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 G Staff Memorandum--Ethics Data Collection Follow-Up * * * * * STAFF MEMORANDUM * * * * * TO: Members of the Advisory Committee on Human Radiation Experiments FROM: Advisory Committee Staff DATE: July 15, 1994 RE: Ethics Data. Collection: Follow-Up Executive Summary The staff continues to review materials from various Federal agencies and other sources that are relevant to ethics policies and practices concerning ionizing radiation experiments-as well as human experimentation, generally. Below is an update on the status of our data collection efforts in this area, focusing in particular on newly acquired materials from the Department of Defense (DOD) and Atomic Energy Commission (AEC) on the need for human radiation experiments, policies regulating such research, implementation of such policies, and historical examples of various experiments. Several new points are brought out by these documents. - Documents from the debate on human experiments relating to Nuclear Energy Propulsion for Airplanes (NEPA) show recognition of the need for appropriate ethics guidelines by proponents of the project.(Refer in this memo to Section I below.) - Regulations applying to Army laboratories were applicable to Army contractors as well. (Section 3) - Liability concerns shaped early (1943) Navy release forms. Concern for patient autonomy did not appear in consent forms until later (1969 and beyond).(Section 4) - In rejecting a proposed experiment in 1953, the Bureau of Medicine and Surgery indicated that the Navy was not to conduct cancer research. The rejection document may raise questions about the likelihood, at least in 1953, that naval research presumed to be solely therapeutic would have been approved. (Section 5) - In response to an accidental exposure of a Japanese fishing boat to radiation fallout, a United States research team referred to the exposure as an accidental experiment with opportunity for the advancement of knowledge. (Section 6) 1 1. 1950 Nuclear Energy Propulsion for Airplane Medical Advisory Committee and Discussions of Need for Human Experimentation Gilbert Whittemore's article included in Briefing Book #4, "A Crystal Ball in the Shadows of Nuremberg and Hiroshima," discusses the Nuclear Energy Propulsion for Airplanes (NEPA) project at length. Two documents described below provide recommendations on the appropriate ethical standards to guide NEPA-related human experimentation. The April 3, 1949 Minutes of the NEPA Medical Advisory Committee on Radiation Tolerance of Military Personnel include the text of the its final report on human experimentation. (Attachment A, p. 3-5.) The function of the NEPA Medical Advisory Committee, according to this report, was "to establish what will happen to humans when necessarily exposed a infrequent times to amounts of radiation that are high relative to the dose set up as the maximum permissible daily (or weekly) dose for workers constantly working where radiation exposure is possible." (Attachment A, p. 3) To this end, .animal data were insufficient to accurately predict the effects of human exposures to radiation. The Medical Advisory Committee recommends that NEPA arrange for human experimentation to proceed in accordance with the 1946 Judicial Council of the American Medical Association principles, which call for voluntary consent, adequate animal models, and proper medical supervision. (Attachment A, p. 4.) The second document discussing ethical standards of NEPA-related human research, a January 31, 1950 paper by Robert S. Stone, M.D., was written upon teaming of the AEC's opposition to human experimentation in this context. (See "A Crystal Ball in the Shadows of Nuremberg and Hiroshima", p. 444, for additional context.) The document apparently formed the basis of a dialogue within the Office of the Secretary of Defense about conducting human experiments that would make it possible to predict the biological effects of radiation exposure. (Attachment B.) Stone was Professor of Radiology at the University of California at San Francisco and a member of the NEPA Medical Advisory Committee. Stone's 9-page paper is a systematic and scholarly defense of the proposition that human radiation testing is both necessary and ethical. The strategic grounds for the argument that such research was needed was formed not only by the nuclear propelled aircraft then being researched, but also by the prospect that soldiers and sailors will be exposed to radiation from weapons as a result of international hostilities. Stone proceeds to note that the use of human subjects in medical experiments is not new, citing Jenner's development of a small pox vaccine, Walter Reed's yellow fever work, the use of federal prisoners by the Public Health Service, and armed forces research on malaria with Illinois state prisoners. (Attachment B, p. 4.) In a section on "The Ethics of Human Experimentation," Stone cites Dr. Andrew Ivy's famous July 2, 1948 article in Science. Dr. Ivy, a medical ethics advisor to the Nuremberg judges, states in his article that the most important ethical requirement is that subjects are volunteers under no "undue pressure" to participate. (Attachment B, p. 5.) Stone also cites the American Medical Association's code of ethics, and the analysis published in JAMA, February 14 , 1948, of a committee appointed by Governor Dwight H. Green of Illinois (and chaired by Andrew Ivy) concerning the use of prisoners as experimental subjects. 