Memorandum to ACHRE from Rebecca Lowen, Consultant to the Advisory Committee: Discussion of the Ethics of Human Experimentation in the Medical and Scientific Literature (Best Available Copy) TAB D-6 TO: Advisory Committee on Human Radiation Experiments FROM: Rebecca Lowen, Consultant to the Advisory Committee SUBJECT: Discussion of the Ethics of Human Experimentation in the Medical and Scientific Literature This research is based on articles and editorials in the Journal of the American Medical Association (JAMA), the New England Journal of Medicine (NEJM), the Annals of Internal Medicine (ANNALS), and Science, between 1946 and 1970. The aim is to provide a guide to the extent and nature of discussion within the medical and scientific communities regarding the ethics of human experimentation. The period 1946 to 1970 is divided into three sections. In the first period, 1946 to 1953, articles and editorials focussed on the behavior of doctors in Nazi Germany and discussed the Nuremberg Code and its relevance to the American medical community. These articles were largely defensive, stating the importance of human experimentation to the advancement of medical science, arguing that the behavior of Nazi doctors was a manifestation of the evil of totalitarianism rather than of human experimentation, and claiming that America's purported democratic culture ensured that human experimentation in the U.S. would be unlikely to pose ethical or moral problems. Medical journals for the period 1953 to 1963, roughly, revealed little discussion of the ethics of human experimentation. In the third period, beginning in 1964 (after reports that doctors from Sloan -Kettering had experimented on patients at the Jewish Chronic Disease Hospital in Brooklyn without their informed consent), medical journals and Science revealed considerable discussion of the ethics of human experimentation and renewed discussion of the Nuremberg Code. This discussion, in contrast with those of the 1946-1053 period, revealed clear disagreement within medical and scientific communities over the ethics of human experimentation, with a few individuals pointing to numerous ethical violations, others pondering the ethical issues involved, and still others (including editorials in medical journals) objecting to the critics and insisting that ethical breached were highly unusual. I. 1946-1953 During this period, the ethics of human experimentation were discussed. largely in the context of the activities of Nazi doctors and the Nuremberg trials. A prominent contributor to this discussion was Dr. A.C. Ivy, who had been the U.S. representative 1 to the doctors' trial at Nuremberg. The general conclusion drawn was that what had happened in Germany could not happen in America because American culture was democratic and focussed on the individual, and thus that American doctors regarded their patients as "ends" and not as "means." The December of 1946 issue of JAMA provided a brief account of a meeting of the AMA's Judicial Council in 1946, at which Dr. Ivy reported on human experimentation in Nazi Germany. JAMA reported that the Council found the experiments described by Ivy to be "absolutely opposed" to the Principles of Medical Ethics of the AMA, and "to be condemned." The Council also declared that for human experimentation to conform to AMA ethics, three requirements had to be met: the experiment had to obtain consent from the subject; human experimentation had to be preceded by animal experimentation' and any experiment had to be performed under proper medical protection and management. This report contained no specific mention of the Nuremberg Code. (JAMA, 28 Feb 1946; 132: 1090.) In November 1946, JAMA's editor, Morris Fishbein, provided a brief history of the AMA's medical ethics. This article mentioned that in 1946, the AMA House of Delegates called upon the AMA's Judicial Council to rewrite the AMA's Principles of Medical Ethics. This article made no mention of the Nuremberg Code, nor did it mention, specifically, human experimentation. (JAMA, 30 Nov 1946; 132:783.) In July 1948, Science published "A History of Ethics of the Use of Human Subjects in Medical Experiments," a paper by Dr. A.C. Ivy for a symposium on Human pharmacological Experiments at the March 1948 meeting of the Federation of American Societies for Experimental Biology. This article may best be read as a defense or both human and animal experimentation. Ivy asserted that the advancement of medicine (and of modern civilization) depended on controlled experimentation on animals and human volunteers. Ivy criticized Nazi Germany for forbidding animal experimentation while permitting human experimentation; he also linked opposition to animal experimentation to the "barbarism and paganism" of the Dark Ages. (1) In defense of human experimentation, Ivy asserted that experimentation is inherent in the doctor-patient relationship; controlled experiments should be seen as an extension of, rather than a departure from, the traditional doctor-patient relationship. In discussing the ethical guidelines for human experimentation (on "volunteers" such as medical scientists and students, soldiers and sailors",) Ivy claimed that all such experiments were conducted according to "certain ethical principles in all countries of the world." (3) Ivy outlined these principles, noting that they were identical to those rules adopted by the AMA's House of Delegates in 1946 and introduced at the Nuremberg trails. 