DISCLAIMER The following is a staff memorandum or other working document prepared for the members of the Advisory Committee on Human Radiation Experiments. It should not be construed as representing the final conclusions of fact or interpretation of the issues. All staff memoranda are subject to revision based on further information and analysis. For conclusions and recommendations of the Advisory Committee, readers are advised to consult the Final Report to be published in 1995. TAB H-2 ----DRAFT - FOR DISCUSSION PURPOSES ONLY---- MEMORANDUM TO: Members of the Advisory Committee on Human Radiation Experiments FROM: Advisory Committee Staff DATE: January 18, 1995 RE: Current Policies and Practices for the Oversight of Human Subjects Protections in Six Federal Agencies (HHS, DOD, VA, DOE, NASA, and CIA) Advisory Committee staff has been gathering information on the human subjects research programs within the six Federal agencies under the purview of the Committee, particularly with respect to the status and oversight of the protections afforded human subjects through their various research programs. A separate memorandum at this Tab sets forth the history and provisions of the Common Rule. This memorandum provides an overview of the administrative structures and procedures to ensure compliance with human subjects protection rules that are currently employed by the six agencies. Beginning over the summer and continuing to the present, Advisory Committee staff asked each of the six agencies to provide information on the following: . the scope of its human subjects research programs . the organizational structure of its human subjects protection efforts and the resources devoted to such activities . the policy issuances and guidances pursuant to the Common Rule that the department or agency prepared and provided to subsidiary agencies and research institutions engaged in human subjects research . monitoring and enforcement activities of the provisions of the Common Rule . sanctions available for noncompliance . the existence of and rules governing classified research involving human subjects . the use or potential use of waivers to any of the provisions of the Common Rule In December, this survey of agency oversight activities in human subjects research was extended to the ten additional Federal agencies governed by the Common Rule. An analysis of the responses to this broader inquiry will be provided later. 1 The following sections summarize information regarding the status of administrative policies and oversight of human subjects research at the Department of Health and Human Services (HHS), the Food and Drug Administration (FDA), the Department of Defense (DOD), the Department of Energy (DOE), the National Aeronautics and Space Administration (NASA), the Department of Veterans Affairs (VA), and the Central Intelligence Agency (CIA). I. THE DEPARTMENT OF HEALTH AND HUMAN SERVICES A. Scope of Human Subjects Research Program HHS is the federal department with the largest presence in biomedical and behavioral research involving human subjects, with research activities conducted or supported in large part by the following agencies of the Public Health Service (a component of HHS): the National Institutes of Health (consisting of separate institutes), the Centers for Disease Control and Prevention, the Health Resources and Services Administration, the Indian Health Service, the Substance Abuse and Mental Health Services Administration, and the Food and Drug Administration. The Public Health Service accounts for over $4 billion of the Department's $6 billion in spending, annually, on research involving human subjects. HHS-supported behavioral research is conducted by other agencies of the Department including the Office of the Secretary, the Health Care Financing Administration, and the Office of Human Development Services. In addition to supporting a limited number of intramural and extramural research activities that involve human subjects, FDA regulates research conducted by private entities that is used in support of new drug, biologics and device applications. Because the statutory basis for FDA regulation of research on drugs and devices is separate and distinct from that for HHS-funded research, FDA rules and oversight practices differ and are discussed separately below. B. Authority for the Protection of Human Subjects Amendments to the Public Health Service Act in 1985 (Public Law 99-158) and in 1993 (Public Law 103-43) provide the current statutory basis for the human subjects protections afforded by HHS research programs. The Health Research Extension Act of 1985 directs the Secretary to require of each applicant for a grant, contract or cooperative agreement for any project or program involving human subjects, assurances that it has established an IRB to review such research in order to protect the rights of the subjects of the research. It further directs the Secretary to establish a program to respond to requests for guidance regarding ethical issues raised in the course of research and to establish a process for responding to information provided to the Director of NIH regarding violations of the rights of human subjects of research funded under the Act. The NIH Revitalization Act of 1993 added specificity to the requirements for IRB review by making IRB review and approval by a majority of IRB members a prerequisite to any HHS funding of the research. 2 C. Organizational Responsibility for Human Subjects Protections HHS oversight of human subjects protections for the research that it conducts or supports is the responsibility of the Office for the Protection from Research Risks (OPRR). OPRR develops and interprets the Department's policies on human subjects protections, provides guidelines for research institutions and IRBs, conducts workshops to educate IRB members and staff (four or five per year, involving 100 to 200 persons each), and negotiates and approves Assurances of Compliance (discussed below) with human subjects protections rules with research institutions. It also investigates claims of noncompliance with these rules. In addition, the Director of OPRR chairs the Interagency Human Subjects Coordinating Committee of the Federal Coordinating Council for Science, Engineering and Technology, under whose auspices the Common Rule was developed. OPRR has twelve staff members and an annual budget of approximately $1 million that is devoted specifically to human subjects protection. This can be compared with to the Department's annual spending on research involving human subjects, both intra- and extramural, of about $6 billion. In contrast, the congressionally mandated Office of Research Integrity, which is charged with assuring the ethical conduct of scientific research and presentation of research results (basically, to investigate cases of research fraud) has 38 staff members and an annual budget of $4 million. D. Policies and Practices in the Oversight of Human Subjects Research The written Assurances of Compliance that OPRR negotiates on behalf of the Secretary of HHS with instititutions (extramural research), including research facilities within HHS (intramural research), are the basic mechanisms for the enforcement of human subjects protections. An Assurance of Compliance commits an institution and its personnel to full adherence with the HHS human subjects protection regulation. The nation's largest research institutions have negotiated Multiple Project Assurances (MPAs) with OPRR. These Assurances can cover a comprehensive array of research activities involving human subjects and are generally in effect for a five-year period. As part of its assurance of compliance, a research institution is required to state the principles governing the institution's activities in the protection of the rights and welfare of human subjects. This statement of principles must govern all research conducted or supported by the institution, not just that which is federally funded. Ninety-three percent of all research institutions that have negotiated MPAs with OPRR have voluntarily agreed to extend the protections of the Common Rule to non-federally supported research as well. Approximately 420 institutions currently have 453 MPAs with OPRR. In addition, there are 2702 Single Project Assurances (SPAs) with HHS in effect, governing the conduct of human subjects research in smaller, newer, or primarily clinical settings, 1073 Cooperative Project Assurances, and 1436 Noninstitutional Investigator Agreements. Four full-time OPRR professionals are responsible for the solicitation and management of the more than 6000 Assurances of all kinds that are currently in effect. 