PAPERBACK
$34.00 • #### Table of Contents • #### Front Matter R1-R12 • #### Executive Summary 1-7 • #### 1 Introduction 8-25 • #### 2 Health Effect of I131 Administration in Humans 26-42 • #### 3 The Ethics of Human Subjects Research 43-61 • #### 4 Conclusions and Recommendations 62-66 • #### 5 References 67-74 • #### A. Thyroid Function in Health and Disease 75-80 • #### B. Summary of the Public Session 81-86 • #### C. Thyroid Radaition Dose Estimates for I131 87-87 • #### D. Secretary of Defense Letter 88-91 • #### E. Informed Consent Elements of Disclosure 92-94 • #### F. Principles for the Conduct of Research in the Arctic 95-98 • #### G. Biographical Sketches of Committee Members 99-100 • #### H. Glossary 101-104 The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001 Copyright Â© National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole. Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages. Do not use for reproduction, copying, pasting, or reading; exclusively for search engines. OCR for page 43 The Ethics of Human Subjects Research This Committee was asked to determine whether the AAL thyroid function study "was conducted in accordance with generally accepted guidelines for use of human participants in medical experimentation," and whether participants had been notified about possible risks. This aspect of the ComTnittee's charge proved to be particularly challenging. Determining whether the }~3] research was conducted according to generally accepted guidelines of the 1950s means first determining what research ethics guidelines should be applied to judge human subjects research that took place at that time in history, and second, applying those general guidelines to the unique circumstances of the }~31 study. To do this with any accuracy, it is necessary to consider the history and evolution of medical ethics and the ethics of research with human subjects. We must understand where we were at the tune the research was conducted in comparison to where we are today, and face the problems inherent in second-guessing the past. To determine whether the AAL thyroid function research followed "generally accepted guidelines," the Committee had to consider both principles and practices. If only the principles of research ethics were considered, then virtually all research would be unethical, as principles can only rarely be employed in a manner that raises no questions at all. Thus it seems reasonable to conclude that considering only principles would hold researchers to an unfairly high standard. If, however, only the actual practices of the time were considered, a different unfairness would result. Requiring researchers only to do what other researchers do would render principles meaningless and change impossible. Thus, considering only practices would justify all research, and such a standard would be unfair to subjects. The challenge, then, when assessing research with human subjects whether the research is in the past or the present is to examine both principles and practices to determine and apply "generally accepted guidelines." This is what the Committee sought to do. In the process, we realized that the evolution of principles and practices of human subjects research has been more gradual than swift, and composed of small and spreading changes rather than of dramatic paradigm shifts. As important as our examination of the }~3} study is, it is even more important to recognize that education about the ethics of human subjects research is a continuing necessity today. 43 OCR for page 43 44 The ALL Thyroid Function Study BACKGROUND To understand the concept of informed consent and the legal/moral underpinnings of human subject experimentation as related to the AAL study, it is necessary to understand how these underpinnings developed. Medical treatment and human subjects research share two ethical mandates: to avoid harm and to respect the patient's self-determination (autonomy). Thus, research must be designed to produce meaningful! knowledge with minimal risk. In addition, subjects must make free and informed decisions about whether to participate. These issues are discussed at length in A History and Theory of Informed Consent (Faden and Beauchamp, with King, 1986), which is drawn upon heavily here. The ethical mandates underlying the conduct of research using human subjects are derived from several sources, including: · the ancient and traditional duty of physicians to benefit their patients, or at least do them no harm;) · the Kantian philosophical view of human beings as "ends in themselves," never to be used merely as means to ends, or for the advantage of others;2 · the political and legal concept of autonomy or self-determination that requires consent to any bodily intrusion;3 and · the requirements of good scientific method in designing and conducting experiments, including: minimization of risk.4 These ethical concepts are often translated into three basic principles that provide a framework for the moral conduct of human subjects research: · The principle of "autonomy," or personal self-governance, "by adequate understanding while remaining free from controlling interferences by others and from personal limitations that prevent choice" (Faden et al., 1986, p. 81. In order for a research subject to make an autonomous choice, the autonomy of the subject must be respected, which includes providing sufficient information for the subject to make an autonomous and informed decision. According to Faden et al. (1986, p. 10), " [A] celebrated principle in the history of medical codes of ethics is the maxim primum non nocere 'above all, do no harm.' Recent scholarship has shown that in the Hippocratic writings the more precise formulation is 'help, or at least do no harm,' thus demanding the provision of benefit beyond mere avoidance of harm." According to Faden et al. (1986, p. 81. "As expressed in Kantian philosophy, autonomous persons are ends in themselves, determining their own destiny, and are not to be treated merely as means to the ends of others. Thus, the burden of moral justification rests on those who would restrict or prevent a person's exercise of autonomy." 3Faden et al., 1986, p. I, p. 7-9, 26-30. 4Federal Common Rule § 1 1 1 (a)( 11-~21. See Appendix E. OCR for page 43 The Ethics of Human Subjects Research . 