CRS Report for Congress Protection of Human Subjects in Research Irene Smith-Coleman Specialist in Life Sciences Science Policy Research Division PROTECTION OF HUMAN SUBJECTS IN RESEARCH SUMMARY Renewed reports of experiments conducted over a 30-year period, in which hundreds of Americans were exposed to radiation, have triggered the reexamination of research ethics relating to human subject experimentation. The cited experiments were funded by the Federal Government and conducted by U.S. investigators during the mid-1940s to the early 1970s. While some investigators have pointed to medical benefits, to research subjects and society, generally, as justification for some of the experiments, critics have voiced skepticism about the ethical merits of such a claim. A fundamental concern is that some of the radiation experiments apparently were done without obtaining informed consent from human subjects. Many of the human subjects used were vulnerable, including prisoners, children, the indigent, the mentally infirm, members of minority groups, and the terminally ill. Although some of the experiments were thought to be therapeutic, others were believed by investigators to be potentially harmful with no therapeutic benefit to subjects. Regulations and professional standards for the protection of human subjects in research and informed consent guidelines, for the most part, did not exist before the late 1940s. Since then, reactions by the public, scientific community and politicians in response to reports of abuses of human subjects in research have served as a catalyst for development of most, if not all, of the current requirements in this area. Before the early 1940s, investigations with human subjects were conducted on a relatively small scale and performed primarily by physicians for therapeutic purposes. Standards to protect such subjects and to obtain informed consent were nebulous. The Hippocratic Oath, the first set of Western writings about medical professional conduct, served as the medical community's principal set of professional standards. However, these did not address essential issues of the physician's ethical research responsibility, such as the role of informed consent in the patient-physician relationship, or the roles of communication and disclosure. The Nuremberg Code originated from the Nuremberg tribunal held in 1945 and 1946. The Code was produced as part of the judgment against Nazi physicians who engaged in atrocious medical experiments on non-consenting concentration camp prisoners, during World War II. The-Code is a set of 10 ethical research principles that states in its first principle, without qualification, that "the voluntary consent of the human subject is absolutely essential." The Nuremberg Code served as a model for numerous professional and governmental codes on protection of human research subjects formulated during the 1950s and 1960s. However, over time, it became necessary to develop more specific guidelines to govern the complex types of situations arising in the expanding fields of biomedical and social science research. This report provides information on the evolution of Federal regulations on protection of human subjects in research, including the role of congressionally created Commissions in the development of these regulations. In addition, a brief discussion is included on international principles in this area. TABLE OF CONTENTS INTRODUCTION 1 INTERNATIONAL PRINCIPLES 1 The Hippocratic Oath 2 The Nuremberg Code 2 The Helsinki Code 4 FEDERAL REGULATIONS FOR THE PROTECTION OF HUMAN SUBJECTS 5 FDA and Thalidomide 5 EVENTS LEADING UP TO DHEW/DHHS 1974 REGULATIONS 7 The Tuskegee Study 10 DHEW'S/DHHS'S 1974 REGULATIONS 11 Requirements for Informed Consent 12 Additional Protections for Research on Human Subjects 12 REGULATIONS AT OTHER FEDERAL AGENCIES 13 SELECTED FEDERAL AGENCIES' POLICIES BEFORE COMMON RULE 14 Department of Energy (DOE) 15 Department of Transportation (DOT) 17 Coast Guard 17 CONGRESSIONALLY-CREATED COMMISSIONS 17 The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 17 The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research 18 RECENT CONGRESSIONAL EFFORTS 20 CONCLUSION 21 APPENDIX A. NUREMBERG CODE 22 APPENDIX B. WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 24 I. BASIC PRINCIPLES 24 II. CLINICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 24 III. NON-THERAPEUTIC CLINICAL RESEARCH 25 Protection OF HUMAN SUBJECTS IN RESEARCH INTRODUCTION Renewed reports of experiments conducted over a 30-year period, in which hundreds of Americans were exposed to radiation, have triggered the reexamination of research ethics related to human subject experimentation in this country. The radiation experiments in question, funded by the Federal Government and performed by U.S. investigators, occurred during the mid-1940s to the early 1970s. Although some investigators have pointed to medical benefits to research subjects and society generally as justification for some of the research, critics have voiced skepticism about the ethical merits of that claim. One reason is that the principal agencies involved, the Atomic Energy Commission (now the Department of Energy) and the Department of Defense, do not have health research as their major missions. Congress, the Clinton Administration, and the scientific and ethical communities are now examining the U.S. standards and requirements to protect human subjects research; those currently in effect and those, if any, that were in place at the time of these radiation experiments. A fundamental concern is that many of the radiation experiments apparently were done without obtaining informed consent from human subjects. Many of the human subjects used were highly vulnerable, including prisoners, children, the indigent, the mentally retarded, members of minority groups, and the terminally ill. While some of the experiments were done to treat subjects therapeutically, other experiments were believed by investigators to be potentially harmful and of no therapeutic benefit to subjects. For example, in the first case, the purpose of some investigations was to treat cancer, and in the latter, to measure how radiation affects human tissue, bones, and organs. This report provides information on the evolution of Federal regulations for protection of human subjects in research, including the role of congressionally created Commissions in the development of these regulations. In addition, a brief discussion is included on international principles in this area. INTERNATIONAL PRINCIPLES Regulations and professional standards for the protection of human subjects in research and informed consent, for the most part, did not exist before the late 1940s.1 Reactions by the public, scientific community, and politicians in ______________________ 1 In 1931, Germany enacted regulations, on ethical grounds, to protect human research subjects. Ironically, this was the only country that appears to have had ethically and legally advanced human subject regulations at that time, and these regulations were binding law prior to and throughout the period of the Third Reich, 1931 to 1945. The provisions included consent requirements both for research involving "innovative therapies" in patients and for human experimentation. For the former, informed consent had to be obtained except in urgent cases where the subject's life must be saved or there is risk of serious damage to health. In the case of human experimentation, consent was absolutely required. Moreover, experimentation on dying persons was not allowed and, on children, was permitted only if there was zero risk of harm. Sass, Hans-Martin. Reichsrundschreiben 1931: Pre-Nuremberg German Regulations Concerning New Therapy and Human Experimentation. J. Med. and Phil. v. 8, Feb. 1983, p. 11-111. CRS-2 response to reports of human subject abuses in research during the 19608 and 19708 served as a catalyst for development of most, if not all, of the current requirements in this area. The Hippocratic Oath2 Before the early 1940s, investigations with human subjects were conducted on a relatively small scale and primarily by physicians to treat the research