3 Every application to HHS for a grant, contract or cooperative agreement is reviewed by the responsible sponsoring office and staff to ascertain whether human subjects are involved in the proposed research, to determine whether the applicant institution has received IRB approval for the proposed research, and to make an independent assessment of human subjects risks and protections. This evaluation is accomplished in conjunction with peer review for technical and scientific merit. Any concerns with the adequacy of human subjects protections or potential risks, or a need to review further documentation, such as the informed consent form itself, is noted in the summary statement on scientific merit and will become part of the application file. The proposal review group must notify OPRR if it has concerns regarding the use of human subjects, even in cases where the institution proposing the research has an MPA with OPRR. If the institution proposing the research does not have an MPA of the necessary scope on file with OPRR, then OPRR must approve an SPA with the institution before the research activity is funded. OPRR does not, however, review individual research protocols on a routine basis for compliance with human subject protections. Oversight of the conduct of human subjects research by OPRR once institutional Assurances of Compliance have been approved takes place only on an exceptions basis, that is, in cases where compliance questions or complaints have been raised or where adverse outcomes are reported to OPRR. OPRR does not routinely audit IRB records nor does it interview research subjects to ascertain that appropriate and effective informed consent procedures have been followed. It does, however, follow up on reports from institutions or investigators, complaints from research subjects, patients or the public, and on information forwarded from the FDA or other agencies. Such information may be about adverse outcomes within the context of research, or about incidents of noncompliance with regulations or with the terms of the particular institutional assurance or approved research protocol. Certain kinds of HHS-funded research are followed and reviewed more closely with regard to the experience of patient-participants. Cooperative Oncology Group (COG) research supported by the National Cancer Institute (a component of NIH) is monitored with on-site audits that include an evaluation of human subject protections. Some NIH-supported multi-center clinical trials are monitored by an independent Data and Safety Monitoring Board that assesses emerging data to ensure subject safety and the relative efficacy of alternative treatments. The outcomes data reviewed by Data and Safety Monitoring Boards might not, however, be readily accessible to IRBs nor to participating clinicians. These Boards are not directly accountable to those entities that are charged with the protection of human subjects, local IRBs or OPRR, for instance. Consequently the existence of Data and Safety Monitoring Boards may appear to provide more protection of research subjects than they actually do. IRBs are required not only to review and approve all proposed research involving human subjects in advance of its submission to a Federal agency, but also to conduct reviews during the course of the research at intervals appropriate to the degree of risk involved, but at least annually. OPRR currently is placing increased emphasis in its guidance to IRBs on the importance of continuing 4 reviews. As IRB workloads have grown, IRBs have increased membership and/or staff support. OPRR reports that as the number of members on an IRB has grown, the IRBs have tended to maintain the representational ratios predicated on the five-member minimum specified in the regulation. Thus, if an IRB has grown to ten members, it is likely to have two community representatives rather than one. OPRR estimates that about half of all reports of incidents or compliance issues that it receives for investigation are self-reports from the research institution, either by the investigator, the IRB, or other responsible official. OPRR has initiated investigations of 233 reports of potential noncompliance or problematic situations over the past five years and has completed 145 of these as of October 31, 1994. Also over the past five years, OPRR has reviewed an additional 424 reports, including 177 institutional incident reports, over 200 FDA audit reports, and 24 unsubstantiated allegations for which it has determined that no investigation was necessary. Most compliance oversight investigations are conducted through correspondence with the institution and do not require an on-site review. Complainants generally receive information about the outcome of OPRR's investigation. At the completion of an oversight investigation, OPRR's findings and report become publicly available. Once an investigation is completed, the final report of findings by OPRR becomes available under FOIA, along with related documents. In 1993, OPRR filled 32 FOIA requests related to human subjects protection compliance reviews and, in the first ten months of 1994, 45 such requests have been filled. Ordinarily there is no official announcement of a compliance review. E. Sanctions for Violation of Human Subjects Protections At any time during an investigation OPRR may suspend an institution's Assurance concerning some or all research activities. If this occurs, the affected research projects cannot be supported by any HHS component until an appropriate Assurance is again approved by OPRR. Other steps that OPRR might take consequently to a compliance investigation are: . requiring prior review of some or all research projects . requiring that investigators receive education in human subject protection . requiring special reporting to OPRR . recommending to appropriate HHS officials that an institution or an investigator be temporarily suspended or permanently removed from participation in specific projects . recommending to HHS that an institution or investigator be declared ineligible to participate in HHS-supported research (disbarment) F. Exceptions to the Common Rule The Secretary of HHS has authority to grant waivers from the requirements of the Department's human subjects protections regulation, including the requirements for informed consent. The single waiver to date of any provisions of the current regulation is from the requirement for local IRB review for the investigational 5 drug d4T, under the "Parallel Track" provision to expand the availability of investigational new drugs for AIDS/HIV patients.2 [Prior to the Common Rule, HHS issued a waiver from the provision of Subpart B of the HHS regulation (45 CFR 46) that prohibits research on fetuses of greater than minimal risk in order to approve a research project involving fetoscopy, a procedure promising substantial benefits.] Under this provision, persons with AIDS and HIV-related diseases who are not able to take standard therapy or for whom standard therapy is no longer effective, and who are unable to participate in ongoing controlled clinical trials, may be given promising investigational drugs. This "Parallel Track" mechanism is a particular instance of the FDA's Treatment Investigational New Drug policy, which provides for therapeutic use of investigational drugs for seriously