DISCLAIMER The following is a staff memorandum or other working document prepared for the members of the Advisory Committee on Human Radiation Experiments. It should not be construed as representing the final conclusions of fact or interpretation of the issues. All staff memoranda are subject to revision based on further information and analysis. For conclusions and recommendations of the Advisory Committee, readers are advised to consult the Final Report to be published in 1995. þþþDRAFT þ FOR DISCUSSION PURPOSES ONLYþþþ MEMORANDUM TO: Members of the Advisory Committee on Human Radiation Experiments FROM: Advisory Committee Staff DATE: November 9, 1994 RE: Experiments on Prisoners A series of experiments involving testicular irradiation were conducted in the Oregon and Washington state prisons between 1963 and 1973. Although attitudes toward using prisoners in research were being reconsidered during this period, there may have been other radiation experiments under way in which prisoners were subjects. The acute and chronic effects of testicular irradiation in humans were not well understood at this time; in addition, there was considerable uncertainty about the likelihood of inducing tumors with the doses of radiation used in these experiments. This research raises important ethical questions about the selection of subjects and the quality of consent. We begin with an historical account of prison experimentation in the United States, proceed to the specific details of testicular irradiation experiments conducted in the Oregon and Washington state prisons, follow with a narrative description of these experiments and conclude with an ethical analysis. I. PRISONER RESEARCH IN HISTORICAL CONTEXT C. Alvin Paulsen, M.D., who was principal investigator for the Washington testicular irradiation experiments, reported in a recent interview with an Advisory Committee staff member 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 for his experiment. However, Dr. Paulsen 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. 1 Of course, the Committee should not rely solely on Dr. Paulsen'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. Paulsen was essentially correct in his impression that the testicular irradiation experiments in Washington and Oregon bridged 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 imbedded 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' Stateville 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 the tropical diseases that ravaged Allied forces in the Pacific Theater. In 1947, a committee was established by the Governor of Illinois and chaired by Andrew Ivy, a medical scientist and the chief expert witness on medical ethics for the prosecutors at the Nuremberg Medical Trial. The Committee pronounced the wartime experiments at Stateville Prison "ideal" in their conformity with the newly adopted rules of the American Medical Association concerning human experimentation. These rules, which Ivy himself had written for the AMA, included provisions stipulating informed and voluntary consent, prior animal experimentation, and the necessity of properly qualified clinical researchers. (See Briefing Book 7, Tab F, Attachment 2 for the complete text of these AMA rules.) Perhaps most significantly, Ivy's committee announced its approval of prison research to the American medical community in a 1948 report published in the Journal of the American Medical Association. (Attachment 6) This report 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 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." (for the full text of this resolution see Attachment 7) 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 quite clearly to the paucity of opportunities open to most prisoners. But even the National Commission for the Protection of Biomedical and Behavioral Research decided in 1976 not to recommend an absolute ban on prison research after interviewing many prisoners who argued convincingly that 2 "outsiders" should not arbitrarily deny a prisoner the opportunity to participate in medical research. Indeed, some prisoners at the State Prison of Southern Michigan, who had served as research subjects in pharmaceutical tests conducted at that institution, filed suit in 1979 in an attempt to block the FDA from regulating away their "right" to participate in drug studies. The common perception among inmates that participating in a medical experiment was a good opportunity also 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), it might be assumed that minorities predominated as research subjects in prisons. The opposite has generally been true; an over-representation of whites in the "privileged" role of research subject. In most prison studies before and during World War II, all of the research subjects were white. In 1975, the National Commission 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" comprised 68% of the general prison population The shift in public opinion against the use of prisoners as research subjects that was no doubt tied to many other social and political changes that were sweeping the country: the civil rights movement, the prisoners' rights movement, 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 29 July 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 an Atlantic Monthly cover story published by Jessica Mitford in January, 1973. 