subject (therapeutic). Standards to protect such human research subjects and to obtain informed consent were nebulous. Before the early 1940s, the medical community's responsibility to human research subjects derived largely from the Hippocratic Oath, the first set of Western writings about medical professional conduct. This set of professional standards did not address essential issues of the physician's ethical research responsibility, such as the role of informed consent in the patient-physician relationship, or the roles of communication and disclosure. Instead, the physician is presumed to have special beneficence skills and ethical commitments to their use when treating patients. The Oath(s) discusses a number of problems associated with truth-telling by the physician, advising them of the wisdom of "concealing most things from the patient, while you are attending to him...turning his attention away from what is being done to him;...revealing nothing of the patient's future or present condition."3 The Nuremberg Code The Nuremberg Code is a set of 10 ethical research principles that originated from the Nuremberg tribunal held in 1945 and 1946. The code was __________________________ 2 Many of the important historical works on medicine that were products of the ancient world are found in a collection of documents known as the Corpus Hippocraticum. It is believed that this material was largely written from the fifth to fourth century B.C. Hippocrates was a Greek physician who traveled throughout Greece and was well known and widely sough out as a healer during his life, reported to have spanned 85 years or more. While the Hippocratic Oath bears his name, it probably was not written by him, but more likely by the Pythagoreans, a philosophical sect started in the latter part of the fourth century B.C. Reiser, S.J. et al. Ethics in Medicine, Historical Perspectives and Contemporary Concerns, The MIT Press (Cambridge, MA and London, England),1977. p. 5-9. 3 Faden, R.R. and T.L. Beauchamp. A History and Theory of Informed Consent. Oxford University Press (NY, Oxford) 1986. p. 60-62. CRS-3 produced as part of the judgment against Nazi physicians who engaged in atrocious medical experiments on non-consenting concentration camp prisoners during World War II.4 Many of the convicted physicians had been university. trained, were university-appointed researchers, and had first-rate medical credentials and sought distinguished careers. The first Nuremberg Code principle states, without qualification, that "the voluntary consent of the human subject is absolutely essential. This means that - the person involved should have the legal capacity to give consent." The research subject also "should be so situated as to be able to exercise free power of choice," and "should have sufficient knowledge and comprehension of the subject matter involved as to enable him to make an understanding and enlightened decision" (see appendix A. for all principles). Principle 1, therefore, requires that consent have at least 4 characteristics: it must be voluntary, competent, informed, and comprehending. The remainder of principle I assigns general boundaries within which a researcher may conduct investigations and defines the conditions under which a subject has the ability to volunteer. While the Nuremberg Code does not specifically state this, the informed consent requirements presumably come into play only after an appropriate risk-benefit assessment has been made.5 The Code does not describe how the research subject's consent may be obtained, nor how the limits of investigational risk are to be defined, because the Nuremberg Court believed these areas were beyond its area of competence. It is worthy of note, as well, that vulnerable populations such as the mentally disabled and prisoners were at that time in some cases being used as research subjects by American researchers. This practice was inconsistent with the Code's principle that subjects should have legal capacity to give consent, and be so situated to be able to exercise free power of choice. However, few of these issues received sustained evaluation in the United States at that time. The ethical principles generated at Nuremberg did not appear to have a significant ________________________ 4 Twenty physicians were tried before the International Military Tribunals at Nuremberg charged with committing "war crimes (and crimes against humanity)...involving medical experiments without the subjects' consent...in the course of which experiments the defendants committed murders, brutalities, cruelties, tortures, atrocities, and other inhuman acts." Experiments included: high altitude experiments in which subjects were placed in a low-pressure chamber in which by simulation atmospheric conditions and pressures were raised up to 68,000 feet; freezing experiments in which subjects were placed in a tank of ice water for periods of up to 3 hours after which warming by various means was attempted; and health subjects were infected with mosquitoes or by injections of mosquito extracts. After contracting malaria, subjects were treated with a number of drugs to test relative efficacy. In passing judgment, the Tribunal determined that ten basic principles, known as the Nuremberg Code, should be observed to fulfill moral, ethical, and legal principles when conducting human subject experiments. Katz, Jay. Experimentation With Human Beings. Russell Sage Foundation (N.Y.), 1972. 5 Faden and Beauchamp, p. 155-156. CRS-4 significant impact on the U.S. research establishment until several years after the development of the Nuremberg Code.6 During the 1950s and 1960s, the Nuremberg Code served as a model for numerous professional and governmental codes that were formulated. However, the Code was limited in scope and soon was seen as inadequate to govern the complex types of situations arising in the expanding fields of biomedical as well as social science research.7 The necessity to develop guidelines that were more specific for these fields increasingly became apparent. The Helsinki Code Over time, the medical research community perceived the gruesome experiments at Nuremberg as a potential threat to the integrity and reputation of biomedical research.8 In 1964, partially in reaction to this perception, the World Medical Association (WMA) adopted the Helsinki Code. This code, the first one prescribed internally by a medical professional body, also includes informed consent as an essential requirement of clinical research involving humans. However, the Helsinki Code makes an important distinction between therapeutic and non-therapeutic research.9 Therapeutic research, defined as research "combined with professional care," is permitted if in the physician's judgment "it offers hope of saving life, re-establishing health, or alleviating suffering." Non-therapeutic research is defined as purely scientific research with no therapeutic benefit to the subject. In the latter case, the purpose of the research and risk associated with it must be explained to the subject. In addition, voluntary consent must be obtained from the subject unless the subject is incompetent; in which case guardian consent should be obtained (see appendix B.). The Helsinki Code does not require informed consent in therapeutic research if consent is not "consistent with patient psychology." The justification for this broad exception is similar to the beneficence-based assumption that supports the physician's therapeutic privilege in the Hippocratic Oath.10 If a physician considers it essential not to obtain consent, then he must state the specific reasons in the experimental protocol, which are transmitted to an independent committee. Some commentators refer to this provision as a so- called "therapeutic loophole," and identify it as a serious flaw. In particular, this is of concern in cases where an inattentive _________________________ 6 Rothman, David J. Strangers at the Bedside. Basic Books, Inc. Harper Collins Publishers, 1991. p. 62. 