ill patients or patients with life-threatening diseases for whom alternative therapies do not exist. The FDA has established a national human subject protections review panel, i.e., a national IRB, in the case of "Parallel Track" protocols because of the difficulties in arranging for local IRBs to oversee and approve the participation of clinical groups and individual practitioners not ordinarily involved in research. HHS considers granting a waiver of the local IRB requirement (for those projects receiving HHS financial support) on a protocol-specific basis. The related issue of a Secretarial waiver of informed consent for the use of an investigational drug and an investigational vaccine by DOD during Desert Storm under FDA rules is discussed below. G. Classified Research HHS neither conducts nor sponsors any classified research. Under the Common Rule, human subjects protections do not differ for classified and unclassified research. OPRR's guidelines do not specifically address the issue of IRB review of classified research or of informed consent within the context of classified research. II. THE FOOD AND DRUG ADMINISTRATION As a subagency of HHS, FDA is subject to the Common Rule for human subjects research that it conducts or financially supports. However, for human subjects research that is subject only to FDA regulation, separate rules under the statutory authority of the Food, Drug and Cosmetic Act apply. In some cases, both sets of regulatory requirements must be met. A. Authority for the Protection of Human Subjects The Food, Drug and Cosmetic Act directs FDA to ensure the protection of the rights, safety and welfare of human subjects who participate in clinical investigations of new drugs, biologics, and devices, and in clinical investigations that support applications for research or marketing permits for products regulated by FDA. 6 (Sections 505(i), 507(d) and 520(g) of the Act.) The regulations governing the conduct of human subjects research that FDA regulates but does not support financially are codified at volume 21, part 50 of the Code of Federal Regulations (CFR) (Protection of Human Subjects) and 21 CFR 56 (Institutional Review Boards). These regulations impose the same structural and functional requirements on IRBs as do the HHS regulations, but include several significantly different substantive provisions. Specifically, policies governing the use and documentation of waivers of informed consent differ, only FDA makes provision for a waiver of IRB review, and FDA does not use institutional Assurances of Compliance. B. Organizational Responsibility for Human Subjects Protections Each operational component of FDA (drugs, biologics, devices) has a Bioresearch Monitoring unit that is responsible for oversight of regulated human subjects research. C. Policies and Practices in the Oversight of Human Subjects Research FDA does not negotiate Assurances with IRBs. FDA's rationale, as presented in the Federal Register announcement of the Common Rule, is that "the increased administrative burdens" that would result from an assurance system geared to IRBs exclusively subject to FDA regulation would not be justified by the benefits, and that therefore FDA would instead continue to rely on its Biomedical Monitoring program, along with educational activities, to achieve IRB compliance. FDA audits IRBs routinely every five years, and reports any findings of noncompliance to OPRR for independent followup by that office as well, if the IRB in question holds an OPRR-approved Assurance. An FDA audit involves a site visit and a standardized review of the documentation maintained by the IRB. IRBs that have been found to have compliance violations are usually re-audited within a year's time. FDA provides IRBs with explicit instructions for the requirement that they conduct continuing (no less than annual) review of ongoing research. Continuing reviews must gather information on the number of subjects initiated into research, describe research subjects' experiences in terms of benefits, adverse effects and withdrawals from the project, report on research results and provide an updated risk-benefit assessment. At any time when unanticipated risks or information bearing on the risk-benefit assessment of the research are discovered, they must be reported to the IRB promptly. Any entity such as a pharmaceutical manufacturer or biotechnology firm that receives any financial support from a Federal agency under the Common Rule must also comply with those provisions as well as with FDA's rules. Practically speaking, this means negotiating an Assurance of Compliance with the funding agency, in addition to being subject to FDA's auditing; having the more restrictive of the two rules apply in the case of waivers of informed consent in emergency circumstances; and in the standards of informed consent for research conducted abroad. The FDA's standard on this latter issue is less flexible than the Common Rule, which allows the funding agency to make a determination that local procedures for consent are at least as stringent as those required by the Common Rule and thus to allow the 7 local procedures to be used instead. Section 56.105 of the FDA regulation provides for research sponsors and sponsor investigators to request a waiver from FDA of the requirement for IRB review of research, but not of the requirements for informed consent of subjects. This provision is intended for use "only where it would be in the best interest of the subjects and where alternative mechanisms for assuring the protection of the subjects are adequate," for example, in the case of treatment investigational new drugs (INDs) for persons with serious or life-threatening disease. (FDA information sheet, "Waiver of IRB Requirements," February 1989.) D. Sanctions for Violation of Human Subjects Protections The FDA also has distinctive sanctions against noncompliant IRBs and research institutions (Sections 56.120-124.) If IRBs and institutions refuse FDA access to IRB records for inspection, FDA may disqualify the evidence provided from a study in support of an application for an FDA research or marketing permit for a new drug or device. In the case of an audit of an IRB that is found to be in noncompliance with FDA regulations, FDA may . reinspect the institution to confirm that corrective measures have been taken . withhold approval of any new studies conducted by the institution or reviewed by the IRB . terminate ongoing studies . notify other State or Federal regulatory agencies or parties with a direct interest in FDA's action . disqualify the IRB or parent institution, which may entail a refusal to consider data from a clinical investigation offered in support of marketing permit E. Waivers from the Informed Consent Requirement A waiver of informed consent in the case of emergency experimental treatments (i.e., medical interventions under a research protocol) has been advocated by some medical specialty groups so that such treatments can be administered to patients unable to give consent, such as those unconscious with head trauma, spinal cord injury or stroke. The randomization of treatment alternatives according to a protocol under such conditions is one problematic aspect for both the FDA regulation and the Common Rule. FDA rules differ from the Common Rule in that they allow for a test article, that is, an investigational drug, biologic or device, to be administered on a one-time emergency basis without prior IRB approval as long as it is reported to the IRB within five days. This provision, however, did not anticipate a situation in which the experimental treatment would be repeated used without informed consent. Under the Common Rule, if a test article is used for emergency treatment without informed consent, data gathered or information resulting from that case cannot be used in any study or scientific report about the test article. 