Conclusion

Chapter 1: The Atomic Energy Commission: A Requirement for "Consent" is Declared at the Creation

The planning for these undertakings required both reflection on high-level matters of policy and attention to matters of small but critical legal and bureaucratic detail. Both legal rules and administrative processes were uncharted. For example, who would be responsible if things went awry and subjects were injured? When could the government tell private doctors or researchers how to conduct treatment or research? The need for rules seemed obvious, but the particular rules that would be arrived at were not.

In April 1947 and again in November, Carroll Wilson, the general manager of the new agency, wrote letters first to Stafford Warren and then to Robert Stone, both of whom played prominent roles in Manhattan Project medical research, Warren as medical director, and Stone as a key member of the Chicago branch of the project. In these letters, Wilson maintained that "clinical testing" with patients could go forward only where there was a prospect that the patient could benefit medically and only after that patient had been informed about the testing and there was documentation that the patient had consented. What was the origin of this position, and what was its reach? It appears that these letters were the products of an agency that was not only seeking to devise rules for new programs but also was trying to glean lessons from the experience with the secret research that had been conducted during the Manhattan Project. In the course of setting rules for the future, the AEC and its research community had to confront whether and how to proceed with human experimentation in the face of human experiments, including plutonium injections, conducted under the auspices of the Manhattan Project, experiments that were conducted in secret and that had the potential for both negative public reaction and litigation.

The First Wilson Letter

A month later, in early March, Warren met with Major Birchard M. Brundage, chief of the AEC's Medical Division, and two AEC lawyers to consider the terms for the resumption of "clinical testing." In a memorandum for the record, the lawyers summarized the meeting. In the case of "clinical testing" the lawyers

expressed the view that it was most important that it be susceptible of proof that any individual patient, prior to treatment, was in an understanding state of mind and that the nature of the treatment and possible risk involved be explained very clearly and that the patient express his willingness to receive the treatment.[7]

Initially, the lawyers had proposed that researchers obtain a "written release" from patients. However, "on Dr. Warren's recommendation," the lawyers agreed that it would be sufficient if "at least two doctors certify in writing to the patient's state of mind to the explanation furnished him and to the acceptance of the treatment."[8]

In his April 30 letter to Stafford Warren, Wilson announced that the AEC had approved Warren's committee's recommendations for a "program for obtaining medical data of interest to the Commission in the course of treatment of patients, which may involve clinical testing."[9] Wilson's letter spelled out ground rules that were agreed upon. The commission understood that "treatment (which may involve clinical testing) will be administered to a patient only when there is expectation that it may have therapeutic effect." In addition, the commission adopted the requirement for documentation of consent agreed upon in Warren's meeting with the lawyers:

[I]t 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.[10]

The commission deferred to Warren's request that written releases from the patient not be required. However,

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.[11]

Carroll Wilson's April letter was sent to Stafford Warren as head of the Interim Medical Advisory Committee, which was responsible for advising the AEC on its contract research program, and forwarded to Major Brundage at the Oak Ridge office.[12] Stafford Warren was at this point dean of the medical school at the University of California at Los Angeles, one of the dozen research institutions involved in the AEC contract research program. With one exception the Advisory Committee on Human Radiation Experiments did not locate documentation that the letter or its contents were communicated to any other research institutions involved with the AEC's contract research program. The exception is the University of California at San Francisco, where there is indirect evidence that someone at that institution had been apprised of Wilson's April letter. Of the eighteen plutonium injections, only the last one, that involving Elmer Allen, or "CAL-3," took place after the April letter. In Mr. Allen's medical chart, there is a notation signed by two physicians indicating that the "experimental nature" of the procedure was explained and that the patient "agreed."[13] Although the note in Mr. Allen's chart suggests an effort on the part of the researchers to comply with Wilson's April letter, the researchers did not comply with the other provision of the Wilson letter, that "treatment (which may involve clinical testing) will be administered to a patient only when there is expectation that it may have therapeutic effect."[14] As is discussed in more detail in chapter 5, there was no expectation at the time that Mr. Allen would benefit medically from an injection of plutonium.[15]

The Second Wilson Letter

Two weeks later, Oak Ridge sent a memorandum to the Advisory Committee for Biology and Medicine (ACBM). The ACBM had succeeded both Stafford Warren's Interim Medical Advisory Committee and the Medical Board of Review, a group appointed by AEC Chairman David Lilienthal to review the AEC's medical program. The memorandum emphasized the need for "medico-legal criteria" for "future human tracer research" because some of that research would be "of no immediate therapeutic value to the patient." The memorandum outlined the pros and cons of "tracer studies":

Pro-

1. Tracer research is fundamental to toxicity studies.

2. The adequacy of the health protection which we afford our present employees may in a large measure depend upon information obtained using tracer techniques.

