By Nicholson Price, Rachel Sachs, Jacob S. Sherkow, and Lisa Larrimore Ouellette
Pregnant people are at increased risk of severe illness from COVID-19, but they have been largely excluded from clinical trials, the process of testing vaccines’ and treatments’ safety and efficacy. They’re consequently left in a bind: there’s not great evidence about the safety and efficacy of products they can take to be safe from COVID-19. This lack of information might be part of the explanation for low vaccine uptake among pregnant people, particularly women of color. And while this lack of data isn’t particularly novel with respect to drug development, generally—we’re historically bad at generating robust safety data for pregnant people—failing to do so for COVID-19 seems to have outsized public health consequences. What’s behind this ongoing exclusion? And how should policymakers consider including pregnant people in COVID-19 clinical trials and beyond?
How have pregnant people been included (or not) in COVID-19 innovation?
As we’ve discussed before, clinical trial design is an important and complex consideration in drug development, and the stakes are even higher in a pandemic. Broadly, clinical trial design for new therapies and vaccines is governed by a patchwork of FDA regulations, guidance documents, agency practice, and best practices. While the FDA ultimately has significant oversight over a given clinical trial’s design—it can, for example, reject “protocol amendments” after a design has been approved—a trial’s overarching design is up to the developer. While there are no direct sanctions for departing from a given clinical trial guidance, developers often hew to the FDA’s advice lest the agency reject their product applications.
To minimize complications on the path toward approval, developers have historically sought mostly healthy, non-elderly men for clinical trials when possible; developers have long shied away from including pregnant subjects. The reasons for this reluctance are manifold. Pregnancy is a complex medical condition on many fronts, including anatomically and endocrinologically. Measuring drug metabolism—pharmacokinetic/pharmacodynamic modeling (PK/PD)—during pregnancy is also difficult. Beyond these scientific reasons, there are also social barriers, such as paternalism; pregnant people were long classified as “vulnerable” in human subjects research, with corresponding limits on when they could participate in clinical trials. That rule was finally changed in 2017 after substantial criticism and reform effort—but exclusion from clinical trials frequently remains the norm. Even after the FDA issued a new draft guidance on including pregnant people in clinical trials in 2018, it retained a default presumption that they’ll otherwise be excluded.
Pregnancy is complex, too, because of difficulties in measuring therapies’ and vaccines’ effects on fetuses and born children. Aside from patent birth defects—the thalidomide disaster in Europe casts a long shadow over testing drugs on pregnant people—there are significant complexities in designing (and funding) long-term studies to measure investigative products’ effects. These include the challenge of developing standard measures of “normal” children at different (and shifting) ages. Expectant parents, too, may be reluctant to subject their soon-to-be born children to experimental products and, even if they’re on board during an earlier stage of pregnancy, may drop out during the course of the study, making obtaining statistical robustness a challenge. There’s also complexities on how long to obtain data about born children: A year after birth? Two? Until adulthood? Beyond? For truly novel therapies, there may not be clear enough answers.
These challenges regarding designing clinical trials to incorporate pregnant people are particularly acute for COVID-19 therapies and vaccines, where speed to market is at a financial and public-health premium. This is true even for products authorized under an emergency use authorization, or EUA, rather than through one of the FDA’s traditional approval pathways. Pregnant people were consequently excluded from the first vaccine clinical trials and too few people in the trial got pregnant during trials to include them in a statistically robust manner. Even preclinical data on the COVID-19 vaccines and pregnancy was limited. More recently, pregnant people were excluded from molnupiravir trials because of concerns about birth defects.
With that said, there is some recent movement to include pregnant people in clinical trials for COVID-19 vaccines. Phase 2/3 clinical trials began in February 2021 for Pfizer/BioNTech and Janssen and included pregnant people. There have also been larger observational studies, including Moderna’s ongoing observational trial, the v-safe smartphone app study, and a Harvard SPH-affiliated registry to observe pregnant people in COVID-19 trials. But these enrolled only a tiny fraction of the number needed to conclusively demonstrate safety and efficacy in the pregnant population. (Nonetheless, all observational results thus far show no particular issues for pregnant people taking any of the FDA-authorized COVID-19 vaccines.)