7 Faden and Beauchamp, p. 156 8 Ibid. 9 Ibid, p. 156-157 10 Ibid, p. 157 CRS-5 review committee examines research protocols.11 The Helsinki Code has been used as a model for development of standards and regulations for informed consent by a number of professional groups and U.S. Federal agency officials. Included in this list are: The American Medical Association, the American Society for Clinical Investigation, the American Federation for Clinical Research, and the Food and Drug Administration. FEDERAL REGULATIONS FOR THE PROTECTION OF HUMAN SUBJECTS Congress has been involved in the examination of biomedical ethics issues since the 1960s, and played a vigorous role in the early history of Federal involvement in protecting human research subjects. Much of this was spurred by public disclosures about events that involved morally unacceptable and often dangerous investigations on human subjects. The Department of Health and Human Services (formally the Department of Health, Education and Welfare, DHEW) was the first Federal agency to develop formal policies for the protection of human subjects.12 Most of the details of the initial policies in this area were developed by two of DHHS' agencies, the National Institutes of Health (NIH)13 and the Food and Drug Administration (FDA).14 FDA is a regulatory agency responsible for ensuring the safety of foods, drugs, medical devices, cosmetics, and a variety of other products. NIH is the principal Federal agency responsible for supporting and conducting biomedical and behavioral research. FDA and Thalidomide The first Federal statute related to informed consent focused on the FDA. On October 10, 1962, Congress passed the "Drug Amendments of 1962" (P.L. 87-781), ___________________ 11 Ibid, p. 156. 12 In addition, the Dept. of the Army nearly simultaneously (1966) published regulations based on the Nuremberg Code. Faden and Beauchamp, p. 201. 13 In 1953, NIH's Clinical Center, which is responsible for virtually all of the agency's intramural clinical research, established a policy for the protection of human subjects. The policy required prior review (by institute and clinical center officials) and approval of all non therapeutic research and all research involving unusually high risk. In addition, informed consent of research subjects was required. Although NIH officials anticipated widespread use of this policy by other Federal agencies and extramural research institutions, it never occurred. Faden and Beauchamp, p. 201-202. 14 FDA did not become part of DHHS until 1968. CRS-6 section 505(i) of the Food, Drug, and Cosmetic Act.15 The law contains a "consent requirement," the genesis of which was due largely to the thalidomide disaster. The drug, thalidomide, had been approved in Europe during the late 1950s as a sedative, but by 1962, was being used widely in Europe and other countries by pregnant women at risk of premature delivery and spontaneous abortions (miscarriages). Thalidomide had not been approved by the FDA for use.16 However, the drug had been supplied to U.S. physicians by the drug maker to conduct investigational studies on human subjects to establish its safety.17 Prior approval of the investigational studies by FDA was not required at that time. In 1962, it became evident first in Europe that thalidomide was harmful to the fetus and the investigational studies were stopped in this country. Some babies were born with a rare defect known as phocomelia (infants limbs are missing or a hand or foot are attached directly to the body). However, by then, 20,000 Americans, 3,750 of childbearing age and 624 reportedly pregnant, had already taken the drug. The exact number of recipients was not known and -identification incomplete, in part because inadequate records were kept by the drug maker and the prescribing physicians.18 Congress, partly in reaction to the thalidomide disaster, enacted P.L. 87-781, which, in addition to the consent revision, required FDA to test drugs for efficacy as well as safety. FDA had received authority for testing drugs for safety in 1938. During 1962 congressional hearings, it was revealed that many of the patients participating in the clinical trials had not been informed that they were part of an investigational study. Nor had many given their consent. Senator Jacob Javits proposed legislation that would require the Secretary of the DHEW to issue regulations to require that no investigational drug be administered to a human subject without obtaining that subject's consent.19 However, because of concern by some Senators that such a requirement would adversely affect the physician-patient relation20, the legislation was changed to give the Secretary more discretion in developing regulations. 15Staff Report. The Protection of Human Subjects in Research Conducted or Supported by Federal Agencies. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Feb. 10, 1978, p. 32-33. 16Thalidomide was in the process of being evaluated by FDA. However, approval was delayed largely because Francis Kelsey, a FDA official, had concerns about the quality of the European test results. The birth defects risk associated with the drug was determined in the interim. Rothman, David J. Strangers at the Bedside. Basic Books, Inc. (U.S.), 1991. p. 64. ______________________ 17 Congressional Record, Aug. 23, 1962, p. 17395-17395-17403. 18 Op. cit., Rothman, D.J. 19 Ibid., p. 64-65. 20 Rothman, David J. p. 63-67. CRS-7 FDA published regulations to implement P.L. 87-781 on February 7, 1963. The "consent" provision required researchers proposing to test investigational new drugs to obtain human subjects' consent, or that of their representatives, "except where they deem it not feasible, or in their professional judgment, contrary to the best interests of such human beings." The provisions defined "not feasible" as circumstances in which the investigator is not capable of obtaining consent because of inability to communicate with the subject or his representative. An example would be if the subject is unconscious or is otherwise incapable of giving consent, his representative cannot be located, and it is imperative to administer the drug without delay (21 CFR 310.102(f)). Critics claimed that the consent provisions of the regulations were poorly developed and led to ambiguities. In particular, they asserted that FDA provided little clarification of the vague wording and broad exception in the law. FDA attempted to resolve some of the ambiguities by publishing, in August 1966, new provisions, "Consent for Use of Investigational New Drugs on Humans: Statement of Policy."21 The provisions were closely modeled after the Nuremberg Code and the Declaration of Helsinki. The regulations, which applied only to experimental drugs, devices, and biologics, contained requirements for obtaining written consent and rules for informing subjects that they could be used as control subjects, that a placebo (inactive material) could be used, and that, if available, alternative therapies exist. EVENTS LEADING UP TO DHEW/DHHS 1974 REGULATIONS By mid-1960, NIH officials were concerned about the agency's traditional practice of relying exclusively on the moral character of investigators to safeguard humans in research. Moreover, NIH had no way to monitor the conduct of the investigators it was funding. Since the end of World War II, NIH's budget had grown, from an appropriations level of $2.8 million in 1945 to one of $958.2 million in 1965 (a 342-fold increase).22 In 1965, NIH awarded 11,000 research grants and about one third of these grants involved experiments on humans.23 With the rapidly expanding number of human subject investigations also came a growing number of reports about unethical human experiments in which many of the investigators were federally funded.24 Some of the most _______________________ 21 Faden and Beauchamp, p. 204. 22 NIH Almanac 1992, NIH, Office of the Director, NIH Publication no. 92-5, p. 111. 23 Rothman, David, p. 54. 