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." A few months after the publication of Mitford's Atlantic Monthly article, Senator Edward Kennedy held hearing to investigate human experimentation. Senator Kennedy was primarily fired into action by the revelations of the Tuskegee Syphilis Study, which made headlines in 1972, but he also devoted time to the issue of prison experimentation. Kennedy's hearings led to the formation of the National Commission, which, among other topics, was specifically charged with investigating experimentation on prisoners. As mentioned earlier, the National Commission did not recommend an absolute ban on the use of prisoners as research subjects. Instead, the Commission called for non-therapeutic research to be limited to prisons that were characterized by a "high degree of voluntariness . . . and openness." The Commission enumerated criteria that a prison would have to meet in order to qualify as a legitimate locus for medical experimentation. After consultation with the American Correctional Association, Secretary of Health, Education and Welfare (HEW) Joseph Califano decided that such an accreditation scheme was not practical. At Califano's direction, HEW produced regulations in 1978 that severely restricted federally funded prison experimentation, a policy that continues to the present. (45 CFR 46, Subpart C) 3 II. SPECIFICS OF THE EXPERIMENTS A. Experiment of Carl G. Heller, Oregon State Penitentiary (OSP) 1. Objectives To determine the nature of the cytological changes, both somatic (Sertoli cell) and germinal (spermatogonia) induced by acute irradiation. To determine the dosage required to produce these changes, as well as the dose to induce permanent damage to spermatogenic cells. To determine recovery time. To determine radiation-produced testicular alteration of such parameters as total gonadotropin, interstitial-cell hormone excretion, estrogen excretion and androgen excretion. 2. Methodology Subjects received varying doses of X-irradiation to both testes from 8 to 600 rad single dose. Testicular changes were determined by histological (light microscopy) examination of pre-and serial post -irradiation biopsy specimens. Sperm counts, motility, morphology and seminal fluid volume were monitored in serial post-irradiation ejaculates. Hormonal excretion was to be monitored by serial urine and plasma analyses. Radiation exposure was controlled by a specially constructed device that assured uniform (+ 5%) irradiation at a dose rate of 100 r/min, approximately 140 kVp with 5 mA tube current, and 2mm A1 filter. Some subjects received 10 uCi 3H-thymidine injected (?) intratesticularly to assess (via autoradiography) effects of irradiation on incorporation into spermatogonia. Subjects agreed to be vasectomized at completion of study. Irradiations were performed by a medical radiotherapist. 3. Number of subjects Total: 74 subjects, 42 subjects received > 100 rad to testicles, 67 subjects were analyzed. Age range: 25-52 years. 4 4. Dates Irradiations were performed August 1963 and May 1971. 5. Rationale for the use of human subjects To determine radiosensitivity of germinal elements in man. According to Dr. Heller, an expert in testicular function, man is unique among commonly studied species such as rat, rabbit, guinea pig, ram, bull, or stallion, in being able to submit to serial testicular biopsy without excessive damage and biopsy-induced testicular artifacts. To determine germinal cell recovery, thereby allowing prognosis in cases of accidental irradiation. 6. Oversight C.T. Gladden, Warden D. Dilaconi, Chief Medical Officer, OSP E.K. Vollmar, Radiological Consultant, OSP Radiation Committee, Oregon State Board of Health T. Dotter, Chief, Department of Radiology, University of Oregon Medical School Mr. Bobbitt, Legal Consultant of OSP Medical Examiners Secretary of the Oregon State Medical Society 7. Consent Signed consent forms were used. The staff has three versions, two of which do not mention risk of cancer. (Attachment 1) The other form lists various risks including "the possibility of testicular tumor," but the list appears on the rear and the subject signed only the front of this form. Moreover the date on the back of the example is ten months later than the date on the front raising questions about whether at least some subjects were never shown this list. While the first form included agreement to submit to vasectomy, which is described as a "tying off of the cords," the second form mentions vasectomy on the back saying, "Subject informed of need for vasectomy " and "Subject informed of consequences of vasectomy." 8. Findings Sperm count reduction and recovery of sperm count is dose related. At 400-600 rad, sperm count was zero at 156 weeks. By autoradiographic studies of 3H-thymidine uptake into spermatocytes in non- irradiated subjects, it was shown that there are approximately 4 cycles of spermatogenesis of approximately 16 days each, so that the complete evolution of spermatogonia to mature sperm is approximately 64 days. This is approximately the same as other mammalian species. 5 Urinary and plasma gonadotropins rose in proportion to testicular dose and fell with germinal recovery Plasma FSH and LH also rose. Urinary estrogen remained unchanged. Urinary testosterone fell slightly after irradiation. Histologically, spermatogonia were the most radiosensitive. Spermatocytes were damaged above 200-300 rads. Spermatids showed no overt-damage. Germinal cell recovery time increased as irradiation dose increased. Complete recovery occurred within 9-18 months for doses of 100 rad and below. Complete recovery required 5 or more years for doses of 400-600 rads. Germinal tissues in man appear to be somewhat more radiosensitive than other studied species. 