2 (Attachment B, p. 5.) Stone concludes that the proposed radiation experiments meetall ethical criteria, and recommends that a subject population be identified that can be followed years after exposure: "Live prisoners are the one group of people that are likely to remain in one place where they can be observed for a great many years." (Attachment B, p. 7.) Other types of subjects were suitable to obtain short term results, particularly "[p]atients with incurable cancer such as those having multiple metastases" as well as certain scientists and some in the "general population." (Attachment B, p. 8.) Stone notes that in these cases, "the possibility of consistent controlled observation is the big handicap." (Attachment B, p. 8.) Individuals under the age of 21 should be ruled out because they lack the legal capacity to volunteer. Furthermore, "those before menopause (unless they have incurable cancer) probably should not be used because of psychological factors." (Attachment B, p. 9.) Stone's paper generated considerable reaction in the DOD and AEC during the months following. The Secretary of the NEPA:Medical Advisory Committee forwarded a copy of Stone's written defense to the Director of the Medical Services Division of the Office of the Secretary of Defense on March 22, 1950. (Attachment C.) An April 24, 1950 memorandum (prepared by Rear Admiral F. C. Greaves) from the Under Secretary of the Navy to the Secretary of Defense, states human subjects must be used to gain information concerning biological effects of radiation exposure, and endorses the procedures suggested by Stone in his paper, including the use of prisoners of "true volunteer status," as meeting "the requirements of accepted American standards for the use of human subjects for research purposes." (Attachment D, p. 1.) Additionally, an April 17, 1950 memorandum from C. F. Behrens, Director of the Atomic Defense Division in the Navy Bureau of Medicine and Surgery (BuMed), to the Deputy and Assistant Chief of the Navy BuMED indicates that the Research and Development Board panel on atomic warfare believes "human experiments are requisite." (Attachment E, p. 1.) We note that the Army in particular seemingly came down on both sides of the debate. In a May 3, 1950 memo from the Assistant Secretary of the Army to the Director of Medical Services of the Office of the Secretary of Defense, the Assistant Secretary argues that animal studies have made progress and should be continued, and reports that the Committee on Medical Sciences, Research and Development Board, (an advisory group to the Secretary of Defense,]did not support the views of the Joint Panel on Medical Aspects of Atomic Warfare (of the Research and Development Board]; at-its 11th meeting, the Committee "revoked its previous endorsement of the action of the Joint Panel on Atomic Warfare in approving the recommendations of the NEPA Medical Advisory Committee with regard to human experimentation, and voted to refer the matter back to the Joint Panel on Medical Aspects of Atomic Warfare for further consideration."(Attachment F, p. 1.) 3 Thus the Army recommends that "the proposed piece-meal experimentation at low levels of exposure to radiation injury not be undertaken" until further animal work had been done. (Attachment F, p. 2.) However, apparently in contrast with its May 3, 1950 statement as quoted above, the Army advanced a different position on November 10, 1950, when the Advisory Board of the Division of Biology and Medicine, AEC, met with representatives of the Armed Forces Surgeons General. The problem that was presented, especially by Navy representative Admiral Greaves, concerned "permissible exposure data if and when nuclear energy is used to provide the power in submarines and other ships." (Attachment G, p. 1.) General Cooney, representing the Army, noted the great discrepancy in permissible dosages when experts were canvassed in 1947 ranging from 25 r to 800 r. He therefore proposed "experimentation on a group of 200 service volunteers to determine the effects of operational effectiveness to dosages of total body radiation within presumably safe limits." (Attachment G, p. 2.) In his role as chairperson of the AEC's Advisory Board on Medicine and Biology, Dr. Shields Warren is on record (December 7, 1949) as opposed to NEPA proposals for human experimentation. (Attachment H.) His firm opposition to total body radiation experiments dates even earlier to a 1948 meeting of the NEPA Advisory Committee on Radiation Exposure of Military Personnel Subcommittee of the on the "Design of Human Radiation Problems," where he stated, "[I] will oppose human experimentation on whole body radiation done anywhere, (by] AEC or other[s]." (See "A Crystal Ball in the Shadows of Nuremberg and Hiroshima," p. 437.) Curiously, Dr. Warren is listed among the regular Advisory Committee members in attendance at the April 3, 1949 meeting of the Advisory Committee on Radiation Tolerance of Military Personnel who unanimously supported NEPA's use of human experiments (Attachment A). The minutes of this meeting do not include specific statements by Dr. Warren himself however. 2. 