2 The last section of Ivy's paper dealt specifically with the use of prisoners for experimental purposes. Ivy stated that experimentation on prisoners, provided that the prisoners had volunteered, should be recognized as having "reformative" potential for the prisoners, and thus should be permissible. Prison volunteers deserved a reward for participating in experiments (but the reward should not be so large as to induce prisoners to volunteer). (Science, 2 Jul 1948; 108:1). Ivy's specific attention to the use of prison volunteers may have been a response to criticism from a Soviet scientist. (Science News Letter, 21 Feb 1948; p. 117). In February 1948, under "Special Articles," JAMA also addressed the issue of prison volunteers, reporting on the work of the Green Committee (a committee appointed by Governor of Illinois Dwight Green, to explore the ethics as the use of prisoners in medical experiments). Members of the Green Committee included A.C. Ivy, Morris Fishbein, and several religious leaders. The Green Committee emphasized that prisoners' participation in experiments should be uncoerced. The committee judged that volunteering for an experiment could be considered evidence of reformation and thus might deserve reward (such as a shorter prison term); the committee did not view such reward to be a subtle of coercion. The committee determined that experiments on any subjects (prisoners, medical students, soldiers) should be in accord with the rules adopted by the AMA House of Delegates in 1946. (These three rules were reprinted in the JAMA article.) (JAMA, 14 Feb 1948; 136:457.) "Nazi War Crimes of a Medical Nature," by A.C. Ivy was the lead article in JAMA on 15 January 1949 (139:131). In this article, Ivy attempted to explain how the highly respected German medical profession became so degraded under the Nazi regime. He dismissed the Nazi doctors' defense--that all physicians, including American doctors, experimented on human subjects--saying that, while the U.S. Air Force and Army has experimental laboratories, as had the Luftwaffe and the Whermsaht, in America doctors obtained consent from human subjects and experimented first on animals. Ivy also drew a distinction between human experimentation in a totalitarian state (fascist or communist) and in a democratic one: "medicine in the democratic state has never been allowed to forget the individual." (131) (In Ivy's view, the "system of state medicine in Germany was in part the cause of...the medical atrocities" committee under the Nazi regime." (134) In October 1951, a symposium on "The Problem of experimentation on Human Beings was held at the Medical Staff Conference, Division of Medicine University of California at San Francisco. Among the invited speakers were Drs. Michael B. Shimkin and Otto E. Guttentag of USCF, and Alexander M. Kidd, School of Law, University of California at Berkeley. (The papers from the symposium were published in Science, 27 Feb 1953; 117:205.) The premise of the three papers was that human experimentation, as well as animal experimentation, was necessary for the advancement of medical science. 3 In Shimkin's view, considerable prejudice against human experimentation existed among the general public and also within the medical and scientific communities. ("The use of human beings for experimental purposes often encounters vigorous opposition. Proposal of such investigations, even to groups trained in scientific disciplines, may result in outright rejection or in the suggestion that animal experiments, that a priori can be seen to be inadequate for the solution of the problem, be substituted." (205)) Because of these "traditional, unanalyzed attitudes, " scientific studies using human subjects could be "inordinately difficult to initiate and to perform," in Shimkin's view. Moreover, because of attitudes about human experimentation, researchers were likely to fail to report "untoward results" of their studies in order to avoid criticism. (205) Shimkin then presented arguments in favor of human experimentation, stating, as had A.C. Ivy, that experimentation is inherent in the doctor-patient relationship, and thus to conduct controlled experiments was in some sense an extension of, rather than a departure from, the traditional doctor-patient relationship. ("There is no basic difference between the experiment on an individual patient and the extension of the experiment to a group of similar patients." (205)) Noting that in absolutist states, experimenters has abused human subjects, Shimkin insisted that `abuse does not preclude use." 9205) He then suggested guidelines for human experimentation, citing the Nuremberg Code (reprinted in full in Science), the ethical guidelines adopted by the AMA in 1946, and the report of the Green Committee. While Shimkin emphasized the similarity between controlled experimentation on humans and the experimentation involved in a physician's treatment