 Section 45 of Final Report of the Advisory Committee on Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Final Report of the Advisory Committee on Human Radiation Experiments. AEC Sponsored TBI at Oak Ridge. At the same time that the University of Cincinnati was conducting TBI experiments for the Department of Defense, DOD, the Medical Division of the AEC's Oak Ridge Institute of Nuclear Studies Orens was also treating patients with selected tumors with TBI. Retrospective and prospective analyses of these data were supported by the National Aeronautics and Space Administration. Orens was established in the late 1940s as a research institution to help advance the field of nuclear medicine through research, training, and technology development. From 1957 to 1974, the Orens RAU Hospital treated 194 patients with TBI. In contrast with the DOD-sponsored experiments at Cincinnati and other institutions, Orens RAU used TBI only to treat patients with radio-sensitive cancers. Indeed in 1972 the RAU Medical Program Review Committee issued a report on the RAU TBI activities in light of the recent revelations about the University of Cincinnati TBI program, noting that the studies were ethically conducted and that survival rates were as good as with other methods of treatment. Nevertheless, similar questions have been raised about the dual-purpose nature of the Oak Ridge program. As happened at Cincinnati, the Oak Ridge TBI experiments, although known in the national and international medical and scientific communities, through presentations and publications, first came to the attention of the general public through the news media. In September 1981 Mother Jones Magazine published an article charging that Orens RAU treated its patients with total body irradiation in order to collect data for NASA. The article focused on one patient in particular, Dwayne Sexton, who suffered from acute lymphocytic leukemia and was treated with TBI and chemotherapy over the course of three years until he died in 1968. That article prompted an investigation and public hearing by the Investigations and Oversight Subcommittee of the House Science and Technology Committee, which was chaired by Representative Albert Gore. Testifying before the subcommittee were patients and patient relatives, administrative officials from Oak Ridge, the AEC and NASA, the medical staff of RAU, and two cancer experts, Dr. Peter Wearnick, director of the Baltimore Cancer Research Center, and Dr. Eli Gladstein, who was then chief of radiation oncology at the National Cancer Institute, and is now a member of the Advisory Committee on Human Radiation Experiments. Orens began treating patients with TBI in 1957. Following a 1958 accident at the Oak Ridge Y-12 production plant, in which eight workers were irradiated and treated by Orens Hospital, Orens took a heightened interest in the use and effects of TBI. As William R. Bibb, then director of the Department of Energy's Research Division at Oak Ridge, testified at the Gore hearing, in order to provide the best possible care in case of an accident, the AEC expected that hematologic data from patients being treated with total body irradiation, in addition to being used to benefit other patients, would also be used to benefit any radiation accident victim. In 1960, the Orens Hospital completed a newly designed irradiation facility that could deliver a uniform dose to all portions of the body, without having to move the patient, known as the medium exposure total body irradiator, METBI. The METBI facility delivered approximately 1.5 rad per minute. Several years later, Orens sought to test the hypothesis that exposure to low doses of radiation over an extended period of time would be more effective than a single administration of a similar total radiation dose to the whole body, in treating certain types of diffuse tumors known to be responsive to radiation. Accordingly, it developed the low exposure total body irradiator, METBI, as a one-of-a-kind system to test this hypothesis. METBI, which could deliver a whole body radiation dose of 1.5 rad per hour, went into operation in 1967, and patients could spend several days or weeks in this facility. AEC sponsored all activities concerned with the construction and operation of the METBI and its use in patient treatment. The results of this treatment approach, however, were found to be no better than others than available, and the use of the METBI was discontinued in the early 1970s. The METBI project was conceived at approximately the same time that NASA had commissioned Orens to study the effects of total body irradiation. NASA was particularly interested in the effects of low dose rate radiation that the METBI would produce, because astronauts would most likely be exposed to low dose cosmic radiation. Accordingly, NASA provided approximately $65,000 to the AEC for monitoring equipment and the radiation sources used for the METBI. At the Gore hearing, officials from the AEC and NASA testified that the METBI program was conceived purely for therapeutic purposes, and that NASA's interest in the data from the METBI exposures in no way influenced the decision to construct the facility or its use for patients. Dr. Clarence Lushbaugh, who ran the METBI facility under Dr. Gould Andrews, and succeeded Andrews as director of the OREU Medical Division, testified, First, neither NASA nor AEC program monitors, to my knowledge, ever attempted to become involved directly or indirectly with the treatment of patients at the Orens OREU Medical Division. Second, the Orens OREU NASA study group never influenced the clinicians in their selection of patients, or the prescription of the exposure dose and dose rates. There was little dispute with the view of the 1972 Medical Program Review Committee expressed above, that at least in the early years TBI was a legitimate form of treatment worth exploring for the radio-sensitive cancers that Orens OREU was treating. The review committee's concern was whether the Oak Ridge Medical Staff conducted their investigations in an effective manner, and whether the AECs or NASA's interest in the data compelled the continuation of this modality at a time when other forms of treatment were considered more effective. Dr. Peter H. Weernick, one of the two expert witnesses, acknowledged, for example, that in the early years it was legitimate to experiment with TBI at the high doses being used to try to improve treatment, because clearly treatment needed to be advanced in those days. The record of the 1972 review suggests that the Orens OREU staff did not engage in the type of rigorous systematic research that would be necessary to evaluate the usefulness of that type of therapy. The Oak Ridge doctors acknowledged that they were not evaluating the long-term effectiveness of single-exposure high-dose TBI, and that fractionated exposures, in which numerous smaller doses are given over a period of several weeks or months, probably offers a preferable approach for total body irradiation therapy. Dr. Lushbaugh explained that because the doctors would administer whatever treatment they thought was best for each patient, they did not adhere to an established research protocol based exclusively on TBI. In commenting on the 1972 report before the Gore Committee, Dr. Gladstein questioned the manner of administration and the uncontrolled nature of the studies. Oncology research, he said, requires an obsession with time, the effect that a given treatment has over months or years. Gladstein noted that the reports he reviewed are interesting in terms of acute radiation effects, but really don't have any substance in terms of oncologic practice. Gladstein summarized his view of the Orens-Ore-U TBI research program. If you're talking about the early sixties, I think this is probably fairly representative of protocols that were going on at that time. By the end of that decade, I believe that this was probably not acceptable. Both Weirnick and Gladstein criticized Dwayne Sexton's medical non-radiation treatment, in particular the decision to withhold maintenance chemotherapy, which was recognized as an effective treatment at that time, in order to attempt a never-before-used experimental procedure. Even if the new treatment was worth pursuing, they argued, it should have been done only as part of a larger protocol, and only when the patient was in secondary remission following the failure of more effective treatments. All patients accepted into the Orens-Ore-U hospital program signed a Patients Admittance Agreement that explained that the hospital operated for the purpose of conducting radiation-related research. The form stated that the patient is being admitted because his physical condition makes me a suitable patient for our currently active clinical research project, that experimental examinations, treatments, and tests may be prescribed for which the patient hereby gives his or her consent, and that the patient can remain in the research hospital only so long as I am needed for research purposes. Additional forms were used to establish consent for experimental treatment, which stated that the nature and purpose of the treatment, possible alternative methods of treatment, the risks involved, and the possibilities of complications, have been explained to me. I understand that this treatment is not the usual treatment for my disorder, and is therefore experimental and remains unproven by medical experience, so that the consequences may be unpredictable. The form made no mention of the possible risk of death from bone marrow suppression or specific side effects such as nausea or vomiting. In 1974 the AEC conducted a program review of the Medical Division of ORIU. It recommended that the clinical TBI programs be closed, having found that the met by and let by programs had evolved without adequate planning, criticism, or objectives, and have achieved less in substantial productivity than merits continued support. At the end of his hearing Gore noted that the subcommittee would issue a report with conclusions and recommendations. Although no formal report was ever completed, the full committee issued the following statement in January 1983. The subcommittee testimony revealed that while many of the conditions at ORIU were not satisfactory, particularly when judged by the routine institutional safeguards and medical knowledge of today, the more scandalous allegations could not be substantiated. Given the standards of informed consent at that time and the state of nuclear medicine, the experiments were satisfactory, but not perfect. Perhaps the most striking contrast between philosophies of the Oak Ridge and the University of Cincinnati TBI programs can be gleaned from an exchange that occurred in 1966. In the year the AEC's Medical Program Review Committee suggested that ORIU consider using TBI for treatment of radio-resistant cancers, similar to what was being done at Cincinnati. The ORIU physicians responded that they had carefully considered treating such diseases, but had declined to do so. We are very hesitant to treat them because we believe there is so little chance of benefit to make it questionable ethically to treat them. Lesions that require moderate or high doses of local therapy for benefit, or that are actually resistant, gastroenteric tract, are not helped enough by total body radiation to justify the bone marrow depression that is induced. Of course in one way these patients would make good subjects for research, because their hematologic responses are more nearly like those of normals than are the responses of patients with hematologic