Why is it important to include pregnant people in clinical trials, including for COVID-19?
Physicians and experts at the World Health Organization and CDC have been among those calling for change and arguing for greater inclusion of pregnant people in trials—with appropriate precautions—particularly for COVID-19. Two important reasons for inclusion are worth emphasizing.
First, pregnant people are not immune from illness—they often get sick with all sorts of diseases, including COVID-19, which is known to be more dangerous in pregnancy. If pregnant people are going to be prescribed medications if they become ill with COVID-19, or vaccinated against the virus, it’s difficult to justify a system in which clinical trials are purposefully designed not to generate information about how those drugs and vaccines will work (and whether they might cause particular problems) in pregnant people. This challenge has been referred to as the “pregnant people’s paradox.” At least some pregnant people have stated that they chose not to become vaccinated against COVID-19 out of concern over the impacts on the health of their pregnancies, suggesting that including pregnant people in the vaccine trials and generating safety information ahead of time might have helped to combat vaccine hesitancy in this high-risk population. Mixed messages from public health agencies may have complicated this situation for patients.
Second, as a matter of societal health equity, we should generally want information about how drugs and vaccines work across all swaths of the population. Pregnant people are people too and should not be excluded from trials as a matter of course, even if their inclusion renders the trial more complex. The historic underrepresentation of women in general—not just pregnant people—from clinical trials has been well-documented, and there is a lack of research in general into issues that predominantly or disproportionately affect women (such as endometriosis). This lack of study and understanding is problematic for everyone.
How can policymakers encourage clinical trials for pregnant people going forward?
Widespread exclusion of pregnant people from clinical trials represents a market failure of our current biomedical innovation system. Manufacturers designing clinical trials exclude pregnant people because the costs to the company—including potential risks—are estimated to exceed the private benefits, even if the social benefits are much larger. These costs to developers include (1) added complications and uncertainty for clinical trials process (such as those suggested by the FDA), (2) a potentially lower likelihood of being authorized or approved due to those complications, and (3) the substantial PR (and potential liability) risk if clinical trials result in harm to pregnant people.
As for other market failures, policymakers interested in addressing this failure can turn to other types of government interventions. Fortunately, they have a large innovation policy toolkit to choose from, which is similar to the toolkit we have previously discussed for encouraging pediatric trials.
First, the FDA could encourage more inclusive clinical trials through regulatory mandates. As long as the FDA continues to not require the inclusion of pregnant people as a condition for authorization or approval, companies will not feel pressure to do so. As explained above, the FDA grants sponsors substantial freedom in clinical trial design, and trial sponsors do not always follow guidance the agency does issue—which has been a longstanding problem in many areas, including for the representation of diverse racial populations in trials. The FDA and its counterparts abroad are beginning to address these problems, in moves the FDA recently described as a global “paradigm shift.” Whether the agency will issue regulations with more teeth or more forceful guidance remains to be seen.
Second, grantmaking agencies like the NIH could provide direct grant funding for clinical trials in pregnant people. For example, MOMI-VAX is an observational study conducted by the NIH that started in summer 2021. Funding could also be provided to other entities with interest in conducting clinical trials, such as healthcare payers who want to avoid paying for interventions that are harmful or ineffective.
Third, Congress could increase the incentives for product sponsors to study their products in pregnant populations by decreasing the cost through targeted tax incentives or increasing the benefits through added regulatory exclusivity. For example, orphan drugs for rare diseases are incentivized through a combination of a 25% credit for clinical trial expenses and seven years of exclusivity, on top of additional grant funding. And Congress has provided six months of added pediatric exclusivity—on top of other exclusivity periods—for companies that conduct pediatric trials of their products. Both statutes have been subject to significant criticism, such as for limited dissemination of pediatric trial results, but have also been successful in incentivizing the targeted type of R&D.
Development of safe and effective treatments and vaccines for the pregnant population is an important public health issue, for COVID-19 and beyond—and as with many areas of underdeveloped medical information, a variety of policy tools could be used by different government institutions to help address the problem.
This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.