45 The principle of "beneficence," which is concerned with the intent and capacity of science and medicine to avoid harm and provide benefit; in the case of research, this requires careful weighing of potential harms against potential benefits. · The principle of "justice," or treatment according to what is fair, due, or owed, which includes avoiding unfairly burdening subjects or communities of subjects in relation to benefits. For every research project involving human subjects, two basic inquiries are necessary. One inquiry must examine the necessity of the research, the expected results, the risk-benefit balance, and minimization of risks. The other inquiry must examine the fairness of subject selection, adequacy of information given to prospective subjects, and voluntariness of subjects' consent to participation. In very general terms, the first inquiry addresses the research's potential for harming subjects and the second addresses the research's potential for wronging them. Also speaking very generally, the first inquiry is beneficence based, whereas the second is concerned with autonomy and justice. Although these two sets of research components are considerably interdependent, it is nonetheless possible to commit harms without wrongs-for example, an unexpected injury can occur in an apparently risk-free experiment before it can be halted. It is also possible to commit wrongs without harms, such as when a minimally risky experiment causes no injuries to subjects, but where the subject selection process or the informed consent process is defective. Harming without wronging may be easier to grasp than wronging without harming. In biomedical settings, the focus on avoiding physical harms can tend to overwhelm other considerations. However, especially in research, according participants full respect and dignity and treating them with fairness and justice is of great importance, independent of physical harm. In some contexts, treating study participants with less than full respect may be more damaging than physical harm' and the effects may be longer lasting. The Committee' therefore' gave equal consideration to the potential for harms and for wrongs. Evolution of Ethical Standards Although use of human subjects in medical experiments is an ancient practice, use of human subjects in scientifically rigorous research only became established in the United States shortly before the outbreak of World War Il. Before the postwar promulgation of the Nuremberg Code, some attention was paid to the ethical issues raised by medical research with human subjects (Faden et al., 1986, pp. 151-153). Early moral and legal concerns about human subjects research focused more on controlling research risks than on enabling autonomous choice by research subjects. It took the Nuremberg Trials, however, to bring human subjects research to public consciousness and to launch the development and Implementation of ethical standards for such research. Although the evolution of standards for the use of human subjects in research does not start with the Nuremberg Code, the Code was a watershed event in bioethics that helped determine the development of contemporary standards. It is essential to understand that the Nuremberg Code was intended, and was understood at the tine, to be an expression of existing and universal moral principles governing research with human subjects (Advisory Committee OCR for page 43 46 The ALL Thyroid Function Stucly on Human Radiation Experiments, 1995). Therefore, despite the fact that the Code had not existed as such at the tune the Nazi experiments were conducted, the Nuremberg Military Tribunal could apply it to condemn the experiments. The Nuremberg Code The Nuremberg Military Tribunal was formed to examine the legal and ethical aspects of human experiments carried out by Nazi physicians before and during World War II. As a result of its investigation, on August 19, 1947, the Tribunal issued a lO-point list of principles delimiting morally and legally permissible human experimentation (see Box 3.~. The Code focuses primarily, but not exclusively, on the subject's free and infonned consent. It requires subjects to have decision-making capacity and to be able to consent freely, without "the intervention of any element of force, fraud, deceit, duress, over-reach~ng, or other ulterior form of constraint or coercion." Subjects must be given information about the nature, methods, duration, and purpose of the experunent, and about all reasonably anticipated risks, hanns, inconveniences, and health effects, in order to enable them to choose with understanding about their participation. Subjects must be able to withdraw from participation at any tune. In addition, Me Code prescribes that research design should ensure that the experunent is capable of yielding worthwhile results, that the degree of risk does not exceed the value of the results, that all risks to human research subjects are minunized, and that research is conducted according to appropriately high scientific standards. After the Code The Code was well promulgated and widely discussed, begs ng in the late 1940s and early l950s. In 1946, while the Nuremberg Trials were going on, the Judicial Council of the American Medical Association (AMA) set out three requirements for human subjects research: (1) voluntary consent of the subject, (2) prior animal experimentation to determine risk' and (3) proper medical management of the experiment.s The February 27, 1953' issue of Science led with a set of short papers from a 1951 symposium under Me title "The Problem of These requirements constituted the Judicial Council's application of the AMA's Principles of Medical Ethics lo human experimentation. The requirements were issued in response lo Dr. Andrew C. Tvy's report on the Nuremberg Trials. Dr. Ivy served as the AMA's official consultant to the Nuremberg prosecutors and played a significant role in the development of the Nuremberg Code (Advisory Committee on Human Radiation Experiments, 1995~. They were published in the Journal of the American Medical Association (lAMA) on December IS, 1946, and reiterated in 1958 when JAMA published the AMA's 1957 Principles of Medical Ethics and Opinions and Reports of the Judicial Council. OCR for page 43 The Ethics of Human Subjects Research 47 OCR for page 43 48 The CAL Thyroid Function Study be eddy mover : emends ~:at ~-:- de::: :~::~1~ ~-~--~-~: ...... . ~ . . ~ ~ ~sdilhte$ ~ At... .... i....~....i.. ..... ~ ~ i. ..... I ... , . I ~ ~ ~ ~ ~ m ~-.~. ~ ~ . ~ ~.~. ~. ~. ~- . ~ ... ~ ~ ~ . . ~ ~ ~ ... ~ ~ ..~ ..~. i: -~..~ I. ... .. . ~ Ax. -~ ~.~.~.~.~.~ . ~, ~.~.,,~.~.~,~, :. ... .. . ~. . ~ . - . . . . ~ . . ~ . . . ~ ~ ~ ~. . . ~ . ~- ~3~:~t MEOW I- =£~a~ .. .. ~ ~ I. ~ . ~ . . . ~ ~ .~.. .~ ~ ~ ?.. I. ~ I. ~ .. ~ ... ~ ~ ~ .~ ~ I. expended -hem . I. ~ ~I ~ ~ ~ . ~ . . ~ ~ ~. ~ ~ Experimentation on Human Beings." These papers included an extensive discussion of the Nuremberg Code, as well as a discussion of rights of military personnel regarding medical treatment and research. The Code's general principles were adopted specifically by both the AMA and the Department of Defense. But in the postwar period, dissemination of and implementation of the Nuremberg Code was, to say the least, uneven. In 1953, the Department of Defense formally adopted the Code in guidelines addressing the use of human subjects for research related to atomic, biological, and chemical warfare, but the document was classified Top Secret because of government sensitivity about these military issues (see Appendix D). This is the earliest instance in which a federal agency that sponsored human experiments adopted the Nuremberg Code, although related discussions were ongoing in other agencies in the same era (Advisory Committee on Human Radiation Effects, 1995~. (The policy remained classified until 1975.) The Atomic Energy Commission discussed informed consent issues in a series of letters dating back to 1947 and developed subject consent requirements for the use of radioisotopes it supplied to medical researchers, but did not systematically promulgate or enforce them (Advisory Committee on Human Radiation Experiments, 1995~. Many medical researchers apparently believed that