disorders. Conclusion When we began our work, the controversy surrounding the Cincinnati TBI research had been rekindled. There was, however, little public awareness that Cincinnati was the last in the line of many years of sponsorship of similar TBI-related research by the Defense Department and other federal agencies. The ethical issues raised by the Cincinnati case are made more acute by the fact that both the government and the medical community already had had decades of experience with TBI, although comparatively less experience with cobalt-60 as a means to deliver higher doses than had been delivered in the earlier era. This history provides compelling evidence of the importance of the rules that regulate human subject research today, prior review of risks and potential benefits, requirements of disclosure and consent, and procedures for ensuring equity in the selection of subjects. The history also highlights four issues in the ethics of research with human subjects that are as important today as they were then—issues that are not easily resolved or even addressed by present-day rules. As discussed below, these issues are, one, how to protect the interests of patients when physicians use medical interventions that are not standard care, two, the effects and attendant obligations of the government when it funds research involving patient subjects, three, the impact on patients when research is combined with medical care, and four, what constitutes fairness in the selection of subjects for research. The first issue is how best to protect the interests of patients when physicians propose to use medical interventions that are not standard care. Today, when non-standard interventions are part of a formal research project, the interests of the patient are protected in theory by the Institutional Review Board, which is charged with determining that the risks of the non-standard intervention are acceptable in light of available alternatives and the prospect for benefit. Patients are also protected by the requirement of informed consent, which is intended to allow the potential patient subject to assess whether the balance of risks to potential benefits is acceptable. There is no federally mandated parallel IRB mechanism of review, however, when a medical intervention that is experimental or innovative or even controversial is to be used outside the confines of a research project, although some institutions voluntarily have adopted mechanisms of peer review. The requirement of informed consent remains, the physician is obligated to inform the patient that the proposed intervention is not standard practice, whether it is controversial within the field and how it compares with alternative approaches, but this requirement provides the patient less protection than would a professional peer review. At the time of the TBI studies none of these mechanisms were well developed. During the Cincinnati project IRBs were in their infancy, and the convention of obtaining informed consent from patient subjects was just emerging. The record is confused and confusing, as to whether and when TBI at Cincinnati was viewed as part of a cancer research project and thus properly the subject of IRB review. It is not clear whether the treatment of the Cincinnati patients with TBI was initially intended to be research. In the practice of medicine there has always been a fine boundary between practices or treatments that are accepted as standard, those that are innovative, and those that are experimental or the subject of research. The use of TBI at Cincinnati is emblematic of the difficulties inherent in sorting through these categories. By the mid-1960s TBI without bone marrow protection was a treatment that had been tried and had not been proven effective for patients with radio-resistant cancers. By this time total body irradiation was not standard treatment for such cases. Nor could it be called innovative treatment, some at the time considered its continued use in patients with radio-resistant cancers to be controversial. The history of medicine, however, is replete with instances in which failure is followed by success. The continued use of TBI in patients with radio-resistant cancers would not have been unethical if the physicians had established clear benchmarks for determining how much additional use was warranted and if the patients had been informed of the speculative nature of the treatment and the gravity of the risks involved. It is not clear that either of these things occurred. What is clear is that neither the university's IRB nor the funding agency reviewed the appropriateness of continuing to treat patients with radio-resistant cancers using TBI without bone marrow protection, despite mounting evidence casting doubt on the utility of TBI treatment for radio-resistant tumors in the absence of bone marrow protection. It is also clear that the consent forms did not disclose that it was by this time at best unconventional to treat patients with radio-resistant cancers with TBI and that no other medical centers were engaged in this practice at the time. Whether physicians told this to their patients is not known. The system of checks and balances that is usually in place today to protect patients' interests was in its early phase at the University of Cincinnati and the system did not work well at the time. The responsibility for failure rests at all levels, but it is reasonably clear that patient protection was compromised. Today, as in the past, there are occasions when non-standard medical interventions are not subject to human research regulations. In such situations neither IRB review nor the rigors of scientific design are in place to help determine whether an experimental intervention should continue to be used. Today, for example, many innovations in reproductive technologies and surgery proceed with little oversight and few constraints on the practices of interventions. A physician wishing to use an intervention that other colleagues in the field believe to be ineffective or inferior, as was arguably the case with TBI and radio-resistant tumors after several years in the Cincinnati program, will find little standing in his or her way to do so, save the fear of malpractice claims, and increasingly the likelihood that such interventions will not be reimbursed, particularly in managed care settings. The Cincinnati experience underscores the importance of, one, establishing benchmarks for judging the propriety of continued use, and, two, providing for special disclosures to patients in all cases where interventions are not standard, without regard for whether that intervention is deemed human subject research or is governed by the common rule, C Chapter 3. The question of what role the Department of Defense should have played in reviewing the appropriateness of TBI as medical care for the patient subjects in its biological dosimetry and radiation effects research points to the second major issue illustrated by our review of the TBI history. Arguably the ultimate responsibility for determining that TBI was acceptable medical practice rested with the physicians at Cincinnati and with the university and associated hospitals. At the same time, however, thirty years of government interest in the effects of TBI also arguably had a significant influence on medical practice. From one vantage the DOD had little or no obligation to consider the value of TBI to the patients who provided the data it was seeking. The DOD was not paying for the irradiation of the patients. It had reason to assume that the decision about the propriety of the treatment would be made by doctors whose judgment in the matter could be trusted. Yet the TBI experience illustrates that when government funds research, particularly over a long period, its funding may well have effects beyond the simple conduct of the science and well beyond the confines of the strict terms stated in the contracts or grants authorizing the research. Over the course of three decades there was a substantial coincidence between the use of TBI on patients with radio-resistant cancers and funding from the Department of Defense and its predecessor. With the exception of work conducted at the City of Hope Hospital, every journal article in the professional literature on the use of TBI with radio-resistant tumors during this period was reporting on work supported by the government for military purposes. In the case of Cincinnati, Dr. Sanger told the advisory committee in 1994 that the irradiation of patients might not have been initiated if it were not for the funding by the DOD, and once initiated might not have been continued if the objective sought by the DED, a biological dosimeter, had been realized early on. As Dr. Sanger explained, while the DOD did not directly pay for irradiation, its funding provided for other items, including laboratory equipment and specialists, that facilitated the initiation and maintenance of the TBI program. Even where the medical care of patients is peripheral to the interests of a funding agency, so long as the research supported by the agency is to be conducted on patient subjects, it is likely that the research will affect the care patients receive. This is particularly true when agencies support research programs extending over many years, as was the case with the Department of Defense and TBI. Such programs can motivate physician investigators to alter their practice and can stimulate the adoption of different approaches to the care of patients. Although there is today a greater appreciation of the impact on medical practice of funding patterns in research, it is not clear even now that funding agencies regularly think through the implications for medical care of the research programs they support, or that they monitor the impact on patients of their programs over time. That the joining of research with medical care can alter what happens to a patient is the third issue in research ethics illustrated by the TBI experience. Each purpose introduced into the clinical setting in addition to the treatment of the patient increases the likelihood that the patient will receive more, fewer, or different medical interventions than he or she would otherwise receive. It is naive to think that either today or thirty years ago research can be grafted on to the clinical setting without changing the experience for the patient, now turned subject. When the demands of science alter the standard medical practice by increasing the monitoring of physiological indicators the additional blood tests or bone scans or biopsies are frequently presented as in the interest of patient subjects. Sometimes this claim is defensible and the patient subjects are indeed advantaged by the more careful monitoring of their medical condition. At other times, however, this claim is in insupportable rationalization and there are no offsetting benefits to patients for the risks and discomforts associated with the additional monitoring. In the case of the Cincinnati experiments the impact of the research protocol on the care of the patient subjects cannot be construed as beneficial to the patients. In addition there is evidence of the subordination of the ends of medicine to the ends of research. The decisions to withhold information about possible acute side effects of TBI as well as to forego pretreatment with anti-imetics were irrefutably linked to advancing the research interests of the DOD. To the extent that this deviated from standard care and caused unnecessary suffering and discomfort it was morally unconscionable, to the extent that the standard