Transportation. (FR Doc. 91-14258 Filed 6-17-91; 8:45 am) Billing Code 4140-01-M 1 Due to an error in the order of the document pages submitted to the Office of the Federal Register, the text of the common rule appears at the end of the common preamble for this document at page 28012. 28024 Federal Register I Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency Forms Submitted to the Office of Management and Budget for Clearance The following request has been submitted to the Office of Management and Budget (OMB) for clearance in compliance with the Paperwork Reduction Act (44 U.S.C. chapter 35). Expedited review by OMB has been requested as described below. (Call PHS Reports Clearance Officer on 202-2421OO for copies of submission) Federal Policy for the Protection of Human Subjects-New-This submission is for approval of the information requirements associated with the common rule for the protection of human subjects of research conducted, supported or regulated by the following Federal departments and agencies; Department of Agriculture, Department of Energy, National Aeronautics and Space Administration, Department of Commerce, Consumer Product Safety Commission, Agency for International Development, Department of Housing and Urban Development, Department of Justice. Department of Defense, Department of Education, Department of Veterans' Affairs, Environmental Protection Agency. -Department of Transportation, Central Intelligence Agency, and Department of Health and Human Services. Adoption of the common Federal policy by these departments and agencies will implement a recommendation of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The Office of Science and Technology Policy established an Interagency Human Subjects Coordinating Committee under the Federal Coordinating Council for Science Engineering and Technology. This group prepared a proposed Model Federal Policy for the Protection of Human Subjects that was published as a proposed policy in 1986 and again as a proposed common rule on November 10, 1988. After revision of the proposed common rule in response to public comments, the final common rule is being published elsewhere in this issue of the Federal Register. The common rule is based on Department of Health and Human Services (DHHS) regulations (45 CFR part 46, subpart A), the basic HHS Policy for the Protection of Human Subjects. Respondents: Individuals or households, State or local governments, businesses or other for-profit, Federal agencies or employees. non-profit institutions, small businesses or organizations. The total number of respondents affected by these information requirements is estimated at 3,831. The total annual response burden for these requirements including all Federal departments and agencies subject to the common rule, is estimated at 187,403 hours divided as follows: 22,982 hours for recordkeeping requirements and 164,426 hours for reporting and disclosure requirements. Additional Information: DHHS has submitted this request for approval to OMB on behalf of all Departments and Agencies governed by this final rule. It is critical to receive OMB review and approval for the information requirements so that the common rule for the Protection of Human Subjects may be effective 6() days after publication. Federal Departments and Agencies have ongoing research programs to which the common rule will apply, and they are seeking the most expeditious time frame in which to begin protection of human subject policies and procedures. In addition, institutions supported or regulated by the involved Departments and Agencies have requested implementation of the final rule as soon as possible to lessen burden of compliance with numerous, sometimes inconsistent, procedures for the protection of human subjects required by the various Federal Departments and Agencies. OMB has been requested to review and approve the information requirements in the common rule on an expedited basis no later than August 2, 1991. In keeping with the requirements for expedited review, we are publishing this announcement in the same issue as the proposed final rule. The information requirements are separately identified in the preamble to the rule, printed elsewhere in this issue. There are no separate forms or instructions for which approval is being sought. OMB Desk Officer: Shannah Koss-McCallum. Because of the time frame in which OMB has been asked to act on this request, any comments and recommendations for the proposed information collection should ba provided directly to the OMB Desk Officer designated above by telephone at (202) 395-7316 or by express mail at the following address: Human Resources and Housing Branch, New Executive Office Building, room 32, Washington, DC 20503. Dated: May 31, 1991. Sandra K. Mahkorn, Deputy Assistant Secretary for Public Health Policy. [FR Doc. 91-14259 Filed 6-17-91; 8:49 am] BILLING CODE 414O-01-M Federal Register / Vol. 56. No. 117 /Tuesday, June 18, 1991/ Rules and Regulations 28025 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 50 and 56 (Docket No. 87N-0032] RIN O9O5-AC52 Protection of Human Subjects; Informed Consent; Standards for Institutional Review Boards for Clinical Investigations AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending its regulations on institutional review boards (IRB's) and on informed consent to conform them to the "Federal Policy for the Protection of Human Research Subjects" (Federal Policy) published elsewhere in this issue of the Federal Register. Existing FDA regulations governing the protection of human subjects share a common core with the Federal Policy and implement the fundamental principles embodied in that policy. EFFECTIVE DATE: August 19, 1991. FOR FURTHER INFORMATION CONTACT: Richard M. Klein, Office of Health Affairs (HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301443-1382. SUPPLEMENTARY INFORMATION: I. Background FDA is charged by statute with ensuring the protection of the rights, safety. and welfare of human subjects who participate in clinical investigations involving articles subject to section 505(i). 507(d), or 520(g) of the Federal Food, Drug. and Cosmetic Act (the act) (21 U.S.C. 355(i), 357(d), or 360j(g)), as well as clinical investigations that support applications for research or marketing permits for products regulated by FDA, including food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products. In the Federal Register of January 27 1981, FDA adopted regulations governing informed consent of human subjects (21 CFR part 50; 46 FR 8942) and regulations establishing standards for the composition, operation, and responsibilities of IRf3's that review clinical investigations involving human subjects (21 CFR part 56; 46 FR 8958). At the same time, the Department of Health and Human Services (HHS) adopted regulations on the protection of human research subjects (45 CER part 46; 46 I:,R 8366). The FDA and HHS regulations share a common framework. In December 1981, the President's Commission for the study of Ethical Problems in Medicine and Biomedical and Behavioral Research (the commission) issued its "First Biennial Report on the Adequacy and Uniformity of Federal Rules and Policies, and their Implementation. for the Protection of Human Subjects in Biomedical and Behavioral Research, Protecting Human Subjects." The commission recommended that all Federal departments and agencies adopt the HHS regulations (45 CFR part 46). In May 1982, the President's Science Advisor, Office of Science and Technology Policy (OSTP), appointed an ad hoc Committee for the Protection of Human Research Subjects (the committee). under the auspices of the Federal Coordinating Council for Science, Engineering, and Technology (FCCSET), to respond to the recommendations of the commission. The committee, composed of representatives and ex-officio members from departments and agencies that conduct, support, or regulate research involving human subjects. developed responses to the commission in consultation with OSTP and the Office of Management and Budget (OMB). The committed agreed that uniformity of Federal regulations on human subject protection is desirable to eliminate unnecessary regulations and to promote increased understanding by institutions that conduct federally-supported or regulated research. The committee developed a model policy which OSTP later modified and, with the concurrence of all affected Federal departments and agencies, published as a proposal in the Federal Register of June 3, 1986 (51 FR 20204). More than 200 comments were submitted in response to the proposal. Published elsewhere in this issue of the Federal Register is the final rule on the Federal Policy. FDA concurs in that final rule. In the Federal Register of November 10, 1988 (53 FR 45678), the agency proposed to amend its regulations in 21 CFR parts 50 and 56 to conform them to the Federal Policy to the extent permitted by the act. The agency is committed to being as consistent final Federal Policy as it can be, given the unique requirements of the act and the fact that FDA is a regulatory agency that rarely supports or conducts research under its regulations. However, as explained in the proposed rule, FDA must diverge from .101(h) and .116(d) of the Federal Policy. FDA received 22 comments on the proposed rule from sponsors of regulated research, institutional review board members and staff, academic institutions, medical societies, and lawyers. Several comments were prepared by organizations, each representing a consortia of institutions that had been polled concerning the proposed rule. A. General Comments 1. The majority of comments supported the agency's efforts to conform to the Federal Policy. 2. The majority of comments received concerned the proposal to amend  56.108(b) to require that IRB's follow written guidelines for ensuring the reporting of scientific misconduct and of unanticipated problems to the IRB. institutional officials, and FDA. Two comments noted that this provision would make the IRB the institutional body that investigates alleged fraud, severely damaging the IRB investigator relationship and possibly diminishing the effectiveness of the IRB in protecting human subjects. Several comments noted that the proposed additional reporting requirements would duplicate investigator and sponsor reporting requirements and would be difficult for the IRB to enforce. One comment said that this section may adversely affect the IRB institution relationship and asked how FDA intended to ensure that reporting occurred. One comment interpreted the provision as applicable to animal studies and wondered whether IRB's would be responsible for contacting sponsors. One comment expressed concern that the workload of the IRB would increase and adversely affect the recruitment of new members. One comment sought to exclude Adverse Drug Reaction reports. One comment argued that the reporting requirement was unauthorized by law. Two comments from sponsors requested that sponsor notification be added under proposed  56.108(b). noting that an investigator engaged in misconduct is unlikely to report that misconduct to the IRB, and that the sponsor is the entity that frequently detects misconduct through its extensive monitoring practices. In addition. these comments requested clarification of the office in FDA to which scientific misconduct should be reported. Several comments requested that FDA define or clarify "scientific misconduct" and "unanticipated problems." Since the proposed model policy was published, the Public Health Service published a final rule concerning fraud and misconduct in science (54 FR 32446, 28026 Federal Register / Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations August 8, 1989). Because that rule directs institutions to establish provisions for the investigation of alleged scientific fraud and misconduct, the mention of "scientific misconduct" has been deleted, as unnecessary. from the model policy. Because FDA only proposed to require that IRB's report scientific misconduct to be consistent with the model policy, it has deleted this requirement from its final rule. This action should allay many of the concerns expressed in the comments. Moreover, FDA believes that the comments misconstrued the intent of  56.108(b). This section requires simply that an IRB have procedures by which it checks to ensure in reviewing each study presented, that provision has been made in the study to notify the IRB, appropriate institutional officials, and FDA in the specified circumstances. Section 56.108(b) does not require that the IRB itself provide the notification to, either the institution or to FDA, unless such reporting would not otherwise occur. Although FDA's regulations include reporting requirements for certain types of investigational articles (see, e.g.. 21 CFR parts 312 (investigational drugs) and 812 (investigational devices), there are no such provisions for other articles that may be the subject of an investigation (e.g. food additives). Because all regulated research to be conducted at an institution will come before the IRB, FDA finds that the IRB is the appropriate entity to charge with the responsibility for ensuring that reporting of the specified problems to the IRB, the institution, and the agency will occur. 3. One comment urged FDA to move toward the adoption of an assurance system as established for the other agencies within HHS to guarantee compliance with regulations for the protection of human subjects. FDA continues to believe that it would be inappropriate for it to adopt this mechanism. As stated in the final rule in the Federal Register of January 27. 1981 (46 FR 8959, comment 2), the benefits of assurance from IRB's that are subject to FDA jurisdiction, but not otherwise to HHS jurisdiction, do not justify the increased administrative burdens that would result from an assurance system. FDA relies on its Bioresearch Monitoring Program, along with its educational efforts, to assure compliance with these regulations. 4. One comment expressed concern over FDA's proposed divergences from sections 101(h) and 116(d) of the Federal Policy. The comment contended that it is sometimes impossible to obtain informed consent, as defined by FDA's regulations, in foreign clinical trials. As stated in the proposed rule (53 FR 45679), FDA does not have the authority to accept the procedures followed in a foreign country in lieu of informed consent as required by the act for studies that are conducted under a research permit that it grants. The comment did not provide any information that would compel a different conclusion. B. Comments on Definitions 5. One comment suggested that the word "discomfort" used in proposed  50.3(i) and 56.102(i) is difficult to define and is subjective. FDA believes that the meaning of "discomfort" is sufficiently clear. FDA interprets this term to have its ordinary meaning; that is, to mean the extent to which a subject may be made uncomfortable by the article that is the subject of the research. 