driven by scientific, ethical, economic, or political considerations? Has AIDS merely accelerated changes that were already occurring in cancer research, or do they represent a clear departure from the practices of the last two decades? When changes have occurred, have they been defined narrowly for AIDS or more broadly constructed? How can change be monitored in the future, and can the likely long-term critical impact of such change be predicted?

This chapter begins with a brief historical perspective on clinical research and drug development prior to the advent of the HIV/AIDS epidemic. It is important that the interplay of politics, science, and ethics in this area be recognized as an ongoing dynamic during the twentieth century; it has been shaped by AIDS but it was not created by it. The chapter then describes drug development from 1981 through late 1991—the age of AIDS—and analyzes the impact of social institutions and events on the process and, conversely, the impact of the process on such institutions as the Food and Drug Administration and the National Institutes of Health. The development of social and political activism is examined as a major force for generating change. Finally, the chapter summarizes how key areas in clinical investigation and drug regulation have been shaped by the HIV/AIDS epidemic.

HISTORICAL PERSPECTIVE1

Several developments of the post-World War II era establish a baseline for evaluating changes driven by the HIV/AIDS epidemic. Those developments relate to four major historical shifts: (1) the development of randomized clinical trials as orthodox research methodology, (2) changes in federal drug regulation, (3) the evolution of protections for human research subjects and the growing recognition of ethical dilemmas inherent in research, and (4) the rise of patient advocacy and the changing dynamics of patient-physician relationships. In the postwar era, and especially since 1960, considerable change has taken place in each of these areas. The AIDS epidemic has had powerful effects on clinical research and the culture of science.

Randomized Clinical Trials

Although experimental approaches to clinical medicine date to antiquity, it was only in the 1940s and 1950s that contemporary approaches to the evaluation of medical treatments and technologies were fully articulated and began to be put into practice. Randomized clinical trials—experiments in which human subjects are randomly assigned to experimental and nonexperimental (control) groups for purposes of comparison—offer researchers



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