Report highlights dangers of excluding pregnant, lactating women from clinical trials

Key takeaways:

• Case reports suggest little if any legal liability when including pregnant people in research studies.
• FDA guidance and congressional action could allow pregnant women to safely participate in drug trials.

Pregnant and lactating women have historically been excluded from most clinical research, often due to perceptions of greater legal liability if a woman, her fetus or infant is harmed by an intervention.

A new report from the National Academies of Sciences, Engineering, and Medicine, titled “Advancing Clinical Research with Pregnant and Lactating Populations,” states that fear of legal liability is “pervasive”; however, actual legal liability is not. The report, which analyzed relevant case law, notes that “liability” is often conflated with other concerns, such as reputational risk, increased costs and trial complexity.

Armed with the report findings, researchers are now hoping to make change by outlining steps that Congress and the FDA can make to ensure more pregnant and lactating people participate in research, according to Margaret (Mimi) Foster Riley, JD, professor of law and the Dorothy Danforth Compton Professor at the University of Virginia School of Law. Riley, who also served as chair of the report, said harms to women and fetuses from the use of thalidomide in the late 1950s, before FDA modernized its drug approval process, “cast a long shadow” that is still felt 60 years later.

Healio spoke with Riley about the history of including pregnant women in clinical research, harms that stem from excluding pregnant and lactating patients, and how agencies and the government can take steps to address the issue. Riley’s Viewpoint article summarizing the report’s findings was recently published in JAMA.

Healio: Your JAMA Viewpoint article states that excluding pregnant and lactating people from clinical trials exposes those populations to harm. How?

Riley: Whenever a pregnant or lactating person needs to use a medication while they are pregnant or lactating, they do not have the data that allows them to make an informed decision. The physiology of pregnancy and lactation are very different than the physiology of a woman who is not in one of those states. As a result, we often do not know proper medication dosing for pregnant patients. We do not even know the full safety profile. We cannot tell them what it would be until conducting the clinical studies. Pregnant women are participating in a vast, uncontrolled study every time they have to use a drug. That is a problem.

Healio: You wrote that many researchers fear there is potential legal liability if you include pregnant or lactating people in clinical research, particularly for trials that involve drugs or devices. But the National Academies of Sciences, Engineering, and Medicine report analyzed case law on this. What does the report tell us?

Riley: What we found was — and no one had done this research before — there was very little evidence of liability in the context of clinical trials involving medications used during pregnancy. We found there was actually almost no liability, and certainly no liability related to harm to a child in the context of lactation. The liability profile for lactation is virtually de minimis. People tend to conflate pregnant and lactating women. However, the physiology of each is different, and in fact, the risks are different. Many drugs do not pass into breastmilk at a sufficient level to cause harm. There are many misunderstandings about how that works.

Can you explain for readers the history of what happened with thalidomide in 1962?

Riley: In the late 1950s thalidomide was prescribed for many reasons, but one of the major purposes was for morning sickness during pregnancy. Another drug commonly prescribed during the late 1950s and early 1960s was diethylstilbestrol, or DES, used to prevent miscarriage, premature labor and related pregnancy complications. Neither drug was tested by any standard that we would consider proper today. Yet, both were widely used. In 1962, thalidomide was confirmed to be the cause of more than 10,000 severe birth defects in children. In response to that tragedy, Congress passed legislation to strengthen the licensure system for new drugs and expanded FDA’s authority to refuse the approval of medications that do not meet safety, efficacy and labeling requirements. However, pregnant and lactating women have not received the full benefits of that legislation. With the case of thalidomide, we have a very stark, visual example of what can happen when someone takes a drug during pregnancy. What you do not see is all the situations of what happens to a pregnant woman who needs a drug pregnancy yet does not take it because she is scared something will happen to her or her fetus. Thalidomide cast a long shadow, one that is now 60 years old.

Healio: The report also cites evidence of harms that did result in legal liability for FDA-approved products used during pregnancy, suggesting some postmarket liability could have been mitigated had pregnant women been included in clinical studies.

Riley: Yes, for more than 1,000 cases. Not every case ended in finding legal liability. Some may have settled; in some instances, the cases failed. But we still found evidence of 1,000 cases involving pregnant women using drugs in the postmarket context. Had clinical trials been conducted for many of those drugs, they would have either avoided those liability risks or they would have, at a minimum, mitigated liability risk. Had trials been conducted carefully, they have found the evidence to use the drug or not or found evidence that might have helped during the legal case itself.

Healio: The report outlines some recommendations to address this issue. How can we include more pregnant women in clinical studies?

Riley: We outline a pathway for how to conduct this type of research safely, effectively, in ways that provide good evidence and also protects women and their fetuses. To do that, we recommend several changes.

Much clearer guidance from FDA is needed. The agency is anxious to include more pregnant women as well. Clear guidance mitigates liability and mitigates harm.

There are also some important places to make change where FDA does not have authority. For example, FDA currently does not have authority to require clinical studies for drugs used by pregnant women. Pregnant women are considered adults. Therefore, the indication for a drug that is on the market automatically includes pregnant women. To make sure FDA has the authority to require inclusion of pregnant women, we recommend Congress make changes that are very closely modeled on the pediatric populations. The Best Pharmaceuticals for Children Act, or BPCA, passed in 2002, encourages the pharmaceutical industry to perform pediatric studies to improve labeling for patented drug products used in children, by granting an additional 6 months of patent exclusivity. The Pediatric Research Equity Act, or PREA, requires companies to assess safety and effectiveness of new drugs or biologics in pediatric patients. These laws created incentives and sometimes requirements for industry to conduct this type of drug research with children.

The BPCA also requires NIH to prioritize medications that are off-patent. Once a drug is off-patent, there is no incentive for the sponsor to do additional research. At that point, you need the government to step in and play that role, using academic researchers or others to conduct those studies. There are hundreds of drugs used by pregnant women or that clinicians think pregnant women should be using where this research would be useful.

The time has come for this. I do notice when we talk to the agencies, there is excitement. They are not resisting this change. They want change. Now, we must make people understand that we are harming people by not including them in research.

References:

• National Academies of Sciences, Engineering, and Medicine. Advancing Clinical Research with Pregnant and Lactating Populations. Available at: https://nap.nationalacademies.org/catalog/27595/advancing-clinical-research-with-pregnant-and-lactating-populations-overcoming-real. Published 2024. Accessed April 22, 2024.
• Riley MF. JAMA. 2024;doi:10.1001/jama.2024.6874.

For more information:

Margaret Foster Riley, JD, can be reached at mimiriley@law.virginia.edu; X (Twitter): @UVALaw.