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 F-1 MEMORANDUM TO: Members of the Advisory Committee on Human Radiation Experiments FROM: Advisory Committee Staff DATE: January 10, 1995 RE: Atomic Energy Commission Ethics Policies (1947-1956), Applicability of AEC Policies to Other Government Agencies, and "Multiple Purpose" Research I. INTRODUCTION At its December meeting, the Advisory Committee asked the staff to address three issues: First, the nature of Atomic Energy Commission (AEC) policies concerning the use of human subjects in AEC-sponsored experiments during the period 1947-1956. Second, whether the Department of Defense (DOD) Wilson Memorandumapplied in instances where research was intended to address both questions related to atomic warfare and questions related to the prevention or treatment of disease (so called dual or multiple purpose research). . Third, whether standards found at AEC and/or DOD should be deemed to apply to other government agencies. The position put forward by the staff for consideration of the Committee can be summarized as follows: The absence of formal and systematic implementation of the statements in General Manager Wilson's 1947 letters is not simply disturbing; it is in part the Committee's raison d'etre. However, the statements were (1) indeed made by and on behalf of high and responsible AEC officials; (2) based on consultation with key biomedical advisors, (3) not countermanded, and (4) made when the AEC was embarking on the promotion of a biomedical research program that it hoped would take hold throughout the country, indeed the free world. In this context, any failure to implement should be read as a failure of policy rather than its absence. We therefore propose that (l) from its 1947 creation high level AEC officials articulated standards that, with the exception of subject selection, address all the analytical elements; and (2) these policies addressed the use of healthy subjects and the use of patient-subjects without any anticipated medical benefit for them. The question of therapeutic intent -- whether a doctor's intention to benefit a patient determines that an intervention is not an experiment -- was not answered. We then propose that the standards set by the AEC should be applied to all human radiation sponsored or conducted by the government. We base this proposition on four points. First, the standards articulated by the AEC were standards articulated by the agency with the most direct and compelling need to focus on the question of the ethics of radiation research. Second, as 1 noted above, the AEC was simultaneously embarking on the vigorous promotion of the use of AEC-produced isotopes in research. While, of course, it hoped that this program would result in major research advances , it also saw this program as the leading edge in the possible promotion of the benefits of nuclear knowledge, and of the AEC's further programs. Thus, the AEC, having determined to put radiation research into the nooks and crannies of research communities, had a moral responsibility for declaring and enacting the needed standards. On this context, the failure to enact the standards cannot be excused on grounds that no policy was existent; policy was required and articulated. Third, the AEC biomedical community was quite closely intertwined with the radiation research communities sponsored by the other agencies, as in the case of planning for the nuclear powered aircraft, for field testing of nuclear weapons, and in cancer research. Finally, we believe that the country would expect that its ethical standards be set at the highest, rather than the lowest, common denominator. As we will show, this is not a matter of applying current moral categories to past behavior, for these standards were articulated at the highest levels during the period in question. There is arguably one caveat to the AEC standards. It might be said that they do not expressly address the dimensions of ethical obligations where research is conducted in a setting of secrecy, and on behalf of national security ends. These considerations, however, were obviously present when the DOD adopted the Wilson Memorandum in 1953. Indeed, the 1953 code was adopted expressly to deal with research related to chemical, biological, and atomic warfare. Thus the DOD's adoption of the Nuremberg Code, as a complement to the AEC's standards, should set a standard where a balance involving national security is required. The above two step analysis would apply to all pre-1974 government-sponsored radiation experiments. II. ETHICS POLICY STATEMENTS AND ISOTOPE DISTRIBUTION RULES IN THE AEC FOR THE PERIOD 1947-1956 The evidence of AEC policies includes (1) policy statements of high AEC officials, and (2) the rules promulgated as part of the AEC isotope distribution process. The policy statements appear in three letters, two in 1947, and one in 1956. The requirement for local human use committees was established in 1946 by the Manhattan Engineering District (MED) and carried over by the AEC. These committees were intended to "insure a more judicious and safe use of available material."1 [June 28, 1947. Minutes of the Subcommittee on Human Applications, Advisory committee on Isotope Distribution, Isotopes Division, Oak Ridge, p.5-7.] The distribution rules appear in documents of the Subcommittee on Human Applications in 1948 and 1949. 