How Good Is “Good Enough”? The Case for Varying Standards of Evidence According to Need for New Interventions in HIV Prevention

Abstract

In 2010, randomized controlled trials (RCTs) of two different biomedical strategies to prevent HIV infection had positive findings. However, despite ongoing very high levels of HIV infection in some countries and population groups, it has been made clear by regulatory authorities that the evidence remains insufficient to support either product being made available outside of research contexts in the developing world for at least two years. In addition, prevention trials in endemic areas will continue to test new interventions against placebo. But the judgments of evidentiary standards are never value-neutral. Using the recent trials and their contexts as case studies, we examine the basis for these decisions, which will potentially delay access to scientific innovation to the people who are most urgently in need of it.

Keywords:

• AIDS
• biomedical research
• human subjects research
• regulatory issues
• research ethics

Acknowledgments

The authors would like to thank Ian Kerridge, Andrew Vallely and two anonymous reviewers who made valuable comments on an earlier draft of this article.

Notes

Microbicides are topical agents, in this case in the form of a gel containing the antiretroviral drug tenofovir, designed to prevent HIV acquisition when applied inside the vagina (products are also being developed for rectal use). In theory a microbicide product could empower women to protect themselves from HIV, as its use could be at a women's discretion and would not need to involve negotiation with a male sexual partner. In practice, development of products in this field has been beset with unexpected difficulties, with the first product ever subject to an efficacy trial being associated with increased risk of HIV acquisition, closely followed by several other products with negative (though not necessarily harmful) results (Padian et al. 2008).

The product consisted of tenofovir—the same active ingredient in the CAPRISA 004 product—together with a second antiretroviral drug, emtricitabine, taken orally. The combination is available as a single pill under the brand name Truvada, and is currently used in the treatment of people with HIV. The advantages of an oral product are again that it can be taken discreetly, but more importantly—like modern hormonal contraception—the act of protection is removed from the sexual context (“non coitally dependent,” in medical parlance). This makes it something that can be integrated into daily routine, arguably facilitating adherence.

Another biomedical strategy prevention strategy was found effective in May 2011. The study HPTN052 showed that early initiation of treatment in a person with HIV prevented HIV acquisition by that person's HIV uninfected sexual partner by 96%. Unlike PrEP and microbicide strategies, this approach works by reducing the infectivity of the index partner rather than directly blocking infection in the HIV negative partner.

This follows from the perspective that the interests of the research participant should take precedence over all other interests, in line with the Declaration of Helsinki (article 6) (World Medical Association 2004).

We use the term “gay men and men who have sex with men” in recognition that homosexually active men have distinct and different identities, and that gay identity ought not to be subsumed under a behaviorist term.

The fifth study is a direct “follow-on” study for iPrEx participants, which offers open-label access to the drug for all, and provides less intensive counseling in order to get a more “real-world” result (AVAC 2010).

Recall that from 1977 to 1993, women were not allowed in early-stage FDA trials due to perceived risk, and data were routinely extrapolated from men (Merkatz and Junod 1994).

Of note, Freedman would take a dim view of the purposeful underpowering of IIb studies: “the results of a successful clinical trial should be convincing enough to resolve the dispute among clinicians” (1987, 144).