of care in this area is uncertain it is morally questionable. As troubling as this is, far more troubling is the evidence, including the testimony of the principal investigator, that TBI might not have been employed as a treatment for the patients or once employed continued in the absence of the government's funding and research requirements. Whether the ends of research understood as discovering new knowledge and the ends of medicine understood as serving the interests of the patient necessarily conflict and how the conflict should be resolved when it occurs are still today open and vexing issues. Increasingly advocates for patients with serious chronic diseases such as AIDS and breast cancer maintain that it is often in the interest of patients to participate as subjects in clinical research. These advocates are particularly concerned to ensure fair access to participation in research for people who are politically less powerful such as the poor minorities and women. This contemporary perspective upends the traditional way of viewing the fourth issue in research ethics raised by the TBI experiments, fairness in the selection of subjects. At both M. D. Anderson Hospital and the University of Cincinnati almost all the patients were drawn from public hospitals and many were African Americans. It was common during this period for medical research to be conducted on the poor and the powerless. In part this practice reflected a general societal insensitivity to questions of justice and equal treatment. In this case people who were poor disproportionately bore the burdens of questionable research to which their interests as ill people were subordinated. The practice also reflected the view, however, that poor people were better off being patients at hospitals affiliated with research-oriented medical schools where they were likely to become the subjects of research as well as subject matter for clinical teaching. Such institutions it was thought offered poor people their best and perhaps their only chance to secure quality medical care. Recently this kind of reasoning has emerged again as constraints on access to medical care from the narrowing of entitlement programs to the narrowing of coverage in managed care medical plans have made participation in research as a route to medical care more attractive. The question of whether the side benefits of being a subject should be weighted in the review of the risks and potential benefits of research remains unresolved today. These findings highlight the contemporary resonance of the TBI story. The issues discussed above are either not now addressed or not addressed adequately by regulation. Neither are they covered by clear conventions or rules of professional ethics. Thus the history of TBI research sponsored by the government is important not only for what it tells us about our past but also for how it illuminates the present. End of Section 45, Recording by Maria Kasper. Section 46 of Final Report of the Advisory Committee on Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Final Report of the Advisory Committee on Human Radiation Experiments. Case Studies, Chapter 9, Part 1. Prisoners A Captive Research Population In July 1949, a medical advisory panel met in Washington, D.C. to discuss psychological problems posed by radiation to crews of a then-planned nuclear-powered airplane. During the meeting, an Air Force colonel noted that crewmen were concerned about anything physically harmful, but especially anything seen as a threat to what he delicately called, using a euphemism of that gentler era, the family jewels. The nuclear-powered airplane was never built, but concern about radiation hazards to testicular function in space flight, weapons plants, nuclear power plants, and on an atomic battlefield, remained. This concern provides some of the context for a brace of almost identical experiments carried out between 1963 and 1973, in which 131 prisoners in Oregon and Washington submitted to experimental testicular irradiations with national security and other societal goals, but no potential for therapeutic benefit for the subjects. The studies were directed by Carl G. Heller, M.D., a leading endocrinologist of his day, and by Dr. Heller's protege, C. Alvin Poulsen, M.D. Perhaps because they involved irradiation of the testicles, they have caused great public concern. They were also noted briefly among the 31 experiments representative Edward J. Markey of Massachusetts, publicized in his 1986 report on radiation research on human subjects. Both studies were funded solely by the Atomic Energy Commission. Dr. Heller and Poulsen were interested in the effects of radiation on the male reproductive system, especially the production of sperm cells. The government was interested in the effects of ionizing radiation on workers, astronauts, and other Americans who might be exposed, in a nuclear attack, for example. Both doctors viewed prisoners as ideal subjects. They were healthy adult males who were not going anywhere soon. In 1963 few, if any, researchers had moral qualms about using them as subjects, although there seems to have been a consensus in the research community on the rules that should govern such experimentation. By 1973, however, some ethicists, researchers, and others, such as the investigative journalist Jessica Mitford, pointed out that incarcerated people were not well placed to make voluntary decisions. In 1976 the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research recommended the banning of almost all research on prisoners. Prison experimentation effectively came to an end in this country a few years after the commission offered its recommendations. The Heller and Poulsen experiments were groundbreaking scientifically, and they were conceived as having an important government purpose, protecting Americans engaged in building the nation's high priority nuclear and space programs. But looking back through the lens of history, there appears to be an inconsistency between the way human subjects were treated in this research and the standards intended to govern their treatment. Although both Dr. Heller and Dr. Poulsen showed sensitivity to some ethical issues, in both cases the researchers themselves and some of those charged with oversight at both the federal and state levels did not completely live up to what appear to have been well understood standards applicable to their research. In this failure they were no different from many, if not most, of their contemporaries. Times were changing, however, and in the end state officials shut down both sets of experiments, bringing practice more into line with the standards already on the books of some government agencies and private research organizations. Among researchers who used prisoners as subjects, as early as 1958 the Nuremberg Code was recognized as a model set of rules for conducting human subject research. It is equally clear that the work in the Oregon and Washington prisons did not carefully follow all these rules. Moreover, the funding agency, the Atomic Energy Commission, had its own rules for the conduct of research with human volunteers, which were not fully observed in these experiments. As discussed in Chapter 1, in 1956 the AEC's Isotope Division Program provided that where healthy subjects were used for research they needed to be volunteers to whom the intent of the study and the effects of radiation have been outlined. A 1966 memorandum from the AEC's Office of General Counsel to the Director of the Division of Biology and Medicine sheds some light on the agency's standards at that time and why it had them. The specific experiments referred to in the memo, plutonium and Promethium injections or ingestion, appear not to have been carried out, but the use of human volunteers in experiments is addressed in general terms. The memo calls for volunteers to sign a written, witnessed agreement attesting to their sound mental state and free will, to their understanding of the purposes and risks of the planned experimentation, and that the experiment was not being done for their benefit. The relevant paragraph concludes, 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. Finally, those attending a 1962 conference on research using prisoners as subjects reached a consensus on a higher standard for subject selection and informed consent than was typically observed in Oregon and Washington. For example, the conferees argued that potential prisoner subjects should have enough information to avoid their being deceived and that inducements to prisoners should not be so high as to invalidate consent. The surviving researchers disagree somewhat about the genesis of the testicular irradiation experiments, which the available documentary evidence does not completely resolve. What follows is a version based on, and consistent with, both the Heller and Paulson accounts. Early in 1963 the AEC held a conference in Fort Collins, Colorado, for investigators who were using radiation in studies of reproduction in animals. Dr. Heller was invited. In a bedside deposition, taken after he suffered a stroke in 1976, he recounted what happened. The whole conference finally focused on man. A given group at Fort Collins was working on mice and another group was working on bulls, and then they concluded what would happen to man. They extrapolated the data from bulls or mice to man. I commented one day to Dr. Paul Henshaw, who was then with the AEC, that if they were so interested in whether it was happening to man, why were they fussing around with mice and beagle dogs and canaries and so on? If they wanted to know about man, why not work on man? According to Dr. Heller, that remark stimulated the AEC to solicit a research proposal from him to study the effects of radiation on the male reproductive system. Dr. Paulson, however, recalled a different scenario in a 1994 interview by committee staff at his office in Seattle. He said he was invited to the AEC's Hanford Washington facility in 1962 to act as a consultant after three workers were accidentally exposed to radiation. Like Dr. Heller, Dr. Paulson had no previous experience with radiation exposure. He said he was brought in because of a chapter he had written on the testes in an endocrinology text. As a result of that experience, Dr. Paulson said, he became interested in doing work on the effects of radiation on testicular function, discussed his idea with colleagues, and contacted the AEC to see if the agency would be interested in funding his work. Whether or not Drs. Heller and Paulson initiated their project separately, the practical result was that both received AEC funding and carried out their research projects during the 1960s and early 1970s in the Oregon and Washington state prisons, respectively. Although the two studies were very much alike in their methods and objectives, there were small differences. They used different consent forms, different levels and means of irradiation, and different subject selection procedures. This chapter provides accounts of the Washington and Oregon experiments that focus on the failure of these two research projects to live up fully to ethical standards of their time, the committee's analysis of the risk to subjects in the two experiments, capsule descriptions of a number of other radiation experiments using prisoners as subjects, and a general ethical analysis of radiation experiments using prisoners as subjects. The Oregon and Washington Experiments Oregon In 1963, Carl Heller was an internationally renowned medical scientist, a winner of the important SIBA Prize. In the field of