Inclusion of Pregnant and Lactating Persons in Clinical Trials

Protecting Pregnant and Lactating Persons through Research

Maggie Little, Georgetown University Kennedy Institute of Ethics, highlighted that in recent years, there has been a shift from discussions on whether or not pregnant and lactating persons should be included in clinical trials to how to make this happen. There are institutions that have a track record of safely and ethically including pregnant and lactating people in clinical trials, added Anna Mastroianni, University of Washington School of Law, which she credits to an institutional culture that prioritizes the safe inclusion of these populations in clinical trials.

Sarah Mancoll, a mother and advocate living with alopecia areata—a chronic autoimmune condition that causes hair loss—explained how when she first considered becoming pregnant, her doctors were unable to provide her with adequate evidence that continuing her treatment plan during pregnancy would be safe. She felt “deeply frustrated” and decided to discontinue treatment throughout her pregnancies and while breastfeeding. Mancoll, is now participating in a clinical trial for a new alopecia areata drug, and said in retrospect that she would have been open to enrolling in a clinical trial while pregnant.

• Learning from Pregnant Individuals’ Perspectives on Research

  Melissa Gorman,⁴ a mother and nurse, said she was “shocked” by the lack of available information for pregnant and lactating persons after experiencing a medical complication during her first pregnancy. However, during her second pregnancy, her neurologist discussed with her the opportunity to participate in a study on the safety of seizure medications during pregnancy and lactation—an opportunity she accepted. Gorman shared that participating in the study was “a wonderful opportunity” that allowed her to help others in similar situations.

  

  “Pregnant people should have the opportunity to choose whether or not they want to participate in clinical trials”
  —Zsakeba Henderson, March of Dimes

  Henderson noted that preventing pregnant and lactating persons from participating in clinical trials limits their ability to make fully informed health care decisions.

• Sharing Information with Pregnant and Lactating Persons

  Thomas Hale, Texas Tech University School of Medicine, directs the Infant Risk Center—a national call center for pregnant and breastfeeding persons—which he described as a resource for individuals with questions regarding medication use during pregnancy and lactation. MotherToBaby is another resource for counseling patients through the risks of using particular medications while pregnant or breastfeeding, contributed Christina Chambers, University of California San Diego. Henderson added that March of Dimes provides information and resources on medication use during pregnancy and lactation through its website.

Enabling Shared-Decision Making for Pregnant and Lactating Persons

Pregnant persons may require medical treatment for pre-existing chronic conditions or for medical conditions that arise during pregnancy. There are benefits and risks in taking a medication during pregnancy and lactation; and there are benefits and risks in not taking a medication. No matter the circumstances, the decision to take or not take a medication should be made after discussions between pregnant and lactating people and their health care providers, explained David Haas, Indiana University. Geeta Swamy, Duke University; Brittany Bettendorf, University of Iowa; and Henderson agreed that managing chronic conditions through pre-conception care and planning is important to achieve the best outcomes for mother and baby. Lynne Yao, FDA, summarized, “The health of a child begins with the health of the mother.”

Veronica Gillispie-Bell, Ochsner Health System, and Haas—who are practicing obstetrician-gynecologists—described the challenge of discussing uncertainty when it comes to the benefit and risk of medication use with pregnant and lactating patients. They explained that this uncertainty is due to a lack of research on the safety and effectiveness of medication use for these populations. Ebony Carter, University of Washington in St. Louis School of Medicine, and Bettendorf endorsed honesty with patients about the available evidence as well as the gaps in the evidence. Bettendorf added that shared decision-making provides the opportunity for providers to share their knowledge on treatments with patients, and patients to share their personal values and preferences with providers. Additionally, Bettendorf and Gillispie-Bell both emphasized the importance of communication among a patient’s full care team (e.g., OB/GYN, midwife, primary care provider, specialist) to promote safe use of medication during pregnancy and lactation, and to share information about clinical trials that may be appropriate for the patient.

• Promoting Clinical Trial Awareness

  Bettendorf suggested that making information about clinical trials available to patients where they receive care (e.g., waiting rooms) could help promote discussions about clinical trials and other studies that may be of interest to the patient. Danielle Askin, a mother and patient, added that social media is a powerful tool to promote clinical trial opportunities, describing how she had found information about trials she participated in through social media.

