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Lessons Learned

LESSONS LEARNED FROM COVID-19 VACCINE TRIALS

Ruth Karron, Johns Hopkins University Bloomberg School of Public Health, began discussion of her case example with a brief review of what was thought about vaccine research in pregnant persons when the COVID-19 pandemic was beginning in March 2020. At that time, the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC Task Force) recommendations had been released in 2018; the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) guidance had been released in 2019 and included 22 recommendations promoting the equitable inclusion of the interests of pregnant persons in the development and delivery of vaccines for emerging epidemics.¹ As well, the value of maternal immunization was acknowledged based on a long history (e.g., maternal influenza immunization during the 2009 H1N1 pandemic), and many obstacles to vaccinating pregnant persons had been addressed. Also in March 2020, there were three companies conducting clinical trials of respiratory syncytial virus (RSV) vaccines in pregnant persons.

Calls for pregnant persons to be included in clinical trials for COVID-19 vaccines and therapeutics began to appear in the media in April 2020 and in the professional literature in May (e.g., Mandavilli, 2020; Whitehead and Walker, 2020). Over time, data on the risks of COVID-19 infection for both pregnant persons and their infants started to accrue, as well as data

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¹ See https://bioethics.jhu.edu/wp-content/uploads/2022/06/PREVENT-Web.pdf (accessed September 6, 2022).

on the benefits of vaccination (e.g., DeSisto et al., 2021; Edlow et al., 2022; Prasad et al., 2022).

Karron reviewed the response to the COVID-19 pandemic relative to four of the PREVENT guidance recommendations (for the full recommendations see Krubiner et al., 2021):

• Recommendation 7, Karron summarized, says that pregnant women should not be left behind as new technologies are developed. In fact, as new mRNA-based vaccines were developed for COVID-19, pregnant women were left behind, she said.
• Recommendation 9, in summary, says that nonclinical studies required prior to clinical evaluation during pregnancy development and reproductive toxicology (DART) studies should be conducted early in clinical development, as promising and appropriate candidates move to phase 2. Preclinical development and reproductive toxicology studies were not yet complete by the time the first vaccines were being awarded emergency use authorizations in December 2020 and, as a result, pregnant people were not enrolled in the clinical studies, she continued.
• Recommendation 11 states, “Pregnant women should have the opportunity to enroll in studies conducted during outbreaks when prospect of benefit [outweighs] risk for pregnant women, their offspring, or both.” Karron said that in the United States, pregnant persons were not able to enroll in the first wave of COVID-19 vaccine trials. Although some later studies begun in 2021 did include pregnant persons, she noted that enrollment was difficult.
• Recommendation 17 states, “Pregnant women should be offered vaccines as part of an outbreak or epidemic response.” Pregnant people were offered vaccines, Karron said, but uptake was delayed.

Karron offered several lessons from the COVID-19 vaccine trials. First, pregnant persons are at equal or higher risk for infectious diseases compared to nonpregnant persons. “At minimum [pregnant people] deserve fair access to clinical trials when benefits exceed the risks,” she said. And, as discussed, what benefits the pregnant or lactating can also benefit baby.

Pregnant people, lactating people, and children are three distinct populations, Karron continued. Further, designating a group as a “special population” does not necessarily serve their best interests. She said that, during Operation Warp Speed, “special populations” were essentially set aside for later, even though it was becoming clear that pregnant people were at greater risk for serious disease than children were. She added that there was no biological reason to exclude lactating people from clinical trials and from receiving the vaccines.

Despite sufficient financial resources, a focus on enhancing diversity in clinical studies, and an environment that was favorable for maternal immunization, pregnant persons were still not included in a timely manner in COVID-19 vaccine trials during a public health emergency, Karron said, noting,

She said, “Legislative remedies should be considered to ensure fair inclusion of pregnant and lactating people in clinical trials.”