endocrinology, he was a preeminent researcher, so it is not surprising that when the AEC decided to fund work on how radiation affects the male reproductive function, they would turn to him. He designed a study to test the effects of radiation on the somatic and germinal cells of the testes, the doses of radiation that would produce changes or induce damages in spermatogenic cells, the amount of time it would take for cell production to recover, and the effects of radiation on hormone excretion. To accomplish this, he had a machine designed and built that would give a carefully calibrated uniform dose of radiation from two sides. The subject lay face down with his scrotum in a small plastic box filled with warm water to encourage the testes to descend. On either side of the box were a matched set of x-ray tubes. The alignment of the x-ray beams could be checked through a system of peep holes and mirrors. Subjects were required to agree to be vasectomized because of a perceived small risk of chromosomal damage that could lead to their fathering genetically damaged children. To carry out this work, Dr. Heller was to receive grants totaling 1.12 million over ten years. Mavis Rowley, Dr. Heller's former laboratory assistant, who was interviewed by advisory committee staff in 1994, said that the AEC was looking for a mechanism to measure the effect of ionizing radiation on the human body. She said testicular irradiation was promising because the testes have a cell cycle and physiology which allows you to make objective measurements of dosimetry in effect without having to expose the whole body to radiation. Although official documentation is fragmentary, it is clear from other evidence, such as interviews and contemporary newspaper articles, that the concerns cited above, worker exposures, potential exposures of the general population as a result of accidents or bomb blasts, and exposures of astronauts in space, were of interest to the AEC. In the case of the astronauts, the National Aeronautics and Space Administration has been able to find no evidence of direct involvement in Dr. Heller's project. Yet Mavis Rowley remembers with clarity that NASA representatives, even astronauts themselves, attended meetings with their research team. In her 1994 interview she said, NASA was also very interested in this. There was a section of activity which was devoted to what effect would the sun flares and so forth, which give out significant radiation, have on the astronauts. And so there were meetings that went on which actually included some of the astronauts attending them. Rowley explained that the astronauts were concerned that reduced testosterone production might make them lose muscle function, which could compromise their mission. But belying the comment of the colonel in the 1949 nuclear-powered airplane meeting, who said that crewmen were concerned about anything physically harmful, she said they seemed altogether unconcerned about their own health. In his 1976 deposition Dr. Heller remarked, What we would like to supply the medical community with is what happens when you give continual, very small doses, such as might be given to an astronaut. Moreover in 1965 Dr. Heller served as a consultant to a space radiation panel of the National Academy of Sciences National Research Council. And finally, Harold Bebeau, an Oregon subject, recalls that Dr. Heller told him, when he signed up for the program, that NASA was interested in the results. At the time the Oregon experiment got underway, using prisoners as research subjects was an accepted practice in the United States. And in this particular study Oregon law was interpreted by state officials as permitting an inmate to give his consent to a vasectomy, which they appear to have seen as analogous to consenting to becoming an experimental subject. However important ethical concerns of today, such as balancing risks and benefits, the quality of informed consent, and subject selection criteria, appear on the whole not to have been carefully addressed, or not addressed at all, by the investigators or those responsible for oversight. With respect to the health risks associated with the testicular radiations, there was very little reliable human information at the time about the long term effects of organ specific testicular exposure to radiation. Hiroshima and Nagasaki bomb data, however, which of course were not organ specific, suggested that the likelihood of inducing cancers with the amount of radiation Dr. Heller planned to use was small. By way of comparison, today's standard radiotherapy of the pelvis for prostate cancer, for example, often results in doses to the testicles in the ranges encountered in these experiments. So what did Dr. Heller tell subjects about the chronic risk? The answer appears to have been nothing in the early years, and later on perhaps a vague reference to the possibility of tumors, but not cancer. In a deposition taken in 1976, a subject named John Henry Atkinson said he was never told there was a possibility of getting cancer or any kind of tumors as a result of the testicular irradiation experiments. Other subjects deposed in 1976 also said they had not been warned of cancer risk, and when asked by one subject about the potential for bad effects, Dr. Heller was reported to have said one chance in a million. When asked in his own deposition what the potential risks were, Dr. Heller said, the possibility of tumors of the testes. In response to the question, are you talking about cancer? Dr. Heller responded, I didn't want to frighten them, so I said tumor. I may have on occasion said cancer. The acute risks of the exposures included skin burns, pain from the biopsies, orchitis, testicular inflammation, induced by repeated biopsies, and bleeding into the scrotum from the biopsies. Using consent forms and depositions as a basis for determining what the subjects were told, it appears that they were adequately informed about the possibility of skin burns, sometimes informed, but perhaps inadequately, about the possibility of pain, informed about the possibility of bleeding only from 1970 on, and never informed of the possibility of orchitis. As far as the quality of consent is concerned, the evidence suggests that many, if not most of the subjects, might not have appreciated that some small risk of testicular cancer was involved. It is also not clear that all subjects understood that there could be significant pain associated with the biopsies and possible long-term effects. In selecting subjects, Dr. Heller appears to have relied on the prison grapevine to get out the word about a project he apparently believed the Atomic Energy Commission did not want publicized. In a 1964 memorandum he was paraphrased as saying, at Oregon State Penitentiary the existence of the project is practically unknown. In a 1966 letter to the National Institutes of Health describing the review process at the Pacific Northwest Research Foundation, a respected, freestanding research center, Dr. Heller and two colleagues wrote that the inmates are well informed by fellow inmates regarding the general procedures concerned, i.e., collecting seminal samples, collecting urines for hormone studies, submitting to testicular biopsies, receiving medication orally or by injection, and having vasectomies. If the volunteers were healthy and normal, they were accepted for a trial period during which they donated semen samples. If all went well, in a matter of weeks they were accepted into the radiation program, as long as the prison's Roman Catholic chaplain certified they were not Roman Catholics, because of the church's objection to their providing masturbated semen samples, and they could pass what appears to have been a cursory psychological screening designed to ensure they had no underlying objections to the required vasectomy. A copy of a form titled Psychiatric Examination, provided by Harold Bebeau and signed with the initials of the examining psychiatrist, W. H. C., for William Harold Cloyde, says in full, 11464, seen for Dr. Heller, never married, quite vague about the future, feels he doesn't want children, shouldn't have any. I agree. No contraindication to sterilization. As far as potential health benefits to the subjects were concerned there were none, and the inmates who volunteered for the research were told so. The benefits were in the form of financial incentives. A review of application for Dr. Heller's program, and depositions of prisoners who sued Dr. Heller, various other individuals, and the state and federal governments for violation of their rights, clearly indicates that money was, in most cases, the most important consideration in deciding to volunteer. In prison industry inmates were typically paid 25 cents a day. For participating in the Heller program they received $25 for each testicular biopsy, of which most inmates had five or more, plus a bonus when they were vasectomized at the end of the program which appears to have been an additional $25. Some inmates indicated that they were grateful for an opportunity to perform a service to society. An obvious ethical question is whether the money constituted a coercive offer to prisoners. During the course of his study between 1963 and 1973 Dr. Heller irradiated 67 inmates of the Oregon State Prison. Normally three institutes had some oversight responsibility for Dr. Heller's work. The Oregon Department of Corrections, the Atomic Energy Commission, and the Pacific Northwest Research Foundation where Dr. Heller was employed. Practically speaking, however, it appears that Dr. Heller conducted his research independently. As an example of his independence, as recounted by Ms. Rowley, the AEC requested that Dr. Heller begin irradiating subjects at 600 rad and work upward, but he refused, and in the end set 600 rad as an upper limit. It is not clear whether Dr. Heller was concerned about risk to the subject health or other research criteria. Dr. Heller was also a member of the Committee at Pacific Northwest Research Foundation that had responsibility for overseeing his research, giving him a voice in the oversight process. This Committee was authorized under a foundation regulation titled, Policy and Procedures of the Pacific Northwest Research Foundation with regard to investigations involving human subjects. In a section on ethical policy the document says, Since 1958 the investigators of this foundation have conducted all research under the ethical provisions of the Nuremberg Code, modified to permit consent by parents or legal guardians. In January 1973, in a rapidly changing research ethics environment, the Oregon Irradiations were terminated when Amos Reed, Administrator of the Corrections Division, ordered all medical experimentation programs shut down, essentially because he concluded that prisoners could not consent freely to participate as subjects. It is not known exactly what was behind the timing of Reed's decision, but according to Oregon Times Magazine he had recently read Jessica Mitford's article in the Atlantic Monthly titled, Experiments Behind Bars, in an article in the Portland, Oregonian, headlined, Medical Research Provides Source of Income for Prisoners. In 1976 a number of subjects filed lawsuits effectively alleging poorly supervised research and lack of informed consent. In their depositions they alleged, among other things, that prisoners had sometimes controlled the radiation dose to which they were exposed, that an inmate with a grudge against a subject filled a syringe with water instead of novocaine, resulting in a vasectomy performed without anesthetic, and