6. One comment asserted that proposed  56.102(m), the definition of "IRB approval," suggests an intent to change the procedural requirements of IRB approval. FDA proposed to add this definition to make the regulations conform to the Federal Policy and to clarify the meaning of the phrase "IRB approval" under this rule. The addition of this definition is not intended to effect a substantive change in part 56. In the preamble to its.August 8, 1978 proposal of the IRB regulation (43 FR 35136 at 35197). FDA presented a thorough discussion of its authority to require IRB review. 7. One comment stated that the reference to 'other institutional and Federal requirements" in proposed  56.102(m) goes beyond FDA's ability to determine other institutional requirements and may be counterproductive where there is conflict between the institutional requirements and FDA or HHS requirements. The suggestion is made to delete "and other institutional * * requirements." This definition is intended to make clear that IRB approval is to be based on a determination that the proposed research is acceptable under any applicable institutional requirements. applicable law, and standards of professional conduct and practice. If there are conflicts between the institutional requirements and Federal law, those conflicts obviously must be resolved in favor of the Federal law. However, institutional requirements often address matters not addressed by Federal law. Therefore, FDA finds it appropriate to mention both institutional and Federal requirements in this definition. 8. One comment suggested substituting "clinical investigation" for the word "research" in  56.102(m). FDA rejects the suggestion. FDA has defined "clinical investigations' in  56.102(c) to be synonymous with "research" (46 FR 8976). Because FDA desires to conform to the Federal Policy and in the absence of a compelling argument to diverge from it, FDA is using the word used in the Federal Policy. 9. Several comments suggested deleting "at an institution" from  56.102(m), contending that this phrase may confuse the original intent of the meaning of IRB approval. Another comment noted that much research today is conducted outside the institutional setting. FDA rejects the comments. In 1981. when FDA adopted the IRB regulations. FDA intentionally defined "institution" broadly to include "any public or private entity or agency" ( 56.102(f); 46 FR 8963, comment 27). Thus.  56.102(m) is consistent with the original intent of the IRB regulations. 10. One comment suggested revising  56.102(m) to read "IRB approval means * * * that the research has been reviewed for undue risk to the subject and may be conducted * * * " FDA rejects the suggestion. The suggested change does not adequately describe the role of the IRB. The IRB's' review of studies and informed consent' documents includes numerous considerations in addition to whether the study presents undue risks to the human subjects involved. C. Comments on Exemptions From IRB Requirements 11. One comment requested that no exemptions from IRB requirements be granted for those populations already identified as vulnerable. FDA did not propose that studies involving vulnerable populations be exempt from IRB review. The only exemptions from the IRB review requirements were established in the 1981 final rule (46 FR 8942; 21 CFR 56.104). The use of an investigational article is exempt from IRB review if the investigation started before July 27, 1981, before the requirement of IRB review was in effect, or if it involves art emergency use of the test article. in which case there is not time for IRB review before the article is used. The agency found that in these circumstances, the considerations that support granting an exemption outweigh those that would support denying it (46 FR 8965, comment 48). The comment did not provide any basis for reconsidering Federal Register / Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations 28027 Federal or revising this judgment. The agency points out that the latter consideration (emergency use), which is the only basis on which a new study would be exempt applies only to particular uses of an article and would not provide the basis for an exemption for the use of an article in a particular population. Therefore, FDA finds that this comment provides no basis for modifying its regulations. 12. One comment suggested that FDA completely exempt "minimal risk" studies from IRB review. FDA rejects the comment. The determination of minimal risk can be made only by members of the IRB, not the investigator or the sponsor. The burden of an expedited review of a protocol to determine if it presents minimal risk is not so great as to justify the requested exemption. D. Comments on IRB Membership 13. Three comments suggested that FDA define in  56.107 the specific members to be included on an IRB. Several comments suggested that FDA-define, in new  56.107(c), "non-scientific" and "scientific." Two comments suggested that the IRE include "one member who has an understanding of the medical risks involved." Another comment suggested that  56.107(c) be clarified to include a statement requiring that at least one member of the IRB have an understanding of the scientific method. FDA rejects these comments. FDA has chosen not to prescribe professional membership requirements for IRE members. The regulations allow for flexibility in the makeup of the IRE (see 46 FR 8966, comment 55). They require, however, that there be at least one member whose concerns are in nonscience areas and one member who has the professional competency to review the proposed research, such as a physician. FDA interprets "competency" in this context to include the ability to understand the scientific method. The agency believes that the membership requirements that it has adopted are adequate to ensure that an IRE will be able to fully consider the issues presented by a study. 14. One comment suggested that the proposed change in  56.107(a), allowing IRE's that regularly review studies that involve vulnerable categories of subjects to consider including as a member an individual knowledgeable about, and experienced in, working with vulnerable populations, will afford less human subject protection than the current regulation. The current regulation states that an IRB that regularly reviews research involving vulnerable populations should include as members individuals who are primarily concerned with the welfare of vulnerable subjects. Revised  56.107(a) lists categories of subjects who are considered vulnerable and requires that the institution, or other authority, consider including individuals knowledgeable and experienced in working with these types of subjects as voting members on the IRB. This revision is not intended to lessen in any way the protections for vulnerable populations under FDA's regulations. As explained in the proposal (53 FR 45679). FDA is making this change only to conform to the language of the Federal Policy. FDA on its own initiative is adding parenthesis to the word "reviewers" in  56.110(b)(1) to permit a continuance of existing IRE review procedures. E. Comments on IRB Functions and Operations 15. Several comments sought clarification of new  56.108(b)(1) with regard to the definition and interpretation of "any unanticipated problems involving risks to human subjects and others" and the level of risk to be reported. FDA interprets this phrase to mean ar unexpected adverse experience that is not listed in the labeling for the test article. Such experience includes an event that may be symptomatically and pathophysiologically related to an even listed in the labeling but that differs from the event because of greater specificity or severity. The word "others" has previously been defined as persons who are participating in clinical trials under the same or similar protocols or who may be affected by products or procedures developed in those trials (see 53 FR 45661, 45665; November 10, 1988). F. Comments on Expedited Review Procedures 16. One comment read the parenthetical change in  56.110(b). "of one year or less," as affecting a change from the current regulations. FDA disagrees with the comment. Under current regulations. the IRE may approve a study that will continue beyond 1 year, such as a longitudinal follow-up study. The IRE is obligated, however, under  56.109(e) (21 CFR 56.109(e)), to conduct continuing review of the research at intervals appropriate to the degree of risk that it presents but not less than once a year. 17. One comment stated that expedited review procedures should never be used in research that involves vulnerable populations. FDA disagrees with the comment. Expedited review procedures may only be used to review research that involves minimal risk as defined in  56.102(i) or to review minor changes in previously approved research ( 56.110(b)). The determination that such conditions apply must be made by the chairperson of the IRB, or by one or more experienced members of the IRB designated by the chairperson. Thus, research involving vulnerable populations will not be subject to expedited review unless a member of the IRB has affirmatively determined that the subjects will not be exposed to any greater risk of harm than they encounter in daily life or during routine physical or psychological examinations or tests, or that a change in research that has been reviewed by the whole IRB is minor. Obviously, in making these determinations, the IRB member must consider the nature of the subject population. Moreover, if expedited review is undertaken, the reviewer may exercise all the authority of the IRB, including the authority under  56.111(a)(3) to ensure that any special problems of vulnerable populations have been addressed. Thus, FDA believes that vulnerable populations will not be involved in research that has been subject to expedited review procedures without full consideration of whether such research should be subject to expedited review, at all and, if So, of their interests. Therefore, FDA does not agree with the comment. C. Comments on Criteria for IRB Approval of Research 18. One comment suggested deleting "* * economically or educationally disadvantaged persons * * *" from new 56.111(a)(3), stating that it would be impossible for the IRB or the clinical investigator to make that determination. FDA disagrees with the comment. As stated in  56.111(b). FDA expects the IRB to make sure that adequate protections are included in those clinical investigations in which vulnerable subjects will be participating. There is no requirement for the IRB to make a determination that individual subjects are disadvantaged. However, the IRB is required to determine whether it is likely that vulnerable individuals will be involved in the study, and, if so, what adequate safeguards have been included to protect the study subjects or whether additional safeguards are necessary. II. Environmental Impact The agency has determined under 21 CFR 25.24(a)(8) that this action is of a type that does not individually or 28028 Federal Register / Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations cumulatively have a significant effect on human environment. Therefore neither an environmental assessment nor an environmental impact statement is required. III. Economic and Regulatory Assessments FDA has examined the economic consequences of the final amendments to its regulations pertaining to IRB's and to informed consent in accordance with the criteria in section 1(b) of Executive Order 12291 and found that these amendments would not be a major rule under the Executive Order. The agency also has considered the effect that the final rule would have on small entities including small businesses in accordance with the Regulatory Flexibility Act (Pub. L. 96-354). The agency certifies that there will not be a significant economic impact on a substantial number of small entities. FDA explained the basis for these conclusions in the proposal (53 FR 45681]. The agency did not receive any comments that suggest contrary conclusions. This final rule contains the information collections subject to the Paperwork Reduction Act of 1980. These information collections have been approved under OME control number 0910-0130. List of Subjects in 21 CFR Part 50 Prisoners, Reporting and recordkeeping requirements, Research, Safety. 21 CFR Part 56 Reporting and Recordkeeping requirements, Research, Safety. Therefore, under the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, 21 CFR parts 50 and 56 are amended as follows: PART 50-PROTECTION OF HUMAN SUBJECTS 1. The authority citation for 21 CFR part 50 continues to read as follows: Authority: Secs, 201, 406, 408, 409, 502, 503, 505, 506, 507, 510, 513-516, 518-520, 701, 706, 801 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 346, 346a, 348, 352, 353, 355, 356, 357, 360, 360c-360f, 360h-360j, 371, 376, 381); secs. 215, 301, 351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241, 262, 263b-263n). 2. Section 50.3 is amended by revising paragraph (l) to read as follows:  50.3 Definitions. (l) Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. PART 56-INSTITUTIONAL REVIEW BOARDS 3. The authority citation for 21 CFR part 56 continues to read as follows: Authority; Secs. 201, 406, 408, 409, 501, 502, 503, 505, 506, 507. 510, 513-516, 518-520, 701, 706, 801 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 346, 346a, 348, 351, 352, 353, 355, 356, 357, 360, 360c-360f. 360h-360j, 371, 376,381); secs. 215, 301, 351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241, 262, 263b-263n). 4. Section 56.102 is amended by revising paragraph (i) and by adding new paragraph (m) to read as follows:  56.102 Definitions. (i) Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. (m) IRB approval means the determination of the IRB that the clinical investigation has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and Federal requirements. 