8 F. The FDA Waiver of Informed Consent Requirements for an Investigational New Drug (IND) and Vaccine during Operation Desert Shield/Storm On October 30, 1990, DOD petitioned the FDA to waive informed consent requirements for the use of several investigational new drugs and an investigational vaccine for use by combat troops in the Gulf War. On December 21, 1990, FDA promulgated an interim final regulation (Federal Register vol. 55, no. 246, p. 52814-17) that provided for the Commisssioner of FDA to determine that certain battlefield conditions warranted the emergency use of investigational products by troops without their prior informed consent and to grant a waiver from the requirement for informed consent. Ultimately the FDA granted waivers on pyridostigmine bromide, a drug licensed for another use, proposed as an adjunct agent in preventing nerve gas poisoning, and pentavalent botulinum-toxoid vaccine, whose use had been investigated for laboratory workers only. Both agents posed a special problem for investigation. Whereas the safety of each could be tested in humans, their efficacy in the uses proposed by DOD could only be extrapolated from animal testing. DOD made this waiver request under provisions of the FDA regulation allowing for emergency treatment use of investigational products. The interim rule made provision for the waiver of the FDA requirement for informed consent in the case of soldiers to whom the administration of investigational drugs is determined to be in their best interests, both individually and as members of a military unit, when it is not feasible to obtain informed consent. In the end, the vaccine was administered on a voluntary basis rather than under orders. Pyridostigmine was dispensed to troops with instructions for self-administration without informed consent and it was used by an estimated 41,650 soldiers. DOD did not view this request as one that sought an exception to standard research practices and human subjects protections and thus did not seek a waiver of informed consent procedures under the Common Rule. Nonetheless, the provision for FDA to waive its informed consent requirements is inextricably intertwined with the practices of human subjects research and protections. First, the interim final regulations require that an IRB review and approve DOD's request that FDA waive informed consent in the administration of an investigational product covered under this exception. This implicates that body which is constituted to protect the rights and welfare of persons involved in research in the decision to abrogate one of those rights. Second, the interim final regulations require that DOD collect information on the effects of the use of such investigational agents on the persons to whom they are administered, which constitutes, in effect, a retrospective study of the agent's efficacy, safety, and/or side effects. This further blurs the distinction between treatment and research. III. THE DEPARTMENT OF DEFENSE A. Scope of Human Subjects Research Program DOD conducts biomedical and behavioral research involving human subjects within each of its Services (Army, Navy and Air Force), and several additional defense agencies, the Uniformed Services University of the Health Sciences (USUHS), the Armed Forces Radiobiology Research 9 institute(AFRI), and the Defense Nuclear Agency (DNA). In addition to mission-specific research, DOD engages in research projects mandated by Congress, such as its women's health and breast cancer research programs. Clinical research involving patients that is sponsored by the three Services takes place only within military medical facilities. Some clinical research within DOD facilities is sponsored by other Federal agencies or by private entities. B. Authority for the Protection of Human Subjects A statutory basis for informed consent was provided by the Defense Department Authorization Act of 1985, which directs that: Funds appropriated to the Department of Defense may not be used for research involving a human being as an experimental subject unless-- (1) the informed consent of the subject is obtained in advance; or (2) in the case of research intended to be beneficial to the subject, the informed consent of the subject or a legal representative of the subject is obtained in advance. (10 U.S.C. 980) DOD has codified the Common Rule at 32 CFR 219. In addition, DOD directives require conformance with Subparts B, C, and D of the HHS regulation (45 CFR 46), which address research involving pregnant women, fetuses, and in vitro fertilization; prisoners; and children. C. Organizational Responsibility for Human Subjects Protections Responsibility for oversight of human subjects protections resides with the Director of Defense Research and Engineering. Operational oversight is delegated to the individual Services or Defense Agencies. Both research and development (R & D) projects with healthy volunteers and clinical investigation efforts involving patients come under the purview of the Services' Surgeons General. In all, DOD estimates a personnel effort of just over 100 full-time equivalents that is devoted to assurance and compliance activities for protecting human subjects. (From the April 11, 1994 letter from Harold P. Smith, Jr., Assistant to the Secretary of Defense to Senator John Glenn, Chairman, Committee on Governmental Affairs, responding to questions for the record posed at a January 25, 1994, hearing.) This includes staff resources devoted to review and documentation of human subjects protection activities (excluding those of IRBs themselves) at all levels of the Department. The clinical investigations program currently is intramural only. The primary responsibility for oversight of clinical research rests with each hospital commander whose facility sponsors a clinical investigation program. This oversight is exercised primarily through the Chief of the department of clinical investigation at each major teaching medical treatment facility, primarily hospitals. Medical monitors are appointed for each study that involves more than minimal risk, to assure the ongoing protection of human subjects involved in each project. Annual review of each protocol involving human 10 subjects by the Human Use Committee, the facility's IRB, is conducted according to the provisions of the Common Rule. Within DOD's biomedical R & D programs, the commanding offices of the medical research laboratories and institutes are ultimately responsible for local institutitonal oversight. More than 50 freestanding facilities may conduct or contract for research involving human subjects. The principal committees within each research institution for review of protocols for scientific merit and the adequacy of protections for human subjects are the Scientific Review and the Human Use Committees, this latter committee being the IRB. A locally assigned physician serves as a medical monitor for each protocol determined to be of greater than minimal risk, as determined by a duly convened Human Use Committee. Each of the three Services has in-house facilities as well as extramural biomedical R & D programs. Within the Army, the Medical Research, Development, Acquisition, and Logistics Command at Fort Detrick, Maryland, oversees protocol reviews for human subjects protections for all intramural and contract biomedical research. Within the Navy, both the Naval Medical Research and Development Command at the National Naval Medical Center, Bethesda, and the Office of Naval Research support human subject research activities. Each of these operations is responsible for oversight of human subjects protections for research that they conduct or sponsor under contract. The Air Force facility most heavily involved with human subjects research is Armstrong Laboratory, Brooks Air Force Base, Texas. Human subjects protection coordination among these facilities is provided by the Headquarters Air Force Medical Operations Agency, Office of the Surgeon General. Within the USUHS, its Research Administration coordinates the oversight and review of research protocols by the University's IRB. AFRI reports