9. Financial Support Contract AST (45-1) 1780, US Atomic Energy Commission: Rowley, MJ; Leach, DR; Warner, GA; Heller, C.G.; Effect of graded doses of ionizing radiation on the human testes, Radiation Research 59:665-678, 1974. (Attachment 2) B. EXPERIMENT OF C.A. PAULSEN, WASHINGTON STATE PENITENTIARY 1. Objective To determine the dose dependent relationship between external irradiation and cell kill and inhibition of mitosis. (Attachment 3) 2. Methodology Subjects with normal ejaculates received 7.5 -400 rad to both testes. The details of irradiation are not specified. Weekly seminal fluid was examined for the end-point response of azoospermia. Duration not specified. 6 Subjects and some controls received periodic unilateral testicular biopsies. Number not specified. irradiated subjects agreed to be vasectomized at completion of the experiment. 3. Number of Subjects Sixty-four subjects, 145 controls. 4. Dates Irradiations were performed between 1963 and 1970. 5. Rationale for the Use of Human Subjects One cannot directly relate animal data to the human male with security. Among other things, the rate of spermatogenesis in man is different from that in various animal species. 6. Oversight Not specified in grant application. Paulsen recalls informal conversations with human research committee at University of Washington. 7. Consent The two consent forms in staff's possession are vague, except for the description of the consequences of vasectomy, which, where it is mentioned, is technical. The subject's spouse is asked to agree to the vasectomy. (Attachment 4) 8. Finding The average pre-sterile period was 142 days. The maximum sterile period was 501 days. Spermatogenesis in man is more radiosensitive than in rodents and recovery time is longer. Man is more radioresistant to complete sterility than rodents. Testicular biopsy by itself can reduce seminal fluid sperm concentration. 9. Financial Support AEC contracts AT (45-1)-1781 and AT (45-1) 2225 7 10. Advisory Committee Staff Notes Risk estimate: The staff was not able to determine the long range potential for the development of testicular tumor or for testicular hormone failure in these subjects. Based on extrapolations from Hiroshima and Nagasaki data it is presumed that the risk of oncogenesis is low or non-observable. The Hiroshima and Nagasaki exposures were not organ specific, however, and require imprecise extrapolations to estimate risk. There is less uncertainty about the risk of cancer now than at the time the experiments were conducted because of longer follow up time (staff could find no references to radiation oncogenesis to the testicles). The risk of acute orchitis attendant upon repeated testicular biopsy may be greater than the radiation hazard. The radiation doses to individual subjects is for the most part documented and this information is available for those subjects who may be interested. A reasonable estimate of potential effects grouped by dose of irradiation and hormones injected also could be given. The names, radiation doses and other drugs administered to many of the subject inmates is apparently retained by the Oregon CDC. A follow-up study of the Oregon subjects has been proposed. (Attachment 5) Standard radiotherapy of the pelvis, e.g., for prostate cancer, often results in doses to the testicles in the ranges encountered in these experiments. III. THE WASHINGTON AND OREGON EXPERIMENTS As noted previously, testicular irradiation experiments were conducted on 131 volunteer inmates of the state prisons in Walla Walla, Washington and Salem, Oregon. Both sets of experiments began in 1963. The Washington experiments ended in 1970 and the Oregon experiments ended in 1973. Sixty of the 64 Washington subjects received a single exposure from an external X-ray source ranging from 7.5 rads to 400 rads (there were four sham irradiations). Each of the 67 Oregon subjects received either single or multiple exposures totaling from 8 to 600 rads. A small number of Oregon subjects (probably two or three) also had tritiated thymidine injected into their testes to label germinal cells. All of the subjects were healthy, non-Catholic male adults and none was more than 52 years old 8 when accepted into the program. All of the subjects in both experiments agreed to have vasectomies because of concern about chromosomal damage. Vasectomies were done in all cases in the Oregon experiments, but 11 Washington subjects did not have vasectomies. The principal investigator for the Oregon experiments was Carl G. Heller, M.D., and his budget was approximately $1.12 million. C.A. Paulsen, M.D. was the principal investigator in Washington and his funding was approximately $505,000. The Atomic Energy Commission was the sole funding source for both sets of experiments. While the two research projects appear to have been similar, and joint meetings were held with an AEC oversight team, they were conducted independently. The AEC's interest in the studies appears to have been related to, at least, occupational and space exposures to ionizing radiation. The research objectives of the two investigators, as expressed in their contract applications, were related to testicular function. Although there is