24 James Shannon, Director of NIH from 1955-1968, learned from the media about one such event in which physicians at a university hospital unsuccessfully transplanted a chimpanzee kidney into a human. NIH partially funded this experiment. While the surgeon reported that the patient had consented to the procedure, there was no prior consultation with other parties, nor evidence of either potential therapeutic benefit or new scientific information. CRS-8 influential reports of such experiments were done by scholars in the rapidly evolving field of biomedical ethics. One such scholar was Henry K. Beecher.25 In January 1960, Public Health Service (PHS) of then-DHEW, awarded a 3-year grant to the Law-Medicine Research Institute in Boston (MA) to study the practices of medical researchers and research institutions in this country with regard to moral problems in the conduct of human subjects research.26 Two years later the institute published results of a survey, to which 52 departments of medicine responded (86 departments were contacted). The survey found the following: (I) few institutions had procedural guidelines governing human subject research; (2) most institution officials indicated they _________________________ 25 Henry K. Beecher, M.D. published a monograph, Experimentation in Man in 1959. This represents one of the earliest publications on research ethics. Spurred by the Nuremberg atrocities, Beecher called for "a long, straight look at our current practice," not only because of Nuremberg, but also because of, at that time, continuing advance into new areas of human biomedical research." Beecher went further by providing a comprehensive review of the major codes existing in this area, at that time. Beecher's monograph served as a basis for the PHS to award a 3-year grant to the Law-Medicine Research Institute at Boston University to investigate the practices of medical researchers. In 1966, Henry Beecher published 22 detailed cases of research which contained serious or potentially serious ethical violations. Out of 50 cases collected form published journals, Beecher selected 22 for publication in the New England Journal. Only two of the 50 cases "mentioned" that consent of research subjects was obtained. Two examples of the violations include the following: (1) rheumatic fever usually could be prevented if a patient with the associated infection, streptococcal respiratory infection, was treated with penicillin. However, in the experiment, servicemen with the infection were divided into two groups; one group received penicillin, and the second group of 109 men received a placebo instead of penicillin; (2) these investigators, and others, had earlier shown that chloramphenicol was an effective treatment for typhoid fever, and reduced the expected mortality by 50 percent, compared to when the drug was not used. This study was done to determine the relapse rate under two methods of treatment: of 408 "charity" patients, 251 were treated with chloramphenicol, and the remaining 157 patients received symptomatic treatment (e.g., providing fluids). Results indicated that 20 of the 251 patients administered chloramphenicol, or 7.97 percent, died, compared to 36 of the 157 patients who received symptomatic treatment, or 22.9 percent who died. According to Beecher, based on the data presented in the study, 23 patients died in the study who would not have been expected to die if they had received the chloramphenicol treatment. Beecher, M.D. Henry K. Ethics and Clinical Research, NEJM, June 16, 1966. p. 1354-1360. 26 Faden and Beauchamp, p. 158. CRS-9 considered even self-regulation by committees to be unacceptable and would rather leave these procedures exclusively to investigators; and (3) only about a third (16) of the institutions had special consent forms for research projects. The report concluded that internal institutional regulation of research was generally callous and erratic. It became clear to NIH officials that federally funded research at times was ethically insensitive and politically eruptive. Furthermore, investigations could be initiated with inadequate peer review and insufficient consent from research subjects. In late 1963, then-NIH Director Shannon asked the agency's research resource division to investigate these problems and make recommendations. A report was presented to the Director in November 1964. It warned of "possible repercussions of untoward events which are increasingly likely to occur" in "unfavorable" circumstances, including events that could "rudely shake" the NIH.27 The report cited the absence of an applicable code of conduct for research and an uncertain legal context, as specific concerns, among others. On February 8, 1966, the U.S. Surgeon General published a policy directive requiring institutional review to assure ethical acceptability of research with human subjects supported by the PHS. This policy, "Clinical Investigations Using Human Subjects," required all institutions receiving Federal grant funding from PHS to provide prior review by a committee for proposed investigations with human subjects. An institutional committee would have to review the rights and welfare of the research subject, the appropriateness of informed consent method, and the balance of risks and benefits.28 However, it was left to institutional committees to determine what constitutes the rights and welfare of human subjects, informed consent, and risks and potential benefits. Confusion ensued about how to interpret and implement loosely framed Federal standards. It became clear, over time, that local institutional review often was arbitrary and irresponsible, and that failure to disclose adequate information to research subjects was widespread.29 The 1966 policy was expanded and elaborated in the 1971 "Institutional Guide to DHEW Policy on Protection of Human Subjects." The Guide developed informed consent requirements and contained detailed considerations of institutional review. The required elements of informed consent were defined _____________________ 27 Ibid, p. 206-208 28 Faden and Beauchamp, p. 208-209. In addition, Marston, M.D., Robert Q. (Director) The Background of the National Institutes of Health (NIH) on Ethical Problems of Clinical Studies, Fertility and Sterility, v. 23, Aug. 1972. p. 596-600. 29 Ibid., p. 211. CRS-10 and explained, and continuing review of ongoing research projects was now also required.30 Although policies relating to research ethics at NIH generally improved by the early 1970s, numerous issues remained, including the composition of the institutional review committees, compensation for injury during an investigation, distributive justice in the research subject selection process, and whether adequate informed consent had been achieved.31 In 1972, the Director of NIH, Robert Q. Marston, created a PHS Committee to examine these issues and others related to the regulation of human research. The Tuskegee Study The 1972 PHS Committee was created largely in response to the publicizing of the Tuskegee Study, which was funded by the PHS. In July 1972, Jean Heller, a reporter with the Associated Press, reported that PHS, for 40 years, had been conducting a study on the effects of untreated syphilis in black men in Macon County, Alabama (in and around the county seat of Tuskegee).32 From 1932 until 1972, PHS investigators had performed a variety of tests and medical examinations on the men--399 with final phase of the disease, and 201 men who were free of the disease. Shortly after the media reported the Tuskegee study, DHEW appointed an ad hoc advisory panel to review both the study and the Department's policies and procedures for protecting human subjects generally. The panel found in its report released in 1973 that the study was ethically unjustified, and that penicillin therapy should have been made available to all study subjects no later than 1953, 19 years before the study was halted.33 The panel also found that neither DHEW, nor any other government agency had policy in place to adequately review experimental procedures, or to adequately obtain informed consent from research subjects. Among other things, the ad hoc panel recommended that Congress create a permanent body with authority, at a minimum, to regulate all federally supported and conducted research involving human subjects. __________________ 30 President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Protecting Human Subjects. GPO stock no. 040-000-00452-1, Dec. 1981. p. 22-23. 31 Faden and Beauchamp, p. 213. 