through the USUHS and thus has access to the University's IRB and other committees should any protocol be submitted that requires the participation of human subjects. DNA currently sponsors very little research involving human subjects. Two projects are ongoing and a third was recently concluded, all three conducted through the Services. Protocol review and project oversight occur through the offices of the participating Service. All human subjects research conducted by or sponsored extramurally by the DOD must be conducted by an institution with a current Project Assurance, either an MPA issued to the institution by OPRR, or an Assurance issued by a military Service or agency. For in-house research, the Director of Defense Research and Engineering has delegated responsibility for management and oversight of the issuance of Project Assurances to the Director, Office of Environmental and Life Sciences. This Office provides policy guidance and maintains information regarding the Project Assurances issued by the agencies and Services that conduct clinical and R & D projects. D. Policies and Practices in the Oversight of Human Subjects Research DOD reports that Service headquarters provide continuous monitoring and audit reviews of the 11 programs under their jurisdiction for compliance with human subjects protections. The Services conduct announced and unannounced site visits to facilities to evaluate program management and to determine compliance with regulations. Over the past three years, the Services have conducted approximately 180 site visits to facilities conducting research involving human subjects. Headquarters offices ensure that adequate records of all research protocols are maintained at the research facility, that approved informed consent forms have been used and maintained, that progress reports have been filed, and that minutes of IRB meetings are maintained. Annual audit reviews of research protocols involving human subjects are conducted by the sponsoring agency or Service. All reviews, audits and site visits are documented. Permanent records of such audits or reviews are maintained by the office conducting or directing the audit. A 1987 Memorandum of Understanding between DOD and FDA states that DOD will comply with FDA regulations on the clinical testing and use of investigational drugs, acknowledges the need for expeditious FDA review of products that are needed to accomplish DOD's mission, and makes special provisions for security in FDA's review of clinical testing within DOD that is classified for reasons of national security. E. Sanctions for Violations of Human Subjects Protections Sanctions for noncompliance include temporary or permanent withdrawal of financial support for a research project and, for intramural researchers, loss of investigator privileges. For military personnel potential sanctions include letters of reprimand, non-judicial punishment and other sanctions under the jurisdiction of military courts. Civilian personnel are subject to sanctions such as reprimands, suspension or termination of employment. F. Exceptions to the Common Rule (See the discussion under FDA of the waiver of informed consent during Desert Shield/Storm, above.) G. Classified Research No classified research involving human subjects is currently being funded by DOD. If classified human subject research were proposed, classified protocols would be reviewed by IRBs in one of two ways. In one case, the chair of the IRB may remove the classified portions of the protocol if he or she judges that those classified portions have no effect on the degree of risk to human subjects involved. Alternatively, the IRB may be constituted by persons with appropriate security clearances and who then review the protocol in its entirety. The Food and Drug Administration maintains security clearances for some personnel so that they may review classified DOD investigational new drug or device proposals. 12 It remains an open question whether, if a research project is classified and also requires a waiver from the Common Rule, OPRR or any other Federal agency would be informed, as required by the Common Rule. The additional provision of the Common Rule that any waiver be announced in the Federal Register would likely pose a problem for a classified research project. IV. THE DEPARTMENT OF VETERANS AFFAIRS A. Scope of Human Subjects Research Program VA operates 171 inpatient medical centers, including short-term hospitals, psychiatric and rehabilitation facilities, and nursing homes. It also operates a number of free-standing outpatient clinics. VA's biomedical research and development program focuses on the health care needs of veterans. This research is almost exclusively intramural, although in limited instances (e.g., at Congressional direction, or when an investigator needs specialized services) biomedical research is performed under contract. VA spends approximately $250 million annually in appropriated monies on research; an additional $110 million of VA clinicians' time is devoted to research. About $210 million (60 percent) of this research effort involves human subjects. Other federal agencies provide roughly $170 million annually for research in VA facilities, the majority of this in clinical research, and research amounting to an additional $100 million is conducted in VA facilities by private nonprofit and proprietary agencies, such as the American Heart Association and pharmaceutical firms. B. Authority for the Protection of Human Subjects The Common Rule is codified for VA at 38 CFR 16. VA has no statutory basis for human subjects protections. C. Policies and Practices in the Oversight of Human Subjects Research VA's appropriation funds approximately 2,000 investigators among its clinicians and facility-based researchers. About 12,000 discrete projects are conducted in VA facilities annually. A quarter of these projects are VA-funded, another quarter to a third are extramurally funded, and the remainder are conducted by VA personnel without specific research funding. All research associated with VA facilities or VA clinicians, whether or not it is explicitly funded, is subjected to the same local review, approval and documentation requirements. All human subjects research conducted in VA facilities or with VA monies is performed subject to the the provisions of the Common Rule. For the most part, individual medical facility staff members generate research proposals and submit them to institutionally based research and development committees. In some cases, however, research priorities are set by legislation, as in the case of HIV/AIDS research, alcoholism and drug 13 dependency, spinal cord injury, and post-traumatic stress disorders. Thus the generation and review of human subjects research projects within the VA is largely a bottom-up process. Individual VA medical institutions have Research and Development Committees that review investigator-initiated research proposals. These R & D Committees have Human Studies Subcommittees, which serve as the institutions' IRBs, and also Subcommittees on Safety, which address the use of hazardous materials and radiation safety, among other issues. There are about 140 Human Use Subcommittees in medical facilities throughout the VA system. Most VA hospitals are affiliated with a teaching hospital or university medical center. This affiliation may be with a medical or dental school, or a school of nursing. The IRB of an affiliated medical center may review human subjects research conducted in VA facilities if the VA facility does not have a Human Use Subcommittee or if the research is collaborative between the two institutions. If VA uses the IRB of an affiliated teaching institution, then at least one VA employee with scientific expertise must be represented on that Board in order to represent VA interests. Similarly, there are limits on the number of members of VA Human Use Subcommittees who may be from affiliated teaching institutions. Any research protocol involving