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Responsible Science: Ensuring the Integrity of the Research Process, Volume II 5 Factors Enhancing Acceptance of Federal Regulation of Research Barbara Mishkin INTRODUCTION This paper analyzes factors important for gaining general acceptance of federal regulations governing the conduct of research. The regulations requiring prior review of research with human subjects by an institutional review board (IRB) provide a good model because their development is well documented and they are now generally accepted. Moreover, the difficulties encountered in applying the IRB model to activities unaccustomed to such requirements demonstrate the importance of preparation, patience, and goodwill in developing new regulations. This paper focuses primarily on the factors in the development of the IRB regulations that affected their acceptance: (1) adequate time frame, (2) constituent participation in policy making, and (3) public access to the deliberative process. Attention to these factors greatly enhanced acceptance of the regulations by the biomedical research community and increased public confidence in their reasonableness and effectiveness. By contrast, inadequate preparation and a lack of constituent participation resulted in initial resistance on the part of many social, education, and behavioral scientists to the extension of IRB requirements to activities not previously covered by such regulations. ADEQUATE TIME FRAME As described elsewhere, the IRB regulations were developed incrementally over approximately 10 years.1 Interdisciplinary attention to the protection of human subjects was reflected both in the lay press and in scientific journals between 1955 and 1965, heightening public awareness of the issues. For example, in 1960, the National Institutes Barbara Mishkin is an attorney with the firm Hogan and Hartson in Washington, D.C.
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II of Health (NIH) awarded a grant to the Law-Medicine Institute of Boston University to study the legal and ethical aspects of conducting research with human subjects. The resulting report, published in 1963, suggested (among other things) "group consideration" or prior review of such research.2 In 1966, the surgeon general adopted that recommendation by requiring NIH grantees to provide prior review of research with human subjects by an institutional committee.3 A year later, Pappworth published a compendium, drawn from reputable journals, of experiments in which people were subjected to a variety of highly risky procedures and suffered a disquieting number of serious adverse effects (including meningitis, shock, liver damage, cardiac arrest, and punctures of main arteries or major organs).4 Pappworth concluded that because self-regulation was clearly ineffective, legislative remedies—including prior review by "Medical Research Committees"—were required.5 Concurrently, legal scholars turned their attention to issues of liability, and some suggested prior review of research as a method of limiting the risk to which subjects would be exposed (thereby limiting potential liability).6 Possibly in response to multidisciplinary pressures, the Public Health Service modified its policies in 1971 to require the broader composition of institutional review committees: The committee must be composed of sufficient members with varying backgrounds to assure complete and adequate review of projects. … The committee should be able to determine acceptability of the proposal in terms of institutional commitments and regulations, applicable law, standards of professional conduct and practice, and community attitudes.7 The revised Department of Health, Education, and Welfare (DHEW) policy, familiarly known as the "Yellow Book," thus imposed additional requirements designed to avoid conflicts of interest in the review process. Scientists initially protested that nonscientists on the review committees would unreasonably impede the conduct of research; however, the public pressures and scholarly recommendations were such that the new requirements withstood the negative pressure from academic administrators and clinical investigators.8 In sum, the IRB system was developed by the Public Health Service incrementally over a period of years and was supported by articles in respected scientific and medical journals, as well as by scholarly writings of experts in law and ethics. At the same time, public pressure for reform appeared in the lay press, and NIH administrators recognized both the need for change and the importance of an interdisciplinary approach to the development of new policies.