32 Jones, James H. Bad Blood. The Free Press, Macmillan, Inc. (NY), 1981, 1993. p. 1. 33 Reiser, J.S. et al. Ethics in Medicine, from Final Report of the Tuskegee Syphilis Study Ad Hoc Advisory Panel, (reprinted from the Report; Washington, D.C., U.S. PHS. p. 5-15), The MIT Press (Cambridge, MA), 1977. CRS-11 DHEW'S/DHHS'S 1974 REGULATIONS On May 30, 1974, DHEW published regulations governing the protection of human subjects (45 CFR 46), thereby replacing the policy the agency first developed in 1966. While the 1966 policy did not apply to research conducted intramurally (i.e., by NIH scientists at NIH facilities) 45 CFR 46 applied to all grants and contracts supported or conducted by the DHEW that involve human subjects, both intramural and extramural, with a few explicit exemptions.34 Another important difference was that the old policy review requirements applied only to research activities judged by the principal investigator to present risk to human subjects, while the 1974 regulations applied to all research with human subjects. The Institutional Review Boards (IRBs), and not investigators, would now determine the extent of any risk involved.35 Each institution that conducts research involving human subjects must first submit written "assurance" satisfactory to the department or agency head that it will comply with the requirements in 45 CFR 46. The assurance should include a statement of principles (e.g., Nuremberg Code, Helsinki Code) the institution will follow to accomplish its responsibilities for protecting human subjects in research conducted or supported by the institution. The institution also must certify that the research has been reviewed and approved, and will be subject to continuing review by an IRB provided for in the assurance. The IRB must be composed of a minimum of five members who have varying backgrounds The members must be sufficiently qualified through experience and expertise to promote complete and adequate review of research activities commonly conducted by the institution. IRB members must be identified to DHHS by name, earned degree, representative capacity, and evidence of experience (i.e., board certification, license). In carrying out specified responsibilities, IRBs must review all research activities involving human research subjects. IRB members have authority to approve, require modifications (to secure approval), or disapprove all such research activities. They must assure that informed consent information given to research subjects is in accordance with requirements in 45 CFR 46. In addition, they can require that information, in addition to that specified in the regulations, be given to subjects if, in their judgment, it would meaningfully add to the protection and welfare of subjects. ____________________ 34 Exemptions include research involving the use of educational tests (cognitive, diagnostic, aptitude achievement) if information from such tests is recorded insuch a way that subjects cannot be identified. For other exemptions, se 45 CFR 46.101. 35 President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. p. 22-23. CRS-12 Requirements for Informed Consent 45 CFR 46 defines the basic elements of information necessary for informed consent to include: (1) A statement that the study involves research, and explanation of the purposes of the research as well as the expected duration of the subject's participation, a description of the procedures that will be followed, and identification of any experimental procedures; (2) A description of any reasonable foreseeable risks or discomforts to the research subject; (3) A description of any benefits to the research subjects or to others which may reasonably be expected from the research; (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the research subject; (5) A statement describing the extent, if any, to which confidentiality of records identifying the research subject will be maintained; (6) For research involving more than minimal risk,36 an explanation about whether any medical treatments are available if injury occurs and, if so, what they consist of, or whether further information may be obtained; (7) An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject; and (8) A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the research subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. Additional elements of informed consent can be found in 45 CFR 46.116. Additional Protections for Research on Human Subjects Since 1974, DHHS has promulgated additional regulations to protect the following groups of human subjects: _____________________ 36 "Minimal Risk" is defined as the probability and magnitude of harm or discomfort expected in the research is no greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. CRS-13 (1) Fetuses, pregnant women, and human in vitro fertilization subjects - Subpart B - "Additional Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization." These regulations were adopted on August 8, 1975. (2) Prisoners - Subpart C - "Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects." These regulations were adopted on November 18, 1978. (3) Children - Subpart D - "Additional Protections for Children Involved as Subjects in Research." These regulations were adopted on March 8, 1983. As is discussed later, congressionally-appointed Commissions played an instrumental role in the development of regulations for additional protection of the human subjects defined in subparts B, C, and D. No other Federal agency has adopted regulations that are as comprehensive as those of DHHS. REGULATIONS AT OTHER FEDERAL AGENCIES Regulations for the protection of human subjects of biomedical and behavioral research for other Federal agencies (those in addition to DHHS) were not officially adopted until June 18, 1991.37 The development of this policy, referred to as the "Common Rule," took 10 years.38 The Common Rule is based on DHHS regulations for the protection of human subjects, but only on Subpart A of 45 CFR 46 - Basic HHS Policy for Protection of Human Research Subjects. The Common Rule replaces the 1981 version of Subpart A of DHHS regulations and governs human subjects research for activities supported and conducted by the Federal agencies listed below. However, subparts B, C, and D of 45 CFR 46 - regulations for additional protection for children, prisoners, and pregnant women, fetuses and human In Vitro Fertilization subjects - apply only to DHHS. The Common Rule was developed by the Interagency Federal Coordinating Council for Science, Engineering and Technology. It applies to the following departments and agencies: Office of Science and Technology Policy, Department of Agriculture, Department of Energy, National Aeronautics and Space Administration, Department of Defense, Consumer Product Safety Commission, International Development Cooperation Agency (Agency for International Development), Department of Housing and Urban Development, Department of Justice, Department of Defense, Department of Education, Department of _______________________ 37 Federal Register, v. 56, no. 117, June 18, 1991, p. 28003-28032. 