From 1962 through 1991, HHS’ system for protecting human research subjects was created, piece by piece, largely in response to disclosures of dangerous or controversial biomedical and behavioral research. (See app. II for more historical information.) The tragic consequences of thalidomide use in the United States and revelation of the Tuskegee syphilis study shocked the public and convinced national policymakers that unregulated biomedical research represented a clear threat to research subjects. Two expressions of this concern were the passage of the National Research Act and the promulgation of human subject protection regulations by the Department of Health, Education, and Welfare (HEW) in 1974. The act also established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to guide federal human subject protection policy. When the core of the human subject protection regulations was adopted by 15 other departments and agencies in 1991, it became known as the Common Rule. The Common Rule requires research institutions receiving federal support and federal agencies conducting research to establish committees to review research proposals for risk of harm to human subjects and to perform other duties to protect human research subjects. It also stipulates requirements related to informed consent—how researchers must inform potential subjects of the risks to which they, as study participants, agree to be exposed. (See fig. 1 for Basic Elements of Informed Consent.) HHS regulations contain additional protections not included in the Common Rule for research involving vulnerable populations—namely, pregnant women, fetuses, subjects of in vitro fertilization research, prisoners, and children. In the late 1970s and early 1980s, HHS considered but did not adopt recommendations by two national commissions for specific regulations to protect institutionalized mentally disabled subjects. A statement stipulating that research is involved, what the purpose of the research is, what the duration of the subject's involvement will be, and what procedures the subject will undergo. A description of foreseeable risks or discomforts to the subject. A description of expected benefits, if any, to the subject and others. The disclosure of alternative procedures or courses of treatment. A statement describing the extent to which confidentiality of records identifying the subject will be maintained. For research that poses more than minimal risk to subjects, an explanation of the availability and nature of any compensation or medical treatment if injury occurs. Names of people to contact for further information about the research, the subjects’ rights, and notification of research- related injury. A statement stipulating that participation is voluntary and no penalties will be imposed for refusal to participate in research; subject can choose to discontinue participation at any time. Within the HHS oversight system, OPRR and FDA are the key federal entities overseeing compliance with informed consent and other human subject protection regulations. Both entities carry out oversight functions central to the operation of the human subject protection system, including policy setting, prevention, monitoring, and enforcement. Institutional review boards (IRB)—that is, review panels that are usually associated with a particular university or other research institution—are responsible for implementing federal human subject protection requirements for research conducted at or supported by their institutions. OPRR is located within the National Institutes of Health (NIH), the principal federal agency responsible for supporting biomedical and behavioral research. About one-half of OPRR’s 28 full-time employees are responsible for overseeing protections in the approximately 16,000 HHS awards involving human subjects. The other half are devoted to ensuring the humane care and use of laboratory animals. Three physician volunteers augment OPRR’s human subject protection staff. OPRR has an annual budget of $1.9 million, about one-half of which is targeted to human subject protection activities. FDA is responsible for protecting the rights of human subjects enrolled in research with products it regulates—drugs, medical devices, biologics, foods, and cosmetics. Our review focused on oversight activities of FDA’s Center for Drug Evaluation and Research, which carries out most of FDA’s human subject protection activities. At CDER, responsibility for human subject protection activities is shared between the Office of Drug Evaluation and the Division of Scientific Investigations. The Office of Drug Evaluation reviews manufacturers’ and researchers’ requests to conduct drug studies on human subjects. The Division of Scientific Investigations reviews FDA’s field inspection reports on IRBs and investigators and makes final determinations regarding compliance violations. Routine and for-cause on-site inspections are conducted by field staff, who are also responsible for examining the integrity of research data, assessing compliance with good manufacturing practices, and examining other issues related to FDA’s oversight of all its regulated products. Within research institutions, oversight is done primarily by IRBs responsible for examining research proposals and ongoing studies. No data exist on the exact number of IRBs in the country but estimates range from 3,000 to 5,000. Most are found at universities, hospitals, and private research facilities; a few are free standing. Human subject research conducted by NIH itself, for example, is governed by the 14 IRBs of the NIH Intramural