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  1. From Our Perspective

FDA and Duke-Margolis Host Workshop on Scientific and Ethical Considerations for Including Pregnant People in Clinical Trials

Part of Longer-Term Effort to Bolster Knowledge about Drug Use During Pregnancy

By Leyla Sahin, MD, and Catherine Sewell, MD, MPH
CDER Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine

Leyla Sahin
Leyla Sahin
Catherine Sewell
Catherine Sewell

Those of us immersed in the topic of pregnancy know these statistics: approximately 6 million people get pregnant every year in the United States.1 There are roughly 4 million live births annually.2 About 90% of pregnant people take a medication, including 70% who take at least one prescription medication.3 Medication use in pregnancy is only expected to increase, as people have babies later in life and chronic conditions like obesity and cardiovascular disease continue to grow.

But there are gaps in our knowledge about how medications affect pregnancy, the pregnant person, and the fetus, partly because pregnant people are underrepresented in clinical research. We need better representation of this population in clinical studies to try to address the knowledge gaps.

For conditions that occur in both pregnant and nonpregnant patients, such as diabetes, pregnant people are often not enrolled in clinical trials. Moreover, there are relatively few trials studying treatments for pregnancy-related conditions such as preeclampsia, a condition characterized by high blood pressure that can be life-threatening. The under-enrollment of pregnant people in clinical trials ultimately results in a lack of effective and safe medicines that pregnant people can use. It also translates to significant gaps in our understanding of drug metabolism (processing) and proper dosing in pregnancy; therapeutic effectiveness; and the medication’s short-term and long-term safety for the pregnant person and the fetus.

In clinical practice, pregnant people and their healthcare providers often do not have the information necessary to decide whether to use a medication during pregnancy and how to use it safely and effectively. As a result, prescribers can be reluctant to recommend the medication. Pregnant people may forego treatments because they fear it may hurt them or their fetus, or they may take the therapy but feel anxious about their decision. Sadly, in some cases, pregnant people decline important treatments that can lead to serious health consequences for them and their fetuses.

Pregnant people may not be included in clinical studies for scientific, legal, logistical, and financial reasons. But these reasons do not apply to every clinical study. At the beginning of each research endeavor, we need to consider if and how to enroll pregnant people as safely as possible.

We understand that enrolling pregnant people in clinical trials can be challenging and nuanced, and society is understandably concerned about any perceived harm to these people or the fetus. But our default response should not be to exclude pregnant people. Instead, we should aim for potential inclusion while taking sufficient precautionary measures. There are many careful, creative, and calculated actions we can take to safely increase the number of pregnant people participating in clinical trials.

After all, that’s what pregnant people want. They often say they wish to participate in clinical research out of a sense of altruism, so that the data can be available to the larger public and ultimately improve the field of obstetric medicine.

Conceiving the Workshop

Improving our knowledge about medication use in pregnancy has been a long-term priority at FDA.

In 2014, we published the Pregnancy and Lactation Labeling Rule, which requires changes on how pregnancy and lactation information is presented in prescription drug labeling.

Plus, over the years, FDA has fielded questions from sponsors on how to collect appropriate safety and effectiveness data in medications used in pregnancy. Eventually these conversations led to the development of three guidance documents: Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials, Postapproval Pregnancy Safety Studies, and Clinical Lactation Studies: Considerations for Study Design.

FDA is also participating in the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC). This task force was established by the 21st Century Cures Act to advise the Secretary of Health and Human Services on gaps in knowledge and research on safe and effective therapies for use during pregnancy and lactation. PRGLAC published a report in 2018 that includes 15 recommendations. It also published a report on the implementation plan last year.

FDA has been involved in conversations with stakeholders in industry, academia, advocacy organizations, and other government agencies. These activities inspired FDA and Duke-Margolis to develop a workshop on the Scientific and Ethical Considerations for the Inclusion of Pregnant Women in Clinical Trials, which was held February 2-3, 2021.

Growing the Nonclinical and Real-World Evidence Knowledge Base

When we think of research, we must recognize that nonclinical models, registries, and clinical case repositories provide valuable information on medication use in pregnancy.

At this time, animal studies are the most consistently collected data about an investigational drug’s safety and effectiveness on prenatal issues, including pregnancy loss, risk of birth defects, and fertility concerns. Sometimes, animal studies can yield information on dosing recommendations.