1966 AEC Policy on "Use of Human Volunteers in Biomedical Sciences" for a Project on Injection and Ingestion of Promethium and Plutonium A memorandum dated May 13, 1966 from Bertram H. Schur, AEC Associate General Counsel to Dr. Charles L. Dunham Director, Division of Biology and Medicine, characterizes AEC policy on the use of human subjects at that time. The letter was written in response to a contemplated new project involving "convicts, college students, and other individuals, twenty one years of age or older", who "will be invited to volunteer, and monetary compensation will be paid for their services. These individuals will ingest or be injected with promethium-147 or plutonium- 237." (Attachment I, p. 1.) The Associate General Counsel recommended that each volunteer sign a "written, witnessed agreement." (Attachment I, p. 1.) The memo stated: "Assuming complete understanding and no unequal bargaining factors (e.g. pressure on prisoners to submit), such an agreement would protect against liability for unauthorized invasion of the person." (Attachment I, 4 p. 2.) The staff has not found any evidence that the study, which was to have been conducted by the Hanford Occupational Health Program, was ever carried out. However, "Markey" experiment number 110, "Promethium administered in humans," was conducted in l967 for the AEC by the Hanford Environmental Health Foundation. Fourteen subjects drank fluids containing promethium-143. 3. Early Army efforts to implement Wilson Memo Documents recently received from the Department of Defense further extends our understanding of Army efforts to implement the Wilson Memo of February 26, 1953. For example, a memorandum dated November 5, 1953 from Secretary of the Army Stevens to his Chief of Staff shows Army compliance with its own June 30, 1953 order implementing the Wilson Memo. (Attachment J.) This memorandum also specifies that "the same basic principles and safeguards" that apply to AM laboratories must be observed by contractors. Further, the footnote on this memo evidences Secretary Stevens' particular concern, noted on previous documents, that a highly classified status will poorly serve the goals of the Department's policy on human subjects. A July 24, 1953 memorandum from the Chief of the Plans and Evaluation Office of the Army Chemical Center in Maryland to the Commanding Officer of that facility, by command of Brigadier General Creasy, refers to the June 30, 1953 Army order concerning the Wilson Memo. It requires a review of the current and planned use of volunteers in human experiments. (Attachment K.) A draft document from the Chemical Corps Medical Laboratories at the Army Medical Center in Maryland, "SOP for Procurement and Use of Military Volunteers" (undated but presumably 1953), suggests that a certain number of volunteers (20) were anticipated as needed each month at that facility. (Attachment L, p. 1.) Also attached is a draft of a Chemical Corps Medical Laboratories consent form. (Attachment M.) 4. Navy Consent and Release Forms, 1943-1980 A number of sample human subject release and consent forms, dated 1943 through 1980, illustrate a temporal shift in the Navy's interest in patient authorization from ensuring liability protection to respecting subject autonomy. The March 6, 1943 release form, drafted for a proposed study of influenza antiserum on prisoners in San Quentin, releases the government and researchers from any responsibility resulting from 5 the administration of any serum or virus by inhalation or injection into [the research subject] that the Naval Research Laboratory may desire and the performance upon [the research subject's] body of such experiments as they in their opinion may decide to be of advantage in promoting the research work they are doing. (Attachment N, p. 2.) Furthermore, the form requires prisoner-subjects to accept "that there are certain phases of this experiment which for good and sufficient reason cannot be disclosed to [them] in detail." (Attachment N, p. 2.) Ross McIntire, Chief of the Bureau of Medicine and Surgery (BuMed), rejected the influenza study for reasons of potential liability despite the strong language used in the release form. Four for this rejection are listed by McIntire on the accompanying memorandum: (1) the release form does not explicitly state what it releases; (2) the form fails to protect against the possibility of negligence; (3) harms from experimentation usually lead to the enactment of special legislative relief (although the staff knows of no precedent in 1943]; and (4) the influenza virus could communicated to individuals not involved in the study. (Attachment N, P. 1.) Unlike the 1943 form the April 28, 1969 "Consent to Participate Voluntarily in a Research, Development, Test, or Evaluation (RDT&E) Procedure" specifies that volunteering does not constitute a governmental release from any future liability. Instead, the 1969 form fulfills the purpose of recording subject informed consent. (Attachment 0.) By 1979 two additional features appear in Navy consent forms: subjects are guaranteed anonymity and the freedom to withdraw from the study without jeopardy to medical care. Also, because the research would be conducted on patients in a Cairo hospital, an Arabic translation of the consent provisions is included on the forms. (Attachment P, p. 4.) The consent form for the 1980 research project entitled "Diagnostic aids aboard submarines: biochemical evaluation of acute myocardial infarction" replaces the guarantee of subject anonymity with a statement explaining the protections of the Privacy Act. (Attachment P, p. 5.) Furthermore, a written record of "subject's inquiries and responses" is included with the 1980 protocol. (Attachment Q, p, 7.) 