5. Section 56.104 is amended by adding new paragraph (d) to read as follows:  56.104 Exemptions from IRB requirement. (d) Taste and food quality evaluations and consumer acceptance studies. if wholesome foods without additives are consumed or if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe. or agricultural, chemical, or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture. 6. Section 56.107 is amended by revising paragraphs (a). (b). and (c) to read as follows:  56.107 IRB membership. (a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. The IRB shall be sufficiently qualified through the experience and expertise of its members. and the diversity of the members. including consideration of race, gender, cultural backgrounds, and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review the specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations. applicable law, and standards or professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners. pregnant women, or handicapped or mentally disabled persons. consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with those subjects. (b) Every nondiscriminatory effort will be made to ensure that no IRE consists entirely of men or entirely of women, including the institution's consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of gender. No IRB may consist entirely of members of one profession. (c) Each IRB shall include at least one member whose primary concerns are in the scientific area and at least one member whose primary concerns are in nonscientific areas. * * * * 7. Section 56.108 is amended by revising paragraph (a), by removing paragraph (c), by redesignating paragraph (b) as paragraph (c), by adding a new paragraph (b), and by adding a parenthetical statement to the end of the section to read as follows;  56.108 IRB functions and operations. * * * * * (a) Follow written procedures: (1) For conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution; (2) for determining which projects require review more often than annually and which projects need verification from sources other than the investigator that no material changes have occurred since previous IRB review; (3) for ensuring prompt reporting to the IRB of changes in Federal Register / Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations 28029 research activity; and (4) for ensuring that changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects. (b) Follow written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of: (1) Any unanticipated problems involving risks to human subjects or others; (2) any instance of serious or continuing noncompliance with these regulations or the requirements or determinations of the IRB; or (3) any suspension or termination of IRB approval. (Information collection requirements in this section were approved by the Office of Management and Budget (OMB) and assigned OMB control number 0910-0130) 8. Section 56.110 is amended by revising paragraph (b) to read as follows:  56.110 Expedited review procedures for certain kinds of research Involving no more than minimal risk, and for minor changes in approved research. (b) An IRB may use the expedited review procedure to review either or both of the following: (1) Some or all of the research appearing on the list and found by the reviewer (a) to involve no more than minimal risk, (2) minor changes in previously approved research during the period (of 1 year or less) for which approval is authorized. Under an expedited review procedure, the review may be carried out by the IRB chairperson or by one or more experienced reviewers designated by the IRB chairperson from among the members of the IRB. In reviewing the research, the reviewers may exercise all of the authorities of the IRB except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the nonexpedited review procedure set forth in  56.108(c). 9. Section 56.111 is amended by revising paragraphs (a)(3) and (b) to read as follows:  56.111 Criteria for IRB approval of research. (a) * * * (3) Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons. (b) When some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence additional safeguards have been included in the study to protect the rights and welfare of these subjects. 10. Section 56.115 is amended by revising paragraph (a)(6) and by adding a parenthetical statement to the end of the section to read as follows:  56.115 IRB records. (a) * * * (6) Written procedures for the IRB as required by  56.108 (a) and (b). (Information collection requirements in this section were approved by the Office of Management and Budget (OMB) and assigned OMB control number 0910-0130) Dated: March 29, 1991. David A. Kessler, Commissioner of Food and Drugs. Louis W. Sullivan, Secretary of Health and Human Services. [FR Doc. 91-142&) Filed 6-17-91; 8:45 am) BILLING CODE 416O-01-M DEPARTMENT OF EDUCATION 34 CFR Parts 350 and 356 Protection Of Human Subjects- Disability and Rehabilitation Research: General Provisions, Disability and Rehabilitation Research: Research Fellowships AGENCY: Department of Education. ACTION: Interim final regulations with an opportunity to comment. SUMMARY: The Secretary amends program regulations for the National Institute on Disability and Rehabilitation Research to add certain protections for handicapped children and mentally disabled persons who are the subjects of research conducted or sponsored by those programs. Specifically, the program regulations would require that when an institutional review board (IRB) reviews research involving these research subjects, the IRB must include at least one person who is primarily concerned with the welfare of the research subjects. The regulations are necessary as the result of the Department of Education's (Department) withdrawal of a departure from the common regulations for the protection of human research subjects. DATES: Comments must be received on or before August 2, 1991. These regulations take effect either August 19, 1991, or later if the Congress takes certain adjournments. If you want to know the effective date of these regulations, call or write the Department of Education contact person. A document announcing the effective date will be published in the Federal Register. ADDRESSES: All comments concerning these interim final regulations should be addressed to Mr. Edward Glassman; Office of Planning, Budget and Evaluation; U.S. Department of Education, Federal Building 6, room 3127, 400 Maryland Avenue SW., Washington, DC 20202-4132. FOR FURTHER INFORMATION CONTACT: Edward B. Glassman, Telephone: (202) 401-3132. Deaf and hearing impaired individuals may call the Federal Dual Party Relay Service at 1-800-877-8339 (In the Washington DC area, 202 708-9300) between 8 a.m. and 7 p.m. Eastern Time. SUPPLEMENTARY INFORMATION: The Office of Science and Technology Policy, Executive Office of the President (OSTP), published a "Proposed Model Policy for the Protection of Human Subjects" in the Federal Register on June 3, 1986 (51 FR 20204). OSTP adopted a final policy for the protection of human research subjects on November 10, 1988 (53 FR 45660). The Final Policy adopted by OSTP was included in proposed common regulations published in the Federal Register on November 10, 1988 (53 FR 45661) by sixteen departments and agencies in the Executive Branch of the Federal Government, including the Department of Education. The final common regulations are published in another section of this Federal Register part. The notice of proposed rule making (NPRM) for the common regulations specifically asked for comments addressing what effect promulgation of the Model Policy would have on each of the agencies involved in the propose rulemaking. The Secretary proposed a departure from the common regulations that would require representation on an Institutional Review Board (IRB) of a least one person primarily concerned with the welfare of the research subjects whenever the research involves handicapped children or mentally disabled persons. As discussed below, 28030 Federal Register / Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations the Secretary has decided to withdraw this across-the-board departure in favor of program-specific regulations under those programs of the Department that are likely to support covered research that involves these research subjects. Composition of the IRB Comment The Department proposed a departure to  107(a) of the common regulations that would have required that, for all programs of the Department, "when an IRB reviews research that deals with handicapped children or mentally disabled persons, the IRB shall include at least one person primarily concerned with the welfare of the research subjects." The remainder of the departure reiterated the common rule:s provision, which required institutions to consider representation on the IRB of persons who are knowledgeable about and experienced in working with certain vulnerable subjects if the IRB regularly reviews research involving those vulnerable subjects. Twenty-one institutions focused on this proposed departure in their comments. The majority of these comments were opposed to the proposed departure. Some commentators, while supporting the proposed general language in ____.107, stated their belief that the departure was not necessary because the policy in .107 already addresses representation of the special concerns of vulnerable subjects on the IRB. Thus, the rights of handicapped children and mentally disabled persons should be represented on any IRB that regularly reviews proposals involving those individuals and there is nothing to be gained by emphasizing these two categories of subjects. Such an emphasis was seen as a precedent with the potential for discrimination against other categories of vulnerable subjects. When special expertise is required, IRBs already have the option, and, they believed, the obligation to seek informed consultants. However, one commentator stated "If in future staffing of our IRB, someone with expertise in this area is available and willing to serve, we would he happy to encourage such participation." One commentator suggested that only when an IRB regularly reviews research that deals with handicapped children or mentally disabled persons should the IRB include at least one person primarily concerned with the welfare of the research subjects. Otherwise, consultation should take place when appropriate. Another suggestion was that handicapped children be added to the list of examples of vulnerable subjects for which an IRB that regularly reviews research might want to consider inclusion of one or more members who are knowledgeable about and experienced in working with these subjects. Some commentators objected to the lack of consistency among Federal agencies and cited the Department of Education's proposed departure as inconsistent with the purpose of the common rule. One commentator indicated that the departure would not pose any problem. Response The language of the proposed departure was rooted in the Secretary's concern that the welfare of research subjects who are handicapped children or mentally disabled persons be adequately protected because of the diminished capacity of such persons to protect their own interests and their corresponding greater potential for harm. It should be noted that, while the common rule does, in general, protect the interests of vulnerable populations, it does not specifically command representation of their interests in all cases. For example, the common rule only requires that when an IRE regularly reviews research involving vulnerable subjects, consideration should be given to including on the IRE a researched experienced in working with such subjects. Thus, the Department believes it is appropriate to offer special protection for handicapped children and mentally disabled persons, and the protection proposed in the departure would have satisfied that need. The comments also appear to misunderstand the intent of the Department's proposed departure. Some commentators believed that the departure would require that an IRE include a permanent member to represent the special populations covered by the departure. Others appeared to believe that the departure would apply to all research of the institution that involved the special populations covered by the departure. The proposed departure would have produced neither of these results. Instead, the proposed departure would have required the addition of one member on an ad hoc basis only when the research is sponsored or funded by the Department of Education and purposefully requires the inclusion of handicapped children or mentally disabled persons. As explained above, the Secretary believes that there is a special need to protect handicapped children and mentally disabled persons. However, given the broad policy objective of providing consistent treatment through common regulations, the Secretary has decided that the IRB special representation requirements contained in the proposed departure are not necessary for most of the programs of the Department, because most programs of the Department do not support research likely to involve those persons. Thus, the Secretary has decided to withdraw the departure. However, the Secretary believes that the concerns addressed by the proposed departure have a particular urgency in those programs of the Department that support a significant amount of research involving handicapped children and mentally disabled persons. Therefore, the Secretary is amending the regulations for the programs of the National Institute on Disability and Rehabilitation Research (34 CFR parts 350 and 356) to ensure that the protections that would have been afforded under the departure are implemented in those specific programs. Although the Secretary has decided to publish this regulation in final form, due to the strong public interest created by the proposed departure. and because a number of commentators appeared to misunderstand the effect of the proposed rule, the Secretary has also decided to offer the public an additional opportunity to comment on the final rule. The address to which commentators should send their comments and thc date by which those comments must be received is stated at the beginning of this preamble. Changes In the notice of proposed rulemaking, the proposed departure was stated as follows: "When an IRB reviews research that deals with handicapped children or mentally disabled persons, the IRB must include at least one person primarily concerned with the welfare of the research subjects." The Secretary has decided to change this language in the program-specific regulations adopted in this document to make clear that the regulation specifically protects handicapped children and mentally disabled persons when those persons are purposefully included in a research protocol, rather than incidentally. Therefore, the language has been changed to state: "When an IRB reviews research that purposefully requires inclusion of handicapped children or mentally disabled persons in the research sample, the IRB must include at least one person primarily concerned with the welfare of the research subjects." Federal Register / Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations 28031 Executive Order 12291 These regulations have been reviewed in accordance with Executive Order 12291. They are not classified as major because they do not meet the criteria for major regulations established under the Order. Regulatory Flexibility Act Certification The Secretary certifies that these interim final regulations will not have a significant economic impact on a substantial number of small entities. The small entities that are affected by these interim final regulations are small institutions receiving research grants or contracts under the programs of the National Institute on Disability and Rehabilitation Research. However, the regulations do not have a significant economic impact on these entities because the regulations do not impose excessive regulatory burdens. These regulations impose minimal requirements that are necessary to ensure the proper treatment of handicapped children and mentally disabled persons under the programs of the National Institute on Disability and Rehabilitation Research. Invitation To Comment Interested persons are invited to submit comments and recommendations regarding these interim final regulations. Comments are specifically invited on whether other research programs of the Department should have added protections for handicapped children and mentally disabled persons. All comments submitted in response to these regulations will be available for public inspection, during and after the comment period, in room 3127, 400 Maryland Avenue, SW., Washington, DC between the hours of 9 a.m. and 4:30 pm., Monday through Friday of each week except Federal holidays. To assist the Department in complying with the specific requirements of Executive Order 12291 and the Paperwork Reduction Act of 1980 and their overall requirement of reducing regulatory burden, the Secretary invites comment on whether there may be further opportunities to reduce any regulatory burdens found in these interim final regulations. Assessment of Educational Impact The Secretary has determined that the regulations in this document do not require transmission of information that is being gathered by or is available from any other agency or authority of the United States. List of Subjects 34 CFR Part 350 Education, Education of the handicapped, Educational research, grant programs-education. 