of an individual patient. Guttentag emphasized the ethical issues raised by the dissimilarity between the doctor-patient relationship and the experiment-subject relationship. In Guttentag's view, the doctor-patient relationship was a relationship between "two I's, like that between lovers, friends, pupil and teacher," and thus the relationship entailed the "mutual obligations of equals." (208) The relationship between human subject and researcher was, in contrast, "impersonal and objective," and thus open to possible abuse. (208) As a check against abuse, Guttentag proposed that research and patient care never be pursued by the same doctor for the same person, and that subjects of experimentation retain their original physicians as personal advisors. Guttentag also addressed the issue of experimentation on humans in the absence of informed consent and in the case of coercion. In his view, "apparently no problem exists in American culture. I think the overwhelming majority of physician-experimenters...are so deeply rooted in the democratic spirit that they agree and will continue to agree, that the use of force is not justified on a single person, even if millions of other lives could be saved by such an act." (209) 4 Guttentag did question whether obtaining informed consent from a lay person was truly possible given the complexity of medical science, and concluded that the gap between a doctor's and a patient's medical understanding could be bridged only by a patient's faith in his doctor. He suggested that patients sign forms stating their understanding of the proposed experiment and that these forms also carry the physician's "affirmation of his utmost effort to protect the patient from harm." (210) In "Limits of the Right of Person to Consent to Experimentation on Himself," Kidd discussed the importance of informed consent, commenting that consent, even if written rather than oral, might not be adequate if the researcher/physician had failed to disclose fully the medical procedure or treatment. Kidd noted that he had "doubt whether the printed forms of consent are adequate in some cases." Moreover, he believed that "in many medical cases this consent is not obtained." (211) Kidd distinguished between experiments conducted by physicians with respect to individual patients as part of their medical treatment, and those experiments conducted for purposes other than the patient's welfare. Although Kidd advocated informed consent in both cases, he noted that experimentation by a physician on a patient's behalf was not condemned by law. Noting that experimentation of no benefit to the human subjects involved was not illegal, and that a court of law would not necessarily condemn such experiments, Kidd warned the medical profession to "consider carefully whether, as a matter of good public relations, nothing should be done to a patient except for his benefit, and whether he should not be used either directly or indirectly as a guinea pig without his consent." (212) Finally, Kidd addressed the question of experimentation on persons for reasons other than their welfare but with their informed consent, stating that it unclear, legally, the extent to which a person could consent to serious injury to oneself. While the use of prisoners, racial minorities, or religious groups for experiments resulting in death had been "universally condemned," Kidd also believed that "we would probably agree that the poor, the aged, the insane, and the feeble-minded should not be guinea pigs for experimentation," because it was unclear whether these people could freely volunteer and give informed consent. Kidd believed that prisoners were usually capable of giving informed consent but warned that consent must not be coerced. II. 1953-1963 There was little discussion of the ethics of human experimentation during this period either in medical journals or in Science. (Popular magazines and the New York Times during this period published a number of human interest" stories on human experimentation, usually focusing on the motives of the "volunteers.") The articles and editorials that did appear in the medical and scientific literature in this period have no particular theme beyond a concern with human experimentation. 5 In October 1960, Science ran an editorial (written by social scientist Dael Wolfle) on psychological research involving human subjects. While in the case of medical experimentation, guidelines had been established, these guidelines were inadequate for human psychological experiments, Wolfle asserted. For example, providing subjects with information about the experiment, and seeking their consent, might well influence the results of a psychological experiment. However, failure to seek informed consent raised ethical problems, the editorial admitted, because some psychological experimentation entailed "some danger to the subjects." The editorial concluded by endorsing the concept of "liability without fault" which had been suggested in an article in Duke Law Journal (#2, 1960). Under this concept, if a subject would be entitled to compensatory damages, provided through government channels. The experimenter would thus be protected from law suits; the