3. New and improved medical applications can only be developed through careful experimentation and clinical trial.

4. Tracer techniques are inherent in the radioisotope distribution program.

Con-

1. Moral, ethical and medico-legal objections to the administration of radioactive material without the patient's knowledge or consent.

2. There is perhaps a greater responsibility if a federal agency condones human guinea pig experimentation.

3. Publication of such researches in some instances will compromise the best interests of the Atomic Energy Commission.

4. Publication of experiments done by Atomic Energy Commission contractor's personnel may frequently be the source of litigation and be prejudicial to the proper functioning of the Atomic Energy Commission Insurance Branch.[17]

The questions raised by Oak Ridge were discussed by the ACBM at its October 11, 1947, meeting, which decided to give the "matter more study."[18] The minutes of the October 11 meeting record that "human experimentation" was then discussed in the context of a request by Dr. Robert Stone to release "classified papers containing certain information on human experimentation with radioisotopes conducted within the AEC research program."[19] The request was part of a continuing effort by Stone and other scientists to obtain permission to publish the research, including the plutonium experiments, that they had conducted in secret during the Manhattan Project. Earlier in 1947, the AEC had reversed a decision to declassify a report on the plutonium injections, citing the potential for public embarrassment and legal liability (see chapter 5). The question of what to do with these requests continued to fester.

The minutes explain that the "problem" raised by Stone had been dealt with by Chairman Lilienthal's Medical Board of Review in June. In a cryptic statement, the minutes record the ACBM's agreement that papers on human experiments "should remain classified unless the stipulated conditions laid down by the Board of Review were complied with."[20]

The "stipulated conditions" referred to are contained in General Manager Wilson's November 5, 1947, letter to Stone. According to Wilson's letter, at a June meeting the Medical Board of Review concluded that "the matter of human experimentation" would remain classified where certain "conditions" were not satisfied. Wilson then quoted from the "preliminary unpublished and restricted draft of the [Medical Board] report read to the Commissioners" as follows:

The atmosphere of secrecy and suppression makes one aspect of the medical work of the Commission especially vulnerable to criticism. We therefore wish to record our approval of the position taken by the medical staff of the AEC in point of their studies of the substances dangerous to human life. We [the Medical Board of Review] believe that no substances known to be, or suspected of being, poisonous or harmful should be given to human beings unless all of 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 [emphasis added].[21]

In other words, the opinion of the Medical Board of Review was presented by Wilson in his November letter as both a prescription for the future conduct of human experiments and a presentation of the criteria that must be met for the declassification of past research. Wilson again referenced these conditions in a letter to ACBM Chairman Alan Gregg, also on November 5. "I am sure," Wilson wrote Gregg, "that this information will assist Dr. Stone in evaluating the present problem and inform him as to the conditions that must be met in future experiments."[22] Thus, as discussed in more detail in chapters 5 and 13, the requirement that research proceed only with consent appears to have been coupled with the decision to withhold from the public information about experiments that failed to meet that standard.

Two points should be made about the term informed consent, which appears in the November letter from Wilson to Stone. First, it is not clear what meaning Wilson and the members of the Medical Board of Review attributed to the term. No further explanation was given. Second, it is nevertheless a matter of some historical interest that this term is used at all. Previous scholarship had attributed its first official usage to a landmark legal opinion in a medical malpractice case that was issued a decade later.[23]

The April and November 1947 Wilson letters have some common elements, in spite of their differences in detail. They both provided that research with humans proceed (l) only where there is reasonable hope of therapeutic effect; and (2) with documentary proof that the patient-subject was informed of the treatment and its possible effects and had consented to its administration.

But there are many remaining mysteries about the AEC's 1947 statements. In interviews with Advisory Committee staff, Joseph Volpe, who served as an AEC attorney in its early days and became general counsel in 1949, explained that a letter authored by General Manager Wilson could state AEC policy and confidently recollected that informed consent from research subjects would have been required by the first AEC general counsel. This requirement, Volpe maintained, should be reflected in the commission's minutes.[24] However, Committee and DOE review of the commission's minutes did not reveal evidence that the "consent" policy was expressly addressed.

Even more troubling is that both Wilson letters precluded research that did not offer patient-subjects a prospect of direct medical benefit. In the context of the concern about the plutonium injections and the other "nontherapeutic" research conducted during the Manhattan Project experiments, this provision readily makes sense. Yet, as Oak Ridge's inquiry to Washington noted, nontherapeutic research in the form of tracer studies had been, and would continue to be, a mainstay of AEC-sponsored isotope research. How could it be that the Wilson letters were intended to ban exactly the kind of research that at the same time the AEC was so actively promoting? It is conceivable that the requirement of the isotope distribution program for risk review prior to the human use of radioisotopes was a means of addressing this notion. However, if the equation between that risk review procedure and the provision in the November Wilson letter seems implicit, the documentary evidence does not provide an express link between the requirement stated in the Wilson letter and the rules of the isotope distribution program.