human subjects must be reviewed and approved by the Human Studies Subcommittee before final review and approval by the full R&D Committee. After this institutional level review, those approved proposals that are requesting VA appropriated funds are submitted to the VA Central Office (VACO) for further review. Here a final merit review is conducted by one of sixteen categorical Merit Review Boards, composed predominantly of non-Federal scientists. (Ten to 15 scientists serve on a Board.) Research for which VA funding is sought may also be reviewed "off-station" by experts at other VA institutions before being submitted to VACO for Merit Board Review. Once a research project has begun, the local R & D Committee forwards annual reports to VACO, which maintains a comprehensive data base on all research conducted in VA facilities, irrespective of whether it is funded or unfunded, or of the source of funding. In addition, the minutes of all meetings of institutional R & D Committees are submitted to VACO and reviewed by staff or consultants. If there are questions or concerns about the involvement of human subjects in proposed or ongoing research that expert reviewers raise, the institutional committee is queried further. VACO does not routinely audit IRBs, but does inspect their records and procedures if there is reason for concern. Inspections are prompted, for example, when expert reviewers have questions about the safety or adequacy of human subjects protections after the local IRB has approved the research, or when adverse drug reactions occur, or when patients require care for adverse outcomes in the course of a study. In the case of large cooperative studies that include several hospitals (sometimes including institutions outside the VA system), participating VA facilities are paid site visits during which consent forms are reviewed and a sample of subjects is selected randomly for firsthand verification that consent procedures have been followed. The data from randomized trials are also closely monitored so 14 that any statistical differences that emerge in treatment outcomes can be detected quickly. The VA National Bioethics Committee is a 20-member advisory panel that meets twice yearly to advise the VA Chief Medical Director and his staff on ethical issues in clinical care, resource allocation, and biomedical research within VA facilities. In 1991 VA established the VA National Center for Clinical Ethics under contract with the clinical ethics group at the Veterans Affairs Medical Center in White River Junction, Vermont, to serve as staff to the Bioethics Committee and to enhance the quality of clinical ethics programs at VA medical centers. This National Center has, to date, worked mainly in areas other than human experimentation, instead focusing on clinical practice and resource allocation issues. The Center will likely become involved in issues entailed by human subjects research in VA facilities in the future. D. Sanctions for Violation of Human Subjects Protections The sanction for violating human subjects protection rules and procedures is withdrawal of support for the research. E. Exceptions to the Common Rule No exceptions to the Common Rule have been invoked by VA. F. Classified Research VA does not now conduct any classified research and does not have original classification authority. V. THE DEPARTMENT OF ENERGY A. Scope of Human Subjects Research Program The Department of Energy conducts and supports research involving human subjects that ranges from diagnostic and therapeutic applications in nuclear medicine to epidemiological and occupational health studies, both within the Deparment's own research facilities and elsewhere under grant and contract. DOE laboratories also receive funding from other Federal agencies such as NIH and from private sponsors of research. In fiscal year 1994, DOE supported 106 projects involving human subjects, 70 at DOE laboratories and 36 at other institutions. An additional 69 projects at DOE laboratories were funded by other agencies. DOE funding of human subjects research amounted to $46 million in this period, with an additional $10 million in support of projects at DOE laboratories coming from other agencies. One project alone, the Radiation Effects Research Foundation in Japan received $20.4 million in DOE funding. 15 B. Authority for the Protection of Human Subjects DOE has codified the Common Rule at 10 CFR 745. There is no statutory provision for human subjects protection within the DOE authority. C. Organizational Responsibility for Human Subjects Protections The Office of Health and Environmental Research (OHER) within the Office of Energy Research is responsible for formulating human subjects research policies and for ensuring Department-wide compliance with the Common Rule, regardless of the DOE agency or office that conducts or sponsors the research. DOE sponsorship and funding of research involving human subjects is dispersed in many offices, divisions and laboratories throughout the Department. D. Policies and Practices in the Oversight of Human Subjects Research All human subjects research that is financially supported by DOE is first reviewed for scientific merit by specialized external peer review committees. Proposals for research involving human subjects then undergoes in-house evaluation of merit and priority for funding. All DOE-funded research involving human subjects, whether intra- or extramural, must first be reviewed and approved by an IRB with a DOE or OPRR Assurance prior to receipt of funding. Work for others performed in DOE facilities is reviewed for scientific merit by the funding organization and for the adequacy of human subjects protections by the IRB of the facility in which it will be performed. Each of the approximately twenty National Laboratories operated by DOE (which account for about 90 percent of intramural human subjects research) has an IRB to review all research proposals involving human subjects that would be performed at the Laboratory. Two such Laboratories, Pacific Northwest and Los Alamos, have MPAs with DOE. Most of the others have MPAs through OPRR at NIH. A few conduct only a small number of studies involving human subjects each year and must apply for a Single Project Assurance (SPA) from DOE. DOE plans to renegotiate MPAs with its own laboratories every three to five years. In February 1994 DOE charged its externally constituted Health and Environmental Research Advisory Committee (HERAC) with the task of reviewing Departmental practices with respect to research involving human subjects under the Common Rule. This evaluation, conducted by a subcommittee of HERAC composed of physicians, ethicists and research scientists, addressed policies and performance both at the research institution and Departmental levels. The report of the subcommittee, Protection of Human Research Subjects, was transmitted to DOE May 27, 1994. In the course of their evaluation, this Subcommittee on the Protection of Human Subjects conducted site visits to eight DOE laboratories and research facilities. This set of site visits constitutes the first routine on-site audits of these institutions' IRBs and human subjects protection activities. DOE 16 has preliminary plans to conduct similar reviews of IRB activities at all DOE research installations over a three-year period and to continue such compliance reviews by "process improvement teams" (consisting of the person responsible for human subjects protections at DOE, a physician or research scientist, an ethicist, and a member of the field office or procurements staff) at all facilities on a three-year cycle thereafter. At the present time DOE investigates IRB activities only in response to reports of noncompliance or adverse outcomes. In brief, the Subcommittee reported the following findings and made related recommendations for IRB and Departmental reforms: . A written delegation of authority from the director of the research lab or facility to the IRB sufficient to allow the