experimenter would not be regarded as at fault but as having acting "in the interest of society." (Science, 14 Oct 1960; 132.) In November 1963, the lead JAMA editorial (written by Harvard University medical professor Henry K. Beecher) focused on the ethics of "placebo operations", which Beecher believed were common. Of particular concern to Beecher was a proposed study, involving 1,000 patients, of the effect of thymectomy for myasthenia gravis. Beecher did not oppose experimentation on patients; the editorial objected only to the involvement of such a large number, given Beecher's estimate of 75 surgical deaths per 1,000 operations. Beecher proposed experimenting on fewer patients (25 thymectomies, 25 controls) with the expectations of a death rate of one or two per 50 operations. Beecher noted that there was "an understandable reluctance to engage in sham procedures of any kind, "but argued that provided that the experiment was well-planned and that patients were fully informed of the nature of the experiment, it should be undertaken in the expectation of eliciting valuable information useful in saving lives. III. 1964-1970 After a ten-year period of little discussion of the ethics of human experimentation in the medical journals or in Science, the subject became the focus of considerable attention after the widely publicized revelations regarding experiments conducted by Sloan- Kettering physicians on patients at the Jewish Chronic Disease Hospital in Brooklyn who had not given informed consent. (The experiment involved injecting chronically ill patients with live cancer cells, to observe the rate at which their bodies rejected foreign cells.) The doctors involved reportedly informed the patients only that they would be injected with "some cells". When the experiments came to light (after three physicians at the hospital resigned in protest) the Sloan-Kettering physicians insisted that they had obtained oral consent. It was then discovered that the patients involved were senile, spoke no English or for other reasons could not have given consent. 6 In February 1964, Science writer Elinor Langer provided a detailed report of the controversy; Science also printed the Nuremberg Code. The article concluded by raising the question as to whether the Nuremberg Code provided adequate guidance in specific situations, pointing to the uncertain legal status of experimentation, and asking whether failure to obtain informed consent was typical. (Science, ILLEGIBLE Feb 1964; 143:551). In reply to Science, Emmanual E. Mandel, research director of the Jewish Chronic Disease Hospital and the person who had arranged for experimentation on the hospital's patients, wrote to the editor to insist that the fact that patients had not been told that they were being injected with live cancer cells was irrelevant because the cells "represented homologous tissue" and were thus certain to be rejected by the patients. Mandel also insisted that the experiment posed no danger to the patients involved, a fact which he believed made informed consent less important. He also argued that not telling patients that the cells were cancer cells constituted conventional practice. For example, the fact that exposure to radioactive substances might increase the risk of contracting leukemia, or that the injection or penicillin might occasionally result in severe illness or even death was not usually imparted to patients before their subjection to these procedures. In reply to Mandel, Langer noted that Mandel's examples involved procedures intended to help the patient, in contrast to the experiments conducted on patients at the Jewish Chronic Disease Hospital. Also responding to the Science article was USCF's Otto Guttentag, who addressed the issue of whether physicians were obligated to submit themselves to the same experiments that they were conducting on human subjects. (The Sloan-Kettering physicians had been reported as saying that they had not injected themselves with live cancer cells because that procedure was not entirely risk-free and that they did not want to take the risk themselves, given their value to society as medical researchers). While noting that, from the scientific point of view, self-experiments served no useful purpose. Guttentag believed that they were necessary so that physicians realized that there was no difference between the value of the physician's existence and that of his experimental subjects. (Science, 21 Aug 1964; 145:768). In February 1966, Science reported on the New York Board of Regents' decision, made after hearings by the Department of Education's medical grievance committee, that the experiment conducted on patients at the Jewish Chronic Disease Hospital represented a violation of medical ethics. According to Science, the physicians involved in the experiment defended themselves 7 before the medical grievance committee by claiming that "no clear- cut medical or professional standards were in force" to be violated. Also, several well known researchers (University of Pennsylvania's vice-president for medical affairs, I.S. Ravin, and director of Roswell Park Memorial Institute, George E. Moore) testified that the practices of