that had been used worldwide to treat sleeping sickness, was identified as having strong in vivo anti-HIV activity and was quickly put into a small, phase I trial in several institutions. Surprisingly, the drug produced severe and apparently new side effects in many recipients and led to at least two deaths. The experience with suramin again appeared to validate the preeminence of orthodox clinical trials.

The Emergence of AZT

In the winter of 1985-1986, preliminary studies of a previously discarded anticancer agent, zidovudine (AZT), were begun by Drs. Samuel Broder and Robert Yarchoan at the National Cancer Institute (Wastila and Lasagna, 1990). The work of Broder and Yarchoan was carried out under the drug development program initiated by the National Cancer Institute (NCI) under the authority provided by the 1971 National Cancer Act. AZT appeared to increase patient well-being and possibly to slow progression of the disease, although it was not obviously curative. Because of acceptable toxicity, a phase II clinical trial was mounted by Burroughs-Wellcome, Ltd., in the late winter of 1986. Originally planned to last for 27 weeks of observation per patient, the trial was halted prematurely in September 1986 because of significantly greater survival rates in those receiving AZT in comparison with those receiving a placebo. At the time the trial was ended, most patients had been observed for only a short period of time. With this dramatic finding, the world of clinical research was turned upside down.

Virtually overnight, AIDS patients and others demanded that AZT be made immediately available. Burroughs-Wellcome established a compassionate-plea mechanism for drug distribution, modeled on the compassionate, investigational new drug (IND) mechanisms developed by NCI in the early years of its drug development program (see below). Physicians were required to document that patients had AIDS as evidenced by PCP or advanced AIDS-related complex (ARC), the characteristics of the trial participants. Generally used only for small numbers of patients with life-threatening conditions, the compassionate IND mechanism was a cumbersome, ad hoc process requiring active participation by individual physicians to obtain a drug and document its use. It had never before been applied in the wide manner an epidemic required. Although immediate problems of access were thus solved, it was clear that this mechanism would be quickly overwhelmed. Faced with urgent demands, the FDA hastened AZT through the regulatory process by easing requirements for animal and preclinical data. On January 16, 1987, the FDA convened a meeting of its Anti-Infective Advisory Committee to consider FDA approval. The advisory committee voted 10 to 1 for licensing AZT despite the expedited procedures (Nussbaum, 1990).



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