AZT (Zidovudine) Trial for AIDS

By 1986 AIDS was spreading fast in the United States, where reported cases would reach 100,000 by 1989, and there was no approved treatment. Once AIDS developed, the immune destruction caused by HIV led to death. The Food and Drug Administration's standard drug approval pathway required years of phased trials, a timeline that was incompatible with the urgency of a uniformly fatal epidemic with no therapeutic options. Patient advocacy groups were demanding access to experimental drugs, and pressure on the FDA and the National Cancer Institute to move faster was intense.

Zidovudine had first been synthesized by Jerome Horwitz at the Detroit Institute for Cancer Research in 1964 as a potential cancer treatment; it failed in that application and was shelved. In 1985 Hiroaki Mitsuya and Samuel Broder at the National Cancer Institute, with Phillip Furman and colleagues at Burroughs Wellcome and researchers at Duke, reported that it inhibited HIV reverse transcriptase and blocked the virus in cell culture. Broder pushed the compound quickly through early safety studies. The double-blind, placebo-controlled trial enrolled 282 patients with AIDS, shown by Pneumocystis pneumonia, or advanced AIDS-related complex; 145 received 250 mg of AZT every four hours and 137 received placebo, for a planned 24 weeks.

An interim safety monitoring board analysis halted the trial early when it found 19 deaths among placebo recipients against 1 among those receiving AZT. By then 27 patients had completed 24 weeks, 152 had completed 16 weeks and the rest at least 8 weeks. Opportunistic infections developed in 45 placebo recipients and 24 AZT recipients. The FDA gave the application priority review and approved zidovudine, sold as Retrovir, on March 19, 1987. The full clinical trial data were published in the New England Journal of Medicine in 1987.

The early benefits were real but incomplete. AZT reduced opportunistic infections and extended survival in patients with advanced disease. In the trial itself, CD4 counts in patients with AIDS rose but fell back to pretreatment values after 12 weeks, and as resistant virus emerged under single-drug treatment, patients who had responded went on to progress. The failure of monotherapy drove the research agenda toward combination antiretroviral therapy, ultimately yielding the triple-drug regimens that suppressed viral replication durably when introduced in the mid-1990s. Zidovudine remained a component of many of those combinations.

Pressure on the FDA grew. In 1987 it issued regulations expanding access to promising unapproved drugs, and in 1988, eight days after more than 1,000 ACT UP members and supporters shut down its offices in Rockville, Maryland, it announced rules to speed approvals. In 1992 it created accelerated approval, which lets drugs for serious conditions with unmet needs be approved on a surrogate endpoint. Many later antiretrovirals and cancer drugs reached patients through that pathway.