that the experimental procedures resulted in considerable pain and discomfort for which they were not prepared. These suits were settled out of court in 1979. Nine plaintiffs shared $2,215 in damages. For the last twenty years all efforts to put in place a medical follow-up program for the Oregon subjects have been unsuccessful. Dr. Heller and Ms. Rowley explicitly favored regular medical follow-up. During the period between 1976 and 1979 the pending lawsuits might have been the reason for the state's reluctance to initiate a follow-up program, but it is less clear why during other periods such efforts have also failed. Two possible reasons suggested by state officials are the cost of such a program and the difficulty of finding released convicts. Other possible reasons are that a follow-up program would not provide a significant health benefit to former subjects and that it would not provide significant new scientific knowledge. According to Tom Toomes, administrator of the Corrections Division of the State of Oregon at the time of the lawsuits, the Corrections Division wrote to the AEC's successor, the Energy Research and Development Administration, in early 1976 recommending medical follow-up for the subjects. Mr. Toomes said there was no record of a response to this request. In 1990 James Ruttenberg, an epidemiologist at the Centers for Disease Control, designed a follow-up program for Oregon, but it has not been implemented. In an interview with advisory committee staff Dr. Ruttenberg said state officials told him that Oregon does not have sufficient funds to carry out his plan. CHAPTER IX Washington C. Alvin Paulson was a student of Carl Heller at the University of Oregon in the late 1940s and in the early 1950s he was a fellow in Heller's Lab. But by 1963 he was ready to direct a substantial research program on his own. His chance came when he was called to Hanford to consult on an accidental radiation exposure of three workers. The upshot of this experience was a $505,000 grant from the Atomic Energy Commission to study the effects of ionizing radiation on testicular function. Dr. Paulson remarked in the 1994 interview with advisory committee staff that the main research questions he was trying to answer were what would constitute a reasonably safe dose of ionizing radiation to the testes, as well as what dose would cause some change in sperm production and secondly to determine the scenario of recovery. He recalled a 1962 letter to the Washington State Department of Institutions in which he wrote that he would like to find out the maximum dose of radiation that would not alter spermatogenesis and the maximum dose of radiation that affects spermatogenesis but only temporarily. Dr. Paulson said in a 1995 telephone interview however that for reasons he could no longer remember he limited dosage to 400 rad not enough to test a maximum dose thesis. In the 1994 interview Dr. Paulson said, When I recognized a tremendous void of information relative to human exposure and space travel had started and there was the question of solar explosions and ionizing radiation exposure in space. The nuclear power plants were going in then, a few men throughout the world were exposed. I then contacted the Atomic Energy Commission to determine whether they would entertain receiving an application. Obviously Dr. Paulson too was interested in the space applications of his research. In 1972 he and a colleague published their work titled, Effects of X-ray Irradiation on Human Spermatogenesis in the Proceedings of the National Symposium on Natural and Manmade Radiation, a NASA-sponsored symposium. And Dr. Paulson said that when he explained his research to potential subjects one of the things he referred to was concern about exposures in space. An August 1st 1963 article in the Oregonian about the Washington experiment said, Although one of the primary benefits of the research will be in space exploration, the findings are also expected to be a value to an atomic industry where an occupational hazard might exist. One major difference between the Heller and Paulson projects was that from the outset Dr. Paulson planned to eventually move from X-rays to neutron irradiation, which among other things is more analogous than X-rays with the radiation encountered in space. A neutron generator was purchased, calibrated, and shielding was developed. However the work took years to complete and this part of the research was never carried out. Dr. Paulson has expressed the belief on a number of occasions that one reason his project was terminated by the State of Washington in 1970 was concern about the possibly greater risks of exposing subjects to neutrons. Another difference was that Dr. Paulson used a standard General Electric X-ray machine, which he says he believed would deliver as precise and well targeted a dose of radiation as Dr. Heller's specially designed machine. Still another difference was that at a certain stage of the Washington study Dr. Paulson used the prison bulletin board to advertise for volunteers. Under the headline, Subject, Additional Volunteers for Radiation Research Project, a notice said, in part, The project concerns effects of radiation on human testicular function and the results of the project will be utilized in the safety of personnel, working around atomic steam plants, etc. It is possible that those men receiving the higher dosages may be temporarily or even permanently sterilized. It should be understood that when sterilized in this manner a man still has the same desires and can still perform as he always has. Submit to surgical biopsy. This is a simple procedure performed under local anesthesia. It is not a very painful procedure. According to a March 9, 1976 report, prepared for then Governor Daniel J. Evans by Harold B. Bradley, Director of the State's Adult Corrections Division, neither Dr. Paulson's 1963 outline of his research project nor the November 1964 announcement to inmates mentioned a requirement to undergo a vasectomy at the end of the experiment to ensure that subjects would not father genetically damaged children. Dr. Paulson said he did not recall precisely when in the recruitment process the vasectomy requirement was conveyed to subjects, but he pointed out that once it was they had the option of dropping out of the project without penalty. Dr. Paulson's review process and consent procedures are less well documented than Dr. Heller's, but he says his research application, including provisions for subject selection and consent, was approved by what he described as a human experimentation committee at the University of Washington. He said the process was very informal, noting that it was done over the phone. Paulson added that, somewhat later, his work was also reviewed by a Radiation Safety Committee. His recollection of both processes is vague. The minutes of a December 10, 1969 meeting of a University of Washington Research and Clinical Investigations Committee at the U.S. Public Health Services Hospital in Seattle includes a recommendation that Dr. Paulson's consent form be modified to indicate that a risk of carcinoma of the testes exists, although it is extremely small. According to Mr. Bradley's report, his department's records show that Dr. Paulson's project was reviewed and approved on two occasions, March 1963 and June 1966, by the University Hospital Clinical Investigation Committee. The report shows no State Department of Institution's review until mid-1969. The Bradley report and related correspondence from 1970 show that at that time some State officials had a sharp concern for research ethics. In mid-1969 a review of all experimentation in the prison system was undertaken by Dr. Audrey R. Holiday, Chief of Research for the Department of Institutions. At this time Dr. Holiday took steps to temporarily halt the irradiation phase of the project. After investigating the origins of Dr. Paulson's research, Dr. Holiday asked the University of Washington to conduct a new review of the study, emphasizing her concern about the State's responsibility to safeguard human rights. The University stood by its initial findings allowing the research to continue, although at about the same time it turned down Dr. Paulson's request to move into the neutron irradiation phase of his project. Dr. Holiday then debated the issue with Dr. William Conte, Director of the Department of Institutions, who was disposed to allow the project to continue. On March 18, 1970, she wrote a letter to Dr. Conte noting, There is no question but what the federal government has made considerable investment in this project. The federal government, however, as a reading of any newspaper will show, has supported a number of projects over which there have been many moral ethical questions, both large and small raised, e.g. nerve gases, toxins, etc. I remind you that the federal government is not responsible for the care, safety, and safeguarding of human rights of populations under the purview of the Department of Institutions. This is a responsibility we must discharge, regardless of the amount of money that the federal government is willing to invest in a project. There is no doubt but what the prison setting is an ideal setting for this type of research. I suppose concentration camps provided ideal settings for the research conducted in them. If, in fact, non-inmates were to volunteer in the substantial number of persons Dr. Paulson needs, then I would have less qualms about offering up a captive population for this research, i.e. I would have some evidence, assuming the volunteers were, in fact, normal, that non-captive populations might make the same decision as a captive population. I am not against high-risk research. I have engaged in some myself. I am not against federally sponsored research. I have engaged in some myself. However, the risk should be commensurate with the probable benefits to be received by the populations or others like it to follow. I don't think we can argue that in this case. Neither am I opposed to the use of a prison population, on a volunteer basis, for research projects that may not be of direct benefit to the population, but which are of clear benefit to society or mankind. I don't think we can argue that in this case, either. Dr. Holliday also argued that the study should have been done on lower-order primates and that if the state allowed Dr. Paulson's study to continue, it would forfeit its right to speak out on behalf of human rights relating to future research proposals. While favoring continuation of Dr. Paulson's research, Dr. Conte authorized a review by the Department of Institution's Human Rights Review Committee. The committee recommended that the study be shut down, noting that the Paulson project seems clearly inconsistent with the standards laid down by the Nuremberg Code for the protection of human subjects with respect to freedom of choice and consent. The recommendation went on to say that within the context of Dr. Paulson's project, it is largely irrelevant whether or not a volunteer declares his desire to undergo vasectomy, since there is no assurance that his real reasons would be ethically, morally acceptable, or that his reasons, whatever they may be, will stand the test of reality after release. It specified that the money paid for participation and the expectation of privileges, real or imagined, could constitute undue inducements. This review, according to the report, recommended that Dr. Paulson's request for continuation of his study be rejected, as it was found to be inconsistent with standards for the protection of the