38 The timetable was 10 years from the time that the congressionally created President's Commission for the Study of Ethical Problems in Medical and Biomedical and Behavioral Research recommended that a uniform "core" of regulations govern all federally supported research involving human subjects. CRS-14 Veterans Affairs, Environmental Protection Agency, National Science Foundation, Department of Transportation, and Department of Health and Human Services (Office of the Secretary and Food and Drug Administration). SELECTED FEDERAL AGENCIES POLICIES BEFORE COMMON RULE The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, in 1981-82, analyzed the adequacy and uniformity of the rules and procedures of the 23 Federal entities reporting that they conduct or support research with human subjects.39 In addition, the Commission analyzed those of FDA, which plays a central role in regulating biomedical research not funded by the Federal Government. In general, the President's Commission's findings were similar to those observed in 1978 by the National Commission for the study of Ethical Problems in Biomedical and Behavioral Research. The basic regulations of DHHS, 45 CFR 46, were regarded by the President's Commission as the benchmark of "adequacy" for protecting human research subjects. This in part was based on the thorough review of human subject regulations of DHHS (then DHEW) performed by the National Commission in 1974-78. According to the President's Commission, DHHS had conscientiously responded to recommendations made by the National Commission concerning the review standards and procedures for research involving competent, non-institutionalized, adults.40 The President's Commission found that 22 Federal entities, other than DHHS, that conducted and supported biomedical and behavioral research involving human subjects had regulations or policies which significantly conformed with DHHS regulations. These Federal agencies required review and ____________________ 39 This Commission is discussed further below. The following agencies were included in the President's Commission's review: American National Red Cross, Central Intelligence Agency, Consumer Product Safety Commission, Dept. of Agriculture, Dept. of Commerce, Dept. of Defense (Army, Navy, Air Force), Dept. of Education, Dept. of Energy, Dept. of Health and Human Services, Dept. of Housing and Urban Development, Dept. of Justice (Bureau of Prisons, Office of Justice Assistance, Research, and Statistics), Dept. of Transportation (Coast Guard, Federal Aviation Admin., National Highway Traffic Safety Admin.), Environmental Protection Agency, National Aeronautics and Space Admin., National Science Foundation, U.S. International Development Cooperation Agency, and Veterans Admin. 40 The National Commission for the protection of Human Subjects of Biomedical and Behavioral Research released a congressionally mandated, Report and Recommendations: Research Involving Those Institutionalized As Mentally Infirm subjects. While these recommendations were published by DHEW (Mar. 17, 1978, FR 11328-11358), as was the department's intent to adopt regulations to implement the recommendations (notice to develop regulations on April 24, 1978; proposed regulations on Nov. 17, 1978), DHEW never adopted them, and never published grounds for not adopting them. CRS-15 approval of proposed research by an IRB or a similar committee, using standards for review and consent provisions that mirrored, or resembled, those in the DHHS regulations. However, the Commission found that with two agenCies, the regulations applied to some, but not to all, of the research conducted or supported by those agencies. The Department of Education's regulations applied to contracts, but not to grants, and the National Aeronautics and Space Administration (NASA) required IRB review for intramural research, but not for extramural research. Agencies had a variety of rules regarding special classes of human subjects. For example, the Army had adopted special protections for the involvement of children, prisoners, and the mentally disabled in Army research activities. However, the Navy simply excluded prisoners and the mentally disabled, and the Air Force, in addition to prisoners and the mentally disabled, excluded children. Moreover, the Department of Agriculture excluded females "unless there is reasonable assurance of no concomitant pregnancy that would place the fetus at risk and if methods adopted for contraception do not place the female subject at increased risk without complete disclosure to the female subject." Four agencies had no formal regulations specifically for the protection of human research subjects: the Department of Housing and Urban Development and three agencies of the Department of Transportation (DOT)--the Coast Guard, the Federal Aviation Administration, and the Federal Highway Administration. The remaining DOT agency, the National Highway Traffic Safety Administration, had rules that paralleled the DHHS regulations. Table I shows results from the President's Commission's 1980-81 survey of the 17 out of 22 Federal entities conducting or supporting research involving human subjects whose regulations or policies substantially conformed with DHHS regulations, 45 CFR 46. The summary of two agencies' rules from the President's Commission's 1981 report follows. Department of Energy (DOE) Most of the biomedical research involving human subjects that was being supported by DOE at the time of the President's Commission's survey consisted of epidemiological research. DOE's regulations and guidelines for the protection of human research subjects conformed with DHHS regulations. DOE accepted assurances approved by DHHS as documentation of institutions' compliance with these regulations, or alternatively, negotiated an assurance directly with the institution receiving DOE funding. DOE staff reviewed assurances for general acceptability. Factors such as the adequacy of the proposed IRB in light of the contemplated scope of the institution's research activities and types of research subject populations likely to be involved, and the appropriateness of the proposed research, as well as continuing review procedures in light of the probable risks were reviewed. CRS-16 TABLE I. Agency Conformity With HHS Regulations (45 CFR 46), 1981 Department Requires IRB Review Consent or Agency or Similar Standards Provisions Notes Committees Similar Similar to HHS to HHS American National Red Cross* * * Central Intelligence Agency* * * Consumer Product Safety Commission * * * Department of Agriculture * * * Department of Commerce * * * Department of Defense: Army * * * Navy * * * Air Force * * * Department of Education: * * * IRBs are required for contracts but not grants Department of Energy * * * Department of Housing and Urban Development * * * Independent review when more than limited potential of harm Department of Justice: Bureau of Prisons * * * Office of Justice Assist., Research, and Statisticssee notes see notes see notes Employs advisory boards; protects confidential ity Dept. of Transportation Coast Guard Federal Aviation Admin. Federal Highway Admin. Natl. Highway Traffic Safety Administration * * * Environment Protection Agency * * * National Aeronautics and Space Administration * * IRB's required only for intramural research U.S. Intl Development Cooperation Agency * see notes see notes (45 CRF 46) provides guidance Veterans Administration * * * Source: President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, "Pro[deleted] Human Subjects Dec., 1981, p.29. CRS-17 Department of Transportation (DOT) U.S. Coast Guard The U.S. Coast Guard supported and conducted research involving safety in recreational and maritime vessels, including research into the efficacy of personal flotation devices for average, as well as physically handicapped individuals. There were no formal regulations or policies for the protection of human subjects conducted or supported by the Coast Guard at the time of the President's Commission's review. However, the Coast Guard used provisions in DHHS regulations as guidelines. Moreover, major Coast Guard research projects involving biomedical and behavioral research (in particular, hypothermia and personal flotation devices for the physically handicapped) had been conducted with institutions who had a general assurance on file at DHHS. These IRBs reviewed the Coast Guard research project, even though they were not specifically required to do so. CONGRESSIONALLY-CREATED COMMISSIONS The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research Some Members of Congress had been attempting to create a national body to assess the ethical, legal, and social implications of biomedical advances since 1968.41 Events like the Tuskegee Study and others increased the support for such a body. In 1974, Congress passed the National Research Act of 1974 (P.L. 93-348), which required that research institutions have institutional review boards (IRBs). P.L. 93-348 also established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. This Commission existed for four years (1974-1978) and was charged to examine ethical, social, and legal issues related to biomedical and behavioral research and to