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II CONSTITUENT PARTICIPATION IN POLICY MAKING From 1974 to 1983, the HEW policies were further refined by the National Commission for the Protection of Human Subjects and the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (hereafter referred to as the National Commission and the President's Commission, respectively). Important aspects of the work of these two commissions were (1) the interdisciplinary composition of their members, staff, and consultants; (2) their openness to the public; and (3) their consideration of the views of all interested parties (including government officials, university administrators, research scientists, public interest groups, and members of the general public). The National Commission set the standard of public accessibility, as required by its enabling legislation and the newly enacted "Government in the Sunshine" laws.9 When the commission held hearings, as it did on each major topic of concern, everyone who requested an opportunity to be heard was permitted to testify. Those who could not appear in person were invited to submit comments in writing. The result was that all constituents correctly felt that they had access to the commission's attention and could participate in a meaningful way in its deliberations. Scientists and academic administrators had equal access, as did federal officials. So, too, did research subjects. The commission made site visits to various institutions at which commission members and staff had an opportunity to inspect the facilities and talk with both research scientists and their subjects. The commission also held hearings on the role and operation of IRBs at various sites around the country, to afford researchers and administrators an opportunity to present their views. PUBLIC ACCESS TO THE DELIBERATIVE PROCESS All of the National Commission's meetings were open to the public and were announced in advance. Copies of all meeting materials distributed to commissioners (including draft documents) were available to anyone who asked, and all correspondence addressed to the commission was photocopied and distributed to each commissioner. (This policy was followed scrupulously, even when the commission received dozens of duplicate postcards from around the country on matters such as fetal research.) In addition, the commission sent regular mailings of meeting agendas and summary minutes to a mailing list of
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II several hundred individuals and organizations. The President's Commission followed the same policies and procedures. RESISTANCE FROM THE NEWLY REGULATED Considerable consternation arose in 1974 from the conversion of the NIH grants administration policies to formal HEW regulations, in an attempt to avoid impending congressional legislation. The problem was the sudden applicability of rules, designed with medical research in mind, to activities of a very different nature (such as social science research, demonstration projects of the "welfare" component of HEW, and behavioral science methodologies such as participant observation and deception). The imposition of the "medical model" to such diverse activities provoked cries of anguish and calls for revision from social and behavioral scientists, suddenly confronted with an entire set of regulations that were both unfamiliar and (they firmly believed) destructive. The education components of HEW held fast to their authority to promulgate their own regulations and refused to adopt the department's new version.10 The National Commission's procedural remedy was to invite social and behavioral scientists to explain the nature of their activities and their concerns, and to encourage them to propose revisions to the regulations that would alleviate the perceived problems without compromising the basic system of IRB review. Some of the most vigorous debates among commissioners and staff revolved around issues such as how to adapt informed consent provisions to research in which disclosure of the methodology and purpose would utterly defeat the exercise (for example, deception research and covert or participant observation). Everyone (witnesses, commissioners, and staff) learned from the exchanges, and ultimately, a consensus emerged that satisfied the social and behavioral scientists without leaving the biomedical scientists and research administrators feeling that they had "sold out." A review of the witnesses who testified at the commission's IRB hearings demonstrates the breadth of concern among behavioral and social scientists. Among the 44 witnesses were 16 behavioral or social scientists, whose testimony focused largely on the difficulty of applying rules derived from a biomedical model to research involving participant observation, survey questionnaires, covert observation, and administration of standardized psychological or educational tests. They emphasized that "informed consent" has no meaning in many of these contexts and could be counterproductive in others. Moreover, a signed consent form could present greater risk to subjects than their
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II participation in certain research (for example, in research concerning illegal activities). Constructive suggestions were offered for clarifying definitions (of such terms as "human subject," "research," and "risk"), for excluding certain categories of research from IRB review, and for modifying the consent requirements under certain conditions. They also suggested that IRBs contain members familiar with the kind(s) of research under review. These suggestions were included in the commission's recommendations and ultimately adopted by the Department of Health and Human Services (DHHS) as amendments to the IRB regulations.11 Biomedical researchers described their own problems with the existing system. For example, they pointed out that very little risk to human subjects is presented by research utilizing tissues and organs removed for diagnostic or therapeutic purposes, unless the tissues are personally identified and