OCR for page 43
The Ethics of Human Subjects Research 49 because the Nazi experiments were so obviously flawed, both ethically and scientifically, the Nuremberg Code was intended only to apply to ill-intentioned human subjects research-"It was a good code for barbarians but an unnecessary code for ordinary ohYsicianst' (Advisory ~ hi. Committee on Human Radiation Experiments, 1995~. At the same time, worldwide attention was being paid to the language of the Code itself, and new guidelines were being drafted to provide better guidance for physicians and researchers than the Code was thought to offer. Professional societies and associations, world bodies, and governmental entities all began to develop guidelines. One set of guidelines became especially influential. This was the Declaration of Helsinki, first drafted in 1961 by the World Medical Association. Like the Nuremberg Code, the Declaration of Helsinki focused on consent as a central requirement (Faden et al., 1986' pp. 156-157). In 1953, the National Institutes of Health's new Clinical Center developed and implemented a rigorous in-house policy requiring informed consent and peer review of risk- bearing research (Faden et al., 1986, pp. 201-2021. And in 1959, Henry Beecher published the first of his influential exposes of research practices with human subjects, the monograph "Experimentation in Man" (Faden et al., 1986, p. 157~. Thus, in the early to mid-1950s the Principles governing research with human subjects were firmly in place, but their implementation In practice was incomplete and even contused. Clear moves toward systematic reform of research practice did not come until the 1960s and 1970s. --a or- ~. ~ ~- - ~ . , . . , , ~ ~ · _- The Evolution of Modern Federal Regulations In the United States, modern guidelines for human subjects research began to take final form in 1974. In 1971 the U.S. Department of Health, Education, and Welfare (DHEW) issued guidelines for the conduct of social and behavioral research that in 1974 were codified into federal regulations governing human subjects research in institutions receiving DHEW funds. Also, legislation (P.~. 93-34S, National Research Act) created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which in 1979 authored what became know as the Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979~. The Belmont Report sets forth the same three basic ethical principles governing human subjects research that were outlined early in this chapter and that underlie the Nuremberg Code: respect for persons, beneficence, and justice. The report points out that respect for persons demands the informed and voluntary consent of the subjects; beneficence demands an assessment of the relative probability and magnitude of risks to subjects against benefits expected from the results; and justice demands equitable selection of subjects and equitable distribution of the research's benefits and burdens between research subjects and the population at large. The 1974 DHEW regulations6 grew into a federal policy for the protection of human These regulations establish a system of Institutional Review Boards (IRBs) charged to review and approve of human subjects research, and set forth approval criteria. These criteria include the following: that risks to subjects be minimized; that risks to subjects be reasonable in relation to anticipated benefits (continued)

OCR for page 43
so The ALL Thyroid Function Study subjects known as the "Common Rule." It is applicable to all human subjects research taking place under the auspices of any federal department or agency, including the Department of Defense. The federal Common Rule was published in the Federal Register on June I8, 1991 (56 F.R. 28003-280321. (The Department of Defense's version of the Common Rule appears in its regulations, Code of Federal Regulations, volume 32, part 219.) The Common Rule provides much more detailed and specific guidance to human subjects researchers and their institutions than was available to the AAL physicians. The regulations develop the principles of the Nuremberg Code and provide guidelines for their implementation, which the Code lacked. In 1993, there was much more information available to assist researchers and their institutions in implementing appropriate protection for human subjects than was available to the AAL researchers in the 19SOs, but the basic underlying principles were the same then as now. The Nuremberg Code as Applied to AAL Research in 1955-1957 During the mid-1950s, the application of ethical standards for the conduct of human subjects research was uneven in the federal government and guidelines for Implementation were inconsistent. Many researchers, policymakers, and governmental and military personnel may have mistakenly considered the Nuremberg Code to apply only to overtly hazardous research or experiments lacking scientifically reasonable goals. As related earlier, Dr. RodahI, when asked directly over the telephone during the public hearing in Fairbanks if he had any guidelines similar to the Nuremberg Code for obtaining informed consent, told the Committee that he did not, but that he had approvals from his supervisors and if there was anything wrong with the research it would not have been approved, and he would not have been allowed to publish his study results. However, the Nuremberg Code itself, in its own language and as set forth in the medical and scientific literature of the times, is unqualified in its application to "the human subject." The Code was developed to be an expression of universal moral principles governing research with human subjects it was considered to represent current research ethics, acceptable and accepted at the time rather than new terrain. Therefore, in the Committee's, opinion the standards outlined in the Code did apply to human subjects research in the 19SOs, including research conducted under military auspices. Regardless of misconceptions about the applicability or scope of the Nuremberg Code, and regardless of the failure of the Air Force to implement to the subjects or from the resulting knowledge; that subject selection be equitable; and that the subjects' informed consent be obtained. Informed consent requirements are set out, including a list of required elements of disclosure. The regulations are supplemented by publications from the National Institutes of Health Office for Protection from Research Risks, which include interpretive guidelines for use by [RBs in the conduct of their work. These guidelines address a variety of questions in detail, including subject selection, research with special populations, and refinements of informed consent. Current AMA (1992) policy on clinical investigation similarly contains requirements for informed consent and "rigorous scientific standards" for research, but with considerably less detail than the federal regulations.