IRB to perform its duties was frequently missing. The Subcommittee recommended that IRBs have formal, documented delegation so that they can readily investigate problems and suspend or terminate approval of a protocol if such an action is contended. . IRB membership requirements sometimes were not met. The Subcommittee recommended that IRBs review their membership for adequate representativeness. . Continuing (annual) review of ongoing research often received inappropriate emphasis, sometimes too involved and other times too superficial. The Subcommittee recommended that IRBs should ensure full and substantive review of protocol renewals and document these reviews carefully. . Consent forms often contained little or no substantive information about the nature of the research and the risks involved. The Subcommittee recommended that all information conveyed in the consent process be in writing and in language understandable by subjects. . Minutes of IRB meetings were often superficial and failed to note the items of information required by the Common Rule. Evidence of communications between IRBs and investigators about proposals under consideration was often absent. The Subcommittee recommended that IRBs follow regulatory requirements on these various kinds of documentation scrupulously. . The Subcommittee recommended that DOE conduct regular audits of IRB performance in DOE facilities, including random sampling of patient records and signed consent forms, analogous to those audits performed by FDA. It further recommended that the DOE research facilities be required to submit to DOE headquarters a copy of all FDA reports of IRB audits. . The Subcommittee recommended that research in DOE facilities that is supported by 17 outside sources be reviewed by DOE for its compatibility with the mission of the Department. This review would not take place as part of human subjects protection activities, however. . Finally, the Subcommittee recommended that, in the case of the Lawrence Berkeley Laboratory, the relationship between the Laboratory's small review panel and the IRB of the University of California at Berkeley be revised. The Laboratory's panel had been screening proposals before submitting them to the IRB at UC. DOE has accepted all of the above recommendations and has plans to put them into effect except for the last one regarding Lawrence Berkeley Laboratory (LBL). (These are DRAFT DOE responses.) In this case DOE asserts that the arrangement that will best protect human subjects is for continued shared review of the Laboratory's human subjects research at UC Berkeley, with strengthened LBL participation. E. Sanctions for Violation of Human Subjects Protections IRBs may suspend or terminate their approval of research that is not conducted according the IRB's requirements, as provided under the authority of the Common Rule. DOE may suspend or terminate funding for any project found to be in noncompliance with the Rule. An institution's or investigator's prior performance with respect to human subjects protections may affect future DOE funding and, where there has been a willful violation of the regulation, the organization or individual may be disbarred from receiving Federal funds. F. Exceptions to the Common Rule DOE has not invoked nor has plans to invoke a Secretarial waiver from the requirements of the Common Rule, including informed consent requirements, for any research involving human subjects for any reason. G. Classified Research DOE conducts or supports a small number of classified research projects each year. No human subjects research project conducted at or supported by DOE is classified, although there may be linkages between unclassified research projects involving human subjects and other classified research. Any research involving subjects must meet the same requirements for informed consent and IRB review and approval as do other projects. Such review may take either of two forms. If the chairman of the IRB determines that no classified information is relevant to the protection of human subjects and that the research will be accurately and fully described to the IRB, the proposed research is reviewed at a regular IRB meeting without disclosure of any classified information. If the proposed research cannot be reviewed under the usual conditions, it must be reviewed by the IRB meeting in a 18 secure environment. To date, this has not been necessary. As required by the Common Rule, a majority of the IRB, including at least one member who is not a scientist, must be present. Each member of the IRB must have the appropriate security clearance. A community member will not participate unless properly cleared. DOE guidelines to IRBs urge those IRBs that regularly review classified research to obtain clearance for the community IRB member. An unresolved, problematic issue that remains for classified research is the adequacy and integrity of the process for obtaining informed consent. The IRB is responsible for the judgment that the prospective research subject will be adequately informed about the nature of the research in the case that it is classified and some aspects of it will not be disclosed in the informed consent process. There is a potential for bias in an institutionally based Review Board's determination that some aspect of a classified research project, if only the identity of the research sponsor, is irrelevant to the process of obtaining a subject's genuinely informed consent to participation. VI. THE NATIONAL AERONAUTICS AND SPACE ADMINISTRATION A. Scope of Human Subjects Research Program NASA conducts ground-based and flight research involving human subjects related to space life and the biomedical sciences more generally. Management and oversight of human subject research within NASA lies with the Division of Life and Biomedical Sciences and Applications. Human subjects research conducted or supported by NASA amounts to between $10 and $11 million per year, divided roughly equally between intramural and extramural research centers. The three NASA field centers that have conducted research involving human subjects are Ames Research Center, Johnson Space Center and the Kennedy Space Center. Johnson Space Center, because of its program of manned space flights, has by far the greatest involvement with human subjects research. Kennedy Space Center stopped conducting research involving human subjects a few years ago, when NASA consolidated its various research functions. B. Authority for the Protection of Human Subjects In 1986, NASA revised its 1972 policy governing the use of human subjects in research to conform with what was then the proposed model Federal policy for the protection of research subjects [NASA Management Instruction (NMI) 7100.8A] The NMI applies to NASA Headquarters and Field Installations and all extramural research in which NASA is involved to any degree. Only in 1986 did human subjects protections become applicable to NASA-supported extramural research as well as to in-house research. The Common Rule is codified by NASA at 14 CFR 1230. The NMI is now under revision to bring it up to date with the 1991 regulation and NASA expects to publish it shortly. NASA has convened a Bioethics Task Force to review and provide recommendations on the content 19 of the draft NMI, and to strengthen NASA's human subjects protections practices overall.