Microbicide gel dosage prompts call for rethink.
Controversy over a ground-breaking study of an experimental HIV prevention tool has underscored the field's need to revamp its approach to clinical trials.
On 23 May, researchers at the Centre for the AIDS Programme of Research in South Africa (CAPRISA) began a US$13.5-million study to test whether a microbicide gel containing the antiretroviral drug tenofovir prevents women from becoming infected with HIV during sex. The trial, funded by the US Agency for International Development (USAID), is the first to test a so-called second-generation microbicide — one that specifically targets the AIDS virus.
Researchers and advocates say that microbicides in the form of gels or creams, applied to the vagina, could provide crucial protection for women who cannot negotiate condom use with their partners. Currently, 11 microbicide candidates are being tested in clinical trials. But some experts are concerned that the “CAPRISA 004” trial, which includes 980 women at two sites in South Africa, is doomed because of its design.
The microbicide development field cannot afford to take a further hit.
“The microbicide development field cannot afford to take a further hit,” says virologist Mark Wainberg of McGill University in Montreal, Canada.
That is because three 'first-generation' microbicides, which make the vagina inhospitable to a range of microbes, have already failed efficacy trials, and two — cellulose sulphate and nonoxynol-9 — actually increased women's risk of infection (see Nature 446, 12; doi:10.1038/446012b 2007). Investigators are due to release the final analysis of the cellulose sulphate trial at the International AIDS Society meeting in Sydney, Australia, later this month. But scientists say the failure of that trial highlights the need to proceed cautiously with further microbicide studies.
The most controversial issue in the CAPRISA trial is the dosage schedule. This requires women to apply the gel once within 12 hours before sex and again within 12 hours after sex. The schedule is designed for women whose partners are home for short periods of time, says study leader Salim Abdool Karim of the University of KwaZulu-Natal in South Africa.
But opponents say there isn't enough published evidence from trials in animals or humans to support this dosage schedule. Some would prefer the women to apply daily doses of the gel. Karim disagrees, saying that “getting these women to use a product every day is going to be a challenge.”
Critics say the proposed dosage regime will result in a poor trial outcome. “It will be hard to link the data to the way the gel is being used, which will potentially make it very difficult to make any interpretation of the data,” says microbicide researcher Robin Shattock at St George's, University of London.
The concern has led scientists and others, including Renee Ridzon of the Bill & Melinda Gates Foundation in Seattle, Washington, and Zeda Rosenberg of the International Partnership for Microbicides based in Silver Spring, Maryland, to call for the CAPRISA investigators to rethink their approach. Such concerns prompted the US Global AIDS Coordinator to convene a telephone conference on 6 June with scientists, advocates and US government agencies to discuss the trial design — a first for a USAID-funded microbicide study.
After the telephone conference, the Office of the Global AIDS Coordinator declined to modify or stop the trial. But scientists are still urging the CAPRISA investigators to reconsider, and Karim has agreed to discuss the issue further, at least informally with some of the critics. “We have put the issue on the table and I feel we are on our way to resolution,” he says.
The situation has caused leaders in the microbicide field to renew calls for better ways of reviewing and coordinating trial plans. Scientists in the field already share and discuss ideas and data through formal and informal meetings, but there is no mechanism for reviewing and disseminating plans for clinical trials. This means that institutions sometimes run redundant trials that are not always backed by good evidence, says immunologist John Moore of the Weill Cornell Medical College in New York.
“Historically, the microbicide field has gotten it wrong by doing multiple simultaneous trials of similar products, and the CAPRISA episode represents a boiling-up of frustration in the field,” Moore says.
The study had already been approved by many bodies — including the South African Medicines Control Council, and ethics review boards convened by the University of KwaZulu-Natal and by Family Health International, the group that is running the trial. USAID staff decided to grant funding for the study in April after conducting its own internal review, says Jeff Spieler, senior science adviser in USAID's office of global and reproductive health.
But few preclinical results have been made publicly available, leaving scientists and advocates uneasy about the trial. Normally, the development of a product such as a microbicide would be sponsored by a private company, which would not be obligated to consult the public beyond regulatory agencies. But such companies are not interested in developing microbicides because they are aimed at poor people, so the field is funded largely by limited public resources. Advocates argue that this means the public deserves full access to all the relevant data.
“We need a transparent, accessible and international mechanism of peer review and reflection for making decisions that are of fundamental importance to the microbicide field,” says Lori Heise, director of the Global Campaign for Microbicides, an advocacy group based in Washington DC.
Spieler says USAID has decided to consult external reviewers for future trials. And the National Institutes of Health's Office of AIDS Research is setting up a microbicide working group. But it is not clear whether this will include a broad enough range of international expertise to ensure that good decisions are made, Heise says. And others say the field is already facing a crucial turning point.
“The microbicide field is drinking in the last-chance saloon,” Moore says. “If it has many more problems, it's finished.”
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Check, E. HIV trial doomed by design, say critics. Nature 448, 110–111 (2007). https://doi.org/10.1038/448110a