2 A. Ethics Policy Statements in the AEC 1. April 30, 1947 letter from General Manager Carroll Wilson to Stanford Warren What seems to be the first AEC policy statement is contained in a letter from AEC General Manager Wilson to the Chairman of the AEC's Interim Medical Advisory Committee: The Commission understands that in the course of the approved program: a. treatment (which may involve clinical testing) will be administered to a patient only when there is expectation that it may have therapeutic effect; b. the decision as to the advisability of the treatment will be made by the doctor concerned. . . . . In any such clinical testing, the Commission continues to request that the same procedure be followed which was agreed upon early in March. That procedure contemplated that it should be susceptible of proof from official records that, prior to treatment, each individual patient, being in an understanding state of mind, was clearly informed of the nature of the treatment and its possible effects, and expressed his willingness to receive the treatment. In view of your recommendation, the Commission does not request that written releases be obtained in such cases, but it does request that in every case at least two doctors should certify in writing (made part of an official record) to the patient's understanding state of mind, to the explanation furnished him, and to his willingness to accept the treatment.2 [April 30, 1947. Letter from Carroll L. Wilson, General Manager of the AEC, to Stanford Warren, at the University of California, Los Angeles.] 2. November 5, 1947 letter from General Manager Carroll Wilson to Robert Stone On January 22, 1951 Leslie Redman of AEC Los Alamos Laboratory "D" Division sent the AEC headquarters an inquiry regarding human experimentation policy.3 [March 5, 1951. Letter from Shields Warren, Director, of the Division of Biology and Medicine, AEC, to Leslie Redman, "D" Division, Los Alamos National Laboratory. The basis for the Los Alamos inquiry remains a mystery. At Los Alamos, the "H" division was responsible for most biomedical research. The "D" division was involved in legal and declassification matters. Los Alamos has not been able to locate further documentation and reports that Mr. Redman has no recollection of particulars.] In a March 5, 1951 response, Shields Warren quoted a November 5, 1947 letter from General Manager Wilson to Dr. Robert Stone, of the University of California, which stated that the Interim Medical Advisory Committee 3 had made a statement that "substances known to be, or suspected of being, poisonous or harmful" should not be used in humans: .... unless the following conditions [are] fully met: (a) that a reasonable hope exists that the administration of such a substance will improve the condition of the patient, (b) that the patient give his complete and informed consent in writing; and (c) that the responsible next of kin give in writing a similarly complete and informed consent, revocable at any time during the course of such treatment.4 [March 5, 1951. Letter from Shields Warren, Director, of the Division of Biology and Medicine, AEC, to Leslie Redman, "D" Division, Los Alamos National Laboratory.] 3. July 5, 1956 letter from Charles Dunham, AEC Division of Biology and Medicine, to Thomas Shipman, Los Alamos National Laboratory In 1956, coincident with Los Alamos' introduction of a human body counter and related human experiments, the Health Division Leader at the Los Alamos National Laboratory (LANL) forwarded an inquiry to the AEC on "the experimental use of human volunteer subjects."5 [June 18, 1956. Letter from Thomas Shipman, M.D., Health Division Leader, to Dr. Charles Burnham, Division of Biology and Medicine.] In response, the Director of the Division of Biology and Medicine stated that tracer doses may be administered under four conditions: that they are true tracer doses, that the procedure be approved by a "senior medical officer of the institution," "that the subjects are bona fide volunteers," and that they are "fully informed as to the procedure involved." Strikingly absent is the reference to written consent described by Warren in 1951 and General Manager Wilson in November, 1947. These rules were then distributed to staff by Thomas Shipman, M.D., the Health Division Leader at LANL.6 [July 12, 1956. Memorandum from T.L. Shipman, Health Division Leader, Los Alamos, to staff distribution regarding the administration of tracer doses to humans.] Six years later, in 1962, Dr. Shipman restated these 1956 rules.7 [March 13, 1962. Memorandum from Thomas L. Shipman, M.D., to C. C. Lushbaugh.] B. Isotope Distribution Review Process: Rules of Subcommittee on Human Applications The AEC had a bureaucratic process for the distribution of radioisotopes. The body responsible for this process was the Subcommittee on Human Applications. The Subcommittee had two kinds of rules that relate to ethics policies. First, the Subcommittee provided for local human use committees, which would focus on risk and safety aspects of radioisotope research. Second, the Subcommittee stated further policies regarding the special circumstances of use and, it now appears, consent itself. 