OCR for page 43
The Ethics of Human Subjects Research 51 or disseminate its classified Code-based policy, in the Committee's opinion, the standards of the Code applied to--the ethical conduct of the AAL research physicians and scientists, and to their superiors, at the tune the research took place. As should be clear from the Committee's description of the AAL research and the process of our inquiry, the l}3} research was far from egregious. Subjects, both Alaska Natives and Air Force personnel, were given some information and an attempt at obtaining informed consent was made. The radioactive tracer was administered in doses believed to be harmless, and the purpose of the research was not to determine the effects of radiation in the human body7. Thus, by comparison with some of the Cold War research examined by the Advisory Committee on Human Radiation Experiments (e.g., plutonium injections and active deception of patient-subjects), it might seem overly scrupulous to be concerned with a close analysis of the |~3i study. Nonetheless, there are three reasons for careful examination of the }~3} study according to the terms of the Nuremberg Code. First, the subjects were normal healthy volunteers and there was no indication that the researchers expected the study to result in unprovement of the subjects' health.9 Second, radioisotopes are potentially harmful substances, and thus the }~3 fit should be noted that the AAL thyroid function study was only one of many studies using }~3 conducted from the 1940s to 1960s. The report Human Radiation Experiments Associated with the U. S. Department of Energy and Its Predecessors (1995), prepared as part of DOE's effort to document human radiation experiments, includes at least 60 studies involving li3} in diagnostic, therapeutic, and research settings. The Advisory Committee on Human Radiation Experiments was appointed by President Clinton in 1994 to conduct an extensive inquiry into the history of government-sponsored human radiation experiments and intentional environmental releases of radiation that occurred between 1944 and 1974. The I,000-page final report found that the government sponsored approximately 4,000 radiation experiments involving tens of thousands of individuals, many of whom had no knowledge that they were participating in radiation research. The committee recommended that the government apologize to people who received no direct medical benefit from participation in research and provide financial compensation for those who suffered physical injury as a result of participation. The committee recommended that subjects in three particular studies (about 30 people) receive financial compensation for being subjected to dangerous experiments without their knowledge, and gave guidelines that might lead to compensation to others. The committee rejected proposals that the government notifier all known participants or their families or provide wide-scale medical follow-up. committee's report and recommendations, and issued an apology to all those who were used as subjects in government-sponsored radiation experiments, and their families. He also established a new body, the National Bioethics Advisory Committee, to develop new policies to guide research in human biology and . . . review ongoing government researc :~. In October 1995, President Clinton accepted the 9The Advisory Committee on Human Radiation Experiments (1995), in discussing the use of healthy subjects in medical research, noted: "The use of patients in medical research appeared in a different historical context from that of healthy subjects. From the perspective of the medical profession, the age-old tradition of the doctor-patient relationship provided a justification for research with the potential to benefit patients, but not, of course, for healthy subjects who were not under medical care."

OCR for page 43
52 The AA1: Thyroid Function Study research was not without theoretical risk. And third, the overwhelming majority of the subjects were Alaska Natives, who may have represented a population of convenience and whose language and cultural differences from the physician-researchers certainly affected the consent process and their role as subjects. It is to elucidate these reasons, and to explore their importance, that we embark upon an application of the terms of the Nuremberg Code to the Ii3i research. Several aspects of the informed consents relationship between researchers and subjects must be examined according to the terms of the Nuremberg Code: (1) subjects' legal capacity and freedom to choose under the circumstances; (2) researchers, disclosure of information about the experiment, and subjects' knowledge and comprehension of this information; and (3) the duty and responsibility of researchers to obtain consent. Although the Code is general and offers no guidance as to how the requirements should be fulfilled, its language is explicit. The following discussion looks at the principal terms of the Code as relevant to the AAL research. i. "bathe person involved should have legal capacity to give consent, [and] should be so situated as to be able to exercise free power of choice, without the intervention of any element offorce, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion. " The conduct of the AAL thyroid function study raises a variety of concerns related to consent and free power of choice. For instance, although the researchers excluded young children from the study, at least seven of the Alaska Native subjects were under 2l, the age of majority in the Territory of Alaska at the time (Compiled Laws of Alaska, §20-1-1, 1949). Minors' unless "emancipated,' lack the legal capacity to give consent. Minors become legally emancipated by participating in certain adult activities such as marriage or military service. Some of these minor subjects of the AAL research were emancipated by marriage; others were not. Parental consent was not sought for any minors, to the Committee's knowledge. The researchers apparently instructed elders and interpreters that they needed "adult or near-adult" volunteers, and then simply recorded the ages of subjects brought to them. The inclusion of minor subjects in research without parental consent is a violation of ethics and law, both for the period of the experiments and in 1993. There were three minor subjects among the U.S. Air Force participants; however, since military service is an emancipating condition' there was no legal conflict in those cases. In addition, the Committee has significant concerns about whether the Alaska Native subjects were "so situated as to be able to exercise free power of choice" under the circumstances. These concerns relate to the use of village authority figures to identify ~°AIthough the term "informed consent" did not come into use until 1957 (Faden et al., 1986, p. 125), the elements that define consent in the Nuremberg Code correspond well to the Committee's contemporary concept of "informed consent," and so that term is used here for convenience. '~There are many modern lists of elements of informed consent to research that are equivalent. For example, a moral definition is: An intentional authorization given to a researcher by a subject who has substantial understanding, and is not substantially controlled by others (Faden et al., 1986, p. 2781. A policy definition is: The competent subject's voluntary consent aRer disclosure that the intervention involves research and about its nature, consequences, risks, benefits, and alternatives (Federal Common Rule, §116~.