no documentary evidence to support involvement by the National Aeronautics and Space Administration, there is evidence that NASA was interested in the experiments. Dr. Heller's grant application (Attachment 8) and his nine-year progress report (Attachment 9) specify an interest in the effects of ionizing radiation on spermatogenesis. His research associate, Mavis Rowley, said in an interview in September 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 and effect. . .without exposing the whole body to radiation" and because "if you could draw a parallel between the testes of humans and the testes of research animals, then you could draw a parallel to the rest of the body of the research animal to the human." Rowley also noted that the AEC wanted Dr. Heller to begin with doses of 600 rads and work up from there, but that Dr. Heller refused. It is not clear whether he was concerned about risk to the subjects' health or other research criteria. Dr. Paulsen remarked in a September interview 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." His research objectives are described in more detail in his grant application (Attachment 3) and on an AEC fact sheet (Attachment 10). When asked in the same interview how the project began, Dr. Paulsen 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." Hints of NASA interest in the experiments have been around from the start. An article in the Portland Oregonian in August, 1963 about the Washington experiments said "Although one of the primary benefits of the research will be in space exploration, the findings are also expected to be of value to any type of atomic industry where an occupational hazard might exist." In a deposition taken shortly before his death, 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." 9 (Attachment 11, p. 91) During her interview, Ms. Rowley said, "NASA also was 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 and efforts that went on which actually included some of the astronauts attending them.. . . ." Rowley explained that the astronauts were concerned about losing muscle function because of a reduction in testosterone production, which could compromise their mission, but she said they seemed altogether unconcerned "about their own health." Dr. Paulsen does not remember astronauts or other NASA representatives attending joint meetings, but there might have been meetings involving only the Oregon team with the AEC oversight team. A report on Dr. Paulsen's prison experiments titled "Effects of X-Ray Irradiation on Human Spermatogenesis," was published in 1972 in a NASA-sponsored symposium titled Proceedings of the National Symposium on Natural and Manmade Radiation (NAS 2440, pp. 229-232). (Attachment 12) As a final note on this matter, Harold Bibeau, an Oregon subject who has become an advocate for the prisoner-subjects, has claimed that when he signed up for the program Dr. Heller told him NASA was interested in the results. Some questions about how the experiments began remain unresolved. Dr. Paulsen stated he became interested in doing work on the effects of radiation on testicular function after a 1962 accident at Hanford during which three men were irradiated. He said he was called in as a consultant because of a chapter he had written on the testes in an endocrinology text. Dr. Paulsen claimed he then contacted the AEC to see if the agency would consider funding a study on how radiation affects testicular function. Ms. Rowley's recollection, however, is that she was told the AEC had contacted both Dr. Heller and Dr. Paulsen to ask them if they were interested in conducting studies on how ionizing radiation affects the testes. During his 1976 deposition, Dr. Heller said that the AEC held a conference in 1963 for researchers using radiation on animals in reproduction studies. At that meeting, Dr. Heller said, he asked: "If they wanted to know about man, why not work on man?" As a result, he continued, the AEC "got together a formal meeting to see what we might do, what questions we might answer with our setup in Salem." In any event, both Dr. Heller and Dr. Paulsen applied for funding and both received contracts. Dr. Heller's contract was through the Pacific Northwest Research Foundation in Seattle and Dr. Paulsen's through the University of Washington. Dr. Heller's radiation research program at the Oregon State Prison followed on the heels of a hormonal research program at the same institution that began in 1957 and on which Dr. Paulsen was an assistant to Dr. Heller. The Board of Control, which oversaw the Oregon prison system in 1957, approved the research with the understanding that all subjects would be volunteers. In Dr. Heller's 1963 application to the AEC, he stated that he consulted widely to make sure there were neither legal nor ethical barriers to his proposed research. (Attachment 8, p. 17) He also specified that consent forms would be used and signed by the subjects. Various concerns were raised by prison officials, but answers acceptable to these officials were provided. 