From Statements to Policy: A Failure of Translation

Consider, for example, a 1951 exchange between the AEC's Division of Biology and Medicine (DBM), which directed the AEC's medical research program, and the commission's Los Alamos Laboratory, which was in routine contact with Washington. An information officer at Los Alamos, Leslie Redman, who was charged to review papers that involved human experimentation, asked the DBM for a "definite AEC policy" on "human experimentation." In the course of his work, Redman wrote, he had been advised by "various persons" at Los Alamos that "regulations or policies of the AEC" on human experimentation were available, but he had been unable to locate more than general information about these regulations. According to his letter, his understanding was that

these regulations are comparable to those of the American Medical Association: that an experiment be performed under the supervision of an M.D., with the permission of the patient, and for the purpose of seeking a cure.[25]

Redman's characterization of the American Medical Association's guidelines, as we shall see in chapter 2, is partly incorrect. The requirement of a therapeutic intent is absent from the AMA guidelines. The possibility of direct therapeutic benefit for the patient was, however, a condition of research according to both of General Manager Wilson's 1947 letters.

Shields Warren, the DBM chief, responded to Redman by citing Wilson's November 5, 1947, letter to Stone and by excerpting the conditions quoted above.[26] But Warren did not term these conditions "standards" or "requirements." Rather, Warren's response to Los Alamos "urges" compliance with these "guiding principles."[27]

Though Los Alamos was provided with the criteria stated by Wilson in November 1947, General Manager Wilson's statements were not routinely communicated in response to requests for guidance from non-AEC researchers. In an April 1948 letter to the DBM, a university researcher explained that the Isotopes Division had approved his request to use phosphorus 32 for "experimental procedures in the human . . . simply for investigational purposes and not for treatment of disease." What, the researcher wanted to know, should be done about "medical-legal aspects" and "permission forms"?[28] The request could have been answered by referring to Wilson's 1947 statements about consent. Instead, the DBM simply referred the researcher to the Isotopes Division at Oak Ridge.[29] In its response, the Isotopes Division did not indicate that consent should be solicited, as Wilson had stipulated. The Isotopes Division, stating it could be "of little assistance," declined to provide "legal advice," save to note that "we understand that most hospitals do require patients to sign general releases before entering into treatment."[30]

From 1947 onward, the AEC had ample opportunity to disseminate a research policy. The AEC routinely provided educational and administrative materials to applicants for AEC funding and to the far greater number of applicants for AEC-produced radioisotopes. The isotopes distribution program, in particular, included a sophisticated structure of regulation, replete with review committees, training courses, and informational brochures (see chapter 6). At the federal level, this included the Subcommittee on Human Applications of the Committee on Isotope Distribution, whose very purpose was "to review all initial requests for radioisotopes to be used experimentally or otherwise in human beings [emphasis added]."[31] The AEC Subcommittee on Human Applications was supplemented by similar committees at the research institutions where the work was conducted.

In principle, there does not seem to be any reason these local committees could not have been instructed by the Isotopes Division on consent requirements.[32] Some evidence suggests that in March 1948 the Subcommittee on Human Applications discussed consent requirements for healthy subjects and patient-subjects. In a document dated March 29, 1948, the Subcommittee on Human Applications appeared to resolve 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:
   1. The subject has full knowledge of the act and has given his consent to the procedure.
   2. 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:
   1. Animal studies have established the assimilation, distribution, selective localization and excretion of the radioisotope or derivative in question.
   2. 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) 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.[33]

We were unable to locate any further references to this document and do not know whether it represented a policy that was adopted. Perhaps it represents the consensus of the Subcommittee on Human Applications, as it had met shortly before that, or perhaps it is simply a draft document prepared by staff.

Whatever the ultimate disposition of this document, it provides some idea of the problems that were under consideration at the time and indicates that views on human use were unsettled. The first numbered item, for example, appears to recommend human radiation experiments when they will offer diagnostic value and therapeutic significance or knowledge about radiation protection. If the document had in fact been adopted, the recognition that isotope experimentation could be undertaken to "contribute to knowledge" (item 1) would appear to revise the Wilson letters' prohibition of nontherapeutic experimentation. The third item also addresses consent and risk of injury to patient-subjects without indicating that there should be any potential benefit. Another peculiarity is found in the second item, which refers to consent from normal human subjects but does not rule out experiments that present risk to the subject.