OCR for page 43
The Ethics of Human Subjects Research 53 participants, language barriers that led to confusion over whether subjects were participating in research or medical treatment, and cultural differences that meant the Alaska Native subjects were hesitant to refuse participation. at the end of this chapter. These issues are further elaborated in the justice section 2. "iT7he person involved should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This . . . requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the elects upon his health or person which may possibly come from his participation in the experiment. " Dr. Robert Elsner (one of the three former AAL researchers who attended the public hearing and the former director of the AAL analytical laboratory) and Dr. Rodah} told the Committee that, to their recollection, fairly complete information was conveyed to both Alaskan Native and military subjects. Dr. Rodah! said he informed the village elders about the purpose of the study and what they wanted the volunteers to do, and that the elders were present as interpreters while the procedures were being done e Dr. Elsner, who worked primarily with military subjects, stated his belief that as much infonnation as possible should be provided to all subjects. However, the interpreters' command of English was variable and in most cases insufficient to adequately explain the research. In addition, the interpreters may not have understood that they were recruiting subjects for research, rather than selecting villagers for medical treatment. Finally, neither military subjects nor Alaska Native subjects were informed that the }~3} capsules they swallowed were radioactive; this stewed from the researchers' conviction that }~31 was harmless and therefore not an important element of disclosure. The lack of terms for "radiation" was an additional barrier to information conveyance In Native languages. The Committee believes that it might reasonably be asserted that experimental administration of a substance known to be dangerous at higher doses should have been accompanied, even in the 1950s, with disclosure about the possibility of unknown future risks. Such caution would be required today for research. Based on the hearing testunony and field interviews at Native villages, the Committee firmly believes that most of the Native participants were not sufficiently briefed on the nature of the research and that some may not have understood that the study was research rather than treatment intended for their benefit (see Appendix B). The AAL research took place within a general context that included multiple visits by a variety of authority figures to Alaska Natives, for study, treatment, and other reasons. In addition, the basic framework of the AAL field investigations into acclimatization tended to blur distinctions between therapeutic and nontherapeutic medical actions, between anthropological and medical research, between essentially risk-free and potentially risk-bearing research, between research and the provision of basic medical care, and between researcher and physician. For example, the AAL physicians with whom the Committee spoke during its meeting in Alaska stated that they ministered to sick and injured villagers as soon as they came to a village because there was so little available care. After giving such care, they then went on to conduct their research studies. This combination of research, treatment, and other interventions created confusion about whether a particular intervention was research or treatment, and bolstered the authority of

OCR for page 43
54 The ALL Thyroid Function Study researchers to obtain participation. If subjects of research are permitted to infer that they are receiving treatment intended for their benefit rather than participating in nontherapeutic research, there is a fundamental flaw in the foundation upon which their understanding and consent are based. In the Committee's view, the researchers' task, even during the 19SOs, was to enable subjects to understand; researchers may not merely assume their subjects' understanding. The AAL researchers should have recognized the possibility of gaps\in subjects' understanding and should have determined whether it was possible to eliminate or reduce those gaps. If the Alaska Native subjects could not "make an understanding and enlightened decision" under the circumstances, the research should not have taken place. It must be emphasized that researchers, are not indeed cannot be- morally required to ensure their subjects' understanding (see Faden et al., 1986; Beauchamp and Childress, 19941. The Committee's criticism of the AAL researchers is based on their lack of efforts to attend to, or reduce, linguistic and cultural barriers- not on their failure to succeed. In the Committee's opinion, what the researchers obtained was closer to mere cooperation than informed consent. Given the cultural attitudes of the time, the AAL researchers may genuinely, though mistakenly, have believed that the subjects' acquiescence was sufficient under the circumstances. Perceptions about justice, cultural bias, and social sensitivity have developed considerably since the 19SOs, and are discussed later in this chapter. Most subjects who spoke with the Committee and to the team that went to the Native villages asserted that they believed they were receiving treatment, and if they had understood that the procedures they underwent were not for their benefit, they would not have participated. The Committee is unable to determine the extent to which the subjects' recollections, as expressed in their testimony, is colored by increased understanding or fear of radiation. However, the Alaska Native belief system lends credence to their assertion. Belief systems at the time were a mixture of traditional, supernatural, and Christian spiritual controls. Man was seen as an integral part of his earthly surroundings. Although a doctor or dentist could treat the physical ailments of a human, a shaman provided the way to communicate with spirit beings for treating the forces of nature and ensuring protection from harm and disease (Marsh, 1954~. These belief systems affected how the Alaska Natives perceived the causes of illness. The traditional concept of illness was based on soul-Ioss, intrusion of a foreign object by sorcery (Chance, 1961), or breaking a taboo (Burch in Smithsonian Institution, 1984, p. 344~. Thus, for Alaska Natives the lack of direct benefit to subjects from the research and the possibility of unknown risks would be associated with the likely occurrence of future harms to subjects or their families. These harms would appear to the researchers as utterly unrelated to the research, but to Alaska Natives could stem naturally from participation. Although the Committee believes that the researchers did offer individuals an opportunity to decline to participate, the offer came after the subjects had been recruited and were about to be tested, making refusal awkward. The Nuremberg Code requires disclosure "before the -

OCR for page 43