Sloan-Kettering physicians did not differ dramatically from those of other researchers. These arguments were rejected by the Regents; Science reprinted in full the Regents's decision. (Science 11 Feb 1966; 151:663). Between 1964 and 1969, a number articles and editorials on the ethics of human experimentation appeared in JAMA, NEJM, and ANNALS. None opposed human experimentation. Those in NEJM and ANNALS; however, raised important questions about the ethics and morality of human experimentation and advocated adherence to articulated ethical codes. JAMA was more defensive, insisting that most experiments involving human subjects adhered to ethical standards. In 1965 and 1966, NEJM ran two "specific articles" on the subject: "Ethical Problems in Human Experimentation," by Paul A. Freund, a lawyer (NEJM, 23 sep 1965; 273:687), and "Ethics and Clinical Research," by Henry K. Beecher, Harvard Medical School (NEJM, 16 June 1966; 274:1354) as well as an editorial on the ethics of human experimentation. Freund, whose article was prompted by the experiments at the Jewish Chronic Disease Hospital noted that the law did not provide clear rules with respect to human experimentation, but emphasized that in other areas, the law was conservative and "deeply protective of human integrity and life." (688) In the case of experiments conducted by physicians in the course of treating a patient, Freund suggested that the most recent and best formulation of a physician's responsibility had been articulated by the representative body of the British Medical Association in 1963. Among the BMA guidelines mentioned by Freund was that statement that "the patient should never take second place to a research project." Further, before embarking on any research, a doctor, according to BMA rules, should ask himself (a) whether the patient knows what the physician proposed to do; (b) whether the physician had explained fully and honestly the risks involved for the patient; (c) whether the patient has given consent freely and in a manner legally valid; and (d) is the procedure to be done one that the physician would unhesitatingly acquiesce to if it were to be undertaken upon the physicians on family members. (690) In the case of experimentation no therapeutic benefit to the subject, the Nuremberg Code was the appropriate guide, according to Freund. Focussing on the provision regarding disclosure and consent, Freund did point to some difficulties such as those posed by "double-blind" experiments, experiments on subjects (children, the mentally incompetent) unable to give informed consent, and whether paying subjects (such as prisoners) amounted to a form of coercion. 8 Freund also suggested possible safeguards against abuses of human subjects in addition to obtaining informed consent. He suggested requiring approval I am designated independent medical authorities for any proposed experiment involving human subjects. He also called for the publication of all research involving human subjects, regardless of the nature of the experimental results. Finally, Freund referred to the Nazi experience. In contrast to previous articles which had discussed the crimes of the Nazi doctors and asserted that doctors in America would never commit such abuses, Freund warned that the Nazi experience was not "wholly irrelevant. That was the hideous pathology of an attitude that, unchecked, can cause great physical and moral suffering." (692) Beecher was similarly concerned about a lack of attention to ethics in human experimentation his article documented twenty-two examples of unethical experimentation on human subjects, drawn from leading medical schools, university hospitals, the Army, Navy, and Air Force, the Veterans Adminstration hospitals, governmental institutes and industry. (Beecher's concern in this article was with "experimentation on a patient not for his benefit.") "Evidence is at hand that many of the patients...never had the risk satisfactorily explained to them and it seems obvious that further hundreds have not known that they were the subjects of an experiment although grave consequences have been suffered as a direct result of experiments." (1354) Beecher referred to a statement by Pope Pius XII warning that science did not possess greater value than other endeavors, but in fact, should be subordinate to other values. In Beecher's view, the quantity, and the amount of money expended on, experiments using human subjects has increased significantly since World War ILLEGIBLE. He suggested that the funds available far exceeded the number of responsible investigators, and speculated that pressure on your researchers to publish in order to obtain promotions and tenure thus resulting in unnecessary grant-seeking and experimentation. In contrast to Freund, Beecher argued that the results of human experiments in which researchers failed to uphold ethical standards should not be publish. Also, in 1964, the NEUM published a report of an experiment involving the removal of the thyroid gland from children who were to undergo operations for congenital heart problems, in order to study the effect of the thymus on the human immune mechanism. A reader then wrote to the editor raising