10 The precise method of subject selection is somewhat vague, but financial incentives were involved. According to a consent form signed by Harold Bibeau on Sept. 29, 1965, he was to be paid $5 a month, $10 for each biopsy and after vasectomy, $100. In his 1963 grant proposal to the AEC, Dr. Heller requested $200 "per individual subject to pay for exposure to radiation." Wages in Oregon's prison industries at the time were 25 cents a day. One of the forms in staff's possession warns that vasectomy causes sterility, and may be irreversible. Cancer is not mentioned, except on the back of one of the forms. The back of the form is not signed by subjects, thus there is no way of knowing if the subjects saw it. A document titled Policy and Procedures of the Pacific Northwest Research Foundation With Regard to Investigations Involving Human Subjects, says in a section titled "Ethical Policy": "Since 1958 the investigators of this Foundation have conducted all research under the ethical provisions of the Nuremburg (sic.) Code, modified to permit consent by parents or legal guardians." (Attachment 13) This document also provides for independent review of research. The review committee for Dr. Heller's project includes Dr. Heller as a member. (Attachment 14) Dr. Paulsen's review process and consent procedures are less well documented, but he says his research application, including provisions for subject selection and consent, were approved by what he described as a "Human Experimentation Committee" at the University of Washington. He said the process was "very informal," adding that it was done over the phone with no written evidence. Paulsen added that "somewhat later" his work was also reviewed by a "Radiation Safety Committee." His recollections of both processes are vague. (We are seeking additional information from the University of Washington.) The three consent forms we have from the Paulsen project are blank and lacking in detail, except in the case of vasectomy, where the language is reasonably detailed, but technical. With respect to radiation-induced injury, the forms say only "I acknowledge that said experimentation may result in permanent sterility and/or other injuries," or "I do hereby acknowledge the possibility of hazardous consequences. . . ." (See Attachment 4) There is no mention of cancer and Dr. Paulsen has acknowledged that at least in the early years, subjects were not told that cancer was a possible result of testicular irradiation at the levels at which they were being exposed. Payments similar to those in Oregon were made to the Washington subjects. In January, 1973, the Oregon irradiations were terminated when Amos Reid, Administrator of the Corrections Division, ordered all medical experimentation programs shut down because he concluded that prisoners could not consent freely to participate as subjects. In July, 1969, Dr. Paulsen was barred by the University of Washington from applying to the AEC for additional funding to use neutron irradiation instead of X-ray irradiation because the risks were said to outweigh the benefits. (Attachment 15) Some concern was also expressed about risks incurred in the X-ray experiments that Dr. Paulsen had been conducting since 1963. Dr. Paulsen's original grant proposal included funding for neutron irradiation. A neutron machine was purchased and sent to Hanford for calibration and the development of shielding. However, this work took years to complete and this part of the research was never carried out. In 1970, a review committee of the Washington prison system stopped the X-ray irradiation . In 1976, a number of Oregon subjects filed lawsuits alleging a lack of informed consent. These suits were settled in 1979. Nine subjects shared $2,215 in damages (Attachment 16, p. 7). There have not been any law suits involving Washington subjects. 11 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 law suits might have been the reason for the state's reluctance to initiate a follow-up program, but it is not clear why during other periods such efforts have also failed. Two possible reasons suggested by state health officials are the cost 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 Toombs, Administrator of the Corrections Division of the State of Oregon, the Corrections Division wrote to the AEC's successor agency in early 1976 recommending medical follow-up for the subjects. (Attachment 16, p. 11) Mr. Toombs said there was no record of a response to this request. He said a similar request was made to Pacific Northwest Laboratories and again there was no record of a response. In 1990, James Ruttenber, a CDC epidemiologist designed a follow-up program for Oregon, but it has not been implemented. (Attachment 5) Dr. Ruttenber said he was told by Oregon officials that the state had insufficient funds to carry out his plan. Dr. Paulsen takes the position that the subjects of the Washington experiments want their privacy protected. As a result he has never released their names so that a follow-up program could be put in place. A review of Paulsen's research initiated by Gov. Dan Evans in 1976 (a copy of this report is on its way to the Committee) recommended that follow-up be undertaken by the AEC, but no follow-up occurred. IV. ETHICAL ANALYSIS The conceptual framework for ethical analysis of the case studies is based on a memorandum in Briefing Book vol. 7, Tab G, "Approach to Ethical Analysis of Historical Cases in Light of Current Ethical Standards." A. Harm-Benefit While there was a general awareness that radiation could cause malignancy at the time the prisoner experiments were undertaken, the likelihood of harm due to radiation exposure to the testes, including long-term cancer or hormonal failure, was unknown. There was an understanding of the remote possibility of chromosomal damage, hence the requirement that the