Technical advances can also shed light on a medication’s safety and efficacy. These technologies can include organs-on-a-chip, which are miniature models of human organs that can be used in drug development. Placentas-on-a-chip are being created to help us study whether medications and other substances can cross the placenta (an organ that develops during pregnancy to provide nutrients to the fetus) and reach the fetus.

In addition, FDA maintains a list of registries that collect real-world information from people taking medications during pregnancy. Plus, the FDA-NIH CURE ID app is a clinical data repository that lets clinicians report new uses of existing medications through a mobile device. The app is being expanded to include a CURE Pregnancy Treatment Repository to collect data from clinicians on using medications to treat infectious diseases and cancer during pregnancy.

The agency has also used FDA’s MyStudies app, which captures patient-reported data, in a pilot study of pregnant people to collect data on chronic and acute health conditions, medication use, and other health behaviors during pregnancy.

Delivering Results: Challenges and Opportunities

While nonclinical and real-world information can give us critical information, there are significant limitations in how much data they can provide. At this point in time, clinical trials remain the gold standard. The FDA-Duke Margolis workshop discussed challenges and potential solutions for enrolling pregnant people safely and ethically in these trials.

One hurdle is the complicated science of pregnancy. It is a time of rapid, continual change for both the pregnant person and the developing fetus. Physiologic changes may affect the way medications are absorbed, metabolized (processed), and eliminated (cleared) in different ways throughout gestation. For example, vomiting during early pregnancy can reduce absorption of medications taken by mouth. Increases in blood volume later on in pregnancy may affect drug metabolism.

There are also complex issues about when to include pregnant people in research. For example, a treatment that helps the pregnant person may potentially harm the fetus and vice-versa, making the benefit-risk consideration complicated at times. In general, preliminary data should show that the medication has an overall favorable benefit-risk profile for the pregnant person and the fetus throughout pregnancy.

The societal moral imperative to include pregnant people in therapeutic research depends upon the situation. This imperative is greater with more serious diseases, conditions that are prevalent in pregnancy, or diseases for which there are few or no current treatment options. Stakeholders, including drug sponsors, governmental agencies, pregnant people and their health care providers, may need more resources on how to respond.

Another big obstacle is economic viability. As pregnancy lasts for only around 40 weeks and people generally become pregnant only a few times in their life, drug companies may think it doesn’t make good business sense to invest in a medication taken for this short time. Complicating this further, some conditions occur in only part of a pregnancy. Nausea and vomiting are common in the first trimester but usually resolve after that point. Anemia and gestational diabetes can affect people usually later in pregnancy. Financial incentives and targeted funds may spur change in this area.

Nursing a Culture Change

The cultural change may be our most daunting task. As we mentioned earlier, there is a default response to keep pregnant people out of clinical research. But there are real consequences from excluding pregnant people from clinical trials without a scientific justification, resulting in large knowledge gaps.

Culture change is never easy. But through the FDA-Duke Margolis workshop, through FDA guidance development, and through collaborations between government, industry, and academic stakeholders, we are helping to shed light on this issue. We hope these conversations spur more journal articles, more guidelines, and more studies. Ultimately, we want our efforts to lead to more consistent enrollment of pregnant people in clinical trials and, eventually, the collection of high-quality information to support the safe and effective use of medications used during pregnancy.

Most of all, we want pregnant people to feel like they are making well-informed, carefully considered treatment decisions. The people carrying our next generation deserve it.

Gerri Baer, MD, and Susan McCune, MD, in FDA’s Office of Pediatric Therapeutics; Christine Nguyen, MD, and Lynne Yao, MD, in CDER’s Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine; and Kaveeta Vasisht, MD, PharmD, FDA Associate Commissioner for Women’s Health, contributed to this piece.

  1. Centers for Disease Control and Prevention (CDC), 2013, Pregnancy Rates for U.S. Women Continue to Drop. National Center for Health Statistics Data Brief No. 136. Accessed February 24, 2021. https://bit.ly/3lijjUv
  2. Martin JA, Hamilton BE, Osterman MJK, et al. CDC. National Vital Statistics Reports, 2019. Births: Final Data for 2018. Vol. 68. No. 13. Accessed March 12, 2021. https://bit.ly/38zy00c
  3. CDC. Treating for Two: Medicine and Pregnancy. Research on Medicines and Pregnancy. Accessed March 12, 2021. https://bit.ly/3vgNOPf


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