Four paradigms of clinical research and research oversight.

The understanding of appropriate ethical protections for participants of biomedical research has not been static. It has evolved over time, with the evolution of biomedical research as well as social values. Since World War II, there have been four major paradigms of research and research oversight operative in the United States (Table 1). These paradigms incorporate different values and provide different approaches to research oversight and the protection of research participants. For hundreds of years, research to test interventions had been sporadic.1 Little distinction was made between experimentation and therapy. Evidence of the effectiveness, and even safety, of medical interventions was rare.2 Until the late 19th century, most therapies could properly be considered experimental in the sense that they lacked empirical evidence for their effectiveness. Researchers were usually physicians, motivated to do what they thought best for their patients, and trusted to do the right thing.3 There were no specific codes of ethics, laws, or regulations governing the conduct of research, but peer judgment and influence served to contain fraud and abuse.4 For instance, in 1897 Giuseppe Sanarelli, an Italian researcher working on yellow fever, declared he had produced yellow fever by injecting a bacillus into five people.5 At a 1898 medical meeting William Osler condemned Sanarelli saying, “To deliberately inject a poison of known high degree of virulency into a human being, unless you obtain that man’s sanction, is not ridiculous, it is criminal.” 6 Systematic biomedical research began to grow as an enterprise after the development of penicillin and the passage of the Food, Drug, and Cosmetic Act in 1938 that required evidence of safety before a product was marketed.7 Just before World War II, there was dramatic growth in research as an enterprise. Large pharmaceutical companies were starting up, both public and private money was devoted to research, and research became increasingly centralized, coordinated, standardized in method, and publicly supported. Since right around World War II, understanding of the ethics and oversight of human subjects research has proceeded through four distinct periods or paradigms. Each period embodies different perspectives on research and its dangers and different conceptualizations of the goals of oversight. Each period also advances a different underlying ethical principle guiding the protections of research participants, empowers different institutions to implement the protections, and has its own way of balancing protection of research participants against other important values in biomedical research. At least in the United States, the change from one period to another has frequently been catalyzed by