sensitive information is involved. They also reported that a large proportion of IRB time was being spent reviewing such secondary uses of discarded tissue. Similar points were made about retrospective reviews of medical records. Their recommendations for further refinement of the definition of risk, and for expedited review of certain categories of research activities, were endorsed by the commission and subsequently adopted by DHHS.12 In short, the deliberative process worked well, due in large part to the clear willingness of the commission to receive and respond positively to the complaints and suggestions of all concerned. In addition, the statutory requirement that DHHS accept and implement the commission's recommendations (or explain in the Federal Register why it could not) reinforced the department's inclination to adopt the commission's recommendations. Goodwill on the part of virtually all concerned further enhanced the process. EVIDENCE CONCERNING IRB PERFORMANCE Both the National Commission and the President's Commission undertook studies of IRBs. The National Commission's study focused on their composition, administration, and operating procedures. Masses of data were collected on IRB membership, structure, and authority; voting and operating procedures; record keeping; administrative support; time spent on specific tasks; relation between the level of risk presented and the amount of time spent reviewing a protocol; number of times that protocols and consent forms were revised; and the reading level of approved consent forms. These data yielded useful (and sometimes surprising) findings. For example, it was discovered that the number of
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II times consent forms were revised bore no relation to the extent to which the final (approved) version met all regulatory requirements.13 Nor did it improve the readability of the forms.14 The National Commission's study also surveyed the attitudes of IRB members and the researchers who submitted protocols to the IRB. The survey results were generally consistent with the testimony of witnesses at the hearings, in that behavioral scientists expressed frustration and disappointment about IRB members' lack of familiarity with the traditional methods of behavioral sciences, while the biomedical scientists complained about the disproportionate amount of time spent in preparing and reviewing protocols presenting no discernible risk to subjects (as in research involving by-products, such as body fluids and tissues, obtained from a diagnostic intervention).15 Interestingly, however, most researchers believed that the IRB system improved research more than it impeded it, and they were generally supportive of the IRB system overall.16 The President's Commission, like its predecessor, evaluated the performance of IRBs. Rather than relying on surveys, however, the President's Commission conducted site visits to observe IRBs in action. Critics had suggested that NIH should have a better system for monitoring IRB performance than reliance on annual promises to comply with the regulations. Those who had been subjected to inspections by the Food and Drug Administration (FDA), however, complained about the difficulties encountered when inspectors, totally unfamiliar with biomedical research, undertook to evaluate IRB performance.17 The shortcomings of the FDA inspections were demonstrated in the commission's study by comparing FDA inspection reports with evaluations of the same IRBs performed by experienced IRB members of the site visit teams.18 The peer site visits also revealed that there was room for further improvement in IRB performance. For example, site visitors found that some IRBs did not provide full IRB review of proposals, others lacked "a clear understanding of their role and responsibility," and there were occasional lapses in commitment to the protection of human subjects.19 In addition, experienced IRB members often could suggest procedural modifications to eliminate problems, increase efficiency, and improve relations between the IRB and the scientists. Clearly, IRBs responded better to site visits by peers than to inspections conducted by personnel unfamiliar with research policies and procedures.
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II PATIENCE, PERSEVERANCE, AND GOODWILL The resolution of policy differences between the Public Health Service (predominantly NIH) and the education and social services component of DHHS was not easy. The prolonged process illustrates what happens when regulatory constraints are applied without warning to activities not previously subject to regulation. As previously noted, problems arose when Public Health Service policies, developed with biomedical research in mind, were converted to DHHS regulations applicable to all "research, development, and related activities" conducted or supported by the department. With one stroke, activities such as Head Start and medical assistance demonstration programs became "research with human subjects" for which IRB review and informed consent would be required. Efforts to incorporate the commission's recommendations into amendments to the IRB regulations became mired in an intramural conflict between officials at NIH (representing the Public Health Service's interests) and staff of the DHHS assistant secretary for planning and evaluation (ASPE), representing the education and social security arms of the department. Draft upon draft of revisions proposed by NIH were unacceptable to the ASPE. The sticking point was the requirement for informed consent (and the right to withdraw at any time) for "demonstration projects" designed to test new ways of delivering public assistance. New benefit programs—or modifications of existing programs—normally include a mandatory evaluation component. As a result, the receipt of public benefits in a demonstration program is normally conditioned upon the beneficiaries' willingness to cooperate with the evaluation of the program (e.g., by responding to survey questionnaires or by permitting follow up tests of educational progress). The requirement to assure the subjects of evaluation research that they could receive benefits to which they were entitled, whether or not they agreed to participate in the research, and that they could withdraw from the research at any time and without penalty, threatened to destroy the department's ability to assess new benefit programs such as Medicare copayment requirements. The proposed amendments to the IRB regulations were nearing adoption when the President's Commission was established, and the commission proposed modifying the exemptions to the IRB and consent requirements. In a letter to then-Secretary Patricia R. Harris, the commission recommended that there be three categories of research normally exempt from IRB review:
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II (a) Research involving questionnaires, interviews, or standard education or psychological tests, in which the agreement of the subjects to participate is already an implicit or explicit part of a research process which itself will involve little or no risk; (b) research in which consent is not typically obtained because the gathering of information involves merely observation of behavior in public places (for which there is no reasonable expectation of privacy), review of publicly available information, or analysis of data containing no personally identifiable information; and (c) social, economic, or health service research conducted under governmental aegis (such as HEW Medicare copayment experiments or the OEO negative income tax experiment) in which consent of "subjects" may or may not be warranted by statute.20 The commission's first two categories of proposed exemptions were adopted in the final rules published in January 1981; however, the third category was not specifically listed as an exemption. Instead, a provision was added permitting the DHHS secretary to waive applicability of the IRB and consent requirements "to specific research activities or classes of research activities otherwise covered by these regulations" providing the secretary published notices of such waivers in the Federal Register.21 Pursuant to the waiver provision, DHHS Secretary Richard Schweiker subsequently published a notice waiving IRB review and consent requirements for demonstration projects designed to test cost-sharing requirements in the Medicaid program.22 Shortly thereafter, the secretary published a proposal to exempt from IRB review "research and demonstration projects conducted under the Social Security Act and other Federal statutory authority and designed to study certain public benefit or service programs, the procedures for obtaining benefits or services under those programs, and possible changes or alternatives to those programs or procedures, including changes in methods or levels of payment."23 Although the President's Commission urged that the exemption be drawn more narrowly,24 the department rejected the commission's proposed modifications and exempted research and demonstration projects designed to evaluate programs under the Social Security Act and other public benefit or service programs, as originally proposed.25 In addition, the regulations were amended to permit IRBs to waive informed consent requirements for similar studies conducted under the auspices of state or local governments. Controversy over IRB review of public assistance demonstration projects continues, even today. The effort to establish uniform federal policies for the protection of human subjects, first suggested by the National Commission in 1978, was reiterated by the President's Commission in 1982.26 It was not until June 1986 that proposed uniform policies were published for public comment, and it was more
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II than 2 years later that proposed uniform regulations were published.27 Final rules were published on June 18, 1991.28 A major factor in the delay has been (as before) the applicability of the IRB and consent requirements to education research and to demonstration projects designed to evaluate public benefit programs.29 LESSONS FOR THE FUTURE The development of IRBs as a regulatory mechanism for protecting human subjects demonstrates that time, collegial interaction, and goodwill are important ingredients for successful rulemaking. When policy conflicts arise, participation in the deliberations by all who wish to be heard not only improves the substantive regulations, but also increases the likelihood of their acceptance and enhances public confidence in the process. In short, the success and credibility of the process are directly related to the extent to which all interested parties are afforded an opportunity to participate. The hazards of proceeding unilaterally were demonstrated recently by the unsuccessful attempt of the NIH to establish ''guidelines" for dealing with conflicts of interest, without affording adequate opportunity to comment. The research community felt it had been blindsided. Responses reflected outrage, a sense of betrayal, and frustration.30 A much fuller airing of the concerns of all interested parties, as well as a public deliberative process, would more likely produce a broadly accepted set of rules. Such an approach also would enhance public confidence in the process and substance of the rulemaking. In the absence of a more thoughtful development of rules, mistrust and resistance probably will continue. NOTES 1. See, for example, Jonsen, A., 1984, "Public policy and human research," pp. 3-19 in Biomedical Ethics Reviews, Humber, J. M. and R. T. Almeder (eds.). Humana, Clifton, N.J. 2. For a brief history of early antecedents, see President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1982, Compensating for Research Injuries, U.S. Government Printing Office, Washington, D.C., p. 30. 3. See President's Commission, Compensating for Research Injuries, 1982, pp. 30-33. 4. Pappworth, M. H., 1967, Human Guinea Pigs, Beacon, Boston. 5. Pappworth, Human Guinea Pigs, 1967, pp. 209-10; see also, President's Commission, Compensating for Research Injuries, 1982, pp. 32-33.