34 CFR Port 356 Education, Education research, Fellowships. Dated: June 6, 1991. Lamar Alexander, Secretary of Education. Catalog of Federal Domestic Assistance Number does not apply.) The Secretary amends title 34 of the Code of Federal Regulations by amending parts 350 and 356 as follows: PART 350-Disability AND REHABILITATION RESEARCH: GENERAL PROVISIONS 1. The authority citation for part 350 continues to read as follows: Authority: 29 U.S.C. 760762, unless otherwise noted. 2. Section 350.3 is amended by revising paragraph (d) and the authority citation at the end of the section to read is follows: .350.3 What regulations apply to these programs? (d)(1) The regulations in 34 CFR part )7, PROTECTION OF HUMAN SUBJECTS, except  97.107(a). (2) Each Institutional Review Board IRB) established under part 97 must have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. The IRB must be sufficiently qualified through the experience and expertise of its members, and the diversity of the members, including consideration of race, gender, and cultural backgrounds, and sensitivity to such issues as community attitudes, to promote respect or its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review specific research activities, the IRB must be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. The IRB must therefore include persons knowledgeable in these areas. When an IRB reviews research that purposefully requires inclusion of handicapped children or mentally disabled persons as research subjects, the IRB must include at least one person primarily concerned with the welfare of these research subjects. If an IRB regularly reviews another vulnerable category of subjects, such an non-handicapped children, prisoners, pregnant women, or handicapped adults, consideration must also be given to the inclusion of one or more individuals who are knowledgeable about the experience in working with these subjects. (Authority: 20 U.S.C. 761a, 762, 42 U.S.C. 300v-1(b)] PART 356-DISABILITY AND REHABILITATION RESEARCH: RESEARCH FELLOWSHIPS 3. The authority citation for part 356 continues to read as follows: Authority: 29 U.S.C. 761a(d), unless otherwise noted. 4. Section 356.3 is amended by revising paragraph (c) and the authority citation at the end of the section to read as follows;  356.3 What regulations apply to this program? (c)(1) The regulations in 34 CFR part 97, PROTECTION OF HUMAN SUBJECTS, except  97.107(a). (2) Each Institutional Review Board (IRB) established under part 97 must have at least five members, with varying backgrounds to promote complete aid adequate review of research activities commonly conducted by the institution. The IRB must be sufficiently qualified through the experience and expertise of its members, and the diversity of the members, including consideration of race, gender, and cultural backgrounds, and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review specific research activities, the IRE must be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. The IRB must therefore include persons knowledgeable in these areas. When an IRB reviews research that purposely requires inclusion of handicapped children or mentally disabled persons and research subjects, the IRB must include at least one person primarily concerned with the welfare of these research subjects. If an IRB regularly reviews another vulnerable category of subjects, such as non-handicapped children, 28032 Federal Register / Vol. 56, No. 117/ Tuesday, June 18, 1991/ Rules and Regulations prisoners, pregnant women, or handicapped adults, consideration must also be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects. (Authority: 29 U.S.C. 761a(d]. 42 U.S.C. 300v-1(b)) (FR Doc. 91-14261 Filed 617-91; 8:45 am) BILLING CODE 4000-01-M DEPARTMENT OF HEALTH AND HUMAN SERVICES 45 CFR Part 46 Federal Policy for the Protection of Human Subjects: Additional Protections for Children Involved as Subjects in Research AGENCY: Department of Health and Human Services. ACTION: Technical Amendment. SUMMARY: This technical amendment is to correct a reference in 45 CFR part 46 subpart D (Additional Protection for Children Involved as Subjects in Research) to subpart A of that part of the Federal Register. In the revision to subpart A, published elsewhere in this issue, the numbering of exemptions in 45 CFR part 46.101(b) changes. The reference to those exemptions in subpart D 45 CFR part 46.401(b) is now amended accordingly. EFFECTIVE DATE: This regulation shall become effective on August 19, 1991. FOR FURTHER INFORMATION CONTACT: Dr. Joan P. Porter, Staff Director, Interagency Human Subjects Coordinating Committee, building 31, room 51359, Bethesda, Maryland 20892. Telephone (301) 4967005. List of Subjects in 45 CFR Part 46 Human subjects. Research, Reporting and record-keeping requirements, Infants and children. PART 46-PROTECTION OF HUMAN SUBJECTS 1. The authority for part 46 is revised to read: Authority; 5 U.S.C. 30; Sec. 474(a), 88 Stat. 352 (42 U.S.C. 2891-3(a)). 2. In subpart D-Additional Protections for Children Involved as Subjects in Research,  46.401, paragraph (b) is revised to read as follows: 46.401 To what do these regulatIons apply? * * * * * (b) Exemptions at  46.101(b)(1) and (b)(3) through (b)(6) are applicable to this subpart. The exemption at  46.101(b)(2) regarding educational tests is also applicable to this subpart. However, the exemption at  46.101(b)(2) for research involving survey or interview procedures or observations of public behavior does not apply to research covered by this subpart, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed. Dated: March 29, 1991. Louis W. Sullivan, Secretary of Health and Human Services [FR Doc. 91-14262 Filed 6-17-91; 8:45 am] BILLING CODE 414O-01-M Editorial Note: This reprint incorporates a correction document published in the Federal Register of June 28, 1991. TAB 4 Research Ethics: Protection of Human Subjects -- Department of Health and Human Services (Title 45 Code of Federal Regulations Part 46) OPRR Reports PROTECTION OF HUMAN SUBJECTS TITLE 45 CODE OF FEDERAL REGULATIONS PART 46 REVISED JUNE 18, 1991 THE PUBLIC HEALTH SERVICE ACT AS AMENDED BY THE HEALTH RESEARCH EXTENSION ACT OF 1985 PUBLIC LAW 99-158 NOVEMBER 20, 1985 "INSTITUTIONAL REVIEW BOARDS: ETHICS GUIDANCE PROGRAM "SEC 491. (a) The Secretary shall by regulation require that each entity which applies for a grant, contract, or cooperative agreement under this Act for any project or program which involves the conduct of biomedical or behavioral research involving human subjects submit in or with its application for such grant, contract, or cooperative agreement assurances satisfactory to the Secretary that it has established (in accordance with regulations which the Secretary shall prescribe) a board (to be known as an 'Institutional Review Board') to review biomedical and behavioral research involving human subjects conducted at or supported by such entity in order to protect the rights of the human subjects of such research "(b)(1) The Secretary shall establish a program within the Department of Health and Human Services under which requests for clarification and guidance with respect to ethical issues raised in connection with biomedical or behavioral research involving human subjects are responded to promptly and appropriately. "(2) The Secretary shall establish a process for the prompt and appropriate response to information provided to the Director of NIH respecting incidence of violations of the rights of human subjects of research for which funds haven been made available under this Act. The process shall include procedures for the receiving of reports of such information from recipients of funds under this Act and taking appropriate action with respect to such violations "FETAL RESEARCH "SEC 498. (a) The Secretary may not conduct or support any research or experimentation, in the United States or in any other country, on a non viable living human fetus ex utero or a living human fetus ex utero for whom viability has not been ascertained unless the research or experimentation- "(1) may enhance the well-being or meet the health needs of the fetus or enhance the probability of its survival to viability; or "(2) will pose no added risk of suffering, injury, or death to the fetus and the purpose of the research or experimentation is the development of important biomedical knowledge which cannot be obtained by other means "(b) In administering the regulations for the protection of human research subjects which- "(1) apply to research conducted or supported by the Secretary: "(2) involve living human fetuses in utero: and "(3) are published in Section 46.208 of Part 46 of Title 45 of the Code of Federal Regulations; or any successor to such regulations. the Secretary shall require that the risk standard (published in Section 46.102(g) of such Part 46 or any successor to such regulations) be the same for fetuses which are intended to be aborted and fetuses which are intended to be carried to term. NOTE: Section 46.102(g) becomes Section 46.102(i) in Title 45 CFR Part 46 as revised on June 18, 1991. THE CODE OF FEDERAL REGULATIONS, TITLE 45 CFR PART 46, IMPLEMENTS THESE AMENDMENTS TO THE PUBLIC HEALTH SERVICE ACT CODE OF FEDERAL REGULATIONS TITLE 45 PUBLIC WELFARE DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH OFFICE FOR PROTECTION FROM RESEARCH RISKS GRAPHIC PART 46-PROTECTION OF HUMAN SUBJECTS Revised June 18, 1991 (Effective August 19, 1991) Page 4 45 CFR 46 PART 46-PROTECTION OF HUMAN SUBJECTS Subpart A-Federal Policy for the Protection of Human Subjects (Basic DHHS Policy for Protection of Human Research Subjects) Sec. 46.101 To what does this policy apply? 46.102 Definitions. 46.103 Assuring compliance with this policy-research conducted or supported by any Federal Department or Agency. 46.104 46.106 (Reserved] 46.107 IRB membership. 46.108 IRB functions and operations. 46.109 IRB review of research. 46.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. 46.111 Criteria for IRB approval of research. 46.112 Review by institution. 46.113 Suspension or termination of IRB approval of research. 46.114 Cooperative research. 46.115 IRB records. 46.116 General requirements for informed consent. 46.117 Documentation of informed consent. 46.118 Applications and proposals lacking definite plans for involvement of human subjects. 46.119 Research undertaken without the intention of involving human subjects. 46.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. 46.121 [Reserved] 46.122 Use of Federal funds. 46.123 Early termination of research support: Evaluation of applications and proposals. 46.124 Conditions. Subpart B-Additional DHHS Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization Sec. 46.201 Applicability. 46.202 Purpose. 46.203 Definitions. 46.204 Ethical Advisory Boards. 46.205 Additional duties of the Institutional Review Boards in connection with activities involving fetuses, pregnant women, or human invitro fertilization 46.206 General limitations. 46.207 Activities directed toward pregnant women as subjects. 46.208 Activities directed toward fetuses in utero as subjects. 46.209 Activities directed toward fetuses ex utero, including nonviable fetuses, as subjects. 46.210 Activities involving the dead fetus, fetal material, or the placenta. 46.211 Modification or waiver of specific requirement Subpart C-Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects. Sec. 46.301 Applicability. 46.302 Purpose. 46.303 Definitions. 46.304 Composition of Institutional Review Boards where prisoners are involved. 46.305 Additional duties of the Institutional Review Boards where prisoners are involved. 46.306 Permitted research involving prisoners. Subpart D-Additional DHHS Protections for Children Involved as Subjects in Research Sec. 46.401 To what do these regulations apply? 46.402 Definitions. 46.403 IRB duties. 46.404 Research not involving greater than minimal risk. 46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. 46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition. 46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. 46.408 Requirements for permission by parents or guardians and for assent by children. 