The Ethics of Human Subjects Research 55 acceptance of an affirmative decision" by the subject. Moreover, to decline to participate in research is very- different from declining what is believed to be beneficial treatment. A subject who misunderstood the nature of the intervention, believing it to be medical treatment, would be unlikely to decline to participate. Most of the surviving subjects who were interviewed remembered many details of the procedures they experienced, but little or nothing that was recognizable as disclosure and solicitation of consent. They remembered being told to "take tests" (an ambiguous term in itself).~3 Two subjects did remember, along with the details of the procedures, being offered the opportunity to withdraw. Because only one military participant was located and interviewed, the Committee was not able to determine understanding on the part of the military subjects. However, given the lack of language barrier, it seems likely that the military subjects' consent to the research was voluntary and with understanding, except for the lack of disclosure of the radioactive nature of the tracer. 3. "The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. " Because of the language barrier and the social and cultural organization of Alaska Native villages, it was necessary and appropriate for the researchers to make use of village authority figures as interpreters and to assist in the recruitment of subjects. However, some aspects of the process of subject recruitment and information-giving were troubling to the Committee. The difficulties of adequate translation in this setting have already been described; in addition, however, the village elders were essentially given unsupervised authority for subject recruitment, under circumstances where no researchers were available to monitor the process, to supplement and correct the information given, or to answer questions before villagers Imade the commitment to participate. Thus, through the recruitment process the researchers delegated to others to others their nondelegable duty to obtain the subjects' informed consent, and compromised the subjects's understanding and voluntariness. It also appears that the interpreters conveyed initial information to prospective subjects without having the researchers present to make corrections or answer questions. Since the researchers did communicate with enrolled subjects Trough Abased on testimony at the hearings and in villages, subjects viewed themselves as obligated participants from the moment they volunteered or were identified by the elder or interpreter, before they had any opportunity to hear details of the research from the researchers. ~ The Committee heard historical testimony (from Robert Fortuine, physician and historian) that health services were provided to Alaska Natives by the U.S. Department of Education before the Bureau of Indian Affairs took on that function. Thus, it seems logical to speculate that Alaskan Natives who recalled "taking tests" and "the studies" were not merely using simple terms for research or experiment, but were also reflecting their confusion at the time over the blurring together of education, health care, and non-therapeutic research. The researchers' emphasis on teaching and learning, while intended to convey respect for Native survival skills, probably added to the confusion. Dr. Rodah] himself stated very emphatically, "We were scientists; we were researchers." His clarity of purpose did not seem to be transmitted to the Alaska Native subjects.

OCR for page 43
56 . . . The CAL Thyroid Function Study interpreters during the conduct of the research to explain what the subjects were expected to do. their failure to take part in the recruitment process is noteworthy. Moreover, although the physicians needed interpreters to communicate and the use of village authority figures accorded respect to village leadership and customs, the approach could convey the impression that participation was expected for the good of the village. Thus, while the Committee believes the elders had to be involved, that involvement should have been carefully orchestrated, with the hill involvement of the researchers, to overcome language problems (both of translation and of conveying concepts like research verson treatment, and radiation) and to help balance the authority of the elders with information and assurances that nonparticipation was acceptable. What happened instead is that the researchers apparently relied on the elders to bring back volunteers, who were assumed to be willing and were then told what to do, carefully and in some detial. The same amount of detail and oversight should have accompanied the recruitment process. The notion of seeking informed consent from individuals was certainly not foreign to Alaska Natives at the time. Although Native peoples, including Alaska Natives, emphasize cooperation and community, individuals still have important rights and interests (see, for instance, Tjsselmuiden and Faden, 1992~. Moreover, Alaska Natives were not outside American legal structure: even though Alaska did not become a state until 1959, Alaska Natives in the Territory of Alaska were United States citizens at the time of the research, according to the Compiled Laws of Alaska §20-~-7 (1952~. Thus, they enjoyed all the rights and interests of American citizens. The Committee agrees that it was appropriate for the researchers to ask village elders to begin the process of subject recruitment, but after this political] courtesy the researchers themselves should have obtained the voluntary and informed consent of individual subjects, using village elders to assist in translation of necessary information during the consent process. ~. J The Common Rule and the AAL Research: Looking Back from the 199Os Although the basic requirements of the Nuremberg Code as applied to the AAL research are still applicable today, under the terms of the Common Rule current concerns give even more emphasis to protecting vulnerable minorities or regions wielding relatively little political influence. Much of this increased attention to and understanding of justice issues is relatively new; many of the questions now framed in justice terms have not yet been well answered (see Beauchamp and Childress, 1994; National Commission for the Protection of Human Subjects of Biomedical and Behaviourial Research, 1979~. Justice in research design, according to the Belmont Report and the regulations that were the precursors to the federal Common Rule, is addressed primarily by the equitable selection of research subjects. Research subjects must be treated individually as capable adult decision- makers, deserving of respect, equal treatment, and fair dealing. Where populations of subjects are vulnerable to exploitation because of cultural differences or economic or social inequalities, special care must be taken to guard against their exploitation as subjects of research. Sometimes minorities are continually sought as research subjects for reasons of administrative convenience,

OCR for page 43
The Ethics of Human Subjects Research 57 such as when they are readily available in settings where research is ongoing. Social justice requires that researchers consider the appropriateness of adding to the cumulative research burden on any particular person and groups. The federal Common Rule, which applies to Department of Defense research, similarly requires that the selection of subjects be equitable, taking into account the purposes of the research, the seeing in which it is conducted, and the special problems of involving vulnerable populations such as economically or educationally disadvantaged persons (Common Rule §111(a)(3)). The perspective of justice becomes clearest in examining the context in which the AAL research took place as a whole, rather than the thyroid experiment in isolation. Although the principle of justice had been invoked in connection with human subjects research prior to the 1950s, at the time of the AAL research the perception of injustice resulting from social biases against minority populations was not well developed. In retrospect, a variety of activities over many decades seem to have made use of the lands and peoples of Alaska as means to the ends of others, with insufficient consideration of Alaska Natives as autonomous persons with interests of their own. Alaska Natives today believe that they and their lands have been unduly burdened, not only by research, but by a variety of other historical impositions. The cultural characteristics of the Alaska Natives and the researchers, combined with the social and historical context at the time of the AAL research, made it highly likely that Alaska