• Engaging in Clinical Trials and Research Studies

  Haas described two types of studies in which pregnant and lactating persons may participate—clinical trials in which patients may take a new drug to treat a condition, and observational studies in which patients already taking a drug are monitored—adding that observational studies are more common in pregnancy.

  • Diana Bianchi, National Institute of Child Health and Human Development, shared that the Maternal Fetal Medicines Unit Network and International Maternal Pediatric Adolescent AIDS Clinical Trial Network are conducting clinical trials on several drugs used during pregnancy and lactation.
  • Toluwalase Ajayi, Scripps Research Translational Institute, discussed PowerMom, an observational app-based research platform she leads that empowers pregnant and lactating persons to contribute their own data from surveys, wearable technology, and electronic health records (EHRs).

  Chambers added that real world evidence from EHRs, claims data, and pregnancy registries can support evidence gathered through clinical trials. Kathryn Schubert, Society for Women’s Health Research, stressed that clinicians can help contribute to clinical evidence generation by enrolling their pregnant and lactating patients who are using medications in pregnancy registries.

  • Ajoke Sobanjo-ter Meulen, Icosavax, shared the example of CDC’s V-safe registry, which is linked to the CDC COVID-19 pregnancy registry.
  • Catherine Sewell, FDA, referred to CURE ID Pregnancy Treatment Repository as a resource for clinicians that will capture data on the use of repurposed drugs for the treatment infectious diseases in pregnant persons.

Building Trust and Engaging Communities in Research

Bettendorf, Carter, Gillispie-Bell, and Henderson highlighted the importance of developing trusted relationships and leveraging community partnerships to recruit pregnant and lactating persons to clinical trials. Iona Munjal, Pfizer, and Bettendorf explained that pregnant and lactating persons considering participation in clinical trials often value the opinion of their partner, and that researchers should be open to having the patient’s partner or other designees participate in discussions about trial participation.

Henderson emphasized the need for academic centers to share information about clinical trials with satellite or community-based practices, as an opportunity to recruit diverse study participants and investigators. Gillispie-Bell and Henderson explained how engaging diverse investigators who reflect the study population can improve the recruitment and retention of trial participants. Carter collaborates with community health centers from the very beginning of a study—for example, community health centers provide input on trial design and grant applications. She added that it takes time and commitment to build these types of trusted relationships and to understand the needs of community partners.

• Designing Research for Patients

  Ensuring that patient input is incorporated into trial design can help to facilitate trial participation, explained Gillispie-Bell and Henderson. Ajayi stressed that researchers “have to create and develop the research with the people that we want [to participate] in mind.” Henderson highlighted that pregnant people are just like non-pregnant people in that they have duties and responsibilities and other life issues that impact their ability to participate in trials (e.g., jobs, childcare, transportation). Munjal described a phase 3 clinical trial on a maternal vaccine for respiratory syncytial virus ⁵ in which pregnant persons and their partners provided input on the study protocol to make it more acceptable to trial participants.

• Building Research Capacity and Enabling Dissemination

  The Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub “serves as a national resource for expertise in maternal and pediatric therapeutics to conduct and foster therapeutics-focused research in obstetrics, lactation, and pediatrics, while enhancing inclusion of people with disabilities,” Bianchi said. She continued, the National Institute of Child Health and Human Development is taking actions to support clinical trials that include pregnant and lactating persons, such as offering training for researchers and open grant solicitations. Gillispie-Bell suggested that disseminating research findings through the American College of Obstetricians and Gynecologists and the American Board of Obstetrics and Gynecology as one approach for directing information to clinicians and can help influence clinical practice.

Navigating Legal Barriers and Liability Risks

“There is a deeply entrenched myth that it is legally impermissible to include pregnant and lactating people in research ”
—Leslie Meltzer Henry, University of Maryland

However, she along with Mastroianni and Aviva Wein, Johnson & Johnson, explained that legal concerns can be addressed, and lawyers can advise on developing creative risk management strategies that can help enable these studies.