Research Program. In general, IRBs are composed chiefly of scientists at their respective institutions. They are required to have a minimum of five members, at least one of whom is a scientist, one a nonscientist, and one a person not otherwise affiliated with the research institution. They are also required to have a diverse membership; in determining membership, consideration must be given to race, gender, and cultural background. The presence of local review bodies and federal oversight agencies appears to have heightened the awareness and sensitivity of the research community to the importance of respecting subjects’ rights and welfare. Written commitments, which bind research institutions to comply with human subject protection requirements, are an important element of the protection system. By requiring individual researchers and IRBs to uphold their institution’s commitments, the system works to prevent harm to participants in most experimental studies. However, the effectiveness of the HHS human subject protection regulations in ensuring compliance by institutions and individual researchers has not been systematically studied. Research institutions must commit to uphold human subject protection requirements before engaging in research with human subjects conducted or funded by any of the departments or agencies that adopted the Common Rule. To be eligible to receive such funding, an institution must enter into a contract-like agreement, called an assurance. This is the written promise of an institution housing research studies to comply with federal ethical conduct standards. OPRR, the federal office within NIH that approves assurances for research funded by HHS, requires assurances to (1) include a statement of ethical conduct principles, (2) stipulate that a review board has been designated to approve and periodically review the institution’s studies, and (3) specify the review board’s membership, responsibilities, and process for reviewing and approving proposals. Assurances serve as one of the system’s chief preventive measures. OPRR’s authority to require assurances derives from the 1974 National Research Act, which formalized the practice of obtaining from institutions receiving HHS funding written assurances of their commitment to the ethical conduct of research. When the legislation was enacted, NIH had already developed assurance-type documents with many universities, which OPRR reviewed. Approving an assurance involves no site visits by OPRR to the institution; rather, negotiations are handled through correspondence and telephone calls with institution officials. OPRR assurances are of several types. Multiple project assurances are approved for universities and other major research centers that conduct a substantial number of studies and have demonstrated a willingness and the expertise to comply with human subject protection requirements. Through a multiple project assurance, an institution does not need to reapply through OPRR for eligibility to receive HHS funds for each new study approved by its IRB. An assurance covers the institution’s human subject studies for 3 years, at which time the institution must renew its assurance. Renewals are for a 5-year period. As a practical matter, multiple project assurances allow institutions to conduct research with no further OPRR involvement until the assurance is up for renewal. As of November 1995, 451 active OPRR multiple project assurances covered more than 500 research institutions. These institutions receive most of HHS’ funding for research with human subjects. Primary responsibility for negotiating all multiple project assurances in OPRR rests with a retired physician who used to be employed for this purpose by OPRR. Since retiring, she has continued this work on an unpaid, part-time basis. Currently, the assurance branch chief is responsible for approving all multiple project assurances OPRR negotiates. At institutions without a multiple project assurance, an assurance agreement must be negotiated with OPRR for each individual study. These are called single project assurances and require OPRR to review, for each study, documentation similar to that required for a multiple project assurance. In addition, OPRR reviews the study’s informed consent form before approving a single project assurance. As of November 1995, OPRR had 3,063 active single project assurances. Primary oversight of these assurances rests with three full-time staff in OPRR’s assurance branch. A third type of assurance—the cooperative project assurance—recognizes that research is frequently conducted at multiple sites under joint institutional sponsorship. One example is the National Surgical Adjuvant Project for Breast and Bowel Cancers, sponsored by the National Cancer Institute and conducted at over 300 sites. OPRR requires each participating institution to have a cooperative project assurance for all its joint research, regardless of other assurances held by the institution. For projects conducted under cooperative project assurances, OPRR designates reviewers to approve each research protocol and a prototype informed consent form. IRBs at the participating institutions must also approve the protocol and the informed consent document. IRBs can require additional explanations to be included in the informed consent document. However, they cannot modify the core elements of the protocol, which is to be consistent across all sites. Nor can they delete or substantially modify the discussion of risks and alternative treatments in the prototype consent document without notice and justification.