Trial issues & FDA
Statement of the Global Campaign for Microbicides
Antiviral Drug Advisory Committee Meeting, US Food and Drug Administration
August 20, 2003, Bethesda, MD
(for the full text, click here)
As an advocacy organisation, the Global Campaign’s foremost consideration is balancing the urgency of the HIV pandemic with protecting the interests of eventual users. We fully recognise that scientific rigor requires time and patience and that rushed results may compromise quality. But the quest for a safe, effective microbicide is occurring in a cataclysmic context --15,000 people are infected with HIV daily, half of the people living with HIV globally are women and more than a third of all women of childbearing age are already infected in some countries.
We must keep the human face of the epidemic before us at all times in our deliberations. As we construct a critical path through this uncharted territory, we must understand that our mission is an urgent one and that the price of delay is paid in human lives.
This Committee faces a challenge of unprecedented difficulty. Designing guidelines for microbicide trials is more difficult than for treatment trials because the field has no clear correlates of protection and prevention trials must enrol healthy --but highly vulnerable-- volunteers.
Fortunately, the FDA has already shown that it can balance the need for scientific rigor on one hand with the need for creative flexibility on the other. Concepts such as “expanded access” and “accelerated approval” did not exist two decades ago. They were created in response to the urgency with which new AIDS treatments were needed and now stand as proof of how flexible the FDA can be when necessary.
We ask that the FDA demonstrate the same level of flexibility and creativity when considering how traditional approaches to drug evaluation can be adapted to meet the challenges of microbicide testing.
Microbicides are not just another new drug or prevention tool in a field of many. Until an effective vaccine is developed, microbicides (even partially effective ones) will stand as the only means of prevention for millions of women who presently have nothing at all with which to protect themselves from HIV.
Data worldwide indicate that even with proper counselling and support, many women are unable to convince their partners to use condoms. This is especially true in the context of on-going relationships, where issues of trust, fidelity and power loom large.
Regrettably, steady partners are increasingly the source of women’s HIV risk globally. This is particularly relevant in settings where cultural norms grant men sexual license to have multiple partners but expect women to remain faithful. In a recent Thai study, for example, 76% of women living with HIV/AIDS had no risk factors other than being in a monogamous union. We recognise that the FDA’s legal mandate is to review products in light of the risk/benefit profile of the United States, but we ask that you keep this global reality in mind.
We also urge you to recognise the impact that FDA pronouncements can have on regulatory thinking and strategy in other countries. Although the FDA’s legal mandate extends only to the United States, its influence extends far beyond that. The FDA and the European Agency for the Evaluation of Medicinal Products (EMEA) often serve as the “default” standard-bearers for regulatory authorities in the developing world. Statements made by the FDA regarding minimal expectations for regulatory approval, will be read and applied in public health contexts very different from our own.
We urge you to frame your recommendations in such a way as to acknowledge that different regulatory authorities may face different realities than those informing FDA decision making. The FDA, for example, may decide that a single phase 3 trial powered to p<.05 would not be adequate to support licensure in the United States. But other countries, responding to the pressure of a far more advanced epidemic, may be motivated to act on such data. Their ability and willingness to do so will be enhanced if the FDA explicitly frames its expectations regarding trial minimums as specific to the US regulatory and epidemiologic context.
Below are our recommendations regarding the key questions before the Committee. We developed them with two imperatives in mind – the need to get valid data into the hands of regulators and policy makers as quickly as possible and the need to know as much as we can, with the highest degree of certainty, about the candidate products.
# 1: The FDA should maintain a high degree of flexibility in its requirements regarding acceptable trial design elements.
# 2: The FDA should NOT require as a matter of policy that sponsors include a “condom-only” control arm in addition to a placebo control.
# 3: The FDA should be open to establishing effectiveness based on a one-year follow-up period.
# 4: Given urgency and scarce resources, a stand-alone phase 2 or 2b trial is only worthwhile if it enables us to determine which is the most promising among several similar products.
# 5: The Agency should seek ethics guidance before assuming that it would not be possible to conduct a second confirmatory trial “due to ethical concerns.”