46.409 Wards. Authority: 5 U.S.C. 301; Sec. 474(a), 88 Stat. 352 (42 U.S.C. 2891-3(a)). Note: As revised, Subpart A of the DHHS regulations incorporates the Common Rule (Federal Policy) for the protection of Human Subjects (56 FR 28003). Subpart D of the HHS regulations has been amended at Section 46.401(b) to reference the revised Subpart A. The Common Rule (Federal Policy) is also codified at 7 CFR Part 1c Department of Agriculture 10 CFR Part 745 Department of Energy 14 CFR Part 1230 National Aeronautics and Space Administration 15 CFR Part 27 Department of Commerce 16 CFR Part 1028 Consumer Product Safety Commission 22 CFR Part 225 International Development Cooperation Agency, Agency for International Development 24 CFR Part 00 Department of Housing and Urban Development 28 CFR Part 46 Department of Justice 32 CFR Part 219 Department of Defense 34 CFR Part 97 Department of Education 38 CFR Part 16 Department of Veterans Affairs 40 CFR Part 26 Environmental Protection Agency 45 CFR Part 690 National Science Foundation 49 CFR Part 11 Department of Transportation PART 46-PROTECTION OF HUMAN SUBJECTS Subpart A-Federal Policy for the Protection of Human Subjects (Basic DHHS Policy for Protection of Human Research Subjects) Source: 56 FR 28003, June 18, 1991. Sec. 46.101 To what does this policy apply? (a) Except as provided in paragraph b) of this section, this policy applies o all research involving human subjects conducted, supported or otherwise subject to regulation by any federal Department or Agency which takes appropriate administrative action to make the policy applicable to such research. This includes research conducted by Federal civilian employees or military personnel, except that each Department or agency head may adopt such procedural modifications as may be appropriate 45 CFR 46 Page 5 from an administrative standpoint. It also includes research conducted, supported, or otherwise subject to regulation by the Federal Government outside the United States (1) Research that is conducted or supported by a Federal Department or Agency, whether or not it is regulated as defined in  46.102(e), must comply with all sections of this policy. (2) Research that is neither conducted nor supported by a Federal Department or Agency but is subject to regulation as defined in  46.102(e) must be reviewed and approved, in compliance with  46.101,  46.102, and  46.107 through  46.117 of this policy, by an Institutional Review Board (IRB) that operates in accordance with the pertinent requirements of this policy. (b) Unless otherwise required by Department or Agency heads, research activities in which the only involvement of human subjects will b( in one or more of the following categories are exempt from this police (1) Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as (i) research on regular and special education instructional strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods. (2) Research involving the use of educational tests (cognitive, diagnostic aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless (i) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation. (3) Research involving the use of educational tests (cognitive, diagnostic aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (b)(2) of this section, if: (i) the human subjects are elected or appointed public officials or candidate for public office; or (ii) Federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter. (4) Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subject. (5) Research and demonstration projects which are conducted by or subject to the approval of Department or Agency heads, and which are designed to study evaluate, or otherwise examine: (i) Public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs. (6) Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture. (c) Department or Agency heads retain final judgment as to whether a particular activity is covered by this policy. (d) Department or Agency heads may require that specific research activities or classes of research activities conducted, supported, or otherwise subject to regulation by the Department or Agency but not otherwise covered by this policy, comply with some or all of the requirements of this policy. (e) Compliance with this policy requires compliance with pertinent Federal laws or regulations which provide additional protections for human subjects. (f) This policy does not affect any state or local laws or regulations which may otherwise be applicable and which provide additional protections for human subjects. (g) This policy does not affect any foreign laws or regulations which may otherwise be applicable and which provide additional protections to human subjects of research. (h) When research covered by this policy takes place in foreign countries, procedures normally followed in the foreign countries to protect human subjects may differ from those set forth in this policy. (An example is a foreign institution which complies with guidelines consistent with the World Medical Assembly Declaration (Declaration of Helsinki amended 1989) issued either by sovereign states or by an organization whose function for the protection of human research subjects is internationally recognized.) In these circumstances, if a Department or Agency head determines that the procedures prescribed by the institution afford protections that are at least equivalent to those provided in this policy. The Department or Agency head may approve the substitution of the foreign procedures in lieu of the procedural requirements provided in this policy Except when otherwise required by statute, Executive Order, or the Department or Agency head, notices of these actions as they occur will be published in the Federal Register or will be otherwise published as provided in Department or Agency procedures. (i) Unless otherwise required by law, Department or Agency heads may waive the applicability of some or all of the provisions of this policy to specific research activities or classes of research activities otherwise covered by this policy. Except when otherwise required by statute or Executive Order, the Department or Agency head shall forward advance notices of these actions to the Office for Protection from Research Risks, National Institutes of Health, Department of Health and Human Services (DHHS). and shall also publish them in the Federal Register or in such other manner as provided in Department or Agency procedures.1 1 Institutions with DHHS-approved assurance on file will abide by provisions of Title 45 CFR Part 46 Subparts A-D. Some of the other departments and agencies have incorporated all provisions of Title 45 CFR Part 46 into their policies and procedures as well. However, the exemptions at 45 CFR 46. 101(o) do not apply to research involving prisoners, fetuses, pregnant women, or human in vitro fertilization, Subparts B and C. The exemption at 45 CFR 46. 101(b)(2), for research involving survey or interview procedures or observation of public behavior, does not apply to research with children, Subpart D, except for research involving observations of public behavior when the investigator(s) do not participate in the activities being observed. Page 6 45 CFR 46  46.102 Definitions. (a) Department or Agency head means the head of any Federal Department or Agency and any other officer or employee of any Department or Agency to whom authority has been delegated. (b) Institution means any public or private entity or Agency (including Federal, State, and other agencies). (c) Legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research. (d) Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy. whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities. (e) Research subject to regulation, and similar terms are intended to encompass those research activities for which a Federal Department or Agency has specific responsibility for regulating as a research activity. (for example, Investigational New Drug requirements administered by the Food and Drug Administration). It does not include research activities which are incidentally regulated by a Federal Department or Agency solely as part of the Department's or Agency's broader responsibility to regulate certain types of activities whether research or non-research in nature (for example, Wage and Hour requirements administered by the Department of Labor). (f) Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes. Interaction includes communication or interpersonal contact between investigator and subject. Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place. and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects. (g)IRB means an Institutional Review Board established in accord with and for the purposes expressed in this policy. (h) IRB approval means the determination of the IRB that the research has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and Federal requirements. (i) Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. (j) Certification means the official notification by the institution to the supporting Department or Agency, in accordance with the requirements of this policy. that a research project or activity involving human subjects has been reviewed and approved by an IRB in accordance with an approved assurance.  46.103 Assuring compliance with this policy research conducted or supported by any Federal Department or Agency. (a) Each institution engaged in research which is covered by this policy and which is conducted or supported by a Federal Department or Agency shall provide written assurance satisfactory to the Department or Agency head that it will comply with the requirements set forth in this policy. In lieu of requiring submission of an assurance, individual Department or Agency heads shall accept the existence of a current assurance, appropriate for the research in question, on file with the Office "or Protection from Research Risers, National Institutes Health, DHHS, and approved for Federal-wide use by that office. When the existence of an DHHS.approved assurance is accepted in lieu of requiring submission of an assurance, reports (except certification) required by this policy to be made to Department and Agency heads shall also be made to the Office for Protection from Research Risks, National Institutes of Health DHHS. (b)Departments and agencies will conduct or support research covered by this policy only if the institution has an assurance approved as provided in this section, and only if the institution has certified to the Department or Agency head that the research has been reviewed and approved by an IRB provided for in the assurance, and will be subject to continuing review by the IRB. Assurances applicable to federally supported or conducted research shall at a minimum include: (1) A statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects of research conducted at or sponsored by the institution, regardless of whether the research is subject to Federal regulation. This may include an appropriate existing code, declaration, or statement of ethical principles, or a statement formulated by the institution itself. This requirement does not preempt provisions of this policy applicable to Department or Agency supported or regulated research and need not be 45 CFR 46 Page 7 applicable to any research exempted or waived under  46.101(b) or (i). (2) Designation of one or more IRBs established in accordance with the requirements of this policy, and for which provisions are made for meeting space and sufficient staff to support the IRB's review and recordkeeping duties. (3) A list of 1RB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions to IRB deliberations; and any employment or other relationship between each member and the institution; for example: full-time employee, part-time employee, member of governing panel or board. stockholder, paid or unpaid consultant. Changes in IRB membership shall be reported to the Department or Agency head, unless in accord with  46.103(a) of this policy, the existence of a DHHS- approved assurance is accepted. In this case, change in IRB membership shall be reported to the Office for Protection from Research Risks, National Institutes of Health, DHHS. (4) Written procedures which the IRB will follow (i) for conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution; (ii) for determining which projects require review more often than annually and which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review; and (iii) for ensuring prompt reporting to the IRB of proposed changes in a research activity. and for ensuring that such changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject. (5) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Department or Agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and (ii) any suspension or termination of IRB approval. (c) The assurance shall be executed by an individual authorized to act for the institution and to assume on behalf of the institution the obligations imposed by this policy and shall be filed in such form and manner as the Department or Agency head prescribes. (d) The Department or Agency head will evaluate all assurances submitted in accordance with this policy through such officers and employees of the Department or Agency and such experts or consultants engaged for this purpose as the Department or Agency head determines to be appropriate. The Department or Agency head's evaluation will take into consideration the adequacy of the proposed IRB in light of the anticipated scope of the institution's research activities and the types of subject populations likely to be involved, the appropriateness of the proposed initial and continuing review procedures in light of the probable risks, and the size and complexity of the institution. (e) On the basis of this evaluation, the Department or Agency head may approve or disapprove the assurance, or enter into negotiations to develop an approvable one. The Department or Agency head may limit the period during which any particular approved assurance or class of approved assurances shall remain effective or otherwise condition or restrict approval. (f) Certification is required when the research is supported by a Federal Department or Agency and not otherwise exempted or waived under  46.101 (b) or (i). An institution with an approved assurance shall certify that each application or proposal for research covered by the assurance and by  46.103 of this policy has been reviewed and approved by the IRB. Such certification must be submitted with the application or proposal or by such later date as may be prescribed by the Department or Agency to which the application or proposal is submitted. Under no condition shall research covered by  46. 103 of the policy be supported prior to receipt of the certification that the research has been reviewed and approved by the IRB. Institutions without an approved assurance covering the research shall certify within 30 days after receipt of a request for such a certification from the Department or Agency. that the application or proposal has been approved by the IRB. If the certification is not submitted within these time limits, the application or proposal may be returned to the institution. (Approved by the Office of Management and Budget under Control Number 9999-0020.) 46.104-46.106 [Reserved]  46.107 IRB membership. (a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. The IRB shall be sufficiently qualified through the experience and expertise of its members, and the diversity of the members, including consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel safeguarding the rights and welfare human subject. In addition to possessing the professional competence necessary to review specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects. (b) Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the institution's consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of gender. No IRB may consist entirely of members of one profession. (c) Each IRB shall include at least one member whose primary concerns are in scientific areas and at least one Page 8 45 CFR 46 member whose primary concerns are in nonscientific areas. (d) Each IRB shall include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution. (e) No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB. (f) An IRB may, in its discretion, invite individuals with competence in special areas to assist in the review of issues which require expertise beyond or in addition to that available on the IRB. These individuals may not vote with the IRB.  46.108 IRB functions and operations. In order to fulfill the requirements of this policy each IRB shall: (a) Follow written procedures in the same detail as described in  46. 