ethical concerns about the experiment (asking whether ILLEGIBLE standard hazards, such as unnecessary immunization against isoantigens, were sufficiently offset by the usefulness of the ILLEGIBLE to be obtained, and whether the unknown, long-term hazards had been noted and explained to the subjects involved). These questions were pertinent, according to the writer, because the medical literature was "flooded with reports of human experimentation based in many cases 9 upon inadequate laboratory data and with insufficient attention to the long-term hazards. In response, the editor of NEUM addressed the question of the morality of human experimentation. He concluded that the Nuremberg Code provided inadequate ethical guidance because it had been formulated in response to the activities of Nazi doctors, whose goal had been genocide rather than healing or the advancement of medical science. Thus, the Code too easily drew distinctions between "good" and "bad" medical practice. The editor also questioned particularly the provision of the Code calling for obtaining the voluntary, informed consent of human subjects, noting that physicians could easily persuade a person to give consent against that person's best interests. The editorial concluded by suggesting that research be conducted "with an understanding of the duty owed to the subject by the conscientious investigator that will leave his conscience clear." (NEJM, 1964: 270: 07, 1014, 1018). In 1966 ,ANNALS ran a "special article" and an editorial on the experimental use of human beings. "Some moral Dimensions of Medicine," (by Samuel E. Stumpf, Department of Philosophy and the Medical School, Vanderbilt University; ANNALS, Deb 1966; 64:460), raised the question: "What are the permissible limits and the proper conditions for experimentation on human beings?" (460) It was Stumpf's opinion that, while "there was a time when `good' medical practice was the same as `customary' practice, it is now frequently the case that `customary' practice is, in an objective sense, bad practice." Stumpf then discussed three examples of human experimentation--the case of thymectomies on children which were unrelated to the patients therapy and had no customary justification; the case of the experimentation without informed consent on patients at the Jewish Chronic Disease Hospital; and a double-blind experiment giving antibiotics to patients undergoing corrective heart surgery. Although the latter experiment resulted in the death of two patients, Stumpf argued that loss of life should not be a determinant of a good or bad experiment. In his view, it was this experiment of the three described that had the intent of advancing medical science and that also "met the test of affirming and protecting life." Stumpf concluded by focusing on the issue of consent. While raising the possibility that patients might not have the right to consent to a procedure that could harm them, he also insisted that the act of giving consent is what is entailed in being a person, and that to fail to obtain consent was thus to treat a person as a "thing". (469) The ANNALS editorial (Aug ILLEGIBLE; 65:371) similarly endorsed experimentation on humans, but emphasized moral and ethical considerations. The editorials endorsed the Declaration of Helsinki (the code of ethics adopted in 1964 by the World Medical Association); the declaration was reprinted in the August 1966 10 issues of ANNALS. The editorial mentioned specifically three rules of conduct: (1) the experimenter must have proper medical and scientific training, and the experiment must have adequate design and scientific background; (2) the patient must be fully informed and must freely consent; and (3) the risks posed to the patient must be commensurate with foreseeable gains in knowledge. The editorial referred to a rising concern, among scientific and medical professionals as well as among "intelligent lay people", about the ethics of human experimentation, and noted the AMA national conference on ethics held in Chicago in March 1966 and plans of the American College of Physicians to hold a symposium on the ethics of human experimentation in April 1967 in San Francisco. The main concern of the editorial was that, now that the public was so alert to the ethical issues, might it be hard to continue to use human subjects in experiments? It concluded by noting the dual role of the physician--to advance medical science and to protect life, health and human dignity, it suggested that when these two roles came into tension, the individual physician, guided buy the Helsinki principles, must decide how to act. This editorial received endorsement in a December 1966 letter to the editor. Dr. Michael Brennan, an oncologist, wrote to urge additions to the principles mentioned: the requirement that suitable facilities be used for human experimentation, and that all results be published. He also suggested that diagnostic tests and exploratory surgery be included under the rubric of human experimentation. In a "critical commentary" for JAMA ("Ethics, Consent, and Controlled Clinical Trial," 7 Nov 1966; 198:169), Dr. Maxwell Finland of Harvard Medical School expressed annoyance with