5. Example of a Rejected 1953 Navy Research Protocol and Justification A previously classified Navy memorandum from O.D. Yarbrough, Chief of the Bureau of Medicine and Surgery (BuMed) to the Chief of the Bureau of Aeronautics dated July 24, 1953, explains the rejection of a proposed study utilizing radioactive iron powder particles for radiation therapy of cancer tumors. (Attachment R) Yarbrough lists several technical reasons why the proposed study is scientifically unsound. Furthermore, he notes that "[i]n any event, studies of cancer are not considered to be in the province of the Medical Department of the Navy" and suggests that studies of this type be referred to the National Cancer Institute of the Public Health Service. (Attachment R, p. 1.) Yarbrough's statement appears to suggest a limit on Navy research designed to have purely therapeutic purposes. If so, then there may be an implication that at least some military purpose was a research criterion (in 1953). 6 6. The Fukuryu Maru No. 5 Incident During the Bikini island atomic bomb test on March 1, 1954, the Fukuryu Maru, a Japanese fishing boat, was accidentally exposed to radiation fallout. A Navy report by John J. Morton, Director of the Atomic Bomb Casualty Commission (ABCC), and Jack J. Lewis, Head of Medicine at the ABCC, describes the difficulties an American team of doctors had gaining access to the Japanese victims. (Segments of this report are included below.) Morton and Lewis blame the bad rapport on a "hysterical sensation-seeking" Japanese press and the Japanese doctors who feared that American doctors would take the data from the patients without crediting the Japanese investigators. Interestingly, the Japanese doctors explain to the public that the American request for access was denied because the Japanese patients were nervous and feared the Americans would use them "as guinea pigs." The report reveals the Cold War attitudes of two prominent American doctors on the connection between science and national security and the importance of any information regarding atomic medicine: The Japanese team by its obstinacy and desire for aggrandizement has irrevocably lost what may be very valuable data for the National Defense to the U.S., the islands of Japan, and the Free World. The field of atomic medicine is in its infancy. The gleaning of knowledge for its own sake becomes even more important because of the vast unknown. Accidentally an experiment was performed on 23 unfortunate men. Compassion must always be present, but for the advancement of man which occurs whenever a truly new segment of data is obtained, the loss of an expert evaluation in this experiment may well outweigh all other reasons for seeing those patients. 7 ATTACHMENTS Attachment A: Minutes of the Advisory Committee on Radiation Tolerance of Military Personnel, Carlton Hotel, Washington, D. C.,April 3, 1949 Attachment B: Paper by Robert S. Stone, M.D., January 31,1950, "Irradiation of Human Subjects as a Medical Experiment" Attachment C: NEPA Medical Advisory Committee letter to Dr. Richard L. Meiling, Director, Medical Services Division, Office of Secretary of Defense, March 22, 1950 Attachment D: Under Secretary of the Navy memorandum to the Secretary of Defense, April 24, 1950 Attachment E: C. F. Behrens, Director of the Atomic Defense Division memorandum to the Deputy and Assistant Chief of the Bureau, April 17, 1950 Attachment F: Assistant Secretary of the Army memorandum to Director of Medical Services, Office of the Secretary of Defense, May 3, 1950 Attachment G: Resume of the meeting with the Advisory Board of the Division of Biology and Medicine, Atomic Energy Commission, November 10, 1950 Attachment H: Series of correspondence regarding the AEC position on human experimentation, 1949-1953 Attachment I: Memorandum from Bertram H. Schur, AEC Associate General Counsel, to Dr. Charles L. Dunham, Director, Division of the Biology and Medicine, May 13, 1966 Attachment J: Secretary of the Army memorandum to the Chief of Staff, November 5, 1953 Attachment K: Chief of the Plans and Evaluation Office of the Army Chemical Center, Maryland memorandum to the Commanding Officer, July 24, 1953 Attachment L: Draft document from the Chemical Corps Medical Laboratories at the Army Medical Center in Maryland, "Research and Development Procedures: SOC for Procurement and Use of Military Volunteers" (undated, but presumably 1953) 8 Attachment M: Draft document, "Volunteer's Participation Agreement Form" Chemical Corps Medical Laboratories at the Army Medical Center in Maryland (undated) Attachment N: Memorandum from Ross T. McIntire, Chief of the Bureau of Medicine and Surgery, to officer-in-Charge of the Naval Laboratory Research Unit No.1 at the University of California, Berkeley, March 6, 1943 and attached "Preferred Form of Release" Attachment O: Navy sample form of "Consent to Participate Voluntarily in a Research, Development, Test, or Evaluation (RDT&E) Procedure," April 28, 1969 Attachment P: Naval research protocol documentation for "Rapid diagnosis and treatment of bacterial meningitis," including participant consent forms, October 10, 1979 Attachment Q: Application to and recommendations of the Navy Committee for Protection of Human Subjects including consent statement, November 15, 1980. Attachment R: Memorandum from Chief of the Bureau of Medicine and Surgery to the Chief of the Bureau of Aeronautics, July 24, 1953 9