New final guidance issued this week by the US Food and Drug Administration (FDA) is meant to clarify the development pathway for vaginal microbicides intended to prevent the transmission of the human immunodeficiency virus (HIV).
The guidance document, Vaginal Microbicides: Development for the Prevention of HIV Infection, follows years of increasing interest in developing products which could supplement or even replace condoms in preventing the transmission of HIV. Vaginal microbicides, which FDA's guidance defines as self-administered, intravaginal drug products that reduce the risk of HIV acquisition, include both drug products and drug-device combinations.
For example, drug products might take the form of a tablet, cream, gel or film. Drug-device combination products have included "drug-impregnated sponges" and implanted drug delivery systems like vaginal rings, FDA noted. The products can also be administered at different times (prior to exposure or after exposure), FDA added.
Testing products intended to prevent the transmission of HIV can be fraught with risk. Conceptually similar products have in some cases increased the risk of HIV transmission, as study participants either failed to take or administer the product as promised, or because the product failed to work as well as intended.
To date, just one product, Gilead Sciences' Truvada, has obtained approval as an oral pre-exposure prophylaxis (PrEP) product in the US.
FDA's guidance contains extensive recommendations regarding the design of pre-clinical and clinical studies.
FDA's guidance notes at several points that among the most important considerations for sponsors to show is that not only is a product effective, but that patients will adhere to the treatment and not engage in riskier sexual behaviors (such as unprotected sex).
"Because usage rates of microbicide and/or other prevention methods as well as sexual behavior patterns are expected to fluctuate over time, and long-term safety events (e.g., epithelial disruptions) may potentially reduce efficacy over time, longer duration efficacy trials are preferred because they can capture the effect of these variables and are more likely to reflect the real-world effects," FDA recommended.
Trials should also measure the rate of new HIV infections, which will also require a large sample size to adequately measure—several thousand at least, FDA said.
In addition, FDA says that risk-reduction counseling and the promotion of the use of condoms are both "ethical imperatives during the conduct of microbicide trials." Sponsors can also offer the use of Truvada (and other PrEP drugs) as part of the trial's preventative measures, FDA explained.
Accelerated approval is not available for vaginal microbicide products, FDA states in the guidance.
Trials should also utilize a comparator product, and use HIV seroconversion (detectable levels of HIV antibodies) as a primary endpoint.
Vaginal Microbicides: Development for the Prevention of HIV Infection