In any event, at a 1948 meeting the Subcommittee on Human Applications articulated a consent requirement as part of a decision to permit patients suffering from serious diseases to receive "larger doses for investigative purposes."[34] This requirement was disseminated to all radioisotope purchasers in 1949.[35] The subcommittee allowed investigators to administer "larger doses" to seriously ill patients but only with the patient's consent. While it is possible that the basis for permitting larger doses was an assumption that smaller ones would be of no potential benefit to subjects, item 3 of the just-quoted March 1948 document suggests the assumption was rather that in seriously ill patients other disease processes would be more likely to take their course before radiation injury was manifested.

There is evidence that at least one AEC-funded entity did routinely provide some form of disclosure and consent in the early 1950s. From its opening in 1950 the AEC-sponsored Oak Ridge Institute for Nuclear Studies (ORINS), a research hospital, advised incoming patients that procedures were experimental. Additionally, patients were given written information that advised them that "probable benefit, if any, cannot always be predicted in advance."[36] Upon admission, the applicant was required to sign a "Waiver and Release" that did not describe the treatment, but included a lengthy release from the patient, the patient's "heirs, executors, administrators, and assigns," for any "causes of action, claims, demands, damages, loss, costs, and expenses, whether direct or consequential," associated with or resulting from the care of the hospital. This form notes that the hospital has described the "character and kind of treatment." Oak Ridge Institute of Nuclear Studies, 1950 ("Waiver and Release") (ACHRE No. DOE-121494-C-3), 1. Patients were also asked to sign a form that indicated that they were "fully advised" about the "character and kind of treatment and care," which would be "for the most part experiments with no definite promise of improvement in my physical condition."[37] Thus, at least in the case of ORINS, and perhaps at other AEC facilities, a local process was instituted apart from any known communication of the statements by AEC officials.

Nonetheless, there is other evidence that the AEC did not communicate the requirements detailed in General Manager Wilson's 1947 letters to its own contract research organizations, which, as in the cases of Argonne, Los Alamos, Brookhaven, and Oak Ridge, had significant biomedical programs and were engaged in human research. When the Division of Biological and Medical Research at Argonne National Laboratory met in January 1951 to discuss beginning a program of human experimentation in cancer research, one of its members asserted that the ACBM had not established a "general policy concerning human experimentation." The minutes of the meeting at Argonne record that the ACBM "has been approached several times in the past for a general policy and has refused to formulate one."[38]

In 1956, Los Alamos asked the DBM to "restate its position on the experimental use of human volunteer subjects" for tracer experiments.[39] The DBM responded by stating that tracer doses might be administered under certain conditions, which included the provision that subjects be volunteers who were fully informed. The focus of this position seems to have been research with healthy people and not patients, and no reference was made to the provisions of the Wilson letters.[40] The DBM's 1956 formulation was given "staff distribution" by Los Alamos and restated in 1962.[41]

Also in 1956, the Isotopes Division did state a requirement for healthy subjects. All subjects were to be informed volunteers. As part of its "Recommendations and Requirements" guidebook for the medical uses of radioisotopes, which was distributed to all medical users of radioisotopes, the Isotopes Division stated:

Uses of radioisotopes in normal subjects for experimental purposes shall be limited to:

a. Tracer doses which do not exceed the permissible total body burden for the radioisotope in question. In all instances the dose should be kept as low as possible.

b. Volunteers to whom the intent of the study and the effects of radiation have been outlined.

c. Volunteers who are unlikely to be exposed to significant additional amounts of radiation.[42]

These requirements apparently applied to all uses of AEC radioisotopes, whether government or private researchers were involved. The "experimental or nonroutine" use of radioisotopes in any human subjects was limited to institutional programs where local review committees existed to oversee the risk to which subjects were exposed. In stating these requirements, the AEC reiterated that "patients" in whom "there is no reasonable probability of producing manifest injury" may be used in some experiments not normally permitted, but did not reiterate the requirement that consent should be obtained from these patients, as was stated in 1948.

What, then, can be said about the rules and policies of the AEC in the 1940s and 1950s? General Manager Wilson's 1947 letters clearly stipulate a requirement of "informed consent" from patient-subjects, at least where potentially "poisonous or harmful" substances are involved. But with the exception of ORINS there is little indication that this requirement was imposed as binding policy on any AEC facility, contractor, or recipient of radioisotopes. By contrast, later requirements that healthy subjects be informed volunteers and that seriously ill patients be permitted to receive higher doses only with their consent appear to have been more broadly communicated and enforced. The only evidence of general attention to matters of consent from patient-subjects comes from ORINS, whose policies and practices show a striking similarity to those that, as we shall see, were being contemporaneously employed at another facility essentially devoted to experimental work, the NIH's Clinical Center. At the same time, there is evidence of considerable attention in both policy and practice to issues of safety and acceptable risk (see chapter 6). Questions of subject selection, as in the case of seriously ill patients, emerge only in this context of safety; there is no evidence that issues of fairness or concerns about exploitation in the selection of subjects figured in AEC policies or rules of the period.