US AIDS activists urge caution on new anti-HIV drugs

BMJ 1994; 309 doi: (Published 24 September 1994) Cite this as: BMJ 1994;309:757
  1. J Roberts

    Three years ago AIDS activists successfully petitioned the US government to accelerate the approval of drugs that showed promise against HIV. Last week many of them asked the government to drop the new system that has allowed at least three anti-HIV drugs to get on to the market faster. The Food and Drug Administration (FDA) spent two days hearing from both sides of a debate that basically comes down to this. If you have a life threatening disease do you want to take a drug that is proved effective, even if you have to wait for two or three years, or would you rather try an unproved drug straight away?

    In 1991 activists chose the latter. As a result promising anti-HIV drugs have been released for sale after preliminary studies have shown that they are safe and after small studies showed some positive effect, such as increasing patients' CD4 lymphocyte counts. Large scale studies, which are typically done before drugs are released for sale, were to be done after anti-HIV drugs went on the market. As a result of the new rule three promising drugs - didanosine (DDI), zalcitabine (DDC), and d4T - got to patients more quickly.

    The FDA was told, however, that once the drugs got on to the market their makers had little incentive to finance large randomised clinical trials that measured clinical outcomes, such as survival. Under traditional FDA rules a drug cannot be publicly marketed until such studies are done. But under the 1991 rule some anti-HIV drugs receive “conditional approval,” which means that they can be sold until a large trial shows that they are not efficacious.

    Zalcitabine is an example. It received conditional approval because it was shown to increase CD4 lymphocyte counts in patients with AIDS. Afterwards small studies showed some marginal clinical benefit, but even the largest trial has not shown clearly that zalcitabine extends life.

    The issue is particularly important now because a new class of anti-HIV drugs is about to be produced. These protease inhibitors work by different mechanisms from the nucleoside analogues such as zidovudine, didanosine, and the others.

    The group leading the move to end accelerated approval is the Treatment Action Group, whose spokesman Spencer Cox said, “We pay huge amounts of money and we suffer through major toxicities, and then we have to take the drug company's word for it that the drugs work.” The group is proposing a new way of studying drugs, “large sample trials,” which have been used in Europe with some cardiac drugs. Relatively healthy patients infected with HIV would be randomly assigned to one of three groups: placebo, low dose, and high dose. Then they would be followed up over several years.

    Another design proposed is the “master trial,” a huge national study that would allow volunteers, once they are randomised to the study drug, to be free to try other treatments as well. The idea is that the sample size would be so big that these potential confounders would be diluted out.

    A few activists still want to maintain the present system, though they want the FDA to be more diligent in forcing drug makers to conduct clinical trials after their products have been placed on the market.

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