recommend ways of protecting human subjects. During its term, the National Commission issued numerous reports and recommendations (17 reports), including informed consent, IRBs, and the proper treatment of human research subjects (including fetuses, children, prisoners, and those institutionalized as mentally infirm). The Commission also prepared the report "A Special Study on the Implications of Advances in Biomedical and Behavioral Research." The Commission's reports and recommendations led to modifications in DHHS policy governing the protection of human research subjects (reflected in 45 CFR 46). Specifically, the Commission's first report, "Research on the Fetus," issued in 1975 in direct response to a congressional mandate under P.L. 93-348, provided the basis for DHHS' 1975 additions to 45 CFR 46, "Additional _______________________ 41 Senator Walter Mondale (MN) had introduced a bill to establish a Commission on Health Science and Society to assess and report on the ethical, legal, social, and political implications of biomedical advances. This generated harsh resistance from the medical and biomedical research communities. Rothman, David J., p. 169-189. CRS-18 Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization" (45 CFR 46.201-46.211). The Commission's work also provided the basis for regulations giving additional protections to prisoners and children, who are involved as subjects in biomedical and behavioral research. These additional protections were added later under 45 CFR 46.301-46.306, and 45 CFR .46.401-4(3.409, respectively. When the National Commission's term expired in 1978, the Secretary of DHEW created a new ethics committee, the "Ethical Advisory Board." This board had been recommended by the National Commission and it continued the discussion on research ethics at the Federal level until it was dissolved in 1980.42 The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (President's Commission) was authorized in 1978, under Title III of P.L. 95-622, the Community Mental Health Centers Extension Act of 1978. The legislative mandate under P.L. 95- 622 expanded upon the duties and responsibilities of the National Commission by directing the President's Commission to consider ethical problems in medicine, as well as in research. The President's Commission issued reports on the ethical aspects of such issues as: the definition of death, informed consent, genetic screening and counseling, differences in the availability of health care, compensation for injured research subjects, and "whistle-blowing" in biomedical research. The President's Commission concluded its work in March 1983. The President's Commission was directed to report biennially (every two years) to the President, Congress, and appropriate Federal departments and agencies on the adequacy and uniformity of Federal rules and policies, and their implementation, for the protection of human subjects in biomedical and behavioral research. To carry out this charge, the President's Commission was directed to review the adequacy and uniformity of current rules, policies, guidelines and regulations in this area and determine the effectiveness of their implementation. _______________________ 42 This Ethical Advisory Board (EAB) was dissolved to fund the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Although Congress authorized $20 million for four years of operations in P.L. 95-622, the statute creating the Commission, funds were never appropriated. Instead, $1.2 million were reprogrammed from the DHEW Ethics Advisory Board's FY 1980 budget and the EAB was dissolved. (See the President's Commission's report, Summing Up, p. 8-9, for more information.) CRS-19 The first Biennial Report of the President's Commission was issued in December 1981.43 The Commission raised three major concerns: (1) lack of conformity among component parts of a department or agency (the Departments of Defense, Transportation, and Justice); (2) inconsistency with regard to applying regulations to all categories of human research within one Federal entity (Department of Education and NASA); and (3) lack of complete uniformity among all Federal departments and agencies. The report found that DHHS was the preeminent Federal agency in the area of protection for human research subjects. Many other agencies with formal policies or regulations governing these activities conformed with DHHS regulations. Some of these agencies imposed additional requirements. However, of great concern was that some agencies involved in human subject research activities had no formal policies to assure protection. This resulted, for example, in a lack of internal consistency in two agencies that apply DHHS standards and policies to some, but not all, research. In addition, the President's Commission expressed concern that the policy statements of several agencies simply referred to DHHS regulations "for guidance." Commission members stated these agencies should produce more explicit directives. The President's Commission concluded that all research involving human subjects that is supported by public funds should conform to a uniform "core" of regulations. Furthermore, the Commission believed the 1981 provisions in 45 CFR 46 provided an acceptable starting point for any effort to obtain uniformity. These recommendations ultimately led to the development of the Common Rule regulations adopted on June 18, 1991. The second Biennial Report to the President's Commission was released in March 1983.44 In it, the Commission found that, although some progress had been made by Federal agencies in response to its 1981 recommendations, the general reaction was "disappointing." The Commission identified numerous deficiencies in the mechanisms being used by Federal agencies to monitor IRB performance and evaluate the adequacy of IRB's implementation of rules to protect human subjects in research. The President's Commission made recommendations, including: (1) DHHS should reestablish an Ethics Advisory Board; (2) a uniform Federal system documenting the implementation of the 45 CFR 46 regulations through prior assurances and periodic site visits should be developed; (3) an assurance process, which provides prior assurance of the adequacy of each IRB's composition, ____________________ 43 President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research Protecting Human Subjects, Dec. 1981, G.P.O. no. 040-000-00452- 1. This Commission's second biennial report, Implementing Human Research Regulations, was published in 1983. 44 President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Implementing Human Research Regulations. Washington, U.S. Govt. Print. Off., Mar. 1983. CRS-20 procedures, and institutional support should be developed; and (4) agencies' educational and monitoring efforts should include a program of site visits to IRBs. To date, virtually none of these recommendations has been implemented. RECENT CONGRESSIONAL EFFORTS As mentioned above, the President's Commission recommended the re-establishment of an Ethics Advisory Board within DHHS. This was due in part to the Commission's belief that a national body was necessary to carefully consider unresolved ethical issues related to human subject research, such as formally extending Federal regulations to non-federally funded research. Moreover, the Commission noted that such a national body would serve as an important forum to discuss and resolve other issues likely to emerge in the future. Legislation was introduced on May 27, 1993 (S.1042 (Hatfield)) which would establish a permanent Ethical Advisory Board within DHHS. This Board would advise, report on, and make recommendations to the Secretary of DHHS and Congress on ethical, legal, and social issues related to biomedical and behavioral research. 