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II 6. See, for example, Calabresi, G., 1969, "Reflections on medical experimentation in humans," Daedalus (Spring):387-405. 7. Department of Health, Education, and Welfare (DHEW), 1972, The Institutional Guide to DHEW Policy on Protection of Human Subjects, DHEW, Washington, D.C., p. 4; see also, President's Commission, Compensating for Research Injuries, 1982, pp. 35-36. 8. Department of Health, Education, and Welfare (DHEW), 1973, Final Report of the Tuskeegee Syphilis Study Ad Hoc Advisory Panel, DHEW, Washington, D.C., p. 38. 9. Public Law 94-348, Title III (88 Stat. 342 ). 10. See National Commission for the Protection of Human Subjects, 1978, "Institutional review boards: report and recommendations," Federal Register 43(November 30):56174, 56184-85. 11. Department of Health and Human Services (DHHS), 1981, "Final regulations amending basic HHS policy for the protection of human subjects," Federal Register 46(January 26):8366-92 (45 C.F.R. Part 46). 12. DHHS, "Final regulations … for the protection of human subjects," 1981. 13. National Commission, "Institutional review boards," 1978, pp. 56174, 56189-90; see also, National Commission, 1978, IRB Report, Appendix to Report and Recommendations: Institutional Review Boards, p. 1-26. 14. National Commission, "Institutional review boards," 1978. 15. National Commission, IRB Report, Appendix, 1978, pp. 1-95 through 1-101. 16. National Commission, IRB Report, Appendix, 1978, p. 1-42. 17. Some referred to the inspectors as "rat inspectors," emphasizing the fact that their training was predominantly in such matters as counting the number of rat droppings at food and drug manufacturing plants. 18. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1983, Implementing Human Research Regulations, U.S. Government Printing Office, Washington, D.C., pp. 105-14. 19. President's Commission, Implementing Human Research Regulations, 1983, pp. 76-97. 20. Letter from Morris B. Abram to Patricia Roberts Harris (September 18, 1980), reprinted in the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1981, Protecting Human Subjects, First Biennial Report, U.S. Government Printing Office, Washington, D.C., pp. 166-167 (Appendix D: Correspondence with HHS on Regulations). 21. 45 C.F.R. Section 46.101(e), as published in DHHS, "Final regulations … for the protection of human subjects," 1981, p. 8386. 22. Department of Health and Human Services (DHHS), 1982, "Waiver of requirements as applied to Medicaid demonstration projects involving cost-sharing (copayments, deductibles, coinsurance)," Federal Register 47(March 4):9208. 23. Department of Health and Human Services (DHHS), 1982, "Exemption of certain research and demonstration projects from regulations for protection of human subjects: proposed rule," Federal Register 47(March 22):12276. 24. President's Commission, Implementing Human Research Regulations, 1983, Appendix D, pp. 177-180. 25. Department of Health and Human Services (DHHS), 1983, "Exemption of certain research and demonstration projects from regulations for protection of human subjects: final rule," Federal Register 48(March 4):9269. 26. President's Commission, 1982, First Biennial Report on the Adequacy and Uniformity of Federal Rules and Policies, and Their Implementation for the Protection of Human Subjects in Biomedical and Behavioral Research, as reprinted in Federal Register 47(March 29):13272; see especially, Part D, Conclusions, pp. 13282-83.
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Responsible Science: Ensuring the Integrity of the Research Process, Volume II 27. Executive Office of the President (EOP), Office of Science and Technology Policy (OSTP) (with 15 affected departments/agencies), 1986, "Proposed model federal policy for protection of human subjects," Federal Register 51(June 3):20204; Executive Office of the President (EOP), Office of Science and Technology Policy (OSTP) (with 15 affected departments/agencies), 1988, "Federal policy for the protection of human subjects: notices and rules," Federal Register 53(November 10):45660-82. 28. Executive Office of the President (EOP), Office of Science and Technology Policy (OSTP) (with 15 affected departments/agencies), 1991, "Federal policy for the protection of human subjects: notices and rules," Federal Register 56(June 18):28003-32. 29. Personal communication, Alicia Dustira, Executive Office of the President, Office of Science and Technology Policy, November 11, 1990. 30. See Palca, J., 1990, "NIH conflicts of interest guidelines shot down," Science 247(January 12):154, and related articles.
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