103(b)(4) and to the extent required by  46. 103(b)(5). (b)Except when an expedited review procedure is used (see  46. 110), review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are a in non- scientific areas. In order for the research to be approved, it shall receive the approval of a majority of those members present at the meeting.  46.109 IRB review of research. (a) An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by this policy. (b) An IRB shall require that information given to subjects as part of an informed consent is in accordance with  46.116. The IRB may require that information, in addition to that specifically mentioned in  46.116, be given to the subjects when in the IRB's judgment the information would meaningfully add to the protection of the rights and welfare of subjects. (c) An IRB shall require documentation of informed consent or a may waive documentation in accordance with  46.117. (d) An IRB shall notify investigators and the institution in writing of its decision to approve or disapprove the proposed research activity, or of modifications required to secure IRB approval of the research activity. If the IRB decides to disapprove a research activity, it shall include in its written notification a statement of the reasons for its decision and give the investigator an opportunity to respond in person or in writing. (e) An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research (Approved by the Office of Management and Budget under Control Number 9999-0020) 46.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. (a) The Secretary, HHS, has established, and published as a Notice s the Federal Register, a list of a categories of research that may be reviewed by the IRB through an expedited review procedure. The list will be amended, as appropriate, after consultation with other departments and agencies, through periodic a republication by the Secretary, HHS, in the Federal Register. A copy of the list is available from the Office for Protection from Research Risks, National Institutes of Health, DHHS, Bethesda, Maryland 20892. (b) An IRB may use the expedited review procedure to review either or if both of the following: (1) some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk, (2) minor changes in previously approved research during the period (of one year or less) for which approval is authorized. Under an expedited review procedure, the review may be carried out by the IRB chairperson or by one or more experienced reviewers at designated by the chairperson from among members of the IRB. In reviewing the research, the reviewer as may exercise all of the authorities of the IRB except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the non- expedited procedure set forth in  46.108(b). (c) Each IRB which uses an expedited review procedure shall adopt a method for keeping all members advised of research proposals which have been approved under the procedure. (d) The Department or Agency head may restrict, suspend, terminate, or choose not to authorize an institution's or IRB's use of the expedited review procedure. 46.111 Criteria for IRB approval of research. (a) In order to approve research covered by this policy the IRB shall determine that all of the following requirements are satisfied: (1) Risks to subjects are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. (2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits than may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). The IRB should not consider possible long range effects of applying knowledge gained in the research (for example, the possible effects of the search on public policy) as among those research risks that fall within the purview of its responsibility. (3) Selection of subjects is equitable. In making this assessment the Iative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions to IRB deliberations; and any employment or other relationship between each member and the institution; for example: full-time employee, part-time employee, member of governing panel or board. stockholder, paid or unpaid consultant. Changes in IRB membership shall be reported to the Department or Agency head, unless in accord with  46.103(a) of this policy, the existence of a DHHS- approved assurance is accepted. In this case, change in IRB membership shall be reported to the Office for Protection from Research Risks, National Institutes of Health, DHHS. (4) Written procedures which the IRB will follow (i) for conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution; (ii) for determining which projects require review more often than annually and which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review; and (iii) for ensuring prompt reporting to the IRB of proposed changes in a research activity. and for ensuring that such changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject. (5) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Department or Agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and (ii) any suspension or termination of IRB approval. (c) The assurance shall be executed by an individual authorized to act for the institution and to assume on behalf of the institution the obligations imposed by this policy and shall be filed in such form and manner as the Department or Agency head prescribes. (d) The Department or Agency head will evaluate all assurances submitted in accordance with this policy through such officers and employees of the Department or Agency and such experts or consultants engaged for this purpose as the Department or Agency head determines to be appropriate. The Department or Agency head's evaluation will take into consideration the adequacy of the proposed IRB in light of the anticipated scope of the institution's research activities and the types of subject populations likely to be involved, the appropriateness of the proposed initial and continuing review procedures in light of the probable risks, and the size and complexity of the institution. (e) On the basis of this evaluation, the Department or Agency head may approve or disapprove the assurance, or enter into negotiations to develop an approvable one. The Department or Agency head may limit the period during which any particular approved assurance or class of approved assurances shall remain effective or otherwise condition or restrict approval. (f) Certification is required when the research is supported by a Federal Department or Agency and not otherwise exempted or waived under  46.101 (b) or (i). An institution with an approved assurance shall certify that each application or proposal for research covered by the assurance and by  46.103 of this policy has been reviewed and approved by the IRB. Such certification must be submitted with the application or proposal or by such later date as may be prescribed by the Department or Agency to which the application or proposal is submitted. Under no condition shall research covered by  46. 103 of the policy be supported prior to receipt of the certification that the research has been reviewed and approved by the IRB. Institutions without an approved assurance covering the research shall certify within 30 days after receipt of a request for such a certification from the Department or Agency. that the application or proposal has been approved by the IRB. If the certification is not submitted within these time limits, the application or proposal may be returned to the institution. (Approved by the Office of Management and Budget under Control Number 9999-0020.) 46.104-46.106 [Reserved]  46.107 IRB membership. (a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. The IRB shall be sufficiently qualified through the experience and expertise of its members, and the diversity of the members, including consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel safeguarding the rights and welfare human subject. In addition to possessing the professional competence necessary to review specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects. (b) Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the institution's consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of gender. No IRB may consist entirely of members of one profession. (c) Each IRB shall include at least one member whose primary concerns are in scientific areas and at least one Page 8 45 CFR 46 member whose primary concerns are in nonscientific areas. (d) Each IRB shall include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution. (e) No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB. (f) An IRB may, in its discretion, invite individuals with competence in special areas to assist in the review of issues which require expertise beyond or in addition to that available on the IRB. These individuals may not vote with the IRB.  46.108 IRB functions and operations. In order to fulfill the requirements of this policy each IRB shall: (a) Follow written procedures in the same detail as described in  46. 103(b)(4) and to the extent required by  46. 103(b)(5). (b)Except when an expedited review procedure is used (see  46. 110), review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are a in non- scientific areas. In order for the research to be approved, it shall receive the approval of a majority of those members present at the meeting.  46.109 IRB review of research. (a) An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by this policy. (b) An IRB shall require that information given to subjects as part of an informed consent is in accordance with  46.116. The IRB may require that information, in addition to that specifically mentioned in  46.116, be given to the subjects when in the IRB's judgment the information would meaningfully add to the protection of the rights and welfare of subjects. (c) An IRB shall require documentation of informed consent or a may waive documentation in accordance with  46.117. (d) An IRB shall notify investigators and the institution in writing of its decision to approve or disapprove the proposed research activity, or of modifications required to secure IRB approval of the research activity. If the IRB decides to disapprove a research activity, it shall include in its written notification a statement of the reasons for its decision and give the investigator an opportunity to respond in person or in writing. (e) An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research (Approved by the Office of Management and Budget under Control Number 9999-0020) 46.110 Expedited review procedures for certain kinds of research involving be carried out without the waiver or alteration. (d) An IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth in this section, or waive the requirements to obtain informed consent provided the IRB finds and documents that: (1) the research involves no more than minimal risk to the subjects; (2) the waiver or alteration will not diversely affect the rights and welfare of the subjects; (3) the research could not practicably be carried out without the waiver or alteration; and (4) whenever appropriate, the objects will be provided with additional pertinent information after participation. (e) The informed consent requirements in this policy are not intended to preempt any applicable Federal, State, or local laws which require additional information to be disclosed in order for informed consent to be legally effective. (f) Nothing in this policy is intended to limit the authority of a physician to provide emergency medical care, to the extent the physician is permitted to do so under applicable Federal, State, or local law. (Approved by the Office of Management and Budget under Control Number 9999-0020) 46.117 Documentation of informed consent. (a) Except as provided in paragraph (c) of this section. informed consent shall be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject's legally authorized representative. A copy shall be given to the person signing the form. (b) Except as provided in paragraph (c) of this section, the consent form may be either of the following: (1) A written consent document that embodies the elements of informed consent required by  46.116. This form may be read to the subject or the subject's legally authorized representative, but in any event, the investigator shall give either the subject or the representative adequate opportunity to read it before it is signed; or (2) A short form written consent document stating that the elements of informed consent required by  46.116 have been presented orally to the subject or the subject's legally authorized representative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subject or the representative. Only the short form itself is to be signed by the subject or the representative. However, the witness shall sign both the short form and a copy of the summary, and the person actually obtaining consent shall sign a copy of the summary. A copy of the summary shall be given to the subject or the representative, in addition to a copy of the short form. (c) An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds either: (1) That the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern; or (2) That the research presents no more than minimal risk of harm to subjects and involves no procedures which written consent is normally required outside of the research context. In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research. 45 CFR 46 Page 11 (Approved by the Office of Management vand Budget under Control Number 9999- 0020.)  46.118 Applications and proposals lacking definite plans for involvement of human subjects. Certain types of applications for grants, cooperative agreements, or contracts are submitted to departments or agencies with the knowledge that subjects may be involved within the period of support, but definite plans would not normally be set forth in the application or proposal. These include activities such as institutional type grants when selection of specific projects is the institution's responsibility; research training grants in which the activities involving subjects remain to be selected; and projects in which human subjects' involvement will depend upon completion of instruments, prior animal studies, or purification of compounds. These applications need not be reviewed by an IRB before an award may be made. However, except for research exempted or waived under  46.101 (b)or (i), no human subjects may be involved in any project supported by these awards until the project has been reviewed and approved by the IRB, as provided in this policy, and certification submitted, by the institution, to the Department or Agency.  