5.1042 was referred to the Senate Labor and Human Resources Committee, which held hearings on it October 14, 1993. Ethicists, researchers, and others have recently voiced a call to reestablish national ethical boards to address unresolved issues related to human subject research. Hearings in the House and Senate on the aforementioned radiation experiments have served as a platform for proponents to stress the importance of such a body.45 Moreover, the congressional Office of Technology Assessment, in a June 1993 report, concluded: Regardless of whether it creates a new, broad-based commission, directs DHHS to establish an EAB with a new mandate, or both, Congress should somehow provide a voice for biomedical ethics in public policy.46 Efforts in Congress and DHHS to establish Ethics Advisory Boards during the past 10 years have been unsuccessful. This is attributed mostly to unresolved issues related to abortion. Many issues to be addressed by such a body, including human embryo and fetal tissue research, have evoked ______________________ 45 To date, the following committees have held hearings: (1) Senate Committee on Labor and Human Resources (field hearing at the Fernald State School, MA), Jan. 13, 1994; (2) House Committee on Energy and Commerce, Subcommittee on Energy and Power, Jan. 18, 1994; (3) Senate Committee on Governmental Affairs, Jan. 25, 1994; (4) House Committee on the Judiciary, Subcommittee on Administrative Law and Governmental Relations, Feb, 2, 1994; (5) House Committee on Veterans' Affairs, Feb. 8, 1994; and (6) House Committee on Science, Space, and Technology, Subcommittee on Energy, Feb. 10,1994. 46 U.S. Congress. Office of Technology Assessment. Biomedical Ethics in U.S. Policy. Washington, U.S. Govt. Print. Off- OTA-BP.BBS-105. June 1993. p. 38. CRS-21 controversy associated with unresolved moral conflicts involving the status of the human fetus. However, momentum may be growing for a biomedical ethics board. It is not clear if such a body should be "ad hoc," with a limited term to address specific issues, or a permanent body, with an indefinite term and more broad-based mandate. CONCLUSION Congress, assisted by specifically appointed Commissions, has played an instrumental role in the development of current regulations for the protections of human research subjects. Public disclosures of abuses in research with human subjects during the 1960s and 1970s, were pivotal in provoking much of the scrutiny. Recently, the Clinton Administration appointed the Human Radiation Interagency Group and the Advisory Committee on Human Radiation Experiments to review questionable federally-funded research experiments, which involved exposure of human subjects to radiation. In addition, numerous congressional hearings, held during the past two months, have provided a public forum to examine the questionable practices. As this investigation continues, significant attention will undoubtedly focus on institutional review boards (IRBs). The responsibility for assuring that researchers comply with human protection regulations, including obtaining informed consent from research subjects, lies chiefly with IRBs. As noted earlier, the President's Commission, in its 1983 Biennial Report, expressed dissatisfaction with the progress of Federal agencies in assuring IRB compliance in this area. The Commission recommended that agencies develop a system to document that regulations were being implemented by researchers. Periodic site visits were identified as being a crucial part of this documentation system. However, to date, little has been done at the Federal level to develop such a documentation system as defined in the 1983 report. On February 17, 1994, President Clinton sent a memorandum to all heads of Executive departments and agencies directing them to review Federal policy for the protection of human subjects.47 Among other things, the President directed: Each department and agency of Government to review present practices to assure compliance with the Federal Policy for the Protection of Human Subjects and to cease immediately sponsoring or conducting any experiments involving humans that do not fully comply with the Federal Policy. It is unclear what role, if any, the Human Radiation Interagency Group will play in assuring compliance with this directive. ____________________ 47 Clinton, William J. Memorandum for the Vice President, the Heads of Executive Departments and Agencies. Review of Federal Policy for the Protection of Human Subjects. Feb. 17, 1994. CRS-22 APPENDIX A. NUREMBERG CODE48 1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and 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 latter element 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 effects upon his health or person which may possibly come from his participation in the experiment. 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. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. 4.. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. ____________________ 48Katz, Jay. Experimentation With Human Beings. Russell Sage Foundation, NY, 1972. p. 305306. CRS-23 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. CRS-24 APPENDIX B. WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI49 ....In the field of clinical research a fundamental distinction must be recognized between clinical research in which the aim is essentially therapeutic for a patient, and clinical research the essential object of which is purely scientific and without therapeutic value to the person subjected to the research. I. BASIC PRINCIPLES 1. Clinical research must conform to the moral and scientific principles that justify medical research, and should be based on laboratory and animal experiments or other scientifically established facts. 2. Clinical research should be conducted only by scientifically qualified persons and under the supervision of a qualified medical man. 3. Clinical research cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject. 4. Every clinical research project should be preceded by careful assessment of inherent risks in comparison to foreseeable benefits to the subject or to others. 5. Special caution should be exercised by the doctor in performing clinical research which the personality of the subject is liable to be altered by drugs or experimental procedure. II. CLINICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 1. In the treatment of the sick person the doctor must be free to use a new therapeutic measure if in his judgment it offers hope of savinglife, re-establishing health, or alleviating suffering. If at all possible, consistent with patient psychology, the doctor should obtain the patient's freely given consent after the patient has been given a full explanation. In case of legal incapacity consent should also be procured from the legal guardian; in case of physical incapacity the permission of the legal guardian replaces that of the patient. __________________ 49 Katz, J., p. 312-313. CRS-25 2.The doctor can combine clinical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that clinical research is justified by its therapeutic value for the patient. III. NON-THERAPEUTIC CLINICAL RESEARCH 1.In the purely scientific application of clinical research carried out on a human being it is the duty of the doctor to remain the protector of the life and health of that person on whom clinical research is being carried out. 2.The nature, the purpose, and the risk of clinical research must be explained to the subject by the doctor. 3a. Clinical research on a human being cannot be undertaken without his free consent, after he has been fully informed; if he is legally incompetent the consent of the legal guardian should be procured. 3b. The subject of the clinical research should be in such a mental, physical, and legal state as to be able to exercise fully his power of choice. 3c. Consent should as a rule be obtained in writing. However, the responsibility for clinical research always remains with the research worker; it never falls on the subject, even after consent is obtained. 4a. The investigator must respect the right of each individual to safeguard his personal integrity, especially if the subject is in a dependent relationship to the investigator. 4b. At any time during the course of clinical research the subject or his guardian should be free to withdraw permission for research to be continued. The investigator or the investigating team should discontinue the research if in his or their judgment it may, if continued, be harmful to the individual.