Natives would submit to the authority of researchers, and that the researchers would take acquiescence as consent. The general context of multiple interventions experienced by Alaska Natives for a variety of reasons by a variety of authorities ensured confusion between research and treatment, and bolstered the authority of researchers to dispense benefits as they chose. Indeed, during testimony to the Committee some Alaska Natives who had been subjects of medical research had difficulty recalling which of the studies they had participated in was under . . c .lscusslon. At the time of the AAL research, villages both welcomed strangers and had grown accustomed to impositions by outside figures in authority. Alaska Natives considered disagreement impolite, and religious, federal, and military visitors expected acquiescence from them. The Committee found that' with the exception of Fort Yukon (which had a private hospital), visits by physicians of any kind to the rural Native villages of this study were rare in the mid-19SOs, and that physicians were welcomed with open arms. Language was clearly a barrier to comprehension in the AAL study. One of the study participants from Arctic Village told the Committee that she and the members of her family, including the tribal leader, spoke no English at the time, so they just nodded at everything the doctor said. Some village council members and tribal elders had begun to speak English as a second language at the time, but effective communication was still difficult. VanStone (1956) wrote on the subject of contacts between the U.S. Air Force and Alaska Natives: Problems of understanding naturally arise between peoples who have been brought up in different language systems, even though one party may have a working knowledge of the other's language. Military personnel will find speakers of English in every Eskimo village in Alaska. In most of the villages of northwest Alaska, a large percentage of the population speaks and understands some English. Only the older people have no working knowledge of the language. l:t should be kept in mind, however, that even when a seemingly successful conversation is being carried on in English, there are many opportunities for mix-understandings to arise. When a person is

OCR for page 43
58 The CAL Thyroid Function Study having difficulty in making himself understood in a language that is not his own, the natural tendency is to agree to whatever assistance the other party to the conversation is giving. It is a very easy matter to put words into another person's mouth as a part of the painful process of trying to help him express himself. Thus, military men attempting to get directions and other types of information from Eskimos should speak slowly and distinctly. The urge to push a conversation along desired lines, though sometimes irresistible, is very apt to lead to misunderstandings, since the Eskimo will not have time to order his thoughts in the foreign language and express himself clearly. The problem of language barriers was also reported more recently by Morrow (1992), who found that in courtroom and legal situations Alaska Native Yup'ik defendants almost always answered the court's scripted questions with predictable "correct" responses, even when it was made apparent that the person did not understand several of the points to which he had agreed. According to Chance (1961), the traditionally passive role of Native women is reflected in responses to medical questioning where they defer to men. He also noted that owing to a cultural emphasis on self-reliance, anxiety is not permitted to be expressed overtly. In the Committee's view, Dr. RodahT and other AAL researchers genuinely seem to have believed that the villagers' welcoming attitude indicated eager cooperation, and that their relationship with the subjects was one of trust and respect. Although this belief may have been paternalistic, it was commonly held (not only in the Territory of Alaska, but among many cross-cultural researchers at the timed, and more culturally astute anthropological guidance was not available to the U.S. Air Force until at least 1 956 (VanStone, 1956), as the AAL research was coming to a close. The complex contextual problems raised by cross-cultural research and research with subjects suffering significant relative economic deprivation continue to this day to give rise to violations of autonomy and justice. Some in the scientific community continue to believe that research without significant risks is justifiable, despite barriers of language and culture. However, both the Nuremberg Code and current standards dictate that if the disclosure process cannot enable subjects to make decisions based on adequate understanding, then the research should be forgone. Another issue related to justice is whether the research itself is designed to benefit the subject population. In weighing the risks and benefits of this study, it is necessary to look at one a~sproport~onate~y nigh numbers or Alaska Natives selected to participate. The AAL research was performed to help prepare Air Force personnel to fight and survive in a possible future war fought in the Arctic. The purpose of the research was to gather information about physiological mechanisms of cold adaptation; the expected benefits were to be directly relevant to the protection of military personnel and indirectly relevant to the protection of all American citizens. Although the disproportionate burden upon Alaska Native subjects might be justified in terms of the greater good of national security, this justification would be sufficient only if it were necessary to use Alaska Native subjects almost exclusively. Indeed, because the research involved the adaptation to exposure to cold, the researchers argued that the Alaska Native population was uniquely suited for study. However, with hindsight there is a flaw in that logic. The purpose of the research was to determine (~) whether thyroid function changed as a result of exposure to cold and (2) whether differences in thyroid function in extreme cold resulted from long-term acclunat~zation to cold or from inherent racial and ethnic differences. If long-term acclimatization to cold was to be effectively distinguished from =4 _ ~ ~. 1 _ 1_ · _ 1 1 r A 1 _ 1 _ ~ ~, · ~, ~

OCR for page 43
The Ethics of Human Subjects Research 59 racial differences in thyroid function, the }~3{ Slay ought also to have included long-term residents of Alaska who were racially and ethnically different from Alaska Natives (the military subjects) were relative newcomers to the environment). When the Committee asked why white Alaskans who were long-term residents had not been included, Dr. Rodah! said that recruitment of such subjects, although desirable, was not possible. This reinforces the impression that the Alaska Natives represented a subject population of convenience. The Committee recognizes that Alaska Natives were needed as subjects to answer the research question; however, their disproportionate numbers by comparison with military personnel, and the researchers' failure to seek out indigenous non-Native subjects, emphasizes that their relative lack of understanding may have made Alaska Natives easier to recruit. _ _ _ _ in, The Committee recognizes the difficulties of research design and subject selection under the circumstances in which the AAL researchers worked. The researchers seem to have considered their repeated use of a population of convenience as an exchange of benefits between two groups. However, the Alaska Natives do not now- and state that they did not then share this understanding. According to the Belmont Report and the Common Rule, today the placement of this undue burden of research participation on the Alaska Native population would require special protection for these subjects. For example, if this research were to be approved today, the researchers might be