46.119 Research undertaken without the intention of involving human subjects. In the event research is undertaken without the intention of involving human subjects, but it is later proposed to involve human subjects in the research, the research shall first be reviewed and approved by an IRB, as provided in this policy. a certification submitted, by the institution, to the Department or Agency. and final approval given to the proposed change by the Department or Agency.  46.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency. (a) The Department or Agency head will evaluate all applications and proposals involving human subjects submitted to the Department or Agency through such officers and employees of the Department or Agency and such experts and consultants as the Department or Agency head determines to be appropriate. This evaluation will take into consideration the risks to the subjects, the adequacy of protection against these risks, thc potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. (b) On the basis of this evaluation, the Department or Agency head may approve or disapprove the application or proposal, or enter into negotiations to develop an approvable one.  46.121 [Reserved]  46.122 Use of Federal funds. Federal funds administered by a Department or Agency may not be expended for research involving human subjects unless the requirements of this policy have been satisfied.  46.123 Early termination of research support: Evaluation of applications and proposals. (a) The Department or Agency head may require that Department or Agency support for any project be terminated or suspended in the manner prescribed in applicable program requirements, when the Department or Agency head finds an institution has materially failed to comply with the terms of this policy. (b)In making decisions about supporting or approving applications or proposals covered by this policy the Department or Agency head may take into account, in addition to all other eligibility requirements and program criteria, factors such as whether the applicant has been subject to a termination or suspension under paragraph (a) of this section and whether the applicant or the person or persons who would direct or has/have directed the scientific and technical aspects of an activity has/have, in the judgment of the Department or Agency head, materially failed to discharge responsibility for the protection of the rights and welfare of human subjects (whether or not the research was subject to Federal regulation).  46.124 Conditions. With respect to any research project or any class of research projects the Department or Agency head may impose additional conditions prior to or at the time of approval when in the judgment of the Department or Agency head additional conditions are necessary for the protection of human subjects. Subpart B-Additional DHHS Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization Source: 40 FR 33528, Aug. 8, 1975, 43 FR 1758, January Il, 1978; 43 FR 51559, November 3, 1978.  46.201 Applicability. (a) The regulations in this subpart are applicable to all Department of Health and Human Services grant and contracts supporting research, development, and related activity involving: (1) the fetus, (2) pregnant women, and (3) human in vitro fertilization. (b) Nothing in this subpart shall be construed as indicating that compliance with the procedures set forth herein will in any way render inapplicable pertinent State or local laws bearing upon activities covered by this subpart. (c) The requirements of this subpart are in addition to those imposed under the other subparts of this part.  46.202 Purpose. It is the purpose of this subpart to provide additional safeguards in reviewing activities to which this subpart is applicable to assure that they conform to appropriate ethical standards and relate to important societal needs.  46.203 Definitions. As used in this sub part: (a) "Secretary" means the Secretary of Health and Human Services and any other officer or employee of the Department of Health and Human Services (DHHS) to whom authority has been delegated. (b) "Pregnancy" encompasses the period of time from Page 12 45 CFR 46 confirmation of implantation (through any of the presumptive signs of pregnancy such as missed menses, or by a medically acceptable pregnancy test), until expulsion or extraction of the fetus. (c) "Fetus" means the product of conception from the time of implantation (as evidenced by any of the presumptive signs of pregnancy. such as missed menses, or a medically acceptable pregnancy test), until a determination is made, following expulsion or extraction of the fetus, that it is viable. (d) "Viable" as it pertains to the fetus means being able, after either spontaneous or induced delivery, to survive (given the benefit of available medical therapy) to the point of independently maintaining heart beat and respiration. The Secretary may from time to time, taking into account medical advances, publish in the Federal Register guidelines to assist in determining whether a fetus is viable for purposes of this subpart. If a fetus is viable after delivery, it is a premature infant. (e) "Nonviable fetus" means a fetus ex utero which, although living, is not viable. (f) "Dead fetus" means a fetus ex utero which exhibits neither heartbeat, spontaneous respiratory activity, spontaneous movement of voluntary muscles, nor pulsation of the umbilical cord (if still attached). (g) "In vitro fertilization" means any fertilization of human ova which occurs outside the body of a female, either through admixture of donor human sperm and ova or by any other means.  46.204 Ethical Advisory Boards. (a) One or more Ethical Advisory Boards shall be established by the Secretary. Members of these Board(s) shall be so selected that the Board(s) will be competent to deal with medical, legal, social, ethical, and related issues and may include, for example, research scientists, physicians, psychologists, sociologists, educators, lawyers, and ethicists, as well as representatives of the general public. No Board member may be a regular, full-time employee of the Department of Health and Human Services. (b) At the request of the Secretary, the Ethical Advisory Board shall render advice consistent with the policies and requirements of this part as to ethical issues, involving activities covered by this subpart, raised by individual applications or proposals. In addition, upon request by the Secretary, the Board shall render advice as to classes of applications or proposals and general policies, guidelines, and procedures. (c) A Board may establish, with the approval of the Secretary, classes of applications or proposals which: (1) must be submitted to the Board, or (2) need not be submitted to the Board. Where the Board so establishes a class of applications or proposals which must be submitted, no application or proposal within the class may be funded by the Department or any component thereof until the application or proposal has been reviewed by the Board and the Board has rendered advice as to its acceptability from an ethical standpoint. (d) No application or proposal involving human in vitro fertilization may be funded by the Department or any component thereof until the application or proposal has been reviewed by the Ethical Advisory Board and the Board has rendered advice as to its acceptability from an ethical standpoint. Sec. 46.205 Additional duties of the Institutional Review Boards in connection with activities involving fetuses, pregnant women, or human in vitro fertilization. (a) In addition to the responsibilities prescribed for Institutional Review Boards under Subpart A of this part, the applicant's or offeror's Board shall, with respect to activities covered by this subpart, carry out the following additional duties: (1) determine that all aspects of the activity meet the requirements of this subpart; (2) determine that adequate consideration has been given to the manner in which potential subjects will be selected, and adequate provision has been made by the applicant or offeror for monitoring the actual informed consent process (e.g., through such mechanisms, when appropriate, as participation by the Institutional Review Board or subject advocates in: (i) overseeing the actual process by which individual consents required by this subpart are secured either by approving induction of each individual into the activity or verifying, perhaps cough sampling, that approved procedures for induction of individuals into the activity are being followed, nd (ii) monitoring the progress of the activity and intervening as necessary trough such steps as visits to the activity site and continuing evaluation determine if any unanticipated risks have arisen); (3) carry out such other responsibilities as may be assigned by Secretary. (b) No award may be issued until the applicant or offeror has certified to the secretary that the Institutional Review Board has made the determinations required under paragraph (a) of this section and the Secretary has approved these determinations, as provided in  46.120 of Subpart A of this part. (c) Applicants or offerors seeking support for activities covered by this subpart must provide for the designation of an Institutional Review Board, subject to approval by the Secretary, where no such Board has been established under Subpart A of His part. 46.206 General limitations. (a) No activity to which this subpart applicable may be undertaken unless: (1) appropriate studies on animals and nonpregnant individuals have been completed (2) except where the purpose of the activity is to meet the health needs of the mother or the particular fetus, the risk to the fetus is minimal and, in all cases, is the least possible risk for achieving the objectives of the activity; (3) individuals engaged in the activity will have no part in: (i) any decisions as to the timing, method, and procedures used to terminate the regnancy, and (ii) determining the viability of the fetus at the termination of the pregnancy; and (4) no procedural changes which may cause greater than minimal risk to the fetus or the pregnant woman will be introduced into the procedure for terminating the pregnancy solely in the interest of the activity. (b) No inducements, monetary or otherwise, may be offered to terminate pregnancy for purposes of the activity. 45 CFR 46 Page 13 Source: 40 FR 33528, Aug. 8, 1975, as "amended at 40 FR 51638, Nov. 6, 1975. 46,207 Activities directed toward pregnant women as subjects. (a) No pregnant woman may be involved as a subject in an activity covered by this subpart unless: (1) the purpose of the activity is to meet the health needs of the mother and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or (2) the risk to the fetus is minimal. (b) An activity permitted under paragraph (a) of this section may be conducted only if the mother and father are legally competent and have given their informed consent after having been fully informed regarding possible impact on the fetus, except that the father's informed consent need not be secured if: (l) the purpose of the activity is to meet the health needs of the mother; (2) his identity or whereabouts cannot reasonably be ascertained; (3) he is not reasonably available; or (4) the pregnancy resulted from rape.  46.208 Activities directed toward fetuses in utero as subjects. (a) No fetus in utero may be involved as a subject in any activity covered by this subpart unless: (1) the purpose of the activity is to meet the health needs of the particular fetus and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or (2) the risk to the fetus imposed by the research is minimal and the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means. (b) An activity permitted under paragraph (a) of this section may be conducted only if the mother and father are legally competent and have given their informed consent, except that the father's consent need not be secured if: (1) his identity or whereabouts cannot reasonably be ascertained, (2) he is not reasonably available, or (3) the pregnancy resulted from rape.  46.209 Activities directed toward fetuses ex utero, including nonviable fetuses, as subjects. (a) Until it has been ascertained whether or not a fetus ex utero is viable, a fetus ex utero may not be involved as a subject in an activity covered by this subpart unless: (1) there will be no added risk to the fetus resulting from the activity, and he purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means, or (2) the purpose of the activity is to enhance the possibility of survival of the particular fetus to the point of viability. (b) No nonviable fetus may be involved as a subject in an activity covered by this subpart unless: (1) vital functions of the fetus will not be artificially maintained, (2) experimental activities which of themselves would terminate the heartbeat or respiration of the fetus will not be employed, and (3) the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means. (c) In the event the fetus ex utero is found to be viable, it may be included as a subject in the activity only to the extent permitted by and in accordance with the requirements of other subparts of this part. (d) An activity permitted under paragraph (a) or (b) of this section may be conducted only if the mother and father are legally competent and have given their informed consent, except that the father's informed consent need not be secured if: (1) his identity or whereabouts cannot reasonably be ascertained, (2) he is not reasonably available, or (3) the pregnancy resulted from rape.  46.210 Activities involving the dead fetus, fetal material, or the placenta. Activities involving the dead fetus, macerated fetal material, or cells, tissue, or organs excised from a dead fetus shall be conducted only in accordance with any applicable State or local laws regarding such activities.  46.211 Modification or waiver of specific requirements. Upon the request of an applicant or offeror (with the approval of its Institutional Review Board). the Secretary may modify or waive specific requirements of this subpart, with the approval of the Ethical Advisory Board after such opportunity for public comment as the Ethical Advisory Board considers appropriate in the particular instance. In making such decisions, the Secretary will consider whether the risks to the subject are so outweighed by the sum of the benefit to the subject and the importance of the knowledge to be gained as to warrant such modification or waiver and that such benefits cannot be gained except through a modification or waiver. Any such modifications or waivers will be published as notices in the Federal Register. Subpart C-Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Source: 43 FR 53655, Nov. 16. 1978.  