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$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

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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)

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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.

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