There are many obstacles to including pregnant women in research, and IRBs may understandably err on the side of caution when it comes to expectant mothers in clinical trials.

The risk of liability is foremost in the minds of legal counsel, who well remember the thalidomide exposures in the 1950s and 1960s, when thousands of babies in Europe were born with birth defects linked to an anti-nausea drug taken by their mothers. In a recent article calling for the inclusion of pregnant women in more clinical trials, a lawyer and bioethicist raise the provocative point that the disaster “arguably could have been mitigated had pregnant women been included in early testing of thalidomide.”1

There also is the fear of so-called “long-tail” liability, where offspring of a mother injured in a clinical trial could seek subsequent redress for their own harms. With good reason, there is no way for an expectant mother to “informed consent” her way past this.

“If you are asking whether an informed consent process that describes risks to the fetus could in some way mitigate the potential for ‘long-tail’ liability, the regulations prohibit waiver of any legal rights — for example, a right to sue, so any waiver-like language is not legally permissible,” explains Anna C. Mastroianni, JD, bioethics expert and professor of law at the University of Washington in Seattle. “Notifying a pregnant woman of the potential risks to her fetus is ethically required as part of a clinical trial under any circumstance. In my opinion, that effort alone would not assuage a lawyer’s concern about long-tail liability. As we alluded in the article, considerations related to insurance and compensation will be important components of any risk management program.”

If the risk can be mitigated, needed research breakthroughs could result. Indeed, one need only look back at the success of preventing HIV transmission to the fetus with early drugs like zidovudine — or the current threat of Zika virus congenital defects — to realize the risk of excluding pregnant women from research carries perils of its own.

“I am confident there are possible policy solutions — and there will need to be more than one approach,” she says. “The 21st Century Cures Act recently signed into law created a committee tasked with taking the first step toward that effort — to identify gaps in knowledge with respect to pregnant women’s health.”

The NIH Task Force on Research Specific to Pregnant and Lactating Women is slated to convene Aug. 21-22, 2017.

Three Strikes

The recently published review article by Mastroianni and colleagues was based on a day-long meeting with a group of legal experts. In addition to the long shadow of liability, there are several other traditional deterrents to including pregnant women in clinical trials. The group concluded that those include these three, which are paraphrased as follows:

• The FDA does not require the inclusion of pregnant women in research studies for basic drug approval, so it makes no “commercial sense” to expand the clinical trial population.

• Pregnancy is widely perceived as generating “background noise” in the overall clinical trial data, potentially complicating the safety and efficacy profile of a profitable product.

• There is no financial incentive to conduct studies with pregnant women. The market for drugs that treat pregnancy-related conditions is small, and drugs for general medical conditions that may arise or persist during pregnancy are frequently prescribed to pregnant women anyway.

An Ethical Obligation?

In the absence of incentives, IRB Advisor asked Mastroianni whether IRBs and their legal counsel have an obligation to pursue paths toward more research inclusion for pregnant subjects.

“There is a legal obligation — imposed by federal regulations — to ensure that the research undergoing review is equitable,” she says. “From an ethics standpoint, this means that IRBs should at least ensure that researchers provide a reasonable justification for the exclusion of pregnant women.”

That includes asking investigators how they plan to respond if a female subject becomes pregnant during a study protocol, despite contraceptive precautions. Those questions could include whether the subject will be able to continue on the study medication and will data continue to be collected, Mastroianni says.

“The responses raise ethical issues, and decisions should be grounded in science, not fear,” she tells IRB Advisor. “Particularly when the woman is suffering from a serious condition that would otherwise go untreated. It is notable that in 2001, the regulations essentially shifted a presumption from exclusion — pregnant women may not be included in research unless ‘xyz’ conditions are met — to inclusion — pregnant women may be included in research if ‘xyz’ conditions are met.”

Off-label Use Inevitable

Still, with few FDA-approved products indicated for pregnancy — due in no small part to their exclusion from clinical trials — off-label use of various medicines is inevitable. That creates risk for both mother and fetus, but the result is a classic Catch-22: Some of the same regulations and policies requiring data also restrict its collection.

“There are a number of actors throughout the research pathway that can play a role in the effort to ensure that the health of pregnant women can benefit from research — whether funders, regulators, IRBs, institutions, legal counsel, researchers, and pregnant women,” Mastroianni says. “This paper was designed to highlight the legal barriers to that research. It would be helpful for lawyers who have successfully managed that risk on behalf of their clients to share their strategies with each other. We have another paper in preparation that we hope will highlight some of the key factors to successfully including pregnant women in clinical trials, including those with HIV.”

REFERENCE

  1. Mastroianni AC, Henry LM, Robinson D, et al. Research with Pregnant Women: New Insights on Legal Decision-Making.” Hastings Center Report 2017: 47(3): 38-45.