recent, specific indictments of immoral and unethical medical practices issued by medical practitioners. (Although Dr. Henry K. Beecher was not mentioned by name, in NEUM) In Finland's view, no doctor had a right to judge another doctor; he also questioned Beecher's competence to judge experiments outside his own field. ("Judge not, that ye be not judged." (633) Finland emphasized that there were many conscientious experimenters whose work would be impeded by the new regulations that were being proposed as a result of heightened public concern about human experimentation. He also argued that the complaints of ILLEGIBLE" were receiving undue attention from the media, and that the voice of the conscientious physician/experimenter was not being heard. Finland also questioned the importance of informed consent, noting difficulties posed by double-blind and placebo experiments. Science returned to the issue of human experimentation in January 1967, with an article by Wolf Wolfensberger, a medical psychologist at the University of Nebraska's Psychiatric Institute. ("Ethical Issues in Research With Human Subjects", Science, 6 Jan 1967; 155:47). In Wolfensberger's view, the ethics of human 11 experimentation was "still rather virgin territory", for which adequate guidelines were lacking. As of 1963, the only scientific organization that had officially adopted an ethical code was the American Psychological Association. The Nuremberg Code, according to Wolfensberger, had never officially been adopted by any scientific or professional group. In the absence of clear rules or codes, researchers has "muddled along in the belief or hope that procedures and conventions either in common use or approved by their peers were proper and ethical". (47) It was also assumed that procedure entailing risk could be made acceptable by having the experimenter share in the risk with the subject, or by using volunteers. In 1967, it was no longer safe to make such assumptions, according to Wolfensberger. Both the scientific community and use "intelligent lay public" had serious concerns about the use of volunteers, the sharing of risk, and the adequacy of peer approval. These concerns had been triggered by several developments--the censure of two esteemed Sloan-Kettering physicians by the Regents of the University of the State of New York ("A landmark in the development of codification of ethics in research" (47); revelations about Project Camelot; the psychological testing movement; and recent publicity over cruelty to research animals. Wolfensberger was particularly concerned with experimentation on human subjects with impaired mental abilities. He conducted a nationwide survey of public attitudes toward behavioral research involving the mentally retarded [Wolfensberger, et al, Mental Retardation, 3 (6), 7 (1965)], which revealed "strong concern for the need to safeguard the rights and integrity of retarded subjects". (48) When the ILLEGIBLE "experiment" was mentioned connection with a handicapped individual, survey responses were, according to Wolfensberger, "not only strong and emotional but at times absolutely irrational". ILLEGIBLE institutions were required to adhere to such sentiments, that would be forced to "exclude virtually all activity identified as research", Wolfensberger warned. (48) Noting the growing tension between concerns for individual rights and the "long-range interests of society, science and progress," Wolfensberger suggested a code of ethics involving ten rules that might eventually be accepted by the AAAS: (1) the more deleterious an experimental effort may be to a subject, the more precautions the researcher should take; (2) "risk-sharing" between subject and experimenter should not be seen as releasing the experimenter form obligation to the subject; (3) the more serious the right that the researcher ILLEGIBLE a subject to surrender, the more effort should be devoted to the problem of consent. In rules (4) through 910), Wolfensberger addressed the problem of consent, suggesting in which instances consent was and was not necessary. ("Wolfensberger suggested that consent was not necessary when experimental activities or procedures used that are not consciously recognized or labelled "research when the activity/procedure was so universal that it could be said to constitute accepted practice, when patient had surrendered ILLEGIBLE autonomy (as in the armed 12 services) (Level 1). Wolfensberger suggested the use of a routine release form in cases where the activity/procedure was identified as "research", but the research was close to the mainstream of knowledge, well-tried and known to be harmless. (Level 2) He suggested a specific and detailed release in cases where the research was believed to be risky to the subject, the procedures were untried, or the outcome was unpredictable. (Level 3) Wolfensberger's article provoked several letters to Science on 31 May 1967 (155:1617). One writer did not address the article specifically but defended human experimentation as necessary to the advancement of science. Another pointed out that "level 1" research in fact produced more avoidable damage than did research levels 2 and 3. A third argued that, with