4 1. Meeting of March 29, 1948 The Subcommittee considered the need for informed consent in 1948. [March 29, 1948. "The Experimental Use of Radioactive Materials in Human Subjects at AEC Establishments," Author Unknown.] Based on the suggestions of Shields Warren, the Subcommittee recommended that: 1. Radioactive materials should be used in experiments involving human subjects when information obtained will have diagnostic value, therapeutic significance, or will contribute to knowledge on radiation protection. 2. Radioactive materials may be used in normal human subjects provided a. The subject has full knowledge of the act and has given his consent to the procedure. b. Animal studies have established the assimilation, distribution, selective localization and excretion of the radioisotope or derivative in question. 3. Radioactive materials may be used in patients suffering from diseased conditions of such nature that there is no reasonable probability of the radioactivity employed producing manifest injury provided: a. Animal studies have established the assimilation, distribution, selective localization and excretion of the radioisotope or derivative in question. b. The subject is of sound mind, has full knowledge of the act and has given his consent to the procedure. . . . . 4. Investigations are approved (1) by medical director or his equivalent at the installation responsible for the investigation, (2) 5 by the Director, Division of Biology and Medicine, and (3) full written descriptions of experimental procedures and calculated estimates of radiation to be received by body structure and organs must be submitted.8 [March 29, 1948. "The Experimental Use of Radioactive Materials in Human Subjects at AEC Establishments," Author Unknown. The motivations behind this statement and to whom it was submitted are unclear. However, evidence suggests that it came out of Shields Warren's concern for the plutonium injections. In an interview conducted as part of the Inspector General's 1974 investigation into the plutonium injections, Shields Warren described the ACBM and the DBM's response to the injections. He stated: I think the way it was handled was that Alan Gregg and I agreed the best way to do was to see that the rules were properly drawn up by the Isotope, Human Applications Isotope Committee, which had then come into being, so that use without full safeguards could not occur, and that we saw no point in bringing this up after the fact as long as we were sure that nothing of this sort could happen in the future.9 [April 9, 1974. Interview with Shields Warren, by L.A. Miazga, Sidney Mark, and Walter Weyzen, pp.10-11.] This statement suggests that Shields Warren and the DBM had a clear understanding that aspects of the plutonium experiments were unethical or inappropriate (presumably the failure to obtain consent), not to be repeated, and that rules to prevent further such conduct were to be promulgated by the Isotopes Division. 2. Meeting of March 13, 1949 The July 19, 1949 minutes of the March, 1949 Subcommittee meeting record special requirements for cases in which patients are suffering from diseases that make possible "the administration of larger doses for investigative purposes." These requirements were: 1. Full responsibility for conduct of the work is assumed by a special committee of at least three competent physicians in the institution in which the work is to be done. This will not necessarily be the local Radioisotope Committee. 2. The subject has given his consent to the procedure. 3. There is no reasonable likelihood of producing manifest injury by the radioisotopes to be employed.10 [July 19, 1949, Letter from S. Allan Lough, Chief, Radioisotopes Branch, Isotopes Division, Oak Ridge Operations, to Dr. Hymer Friedell, Dr. G. Failla. Dr. G. Hamilton, and Dr. A. H. Holland, and "Revised Tentative Minutes of March 13, 1949 Meeting of the Subcommittee on Human Applications of the Committee on Isotope Distribution of the AEC, pp. 5-6.] 6 The minutes of this meeting also record that "in general the use of radioisotopes in normal children should be discouraged." This policy comes out of an analysis of safety concerns and is reached from a balancing of risks and benefits. In terms of a harm-benefit calculation, the Subcommittee stipulated that research on children would be considered "for use in important researches, provided the problem cannot be studied properly by other methods and provided the radiation dosage level in any tissue is low enough to be considered harmless."11 [July 19, 1949, Letter from S. Allan Lough, Chief, Radioisotopes Branch, Isotopes Division, Oak Ridge Operations, to Dr. Hymer Friedell, Dr. G. Failla. Dr. G. Hamilton, and Dr. A. H. Holland, and "Revised Tentative Minutes of March 13, 1949 Meeting of the Subcommittee on Human Applications of the Committee on Isotope Distribution of the AEC, p.10.] Following this meeting, a supplement to the July 1949 "Catalogue and Price List" was issued in September 