subjects agree to a subsequent vasectomy. The resultant loss of fertility may have been a harm to some of these men. Others expressed a desire to have a vasectomy. A description of acute effects of irradiation was not provided in these studies. However, at high dose temporar No medical benefits to the subjects were anticipated as a result of study participation. B. Subject Selection The method of subject selection is not entirely clear, although there seems to have been some reliance on the prison grapevine and financial incentives were offered. According to Harold Bibeau's consent form, for example, he was to be paid $5 a month, $10 for each biopsy, and $100 following a vasectomy, for a total financial payment of at least $115, depending on the number of biopsies performed. Wages in prison industry at that time were 25 cents a day, for a maximum of $5.25 per month for a 5-day work week. 12 Under current regulations selection of prisoners as subjects for this research project would not be permitted, and even if such research on prisoner-subjects was authorized, this level of financial compensation might not be allowed. (For details, see Current Regulations below.) C. Information Disclosure Five consent forms are in the possession of the Advisory Committee, two used by Dr. Paulsen and three used by Dr. Heller. There is no explanation of the nature or potential harms of the experiment on the forms used by Dr. Paulsen, one of which asserts that the "nature and consequences" of the experiment have been described to the subject. We have no reliable record of what may have been said to potential prisoner-subjects by way of an oral disclosure. The form also acknowledges the uncertainty of medical experiments and expresses the subject's assumption of risk. An Oregon consent form signed by Harold Bibeau in 1965 includes information on vasectomy. (Attachment 1) It is described in layman's language as "tying off of the cords." There are no statements about possible harms from the radiation itself, other than "skin burn." Only Dr. Heller's consent form, dated June 18, 1970, mentions that there are hazards associated with the biopsy, including pain and internal bleeding. There is no mention in the form of the danger of infection. On the reverse side of the form there is an itemized list of potential harms of irradiation, drug administration, and testicular biopsy. This list does include the risk of infection, but it is dated April 22, 1971. (Attachment 1) It is not possible to tell if or when subjects had an opportunity to read the reverse of this form. Today what is known about the nature and likelihood of possible harms must be explicitly stated in the consent form. Curiously, a later Heller form entitled "Agreement for Radiation Program," dated July 1972, does not mention potential harms at all. (Attachment 1) None of these forms meet the level of disclosure that would be considered adequate today. D. Consent Inadequate disclosure invalidates any apparent consent by a research subject and inappropriate incentives constitute an undue inducement thereby compromising the voluntariness with which consent is granted. This is even more emphatically the case when there is no intended benefit for the subject and some risk of significant harm. 13 E. Prior Review It appears that Dr. Paulsen's 1963 research application, including provisions for subject selection and consent, was approved by the human experimentation committee at the University of Washington, but the process was highly informal. It consisted of a telephone conversation. Paulsen does not remember meeting with the committee in subsequent years, nor does he remember submitting written applications for renewal. (Staff is seeking additional information from the University of Washington.) Dr. Heller's 1970 study was approved by the Review Committee for Investigations Involving Human Subjects of the Pacific Northwest Research Foundation. F. Current Regulations In order to receive IRB approval today, prison experiments must meet several conditions, including: (1) any advantages of participation are not of such a magnitude that they would affect one's ability to weigh the risks of the research; (2) the risks are commensurate with those that would be acceptable to non-prisoner volunteers; (3) procedures for subject selection within the prison are fair; (4) the information is presented in a manner that is understandable to the subject population; (5) there is adequate assurance that the parole board will not take subject participation into account; and (6) there will be appropriate follow-up care (45 CFR 46, Subsection 46.305(2)-Attachment 18). These prisoner experiments did not appear to meet all of these conditions. In order to receive approval by the Secretary of Health and Human Services today, prison experiments must be one of these four types of research: (1) studies of the possible causes and effects of incarceration and criminal behavior; (2) studies of prisons as institutional structures or of prisoners as incarcerated persons; (3) studies of "conditions particularly affecting prisoners as a class"; or (4) studies of practices with a "reasonable probability of improving the health or well-being of the subject." (45 CFR 46, Subsection 46.306(A)-(D), Attachment 18) These prisoner experiments did not appear to meet any of these conditions. VI. CONCLUSION A prison experiment could only be approved today if it met the conditions stated above. 14