individual as a research subject. The essential issue raised by departmental personnel was that of informed consent. On March 23, 1970, Dr. Holliday wrote to Dr. Paulson to inform him that his project was over. The Bradley report added that, so far as is known to departmental personnel, no ill effects have been reported by subjects of the experiments. In 1994, however, a former Washington state inmate, named Martin Smith, told Carendorn Steele of the Spokane Spokesman Review that ever since participating in the experiment he has suffered testicular pain. Dr. Paulson notes, however, that Smith was a control and therefore not actually irradiated, although he did have one testicular biopsy. There has been less debate than in Oregon on the subject of medical follow-up. This may be in part because Dr. Paulson has taken the position, based on his conversations with inmates, that the subjects of the Washington experiments want their privacy protected, and he has refused to disclose their names. A December 1975 AEC memorandum from Nell W. Fraser, a government contract administrator, to Oscar J. Bennett, director of the contracts and procurement division, paraphrases Dr. Paulson as saying that a follow-up program was not medically indicated, and a follow-up program would be harmful because most of the prisoners wish to disassociate themselves with the prison experience. According to the memorandum, Dr. Paulson also noted that his medical malpractice insurance would apply in the event that litigation resulted from his radiation study. In recent years, however, a handful of former subjects have told reporters, such as Karen Dorn Steele, that they would like to be followed up. In late 1994, state officials said they would seek federal funds to carry out a follow-up program, or ask the Department of Health and Human Services to mount such a program. The advisory committee conducted its own analysis of the risks incurred by the Oregon and Washington testicular irradiation subjects, based on a 600-rem dose, which was the maximum testicular exposure of any subject in either state. For purposes of this analysis, we assumed that the testicles have an average radiation sensitivity, that there is a linear relationship between cancer incidence and dose, and that there is a linear relationship between the risk of cancer and the amount of tissue exposed. Using these assumptions, we calculated that it would take more than double the dose received by any prisoner subject to yield an effective dose of one rem. This means that the predicted increase over the expected cancer rate for the individuals who received the greatest exposure would be less than four hundredths of one percent. For those who received smaller doses of radiation, the risk would of course be smaller too. Other Radiation Experiments There is no comprehensive list of radiation experiments with prisoners as subjects, but in the course of the advisory committee's historical research a handful of such experiments other than those in Oregon and Washington has been identified. In many cases there is only fragmentary information available, which the committee has not always been able to verify. To provide a sense of what else might have been going on at the time, which may or may not have been representative, consider the following. A former prison administrator in Utah has confirmed that experiments were conducted on prisoner subjects in the late 1950s or early 1960s in which blood appears to have been removed, irradiated, and returned to the body. Prisoners at the time, who were interviewed by the Deseret News, a Salt Lake City newspaper, said they believed that about ten prisoner volunteers were studied in this way. One subject said, they told us nothing about the tests, they just said it wouldn't bother us. In a 1959 confidential report to the President of the University of Utah, Lowell A. Woodbury, the Radiological Safety Officer said, one group of medical experimenters with authorization for human experimentation was administering isotopes to volunteers at the State Prison. This was in direct violation of the terms of their license, and while not an extremely serious violation, was apt to result in a citation from the Atomic Energy Commission. Experiments were conducted at the Medical College of Virginia in the early 1950s under the sponsorship of the Army and possibly the Public Health Service using radioactive tracers. The goal was to study the life cycle of red blood cells. As discussed in more detail in Chapter 13, Dr. Everett I. Evans, in a letter to the Superintendent of the State Penitentiary, quoted from a letter from Colonel John R. Wood of the Army Surgeon General's Office, which provided that no information related to research being conducted for the Army Surgeon General be released without review by the Public Information Office of the Defense Department. Dr. Evans said, the reason for this was that the problem of the use of prisoner volunteers is not yet clarified. During the 1960s, prison volunteers in the Colorado State Penitentiary were used as subjects in an experiment designed to determine the survival time and characteristics of red blood cells during periods of rapid red cell formation and during periods of severe iron deficiency. Red cells transfused into normal recipients were tagged with either radioactive iron or radioactive phosphorus. In a 1976 report on the study, which used five subjects, the investigators wrote, the rights of the prisoners were respected in conformance with the Helsinki Declaration of the World Health Organization and the Nuremberg Code. Approval was obtained from the Governor, Attorney General, and Director of Institutions of the State of Colorado, the Warden and Psychiatrist of the Colorado State Penitentiary, and the nearest of kin of each volunteer. It is not clear from this publication or other documents available to the committee precisely what use was made of the principles stated in the Nuremberg Code and the Declaration of Helsinki in obtaining the consent of the prisoner subjects in this experiment. However, if the investigators did accept Nuremberg and Helsinki as standards for consent in the 1960s, it adds weight to other evidence. For example, the citation of Nuremberg by the Human Rights Review Committee for the Department of Institutions in the Washington Testicular Irradiation Experiment that these standards were considered relevant to research on prisoners in the 1960s. Other federally-sponsored experiments on prisoner volunteers appear to have been conducted in Pennsylvania, Holmesburg State Prison, the effects of radiation on human skin, Oklahoma, Oklahoma State Penitentiary, routine metabolic studies of experimental drugs using tracer amounts of radionuclides, Illinois, Statesville Prison, measurements of radium burden received from drinking water, and California, San Quentin, tracking movement of iron from plasma to red blood cells using a radioactive marker. Final Report of the Advisory Committee on Human Radiation Experiments Case Studies, Chapter 9, Part 3 History of Prison Research Regulation Dr. Paulson reported in a recent interview that he had asked a lot of people in 1963 about the use of prisoners as research subjects. He went on to say that at that time no one said no to the use of such subjects in his research. However, Dr. Paulson explained in the same interview that he had started to sense a shift in public opinion around 1970. In particular, he pointed to comments critical of prison experimentation that he had heard at a New York Academy of Sciences conference, New Dimensions in Legal and Ethical Concepts for Human Research, which he attended in the spring of 1969. Of course, we cannot rely solely on Dr. Paulson's recollections to provide historical context for experiments in which he was so intimately involved, and which have now become controversial. But ample evidence suggests that Dr. Paulson was essentially correct in his impression that testicular irradiation experiments in Washington and Oregon reached a transitional period in the history of human experimentation generally, and particularly in the history of experimentation in American prisons. Isolated incidents of prison-based research before World War II formed the foundation for a practice that would become firmly embedded in the structure of American clinical research during World War II. Perhaps the most significant wartime medical research project in which American scientists employed prisoners as research subjects was centered in Illinois' Statesville Prison. Beginning in 1944, hundreds of Illinois prisoners submitted to experimental cases of malaria as researchers attempted to find more effective means to prevent and cure tropical diseases that ravaged Allied forces in the Pacific Theater. In 1947, a committee was established by the Governor of Illinois to examine the ethics of using state prisoners as research subjects. The committee was chaired by Andrew Ivey, a prominent University of Illinois physiologist and the chief expert witness on medical ethics for the prosecutors at the Nuremberg Medical Trial, where prison research was a salient topic. C. 2 The committee pronounced the wartime experiments at Statesville Prison ideal in their conformity with the newly adopted rules of the American Medical Association concerning human experimentation. The AMA rules, which Ivey had played a key role in developing, included provisions stipulating voluntary consent from subjects prior animal experimentation and carefully managed research under the authority of properly qualified clinical researchers. Perhaps most significantly, the findings of Ivey's committee were announced to the American Medical Community when the group's final report was reproduced in the Journal of the American Medical Association. The appearance of this report in the nation's leading medical journal both represented and reinforced the sentiment that prison research was ethically acceptable. Publicly aired assertions that experimentation on prisoners relied on exploitation or coercion were extremely rare in the United States before the late 1960s. One criticism of medical research behind bars did, however, emerge with some frequency. Prisoners who participated in research were somehow escaping from their just measures of punishment. Inmates were usually offered rewards in exchange for their scientific services, ranging from more comfortable surroundings to cash to early release. Perhaps the most powerful statement of the concern that convicts should not receive special treatment because they had participated in an experiment came from the AMA. In 1952 this organization formally approved a resolution stating its disapproval of the participation in scientific experiments of persons convicted of murder, rape, arson, kidnapping, treason, or other heinous crimes. The AMA was alarmed that some such criminals have not only received citations, but have in some instances been granted parole much sooner than would otherwise have occurred. In the Oregon Testicular Irradiation Experiments it appears that this recommendation against using inmates accused of heinous crimes was not always observed. It should be noted that the use of prisoners as research subjects seems to have been a uniquely American practice in the years following World War II. The large-scale successes of prison experimentation during World War II and the authoritative pronouncement of the Ivy Committee that prison research could be conducted in an ethical fashion seem to have given the practice a kind of momentum in this country that it did not have elsewhere. In other