• Minimizing Risk through Collaboration

  Liability risks can be a major barrier to including pregnant and lactating persons in clinical trials, explained Henry and Wein. Mastroianni added that lawyers should be engaged early on in a study and informed that addressing liability risks for including pregnant and lactating persons in trials is a priority. Jessica Cohen, PATH, stressed the importance of collaboration across her institution—including legal affairs, product development, ethics committee, and the office of research—for enabling PATH to address legal and liability risks.

  Mastroianni highlighted the University of Washington and the University of Southern California as examples of research institutions that prioritize the inclusion of pregnant and lactating persons in research and have been successful in navigating legal and liability risks. She explained that the University of Southern California established a Flexibility Coalition to discuss flexibility in research regulations and disseminate best practices to other institutions. Cohen and Mastroianni agreed that clinical trial insurance or other compensation programs for harm incurred from clinical trial participation facilitate the conduct of clinical trials with pregnant and lactating persons at their institutions.

• Overcoming Perceptions of Risk

  Katherine Wisner, Northwestern University, shared that institutional review boards (IRBs) are often hesitant to approve studies that include pregnant or lactating persons, and may not have expertise in obstetrics or pharmacology to evaluate the appropriateness of these studies. Swamy described how the IRB at Duke University benefited from the involvement of researchers who regularly conduct research with high-risk populations (e.g., obstetricians, pediatric oncologists). Carmen Zorrilla, University of Puerto Rico, added that study protocols, which require dismissal of participants from a trial once they become pregnant, can be a source of frustration for researchers and patients, and are a missed opportunity to collect data for these populations. Swamy made the point that, “pregnant and lactating persons are people who are pregnant or lactating at the time,” and advocated that pregnant and lactating persons be considered for trial enrollment the same way non-pregnant people are.

• Promoting Guidance and Best Practices for Inclusion

  Workshop participants noted the availability of resources to guide trial sponsors and research institutions in conducting trials with pregnant and lactating persons. Ruth Karron, Johns Hopkins University, highlighted the PREVENT guidance, which provides a roadmap for including pregnant people in the development of vaccines for emerging epidemics. Jeff Roberts, Merck, and Sewell described guidance from the U.S. Food and Drug Administration that aims to help researchers and the institutions that conduct research to safely include pregnant and lactating persons in clinical trials. Bianchi pointed to the ongoing implementation of the recommendations from the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) as a source of forthcoming guidance and resources.

Incentivizing the Inclusion of Pregnant and Lactating Persons in Trials

Henry and Little explained that legal barriers to the inclusion of pregnant and lactating persons in clinical trials remain. Henry, Little, and Wisner described opportunities to address the ambiguity in the terminology used in regulations⁶ covering protections for pregnant persons participating in research, especially in regards to the concept of “minimal risk” to the fetus. The ambiguity of minimal risk allows for more cautious interpretations of the term, which can be used to exclude these populations from clinical trials, they continued. In addition to clarifying terminology, Bianchi and Henry also advocated for harmonizing FDA regulations—which identified pregnant persons as a vulnerable population⁷—with the Common Rule,⁸ which acknowledges pregnant persons as a complex population.

• Considering Protection of Human Subjects in Research

  Wisner suggested there could be a role for policymakers to develop a centralized IRB review process—an agreement that multiple study sites could rely upon—for institutions that lack the expertise to evaluate study protocols that include pregnant and lactating persons. Swamy suggested that the Secretary's Advisory Committee on Human Research Protections in the Office for Human Research Protections could provide support to improve inclusion of these populations.

• Learning from Pediatric Research

  Yao pointed to the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA), which incentivized and required, respectively, clinical trials to be conducted in pediatric populations. She explained that legislation has been successful in generating evidence on the safety and effectiveness of medications for children, and there may be an opportunity for similar approaches to improve the evidence base for pregnant and lactating persons. Bianchi added that the PRGLAC Task Force recommended BPCA serve as a model for the development of programs to study drugs used off-patent in pregnant and lactating persons. Henry concluded, “until we have a statement that requires a justification for exclusion of pregnant and lactating people from research, it will still be possible for those who fear any kind of legal risk to take the more conservative interpretation of any regulation.”