Opening the black box ...

As reported in a news blurb that nearly escaped my attention because the major newspapers and websites either failed to report it or buried it deep, the US Food and Drug Administration (FDA) is proposing to replace its current pregnancy labels for a new system that clearly lists what is known and not known about use of particular drugs by pregnant or lactating women.

Under the old system, drugs were categorized into one of five categories - A, B, C, D and X – based on the amount of animal and human safety data available. Only a handful of currently marketed drugs fall into category A: safe for use based on extensive animal and human safety data. More drugs fall in category X: conclusive animal and human data demonstrating fetal risk.

The problem is that the vast majority of drugs fall into categories B and C. For most these compounds, there may or may not be data from animal models to suggest that the drug is safe and no good human studies to confirm these pre-clinical results. Use of these drugs by pregnant or lactating women is thus a crap shoot, with women and their physicians given little guidance to help them weigh the risks and benefits of these treatments. The new labeling rules would provide more information about the potential risks and benefits to pregnant or lactating women and their children or fetuses.

Still, I wonder whether the FDA realizes the Catch-22 that many researchers face regarding pregnant and lactating women. In the HIV prevention field, for example, microbicide and PrEP (pre-exposure prophylaxis) studies generally exclude pregnant and lactating women from enrolling, and study participants who become pregnant must discontinue product use. However, in the resource-poor countries when many of these trials take place, women spend approximately one-third to one-half of their reproductive years pregnant or breastfeeding. Not only do unexpected pregnancies adversely impact the power of these studies to detect a protective effect, but these restrictions also mean that a large number of women in the developing world who want to participate in these HIV prevention trials cannot. Alternatively, they be required to use a limited number of contraceptive methods that might otherwise be unacceptable to them.

Finally, it is unclear how HIV prevention researchers can collect the necessary data to demonstrate that these products are safe and effective for pregnant and lactating women to use. Most of these data come from pregnancy exposure registries, in which women who use category B, C and D drugs are monitored for the effect of these compounds on fetal development. But does it make sense to rely on such “natural experiments” rather than collect the necessary safety data in a controlled clinical trial using fully informed and willing participants? … particularly for compounds like topical microbicides and PrEP which, if effective, will be used primarily in countries in which collecting data for pregnancy exposure registries is likely to be difficult at best?