respect to "level 3" research, obtained consent was less significant than either using volunteers or requiring the experimenter to experiment first on himself. In response, Wolfensberger insisted that the use of volunteers, end even fully enforced volunteers did not relieve the medical and scientific community from exploration of the moral and ethical issued posed by human experimentation. In late 1967 and late 1969, NEJM reported, without editorial comment, information about federal regulations regarding human experimentation, in a column called "Law Medicine Notes". (NEJM, 2 Nov 1967; 277:974; NEJM, 2 Nov 1969; 281:781). In late 1967 and late 1969, JAMA published several articles on human experimentation which focused on specific types of subjects- prisoners and children. "Why Prisoners Volunteer to Be Experimental Subjects", by Dr. John C. McDonald of SUNY Buffalo (JAMA, 6 Nov 1967; 202:175) sought to put to rest concerns raised by medical colleagues over the use of prisoners as experimental subjects. ("I became rather perplexed by the reaction of colleagues to the program [involving experiments on inmates at a New York state prison]. There was considerable interest in why inmates subjected themselves to such experimentation. The question most frequently raised concerns what rewards were given to such volunteers, and the prevailing attitude seemed to be that this was a group of men who were simply being exploited, albeit for a good cause"). McDonald insisted that prisoners did not see themselves as exploited, but found volunteering had intrinsic rewards, including a break in their monotonous routine, and a boost to their egos. Also published in this issue of JAMA was a report, "The Use of Prisoners for Medical Research," Drs. R.E. Hodges and W.B. Beam, which detailed the use of prisoners for research by the University of Iowa and assured readers that "this has been a rewarding experience both for the physician and for the subjects". (179) In October 1969, JAMA address the issue of "Experimentation in Children", (by William J. ILLEGIBLE and H.K. Beecher; JAMA, 6 Oct 1969; 10:77). The authors point out that ethical guidelines and legal principles regarding human experimentation were vague with 13 respect to the standards for the use of children in clinical investigation. (They also ILLEGIBLE that the much-cited M.H. Pappworth's Human Guinea Pigs, London, 1967) stated erroneously that the law, in England and America, clearly stated that parents could not give valid legal consent to any action not for the immediate benefit of the ILLEGIBLE concerned. The authors then proposed a set of guidelines as to when a minor could or could not give consent, and when parents could or could not give consent. Finally, between 1969 and 1970, two articles in Science addressed the issue of compensation for subjects injured in the course of an experiment: "Human Studies", by Henry K. Beecher (Science, 13 Jun 1969; 164:256), and "Compensating Persons Injured in Human Experimentation", by Clark C. Havighurst, professor of law, Duke University (Science, 10 Jul 1970; 169:153). Beecher's article objected to the reliance, by jurists and legal writers, on case law which abjured experimentation in the treatment of patients. According to Beecher, this formulation was based on cases in which doctors has experimented on patients in the absence of consent and with the patients believing that they were receiving conventional therapy. Beecher, echoing A.C. Ivy's earlier pronouncements, insisted that the practice of medicine required experimentation. Beecher was thus interested in considering how subjects harmed in the course of experimentation might be compensated. Beecher cited the concept of "liability without fault", first introduced in a 1960 article in the Duke Law Journal. He also noted that there was precedent or institutional or governmental provision of insurance. (He cited the allowances for liability insurance made in grants by the NIH under the 1957 Price-Anderson amendments to the Atomic Energy Act; the purchase of liability insurance by the National Foundation for Infantile Paralysis before embarking on Salk Vaccine ILLEGIBLE studies; and an NIH study of seatbelts for which accident insurance was purchased.) The article by Havighurst similarly emphasized the importance of compensation, and noted that in the past decade of discussion about experimental ethics, this issue had been virtually ignored. havighurst also endorsed the ILLEGIBLe of shifting responsibility, in the case of harm to a subject, from the individual investigator, to a larger group, in this case, not just "society", but specifically, the entire "research industry"--educational institutions, corporations, the federal government, philanthropic groups. He suggested that the research industry should not wait for changes in the law, but should simply assume the burden of compensation for injury that was currently being ILLEGIBLE by the injured subjects. He also suggested that the USPHS and the FDA review their policies and consider requiring experimenters or institutions to purchase insurance, and that medical centers allocate part of their research budget for the purchase of insurance. 14