required to take special care to minimize the risks of the research and to ensure the integrity of the process of informed consent. Specifically, it would become even more important for researchers to communicate, and for subjects to understand, that they were involved in research, not treatment, and that the purpose of the research according to the research protocol was primarily to benefit military personnel. The Committee does not mean to imply that Alaska Natives should never be involved in research, or to assume that they are incapable of informed decision-making. It would certainly be wrong to deny any population the opportunity to contribute to the development of knowledge. However, when."vuInerable populations" with language and cultural barriers, like Alaska Natives, are subjects of research today, researchers face an extra burden of responsibility to balance the potential benefit from the research with the interests of, and risks to, the vulnerable population. Finally, the Committee also considered whether the AAL researchers identified and took action to help ameliorate the endemic goiter problem in Arctic Village and Anakruvuk Pass. The Committee could not find evidence showing that the AAL provided medical follow-up after the research, or that any explanation of the potassium iodide control experiment results was provided to the research subjects. Dr. Rodah} told the Committee that he and his collaborating physicians communicated regularly with physicians of the Alaska Native Service (ANS). He maintained that a benefit of his work was that it called attention to the problem, so that the salt supply in the local stores was replaced with iodized salt. Because of the lack of availability of historical records from the AAL and the Indian Health Service from that time period, the Committee was not able to verify the actual connection between the AAL research findings and actions by the ANS to take corrective steps in locations with endemic goiter. However, AAL information about the reduced salt intake and use of uniodized salt in those interior villages was conveyed at scientific meetings in Alaska during 1956 and in subsequent papers. No Native interviewed could remember follow-up return visits by U.S. Air Force or ANS doctors in the following years, although this does not prove that the salt supplies were not changed. The Committee was

OCR for page 43
60 The CAL Thyroid Function Study told that a few subjects of the tests in Anaktuvak Pass subsequently had thyroidectomies; this indicated there was an awareness of the problem in the medical community and possible communication between the AAL physicians and the ANS. If research by physicians uncovers a treatable condition, the duty of beneficence suggests that the physician researchers have some follow-up responsibility to those subjects. The provision of iodized salt, to be made available in the areas of endemic goiter, or even the attempt to educate the affected communities, would have provided a benefit that did not interfere with the research. Failure to take positive action that prevents harm is a lesser wrong than taking action that causes harm. Nonetheless, having intervened in the lives of their subjects in the course of their research, and having identified and studied the goiter problem, the AAL physician-researchers had some obligation to ameliorate the situation of their subjects. CONCLUSION During the period of the mid-1950s when the AAL thyroid experiments took place, the 10 points of the Nuremberg Code set standards for the conduct of human subjects research. Although the Code was established in response to an egregious abuse of scientific research and prohibits research that is unnecessarily or excessively risky or harmful, as well as research that is not designed to produce socially useful results, this does not mean that "good" research was not subject to the Code's standards. In recognition of the importance of the Code, the AMA had adopted its principles as a standard in 1947, and issues of informed consent and the Code were discussed at length by the American Association for the Advancement of Science in ~ 953 in the journal Science. By adopting the Code's main points in the Department of Defense, classified memorandum of 1953, the Air Force Surgeon General became responsible for ensuring that these consent requirements were met by the physicians trader his command, including the AAL. In turn, the AAL physicians and the Air Force were responsible for ensuring that they received the voluntary and informed consent of individual subjects. The Committee determined that because information on the nature of the {~3] tracer was not disclosed, the military and Native subjects were not completely informed about the nature and risks of the experiments. This omission was a wrong to the subjects, even though the risk of hann was believed at the time to be nonexistent and has since been determined to be quite low. In most of the Native villages, the AAL physicians accepted as volunteers those Natives who were brought to them by village elders or other Native intermediaries without inquiring as to what the subjects had been told. The elders or other intermediaries used by the AAL physicians did not have sufficient training in medicine or science to explain the research adequately, and many of the Native witnesses for the Committee thought they were receiving a beneficial medical treatment. Minor children were used as research subjects without adequate parental consent. Few of the Alaska Native subjects understood that they were participating in research. None of the subjects, neither Alaska Natives nor military personnel, were informed that they were taking a radioactive tracer. Thus, the Committee believes that the experiments were conducted without informed consent, even according to the standards of the time.

OCR for page 43
The Ethics of Human Subjects Research 61 Under current standards (represented by the Common Rule adopted by the Department of Defense), the--complete experiment, its purpose, and potential risks and benefits would have to be explained to the subjects, and permission to proceed would be required (usually in writing). Thus, the AAL experimental design and consent procedure would fall short by modern informed consent standards. The experiments raise justice concerns according to current ethical standards by virtue of the way a minority population was used. The Committee's examination strongly suggests that the Native population was used primarily because it was a convenient research pool, with an assumed understanding that the research would be conducted in exchange for medical care- giving but without full disclosure about the nature of the research. Although the Alaska Natives brought special physiological characteristics because of their long-term adaptation to the climate, Tong-term white Alaska residents were not sought. The AAL researchers held a genuine belief, justifiable at the time, that the research they were conducting was both harmless and necessary. However, the Committee's examination shows that the process by which the researchers obtained consent was flawed because none of the subjects were provided with a full understanding of the nature of the research. The Alaska Native subjects also were wronged by the nature of the subject selection process and by the exploitation (even if unintentional) of language and cultural differences, which substantially reduced the likelihood that they would even understand that they were the subjects of research rather than the beneficiaries of medical treatment. Given that the researchers and their Air Force superiors made errors of omission that were typical in the research of the times, it is important not to assign blame for these deficiencies. instead, the appropriate response is to acknowledge their errors in the hope of ensuring that similar ones do not occur again.