46.301 Applicability. (a) The regulations in this subpart are applicable to all biomedical behavioral research conducted or supported by the Department of Health and Human Services involving prisoners as subjects. (b) Nothing in this subpart shall be construed as indicating that compliance with the procedures set forth herein will authorize research involving prisoners as subjects, to the extent such research is limited or barred by applicable State or local law. (c) The requirements of this subpart are in addition to those imposed under the other subparts of this part.  46.302 Purpose. Inasmuch as prisoners may be under constraints because of their incarceration which could affect their ability to make a truly voluntary and uncoerced decision whether or not to participate as subjects in research, it is the purpose of this subpart to provide additional safeguards for the protection of prisoners involved in activities to which this subpart is applicable.  46.303 Definitions. As used in this subpart: (a) "Secretary" means the Secretary of Health and Human Services and Page 14 45 CFR 46 any other officer or employee of the Department of Health and Human Services to whom authority has been delegated. (b)"DHHS" means the Department of Health and Human Services. (c) "Prisoner" means any individual, involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing. (d) "Minimal risk" is the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in he routine medical, dental, or psychological examination of healthy persons. 46.304 Composition of Institutional Review Boards where prisoners are involved. In addition to satisfying the requirements in  46.107 of this part, an Institutional Review Board, carrying out responsibilities under this part with respect to research covered by this subpart, shall also meet the following specific requirements: (a) A majority of the Board exclusive of prisoner members) shall have no association with the prison(s) involved, apart from their membership in the Board. (b) At least one member of the Board shall be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity, except that where a particular research project is reviewed by more than one Board only one board need satisfy this requirement. 46.305 Additional duties of the Institutional Review Boards where prisoners are involved. (a) In addition to all other responsibilities prescribed for Institutional Review Boards under this art, the Board shall review research covered by this subpart and approve such research only if it finds that: (1) the research under review represents one of the categories of research permissible under  46.306(a)(2); (2) any possible advantages accruing to the prisoner through his or her participation in the research, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, are not of such a magnitude that his or her ability to weigh the risks of the research against the value of such advantages in the limited choice environment of the prison is impaired; (3) the risks involved in the research are commensurate with risks that would be accepted by nonprisoner volunteers; (4) procedures for the selection of subjects within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners. Unless the principal investigator provides to the Board justification in writing for following some other procedures, control subjects must be selected randomly from the group of available prisoners who meet the characteristics needed for that particular research project; (5) the information is presented in language which is understandable to the subject population; (6) adequate assurance exists that parole boards will not take into account a prisoner's participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on his or her parole; and (7) where the Board finds there may be a need for follow-up examination or care of participants after the end of their participation, adequate provision has been made for such examination or care, taking into account the varying lengths of individual prisoners' sentences, and for informing participants of this fact. (b) The Board shall carry out such other duties as may be assigned by the Secretary. (c) The institution shall certify to the Secretary. in such form and manner as the Secretary may require, that the duties of the Board under this section have been fulfilled.  46.306 Permitted research involving prisoners. (a) Biomedical or behavioral research conducted or supported by DHHS may involve prisoners as subjects only if: (1) the institution responsible for the conduct of the research has certified to the Secretary that the Institutional Review Board has approved the research under  46.305 of this subpart; and (2) in the judgment of the Secretary the proposed research involves solely the following: (A) study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects; (B) study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects; (C) research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prison: than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) provided that the study may proceed only after the Secretary has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of his intent to approve such research; or (D) research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. In cases in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after the Secretary has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of the intent to approve such research. (b) Except as provided in paragraph (a) of this section, biomedical or behavioral research conducted or supported by DHHS shall not involve prisoners as subjects. 45 CFR 46 Page 15 Subpart D-Additional DHHS Protections for Children Involved as Subjects in Research. Source: 48 FR 9818, March 8, 1983; 56 FR 28032, June 18, 1991  46.401 To what do these regulation apply? (a) This subpart applies to all research involving children as subjects, conducted or supported by the Department of Health and Human Services. (1) This includes research conducted by Department employees, except than each head of an Operating Division or the Department may adopt such nonsubstantive, procedural modifications as may be appropriate from an administrative standpoint. (2) It also includes research conducted or supported by the Department of Health and Human Services outside the United States, but in appropriate circumstances, the Secretary may, under paragraph (e) of  46.101 of Subpart A, waive the applicability of some or all of the requirements of these regulations for research of this type. (b) Exemptions at  46.101(b)(1) and (b)(3) through (b)(6) are applicable to this subpart. The exemption at  46.101(b)(2) regarding educational tests is also applicable to this subpart. However, the exemption at  46.101(b)(2) for research involving survey or interview procedures or observations of public behavior does not apply to research covered by this subpart, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed. (c) The exceptions, additions, and provisions for waiver as they appear paragraphs (c) through (i) of  46.101 of Subpart A are applicable to this subpart. -46.402 Definitions. The definitions in  46. 102 of Subpart A shall be applicable to this subpart as well. In addition, as used if this subpart: (a) "Children" are persons who have not attached the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. (b) "Assent" means a child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent. (c) "Permission" means the agreement of parent(s) or guardian to the participation of their child or ward in research. (d) "Parent" means a child's biological or adoptive parent. (e) "Guardian" means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.  46.403 IRB duties. In addition to other responsibilities assigned to IRBs under this part, each IRB shall review research covered by this subpart and approve only research which satisfies the conditions of all applicable sections of this subpart.  46.404 Research not involving greater than minimal risk. DHHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in  46.408.  46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects. DHHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject's well-being, only if the IRB finds that: (a) the risk is justified by the anticipated benefit to the subjects; (b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and (c) adequate provisions are made, for soliciting the assent of the children and permission of their parents or guardians. as set forth in  46.408.  46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition. DHHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject, only if the IRB finds that: (a) the risk represents a minor increase over minimal risk; (b) the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; (c) the intervention or procedure is likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition; and (d) adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in  46.408.  46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. DHHS will conduct or fund research that the IRB does not believe meets the requirements of  46.404,  46.405, or  46.406 only if: (a) the IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and (b) the Secretary, after consultation with a panel of experts in pertinent Page 16 45 CFR 46 disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either: (1) that the research in fact satisfies the conditions of 46.404, 46.405, or 46.406, as applicable, or (2) the following: (i) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) the research will be conducted in accordance with sound ethical principles; (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in 46.408. 46.508 Requirements for permission by parents or guardians and for assent by children. (a) In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine that adequate provisions are made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent. In determining whether children are capable of assenting, the IRB shall take into account the ages, maturity, and psychological state of children involved. This judgment may be made for all children to be involved in research under a particular protocol, or for each child, as the IRB deems appropriate. If the IRB determines that the capability of some or all of the children is so limited the they cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research, the assent- of the children is not a necessary condition for proceeding with the research. Even where the IRB determines that the subjects are capable of assenting. the IRB may still waive the assent requirement under circumstances in which consent may be waived in accord with  46.116 of Subpart A. (b) In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine, in accordance with and to the extent that consent is required by  46.116 of Subpart A, that adequate provisions are made for soliciting the permission of each child's parents or guardian. Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for research to be conducted under  46.404 or  46.405. Where research is covered by  46.406 and  46.407 and permission is to be obtained from parents. both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child. (c) In addition to the provisions for waiver contained in  46.116 of Subpart A, if the IRB determines that a research protocol is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive the consent requirements in Subpart A of this part and paragraph (b) of this section. provided an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further that the waiver is not inconsistent with Federal, State, or local law. The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition. (d) Permission by parents or guardians shall be documented in accordance with and to the extent required by  46.117 of Subpart A. (e) When the IRB determines that assent is required, it shall also determine whether and how assent must be documented.  46.409 Wards. (a) Children who are wards of the State or any other agency. institution, or entity can be included in research approved under  46.406 or  46.407 only if such research is: (1) related to their status as wards; or (2) conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards. (b) If the research is approved under paragraph (a) of this section, the IRB shall require appointment of an advocate for each child who is a in addition to any other individual acting on behalf of the child as guardian or in loco parentis. One individual may serve as advocate for more than one child. The advocate shall be an individual who has the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child's participation in the research and who is not associated in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization. 45 CFR 46 Page 17 RESEARCH ACTIVITIES WHICH MAY BE REVIEWED THROUGH EXPEDITED REVIEW PROCEDURES Research activities involving no more than minimal risk and in which the only involvement of human subjects will lie in one or more of the following categories (carried out through standard methods) may be reviewed by the Institutional Review Board through the expedited review procedure authorized in  46.110 of 45 CFR Part 46. (1) Collection of: hair and nail clippings, in a nondisfiguring manner; deciduous teeth; and permanent teeth if patient care indicates a need for extraction. (2) Collection of excreta and external secretions including sweat, uncannulated saliva, placenta removed at delivery, and amniotic fluid at the time of rupture of the membrane prior to or during labor. (3) Recording of data from subjects 18 years of age or older using noninvasive procedures routinely employed in clinical practice. This includes the use of physical sensors that are applied either to the surface of the body or at a distance and do not involve input of matter or significant amounts of energy into the subject or an invasion of the subject's privacy. It also includes such procedures as weighing, testing sensory acuity, electrocardiography, electroencephalography, thermography, detection oil naturally occurring radioactivity, diagnostic echography, and electroretinography. It does not include exposure to electromagnetic radiation outside the visible range (for example, x-rays, microwaves). (4) Collection of blood samples by venipuncture, in amounts not exceeding 450 milliliters in an eight-week period and no more often than two times per week, from subjects 18 years of age or older and who are in good health and not pregnant. (5) Collection of both supra- and subgingival dental plaque and calculus, provided the procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques. research purposes such as investigations of speech defects. (7) Moderate exercise by healthy volunteers. (8) The study of existing data, documents, records, pathological specimens, or diagnostic specimens. (9) Research on individual or group behavior or characteristics of individuals, such as studies of perception, cognition, game theory, or test development, where the investigator does not manipulate subjects' behavior and the research will not involve stress to subjects. (10) Research on drugs or devices for which an investigational new drug exemption or an investigational device exemption is not required. Source: 46 FR 8392; January 26, 1981