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Reprinted from The Nebraska Medical Journal, September, 1983, 68(9): 293-295. Evolution, Structure and Function Historical Antecedents ERNEST D. PRENTICE, Ph.D., Associate Professor of Anatomy and Administrator of the University of Nebraska, IRB; ROWEN K. ZETTERMAN, M.D., Associate Professor of Internal Medicine and Chairmen of the University of Nebraska IRB, Omaha, NE 68105 The first significant governmental and public focus on human subject research is usually dated to 1946 when the Nuremberg Trials1 brought to the world's attention the abuses of Nazi "scientists" carried out in the name of medical research. The Nuremberg Code,2 which addresses the ethics of medical experimentation, was formulated as a reaction to the Nazi experiments conducted on prisoners in concentration camps. In 1964, after nearly two decades of greatly expanded biomedical research and little emphasis on human subject protection, the 18th World Medical Assembly adopted the Declaration of Helsinki3 as a code of ethics for human experiments. One year later, human subject research once again became a public issue when the press reported the Jewish Chronic Diseases Hospital study concerning transplant rejection.4 This study, which involved the subcutaneous injection of cancer cells in senile patients without their knowledge, provoked widespread public outrage. In 1972, public opinion was inflamed further by the infamous long term Tuskegee Syphilis study5, 6 in which over 400 black males with diagnosed syphilis were recruited without informed consent, misinformed about the nature of the study, and purposely left untreated even after penicillin therapy became available. Incredibly, this study begun in 1932, sponsored by the USPHS, was in full progress during the 1960's at the time the USPHS and DHEW began formulating the Federal regulations governing human subject research and prior committee review. At approximately the same time the Tuskegee syphilis study achieved public notoriety, other reports of human subject investigations precipitated increased judicial attention to individual rights. Among the most notable cases were Kaimowitz V. Department of Mental Health7 and Wyatt V. Stickney8. In the Kaimowitz litigation on behalf of a mental patient, a study designed to evaluate psychosurgery vs. hormonal treatment was halted. The Wyatt V. Stickney case involved institutionalized mentally infirm individuals subjected to non-therapeutic experiments without their consent. Thus, it was in a highly charged emotional atmosphere fueled by public concern that the legislature established in 1974, by Public Law 93-348, The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research9. After five years of study concerning various ethical issues and a detailed review of the first edition of the DHEW regulations (45 CFR 46) issued in 1974, this commission published "The Belmont Report"10. The Belmont Report contains ethical principles and guidelines for the protection of human research subjects and serves as the basis for the final DHHS11 and FDA12 Federal regulations that now govern human subject research and the operation of the thousands of University and Hospital institutional review boards (IRBs) that must review and approve this research. Responsibilities of the IRB The National Commission in its report on IRBs13 articulated the primary purpose of the IRB: "Investigators should not have sole responsibility for determining whether research involving human subjects fulfills ethical standards. Others who are independent of the research must share this responsibility, because investigators are always in positions of potential conflict by virtue of their concern with the pursuit of knowledge as well as the welfare of the human subjects of their research". Additional IRB responsibilities specifically imposed by the Federal regulations are: Determination of the acceptability of research projects in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice14, and suspension or termination of research projects not being conducted in accordance with Federal and IRB requirements15. Considering the nature of the federally mandated IRB responsibilities, it is obvious that the IRB, of necessity, occupies an important and credible position within the research and administrative structure of the institution it serves. Structure of the IRB The composition of the IRB is specified in the DHHS regulations. The IRB must be comprised of male and female members from diverse backgrounds who possess the professional competence necessary to review the specific research activities submitted to the Board. In addition, the IRB should reflect an appropriate racial and cultural balance as well. as a sensitivity to such issues as community attitudes toward medical research. At least one member of the IRB must be a lay community representative with no formal relationship with the Institution. Lay members of the IRB are not expected to possess the necessary technical expertise to review the scientific aspects of most medical protocols. They should, however, be competent to review the consent process and the consent form. Review Procedures of the IRB The logistics of IRB review varies from institution to institution. The major principles underlying IRB review, however, do not. First, the IRB must make a decision based on common sense and sound professional judgement as to whether or not the proposed research places the subject "at risk". A subject is considered to