countries it seems that the first clause of the Nuremberg Code was interpreted to preclude the use of prisoners in experimentation. This clause begins with the assertion that the only acceptable experimental subjects are those who are so situated as to be able to exercise free power of choice. It is difficult to overemphasize just how common the practice became in the United States during the post-war years. Researchers employed prisoners as subjects in a multitude of experiments that ranged in purpose from a desire to understand the cause of cancer to a need to test the effects of a new cosmetic. After the Food and Drug Administration's restructuring of drug testing regulations in 1962, prisoners became almost the exclusive subjects in non-federally funded phase one pharmaceutical trials designed to test the toxicity of new drugs. By 1972, FDA officials estimated that more than 90% of all investigational drugs were first tested on prisoners. It appears that throughout the history of medical experimentation on American prisoners many inmates have valued the opportunity to participate in medical research. One must quickly add that such an observation points to the paucity of opportunities open to most prisoners. The common perception among inmates that participated in a medical experiment was a good opportunity has had an important impact on the racial aspects of prison experimentation. Because of the large numbers of African Americans in prison and the overt racial exploitation of the notorious Tuskegee syphilis study in which black men with syphilis were observed but not treated, it might be assumed that minorities predominated as research subjects in prisons. The opposite has generally been true. White prisoners have usually been overrepresented in the privileged role of research subject. In most prison studies before and during World War II it seems that all of the research subjects were white. In 1975 the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research carefully examined the racial composition of the research subjects at a prison with a major drug testing program. The commission found that African Americans made up only 31% of the subject population while this racial minority formed 68% of the general prison population. The shift in public opinion against the use of prisoners' research subjects, which began in the late 1960s, was no doubt tied to many other social and political changes sweeping the country. The civil rights movement, the women's movement, the patients' rights movement, the prisoners' rights movement, and the general questioning of authority associated with the anti-Vietnam War protests. But as has been common in the history of human experimentation, scandal galvanized public attention, brought official inquiry, and resulted in significant change. A major scandal in prison experimentation came when the New York Times published a front page article on July 29, 1969 detailing an ethically and scientifically sloppy drug testing program that a physician had established in the state prisons of Alabama. Even more sensational was Jessica Mitford's January 1973 Atlantic Monthly article. In this article, Mitford portrayed experimentation on prisoners as a practice built on exploitation and coercion of an extremely disadvantaged class. When the article reappeared later in 1973, as a chapter in her widely read book, Critiquing American Prisons, she had come up with an especially provocative and suggestive title for this section of the book, Cheaper Than Chimpanzees. Mitford, and most of the growing number who condemned experimentation on prisoners during the 1970s and after, offered two arguments against the practice. First, prisoners were identified as incapable of offering voluntary consent, because of a belief that most, some argued all, prisons are inherently coercive environments. Another line of argument was based on a principle of justice that stipulated that one class, especially a disadvantaged class such as prisoners, should not be expected to carry an undue burden of service in the realm of medical research. A few months after the publication of Mitford's article, Senator Edward M. Kennedy of Massachusetts held hearings to investigate human experimentation. Kennedy was primarily fired into action by the revelations of the Tuskegee Syphilis study, which made headlines in 1972, but he devoted one full day of his hearings to the issue of prison experimentation. The chief outcome of Kennedy's hearings was the formation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which, among other topics, was specifically charged with investigating experimentation on prisoners. The eleven commissioners, including advisory committee member Patricia King, with the assistance of twenty staff members, gathered a wealth of data on prison medical research, made site visits to prisons, held extensive public hearings, and engaged in long debates among themselves. After their deliberations, the commission concluded that it was inclined toward protection as the most appropriate expression of respect for prisoners as persons. But the commission did not call for an absolute ban on the use of prisoners in medical research. A steadfast minority on the commission held to the belief that prisoners should not arbitrarily be denied the opportunity to participate in medical research. An excursion to the State Prison of Southern Michigan, where Upjohn and Park Davis Pharmaceutical Companies had cooperatively built and maintained a large phase one drug testing facility, served to reinforce the opinions of this contingent. Encanted conversations with the visiting commissioners, randomly selected inmates spoke in convincing terms about their support for the drug testing program in the Michigan prison. The commission's final report reflected this hesitancy to call for a complete halt to the use of prisoners in non-therapeutic experimentation. The commission recommended that prisoners could be considered ethically acceptable experimental subjects if three requirements were satisfied. One, the reasons for involving prisoners in research were compelling. Two, the involvement of the prisoners satisfied conditions of equity. And three, subjects lived in a prison characterized by a great deal of openness in which a prisoner could exercise a high degree of voluntariness. The final requirement involved a detailed prison accreditation scheme intended to ensure the possibility of voluntary consent. The National Commission derived its primary power from the fact that the Secretary of the Department of Health, Education, and Welfare, DHEW, was legally compelled to respond to the commission's findings and to justify the rejection of any commission recommendations. Joseph Califano, DHEW Secretary in the Carter Administration, spent nearly a year formulating his response regarding the use of prisoners in medical research. Califano explored the possibility of an accreditation scheme as suggested by the commission. However, in a letter to the commission, Califano reported that the American Correctional Association, the one currently qualified prison accrediting organization, had no interest in accrediting correctional institutions as performance sites for medical research. On the contrary, Califano went on to explain, the ACA had recently decided it would not fully accredit any institution which permitted research on prisoners. After his interchange with the ACA, Califano ultimately decided to issue regulations that, for almost all intents and purposes, brought an end to federally funded, non-therapeutic medical research in American prisons. In the interest of uniform federal regulations, Secretary Califano also directed the FDA to issue similar rules governing the use of prisoners in research that the FDA accepted to satisfy its regulatory requirements. The FDA published final rules in the spring of 1980 that were intended, on the planned effective date of June 1st, 1981, to eliminate prisons as acceptable sites for non-therapeutic pharmaceutical testing. However, in July of 1980, almost a year before the FDA's regulations were scheduled to take effect, a group of prisoners at the State Prison of Southern Michigan filed suit against the federal government. These inmates claimed that the impending FDA regulations threatened to violate their right to choose participation in medical research. The case was settled out of court when FDA attorneys decided to reclassify the agency's prison drug testing regulations as indefinitely stayed. The FDA's regulations still exist in this bureaucratic limbo. But even before the FDA issued its proposed regulations on the use of prisoners in drug testing, pharmaceutical companies had already largely abandoned a practice that had been so widespread only a few years earlier. Most significantly, pharmaceutical researchers, along with other medical scientists, had discovered that sufficient numbers of experimental subjects could be found beyond prison walls. Students and poor people proved to be especially viable alternative populations from which to draw participants for non-therapeutic experiments, if the cash rewards were sufficient. The growing controversy surrounding the use of prisoners as research subjects combined with the realization that they could find enough alternate subjects for their needs led drug companies to make decisions that were based not so much on ethics as expediency. The comments of an administrator associated with an Eli Lilly testing operation at an Indiana prison are revealing and provide a fitting conclusion to this brief historical analysis. The reason we closed the dog-on thing down was that we were getting too much hassle and heat from the press. It just didn't seem worth it. Ethical considerations. It is quite clear that all of the radiation experiments that have come to the advisory committee's attention in which prisoners were employed as research subjects would have been in violation of federal standards as they exist today. Federal regulation stipulates an extremely limited range of permissible medical research in prison populations. Only four types of investigations can currently receive approval. 1. Low-risk studies of the possible causes, effects and processes of incarceration and of criminal behavior. 2. Low-risk studies of prisons as institutional structures or of prisoners as incarcerated persons. 