1949 that detailed these rules.12 [September 1949. Supplement No. 1 to Catalogue and Price List No. 3, July 1949.] Importantly, however, the Supplement does not describe how consent is to be certified or documented, as General Manager Wilson had required. III. APPLICATIONS OF POLICIES TO ETHICAL STANDARDS A. Favorable balance of harms and benefits Both the April 1947 and the November 1947 letters from General Manager Wilson required that administration of radioisotopes be accompanied by therapeutic intent ("expectation that it may have therapeutic effect," "reasonable hope exists that [the radioisotope will improve the condition of the patient"). The Subcommittee on Human Applications, however, listed "therapeutic significance" as only one of three valid purposes, the others being "diagnostic value" and contribution to "knowledge on radiation protection." These statements are consistent if the 1947 letters did not intend to exclude these other purposes; such an exclusion would have been odd. The letter states that experimental tracer doses may be administered only if they are truly tracer doses. The Subcommittee on Human Applications "discouraged" the use of radioisotopes in "normal children" on safety and harm-benefit grounds, with exceptions possible if the problem cannot be studied in any other way and if the doses are "low enough to be considered harmless." Additionally, the Subcommittee "strongly discouraged" the use of radioisotopes in pregnant women when "no therapeutic benefit is to be derived." 7 All of these conditions are consistent with the requirement that in the experimental use of radioisotopes there must be therapeutic intent or the administered doses must be so low as to present no plausible risk of harm to the subject. In a variation on the latter point, the Subcommittee was prepared to approve the administration of higher doses for investigative purposes depending on the disease from which the patient was suffering, suggesting that only patients "beyond harm" from higher doses could be used in this way. B. Selection of subjects There is no discussion in any of these statements about equity in subject selection. However, perhaps this would have been covered under the rubric of compensation for research-related injuries because researchers might have chosen to use only subjects already insured for injury, such as soldiers. C. Information provided Both 1947 letters stipulated that patients be informed of the proposed treatment, and the Subcommittee required "full knowledge of the act" by the tracer subject. The 1956 letter required that subjects be "fully informed." D. Consent The first 1947 letter stated that the patient must have "expressed his willingness to receive the treatment," the second uses the expression "complete and informed consent." The Subcommittee specified subject "consent to the procedure" for both tracer and higher doses, and the 1956 Shipman letter referred to "volunteers." There was some confusion in 1947 about written subject consent, but it seems finally not to have been implemented, though physician confirmation of consent was required. We note that in the case of either of the standards set in the two 1947 letters, the subject (or family) would be the beneficiary of a written record of the consent process (either by doctor attestation "susceptible to proof" or patient writing). E. Prior review The Subcommittee required that investigations be approved by the local medical director and the Director of the AEC Division of Biology and Medicine. In 1949 it further required that local physician committees take responsibility for projects involving sicker patients who are receiving higher doses for investigative purposes. 8 In summary, the stream of AEC policies in this period clearly considered healthy volunteers and patients for whom benefit was not anticipated. Exposures were not to be harmful, relative to the condition of the subject or patient, and consent and information were required, including tracer doses in healthy patients. There is less clarity about policies concerning patients whose exposure is accompanied by therapeutic intent. At times they are explicitly distinguished from other cases, as in the Subcommittee's discussion of pregnant women. On the other hand, the 1947 letters made no such distinction and seemed to apply policies across-the-board for all persons being exposed to radioisotopes (including an informed consent requirement, etc.). Subject selection and prior review were also less well-developed themes, but--in a twist that might have been unique to radioisotope usage at that time--prior review mechanisms were required by the Subcommittee on Human Applications. IV. APPLICABILITY OF AEC POLICIES TO OTHER GOVERNMENT AGENCIES We propose that the AEC standards, at least for radiation research, and as supplemented by the DOD 1953 Wilson Memorandum in the national security setting, be interpreted as applicable to radiation research conducted or supported by other government agencies. There are several bases for this proposal. First, the AEC was the a vigorous and primary sponsor and promotor of radiation-related biomedical research. In addition to the research it sponsored