[ The NASA Bioethics Task Force members consists of six members, representing professional expertise in medical and behavioral research, bioethics, and health policy. ] C. Organizational Responsibility for Human Subjects Protections Within each field center the Human Research Policy and Procedures Committee (HRPPC), i.e., the center's IRB, reviews not only the research conducted at or by that center (including pre-flight, inflight, and post-flight studies,) but also extramural human subjects research that involves NASA in any way. Such extramural research sponsored by NASA must be approved by a local OPRR-assured IRB and then must undergo HRPPC review at the relevant field center as well. Local IRB approval is required for a research proposal prior to its scientific review, first within NASA and then by extramural peers, organized by the American Institutes of Biological Sciences. D. Policies and Practices in the Oversight of Human Subjects Research Biomedical studies conducted in space undergo a more rigorous review process because of special risks and the subjects' involvement in a mission, with an obvious tension existing between voluntary participation in human subject research and job performance in manned space flight. The HRPPC reviews two types of protocols for a given space-based study, Master and Training. A Master Protocol consists of a detailed description of all aspects of the study. It is the first document to be submitted to the HRPPC for approval. The Training Protocol consists of a detailed description of the activities of a specific training tour, which is conducted prior to a space flight and serves as a "dry run" of the proposed space-based experiments and studies, and usually pertains only to Spacelab investigators. It will include objectives of the specific tour as well as a daily schedule of the training procedures and equipment to be used. At least six weeks before a training tour, the investigator must provide the HRPPC with the Training Protocol to be used in the tour so that there is adequate time for its consideration. No crew training or ground-based study may begin unless a Master Protocol has received original approval, the detailed procedures have been approved six weeks prior to a training tour, and consent forms have been obtained from the subjects and filed with the HRPPC. In addition to HRPPC review and approval at the field center originating the proposed research, Johnson Space Center's HRPPC reviews all proposals for research involving human subjects to be conducted in space. E. Sanctions for Violation of Human Subjects Protections NASA's sanctions for noncompliance with the requirements of the Common Rule are suspension or termination of support for the research project in question. 20 F. Exceptions to the Common Rule NASA ethics policies of the late sixties and early seventies waived human subjects protections in the case of tests, experiments or other evaluative procedures [i]nvolving as a human subject a specially trained adult who knowingly follows a specialized calling or occupation generally recognized as hazardous, and for whom the test, experiment or evaluative procedure forms an integral part of his calling or occupational performance. For example, a test, experiment or evaluative procedure concerning air or space flight and involving a test pilot or astronaut ordinarily would fall within this exception. However, if a test pilot or astronaut is asked to serve as a human subject in an experiment requiring, for example, cardiac catheterization, the human research could not reasonably be considered as within the scope of his specialized calling or occupation. (NASA Management Instruction 7100.8, 2/2/72) No such explicit waiver or exemption exists in the current NASA policy. The draft NMI takes into account the special circumstances under which space flight personnel are engaged as research subjects by requiring detailed protocols well in advance of flight-based studies so that the participants' considered consent can be gained ahead of time. It also makes provision for flight personnel to decline to participate in a proposed study under some circumstances that will not prejudice decisions about the subject's participation in the flight. There is ongoing discussion within NASA with regard to the problem of studies involving space flight personnel and the explicit requirement of the Common Rule that subjects be free to withdraw from the experiment at any time. Because flight personnel function within a highly structured environment and with fellow crew members with interdependent regimens, the ability to withdraw from an experiment at any time may not be possible. G. Classified Research NASA currently conducts no classified research that involves human subjects, and has not in the past. (NASA is confirming this latter claim.) NASA does have classification authority and conducts some classified research that does not involve human subjects. VII. THE CENTRAL INTELLIGENCE AGENCY A. Scope of Human Subjects Research Program The CIA supports or conducts a small number of research studies involving human subjects each year. B. Authority for the Protection of Human Subjects Executive Order 12333, Section 2.10, issued December 4, 1981, directs the CIA to follow HHS guidelines in the conduct or sponsorship of any research involving human subjects. CIA Headquarters Regulation 7-1a (6) (c) further specifies that the requirements for approval of 21 human subjects research by the CIA's Human Subject Research Panel (HSRP) are those codified at 45 CFR 46, the HHS codification of the Common Rule plus Subparts B, C, and D, which provide additional protections to special populations. C. Organizational Responsibility for Human Subjects Protections The Director of Central Intelligence must personally approve all research involving human subjects. The HSRP is responsible for reviewing and certifying to the Director that the research proposal is in conformance with the HHS rules. For extramural research, the HSRP acts as an oversight body for the local IRB. For intramural research, the HSRP acts as the IRB for the Agency. Currently, the HSRP is composed of CIA employees only. The chair is a senior physician with the Office of Medical services, and other members are representatives from the Directorates of Operations, Intelligence, Science and Technology. A non-voting representative of Office of the General Counsel must attend all HSRP meetings to provide legal advice. According to the CIA's regulation, the HSRP may include outside experts and consultants. D. Policies and Practices in the Oversight of Human Subjects Research Proposals for research may originate with any operational unit but are usually coordinated by the Office of Research and Development. A submission to the HSRP consists of a description of the research proposal, a statement of work, a letter of assurance from an IRB that the research proposed is in compliance with the institution's policy and with Federal and state laws (if the proposed research is extramural), and a copy of the consent form. The HSRP meets to review the proposal and the consent form. The agency officer coordinating the research application attends the meeting, describes the proposal, and provides information on the purpose, mechanics, and risks and benefits of the study. This officer conveys HSRP questions, comments and recommendations to the researcher proposing to conduct the study. The HSRP must unanimously agree that the informed consent process for a project is completely adequate in order to approve the project. The CIA contracting technical representative (not necessarily the person who serves as liaison between the HSRB and the investigator during the initial proposal review) is responsible for monitoring the progress of the research. This contracting technical representative is responsible for reporting any adverse effects of the research to the Office of Medical Services and the Office of General Counsel. E. Exceptions to the Common Rule The CIA reports that all CIA-funded research since the HSRP was formed in 1982 has conformed to the requirements of the HHS regulations. 22 F. Classified Research Classified research is subject to the same requirements for human subjects protection as unclassified research. CIA claims that it is able to inform human subjects of the specific nature of the study in which they are participating, including that the CIA is the research sponsor, even if the general purposes of the research are classified. CIA also claims that, since the formation of the HSRP, the sponsorship of the CIA is publicly acknowledged in all extramural research. 23