In August 2003, the U.S. Food and Drug Administration's (FDA) Antiviral Drugs Advisory Committee met to discuss clinical trial designs for topical microbicides. The FDA has received several sponsor applications to conduct trials of candidate microbicides with an eye to approval. From the agency's standpoint, two anxieties hung over the discussion. The first was the sobering lesson of the COL1492 study of nonoxynol-9, which turned out to actually increase HIV risk. The second was agency skepticism, and palpable fear, about releasing a product that might be less effective than what is considered the U.S. gold standard: condoms.

The microbicide advocacy and research community brought its own anxieties, over cost (that sponsors can not afford, or do not want to fund these trials, or that funding will dry up if one of the first trials fail) and a pervading dread that if the field does not move forward soon, an incalculable number of lives will be lost.

Earlier this year, two products (Buffer Gel and Pro 2000) were slated to go head-to-head in HPTN 035, an 8,000 woman, placebo-gel controlled trial. But the FDA asked for changes, arguing that the trial should aim to produce data that could support product licensure. They proposed a dramatically more stringent statistical test and added a fourth arm that offered no treatment, only the condoms and counseling that every arm received. These changes would have boosted the number of participants by several thousand and added millions to the cost. When the NIH said it wouldn't fund such a costly trial, the design was amended to a Phase IIB, 3,100 woman trial that will include the fourth, no-treatment arm.

At the FDA meeting, the committee was asked to consider the no-treatment arm. They also discussed if one trial could serve as well as two without difficult to meet statistical tests and how long a Phase III trial must last. Each of these questions involves complications that could set back microbicide clinical research by years. And on each issue, the FDA seemed to take a hard line.

One thing this meeting did was force the microbicide community to come together and think hard about the strategic plan for microbicide R&D. The testimony that day reflected an overwhelming consensus that FDA must not heap requirements onto these trials that would spike their cost, cause delay, produce uninterpretable data, or otherwise drain a resource-scarce field. In particular we heard that a no treatment, condom only arm could introduce confounding behavioral variables, which may result in uninterpretable data or a false declaration of product failure.

What we need to know from the FDA is whether any of these candidates are safe and moderately effective. That's the strict regulatory question before them, it's the question that matters to countries that desperately need these products, and it's the question the agency should stick to. The FDA should not concern itself with hypothetical questions about what might happen to condom use if a microbicide were available.

While the FDA only has jurisdiction within the U.S., it's influence extends much further. It must recognize this and think creatively and flexibly to consider strategies that allow for moderately effective products to be detected and moved forward -- not weeded out. A product demonstrating moderate effectiveness (50-60 percent) would not likely be approved for U.S. licensure. But in another country, that same product might be considered essential. As committee member Lynn Paxton put it, "If I'm a regulator in a country where 1 out of 3 women is infected, I might be willing to take a risk."

So, what does this mean for the FDA? Does it have an ethical obligation not to set policy that would harm people outside of the U.S.?

The European regulatory agency (EMEA) and the World Health Organization (WHO) has initiated an entirely new process to approve and review drugs for safety and effectiveness in a developing country context. The Alliance for Microbicide Development, representing consensus from the research community, asked the FDA to "recognize contextual realities" of global AIDS and urged the Agency to "actively engage in the new WHO/EMEA process." Seeking to balance speed, flexibility and good science, this process may offer a way to accommodate the differing risk/benefit demands that we will continue to see globally.