on contract or grant, its isotope distribution program was the source of isotopes for an extraordinarily quickly growing and large research program, conducted in hundreds, probably thousands, of institutions throughout the country. The AEC's promotion efforts resulted in the widespread conduct of human radiation experimentation. Second, at its onset the AEC clearly had both cause and professional intelligence needed to reflect on the question of research ethics. The AEC was emerging from the Manhattan Project research program, which was both terribly ambitious, and raised serious ethical questions that were presented directly to the new AEC. The new AEC focused at the onset on continuing and expanding the Manhattan era research ambitions, seeing quite clearly the need for policies and mechanisms that would permit the system to work in a post-war world. Finally, the new AEC brought to the meeting room to discuss the AEC medical programs established members of the radiation research community (indeed, the biomedical research community). Third, the members of the AEC core biomedical research group played central roles in the development of radiation research programs in other agencies. The role of AEC advisors in the 1949-1950 DOD/AEC discussions of potential experimentation with the nuclear airplane (which included related ethical discussions) has previously been chronicled.13 [Department of Energy/Atomic Energy Commission Ethics Policy History, December 13, 1994.] The HHS predecessor radiation research community also was closely intertwined with the AEC (and VA/DOD) radiation research group. 9 Several of the five members of Veteran's Administration (VA)'s Central Advisory Committee on Radioisotopes, established in late 1947 to develop and shepherd VA's radioisotope program, had previously played principal roles in the Manhattan Project and/or the nascent AEC. Dr. Shields Warren served as the first Director of the AEC Division of Biology and Medicine. Dr. Hymer Friedell served on the AEC Subcommittee on the Human Use of Radioisotopes. Dr. Stafford Warren served as medical director of the Manhattan Project and chaired the AEC's Interim Medical Advisory Board. These three served as "special advisors" to the VA radioisotope units in the eastern, central and western portions of the country, respectively, and interacted closely with those field units. A December 3, 1947 letter from George Lyon, the first Chief of the Radioisotope Section in VA's Central Office, to Stafford Warren discusses (1) Shields Warren's travel to the Bronx and interaction with the Boston unit, (2) Hymer Friedell's assistance in setting up the Cleveland and Minneapolis field units, and (3) Stafford Warren's activities to establish the Van Nuys and Los Angeles units. The minutes of the September 1948 Central Advisory Committee meeting include discussion by these three of the activities in the units in their respective parts of the country. The backgrounds of key VA staff, as well as those of advisors to VA field radioisotope units, also militate strongly in favor of the application of AEC standards to VA. Dr. George Lyon had been a safety advisor to the MED. At VA, Lyon was charged with serving as liaison to numerous agencies, including AEC. Moreover, those Lyon recruited to VA's field radioisotope units were sometimes part of, or closely connected to, that cadre of early researchers. For example, George V. LeRoy of the Hines (IL) radioisotope unit, also served on the Joint Panel and as a consultant to the AEC. Finally, AEC staff advised VA field radioisotope personnel. For example, Drs. G. Failla and Edith Quimby offered assistance to the Bronx VA radioisotope unit. In fact, even prior to the inception of VA's radioisotope program, military and other researchers received radioisotope training at the Donner Laboratory under the auspices of AEC. Fourth, the standards stated by the AEC, as discussed above, reflect those that were, in fact, subsequently developed by the other agencies. (Indeed, in the case of the DOD, as chronicled elsewhere, the tradition of voluntary consent and a review mechanism for experimental proposals pre-dated World War II). In 1953 the NIH Clinical Center required subject consent and prior review for ethically problematic experiments. Neither the CIA nor the VA appear to have had policies that contradicted these. (Written subject consent was less uniform, required in all cases in the DOD, in no cases in the AEC, and in some cases in the Clinical Center.) Subject selection was probably constrained by the possibility of insurance and compensation arrangements. 10 Whether disseminated and implemented or not, certain elements of a minimal but uniform policy governing the use of human subjects were consistent in the federal government by 1953: subjects were not to be exposed to significant harm, and there was to be informed consent. These emerged in both the AEC and the DOD by 1953. But ambiguity reigned concerning patients for whom the research intervention might be therapeutic. Thus, even if the government in fact spoke out of both sides of its mouth (policies from one corner, practices in another), it at least did so with one voice. 11