3. Research on conditions particularly affecting prisoners as a class. For example, vaccine trials and other research on hepatitis, which is much more prevalent in prisons than elsewhere. And 4. Research that has the intent and reasonable probability of improving the health or well-being of the subject. Almost certainly none of the various episodes of radiation research on prisoners treated in this chapter would have fallen into any one of these categories. But as noted above, widespread concern about coercion and exploitation of prisoner subjects, which brought about these restrictive federal regulations, arose relatively recently in this country. For the period before roughly 1970 it is almost certainly unfair to condemn, in retrospect, a research program as unethical solely because researchers employed prisoners as subjects. Historical sensitivity demands some appreciation for what seems to have been a genuine lack of widespread professional or public concern for the ethical problems of prison research that came to the fore during the 1970s. Only in the case of the Washington and Oregon testicular radiation experiments do we know enough to make any legitimate claims about the extent to which researchers conformed with reasonable contemporary standards for the ethical conduct of prison experimentation. And even for these relatively well-known studies the individual complexities of each series of experiments have grown hazier with time. One of the first known efforts to examine the ethics of using prisoners as research subjects was organized by the Law Medicine Research Institute, LMRI, of Boston University. The conference was called the Participation of Prisoners in Clinical Research, and it opened on February 12, 1962. The conference was part of a larger LMRI project to study and report on the actual practices, attitudes, and philosophies currently being applied in the legal and ethical aspects of clinical investigation. See Chapter 2. LMRI's conference on prison research was one of several invitational work conferences organized to gather information on several important topics in human experimentation. Other conferences were devoted to the concept of consent, pediatric research, and pharmaceutical testing. The participants at each conference received an agenda and briefing book in advance of the meetings, but discussions tended to be free-ranging. Those who attended the conferences understood that their words were being recorded, but they tended to speak in a frank and revealing fashion, because LMRI pledged to preserve their anonymity when reporting on the meetings. A copy of the list of participants at the conference on the Participation of Prisoners in Clinical Research, which survives at Boston University, confirms the following characterization of those who attended. The 36 invited participants comprised two main categories. The first was composed of clinical research administrators and clinical investigators with a variety of academic, commercial, and governmental affiliations who have had experience in conducting medical studies with prisoners as subjects. The second category consisted of prison administrators and prison medical officers with various federal, state, and municipal correctional programs. Also participating in the conference were representatives of various related fields, such as behavioral science, criminal law, organized medicine, pharmaceutical manufacturing, and the military services. Unfortunately, a copy of the actual meeting transcript has not survived. However, the lengthy unpublished analytic summary, which contains many anonymous transcript excerpts, seems to be a fair representation of the day-long meeting. It is relatively easy to extract several important points of agreement about the proper conduct of experimentation in prisons from this report. And, given the broad cross-section of those involved in prison experimentation who attended this 1962 conference, it seems reasonable to employ the standards enunciated at this conference as evidence of prevailing interpretation of ethical standards for prisoner experiments that began in 1963. First, the conferees generally agreed that experimental risks must be balanced against benefits. In the case of research that was not intended to be a potential direct benefit to the subject, which was generally the case in prison experiments, most meeting participants believed that the social or scientific value of new knowledge that might result from an experiment should be weighed as a benefit. However, when confronted with the direct question of whether or not a relatively high degree of risk can ever constitute a legitimate reason for the use of prisoner subjects, the conferees were almost unanimous in rejecting this position. Interestingly, those at the conference believed that the general public was less inclined to worry about subjecting prisoners to high levels of experimental risk. Two brief transcript excerpts are revealing. When the public hears that inmates are participating in a seemingly very hazardous study, they rationalize, well, I wouldn't do it, but it's all right with prisoners. The public will allow the investigator to go a lot further with regard to risks taken with prisoners than the investigator would go himself. The conferees spent a large portion of their day together discussing the matter of consent. They reached agreement that meaningful consent should be both voluntary and informed, provided the reach of these terms is carefully circumscribed. The report stated, The legal prerequisites of consent are, first, not absolute free will, but sufficient free choice to avoid coercion or duress, and second, not absolutely perfect knowledge, but enough information to avoid fraud or deceit. The conference participants unanimously agreed that rewards offered to prisoner volunteers should not be so high as to invalidate their consent to participate as research subjects. There seems to have been considerable disagreement about exactly where to draw the line between ethically acceptable and unacceptable rewards to prisoners for service as experimental subjects. But there was a general desire to minimize rewards, because it was consistent with the penological desirability of maximizing prisoners' opportunity for altruism. As for sentence reductions, some thought that small amounts of good time credits were appropriate, but all agreed that maximum rewards of this type, i.e. definite promises of pardon or parole, should not be given. There seems to have been little discussion of the possibility that the authoritarian structure of prison life was in itself coercive, and therefore limited a prisoner's ability to make an autonomous decision. The disclosure component of consent received extensive attention at the conference. The following was offered as a summation of what the conferees perceived as the essential content and emphasis of the information that should be conveyed to prospective prisoner subjects. The explanation of a clinical research project should describe completely the procedures entailed, and should stress the possible consequences of these procedures. Even though it may be necessary to stop somewhere short of full revelation when you reach intricacies a layman would never comprehend, there should be no emission of any adverse consequences, detriments, or risks. To strive toward this level of communication, the conference participants cited procedures that were usually followed in most prison experiments. A general announcement of the research project to the inmates, usually by notices posted on bulletin boards or printed in prison newsletters. A general explanation of the project, often in an auditorium, to groups of prisoners who expressed initial interest in an experiment, and finally one-on-one meetings between prospective participants and research personnel. Conferees who had administered or conducted prison experiments also reported that prisoner subjects usually signed some type of consent agreement. Generally speaking, the provisions specified above were followed in the Washington and Oregon experiments, but the information provided was often inadequate. Even with all of these measures, some meeting participants asserted that the ideals of comprehension, evaluation, and decision on the part of prisoners were seldom attained in practice. They pointed to two general difficulties in achieving these ideals. First, the lack of intelligence, education, or medical sophistication among many prisoners. Second, they cited various motives or pressures which so often stand in the way of objective understanding. The participants in the conference also recognized that the consent forms used in prison experiments were often less than perfect. They understood that the waiver or release components of many forms were probably inappropriate. They also recognized that reasonably predictable risks of an experiment were not always carefully listed on consent forms, but at the same time they agreed that no serious risk should ever be disguised or concealed on these forms. In sum, the records from this conference suggest that even apart from formal federal rules for experimentation on prisoners, ethical conditions for the conduct of prison research were articulated in the early 1960s. Now, with these conditions in mind, let us turn to a more detailed analysis of the Washington and Oregon testicular irradiation experiments. As we have noted, the committee's ability to assess the quality of consent obtained from a research subject 30 or 40 years earlier can be confounded in a thousand ways. To begin with, the records are invariably incomplete. Then the investigators are either no longer alive or their memories have grown hazy or selective with time. The same is true of subjects, and of course there are confidentiality considerations which limit the availability of records, the concern of researchers for their reputations, and so on. All of these considerations to greater or lesser degrees apply to the Oregon and Washington experiments. With respect to these experiments, however, we believe we have a clear enough picture of the standards and practices of the time to evaluate the conduct of the research against them without reference to the standards and practices of today. In both Oregon and Washington some subjects were not warned, warned only after enrolling in the experimental program, or inadequately warned, that there was potential risk, albeit small, of testicular cancer. While it might not have been uncommon at the time for physicians to avoid using the word cancer with sick or even terminally ill patients for paternalistic reasons, such avoidance is harder to justify even by the standards of the time in the case of healthy subjects who are participating in research that offers them no direct benefit. As far as acute effects are concerned, the pain of testicular biopsy may have been understated in both programs, and the risk of orchidis from repeated biopsies seems to have been ignored. Some former subjects have complained of long-term pain, sexual dysfunction, and skin rashes. It is not clear whether these conditions were caused by the experiments, nor is it certain that long-term medical follow-up can answer this question. Subjects in both sets of experiments were required to have a vasectomy at the end of the program because of concerns about possible chromosomal damage. In both cases, the vasectomy consent forms signed by the subjects and their wives if they were married adequately describe the procedure, its consequences, and the small possibility it could be reversed. However, appropriate questions have been raised about the reasons inmates might agree to vasectomy in the circumstances of prison research, and the possibility has actually occurred in a number of cases that in the end the subject would refuse to undergo the procedure. Finally, there appears to be little doubt that the financial incentives offered for participation were the main reason most inmates volunteered. Payments totaling more than $100 could be seen as unduly influencing the judgment of potential volunteers. While money also is a powerful incentive for research participation outside prison walls, we believe that the conditions of confinement can magnify the perceived value of the reward. Whether the payments offered to participants in these programs constitute an unfair inducement to participate in research may vary from inmate to inmate. While the prison experiments were unethical with respect to current requirements for disclosure of risk and non-coercion, the researchers functioned during a period of rapid evolution of the interpretation of ethical principles in the prison context. Their actions, however, were less than fully consistent with the existing AEC requirements, especially concerning the information the prisoner subjects were provided.