be at risk if he may be exposed to the possibility of harm, whether physical, psychological, sociological, or other, as a consequence of any activity which goes beyond the application of those established methods necessary to meet his needs. The IRB must consider the fact that certain subject populations (e.g. minors, pregnant women, prisoners, mentally retarded) may be at greater risk than others. Certain risks are inherent in life itself, but the IRB is not concerned with the ordinary risks of public or private living. Risk as applicable to DHHS policy is most obvious in medical and behavioral science research projects involving procedures that may induce a potentially harmful altered physical state or psychological condition. The most obvious examples include surgical procedures; the administration of drugs or radiation; the requirement of strenuous physical exertion and an intervention that precipitates an emotional disturbance. There is also a wide range of medical, social and behavioral procedures and projects in which, although there may be no immediate risk, procedures may be introduced which involve discomfort, anxiety, harassment, invasion of privacy, or constitute a threat to the subject's dignity. There are also medical and biomedical projects concerned solely with organs, tissues, body fluids, and other materials obtained in the routine performance of medical services which obviously involve no element of physical risk to the subject, but their use for certain research, training, and service purposes may present psychological, sociological, or legal risks to the subject or authorized representatives. Finally, the risk element should be determined for those studies dependent upon existing information or stored data which have been obtained for quite different purposes but which, when used in a research context, may present risk to the human subject. If it is judged that the proposed research project will expose a subject to risk, then the IRB must assure itself that (a) the rights and welfare of the subject are adequately protected, (b) the methods used to obtain informed consent are adequate and appropriate, (c) the risks to the subject are outweighed by the potential benefit to him or by the importance of the knowledge to be gained, and (d) the selection of subjects is equitable. The IRB is not responsible for considering scientific merit or methodology unless an alternative experimental design will decrease the potential risk(s) to the subject and still yield the same potential benefit(s). Upon completion of the review process and investigator compliance with all modifications recommended by the IRB, an approval to begin the study is issued. Approval is for a maximum period of one year at which time annual review is required. If a project involves an unusual degree of risk to the subject, approval may be for a period of less than one year as determined by the IRB. Discussion Institutional Review Boards (IRBs) are located at every major university and hospital in the United States. Spurred into existence by public indignation concerning medical experimentation, the IRB represents both the Federal and the institutional commitment to the ethical review of human subject research. The principal role of the IRB is to assist the investigator in the protection of the rights and welfare of the human subject. To this end, the IRB helps the investigator to both interpret and comply with the DHHS and FDA regulations governing human subject research. Although the operation of the IRB is governed by Federal regulations, there is a great deal of institutional flexibility in terms of the administrative structure of the IRB and methods of review. The procedures an institution chooses to implement must be based upon the volume; complexity and nature of the research to be reviewed. Given these factors, it is not surprising that there is a great deal of diversity in the methods by which IRBs fulfill their federally and institutionally mandated responsibilities. The following five fundamental principles of successful IRB operation should, however, be adopted by all institutions conducting human subject research: 1) there should be detailed IRB guidelines for investigators to follow; 2) the review procedure should be efficient and investigators should be apprised of the status of their proposal during the review process; 3) there should be an efficient medical emergency approval system; 4) every attempt should be made to eliminate unnecessary bureaucracy; and 5) there should be open communication between investigators and members of the Board. Any IRB system that fails to operate according to the above stated principles will frustrate investigators and undermine their research efforts. More importantly, the protection of human subjects, which is the prime responsibility of both the investigator and the IRB, may be compromised. Finally, the IRB should never be viewed as an adversary or a police force. It exists to aid the investigator in the protection of human subjects and to foster human subject research for the benefit of the subject in particular and mankind in general. References 4. Hymen V. Jewish Chronic Disease Hospital, 206 N.E. 2d 338, 1965. 8. Wyatt V. Stickney, 344 F. Supp 373 (M.D. Ala, 1972). 9. Pub. Law 93-348, The National Research Act. 11. DHHS Regulations 45 CFR 46. Fed. Reg 46 (16), January 26, 1981. 12. FDA Regulations 21 CFR 16, 50, 56. Fed. Reg. 46 (17), January 27, 1981. 14. DHHS Reg. 45 CFR 46.107 (a). [Online Documents] |