LESSONS LEARNED FROM DRUG TRIALS FOR MOOD DISORDERS

“Mental health is fundamental to health,” said Katherine L. Wisner, the Norman and Helen Asher professor of psychiatry and obstetrics and gynecology, and director of the Asher Center for the Study and Treatment of Depressive Disorders at Northwestern University. Perinatal mood disorders are common in pregnant persons, and a study by Wisner found that 14 percent (1 in 7) of 10,000 women screened for depression 4- to 6-weeks postpartum screened positive. The majority had major depression with a coexisting anxiety disorder, while 20 percent had bipolar disorder (mostly undiagnosed). She noted that the illnesses identified during the postpartum screening included preexisting chronic illnesses (onset prior to pregnancy, 27%), conditions with first onset during pregnancy (33%), and illnesses that presented in the first 4 to 6 weeks postpartum (40%) (Wisner et al., 2013).

In a 2017 consensus statement, the American College of Obstetrics and Gynecology (ACOG) stated, “Perinatal mood and anxiety disorders are associated with increased risks of maternal and infant mortality and morbidity and are recognized as a significant patient safety issue” (Kendig et al., 2017, p. 422). Wisner said that negative obstetric and neonatal complications (e.g., miscarriage, preeclampsia, low birth weight) are more common in mothers who have mental illnesses during pregnancy, as are early social and emotional effects (e.g., poor infant self-regulation, insecure attachment) and long-term impairments (e.g., developmental and cognitive delays, behavioral problems) in the child.

Although there has been increased attention to the need to treat pregnant persons with mental illness, barriers to clinical studies persist, and Wisner shared two case examples from her work. The key lessons, she summarized, are that stigma about mental health persists and affects the ability to study mental illnesses, and that mental health and psycho--

pharmacology perspectives need to be represented on study sections and institutional review boards, as well as among the peer reviewers for journal submissions.

Silos and Stigma

Mirtazapine is an FDA-approved antidepressant for the treatment of major depressive disorder; however, it is also used to treat chemotherapy-induced nausea and vomiting, and to prevent postoperative nausea and vomiting—indications that are not FDA-approved. Wisner has funding from the National Institute of Child Health and Human Development to study repurposing mirtazapine to treat severe nausea and vomiting in pregnancy, and she described the types of comments she received from the study section review.

One comment centered on why mirtazapine would be used over ondansetron (another antiemetic) when they both antagonize the same receptor (the 5-HT3 receptor) and one reviewer said that psychotropics should not be used without an indication. Wisner noted that the ACOG practice guideline for severe nausea and vomiting in pregnancy includes two psychotropic drugs that are indicated for both nausea and vomiting and for schizophrenia (for use as later-line therapies). Another comment said that the study team (Wisner, trained in psychiatry, and a colleague who is an obstetrician/gynecologist [OBGYN] pharmacologist) had focused on mental health disorders of pregnancy and postpartum, and had less experience with the “medical” indication for mirtazapine, seeming to imply that mental health disorders were not a medical indication. She continued to address these and other technical questions over the course of four submissions.

Based on her experience in this case, Wisner said that members of scientific panels, institutional review boards (IRBs), and others who review studies are just as influenced by perceptions that lead to stigmatization as members of the public are, and that “psychiatrically ill women who are also pregnant are doubly stigmatized.”

IRB Hesitancy

Many drugs used to treat mental illness are used chronically and continue to be used during pregnancy, Wisner said. Cytochrome P450 3A4 (CYP3A4) is involved in metabolizing more than half of existing drugs. It is known that the activity of this enzyme increases across pregnancy and, as a result, plasma levels of drugs can decrease (Abduljalil et al., 2020). The challenge, she said, is how to maintain a steady dose in a pregnant patient from conception through the postpartum period. One

approach to assessing the activity of this enzyme is using probe drugs. A selective probe for CYP3A4 is the psychotropic drug, midazolam (a benzodiazepine). In an effort to understand the activity of CYP3A4 in pregnancy, Wisner and her colleague sought out to conduct a probe study at the end of the first, second, and third trimesters and postpartum in healthy pregnant persons.

In their IRB submission, they indicated that “there is no prospect of benefit to the fetus” and “the risk to the fetus is not greater than minimal risk.” Their justification for the study was based on a published study showing the clearance of midazolam at 28 to 32 weeks in pregnancy was more than twice that postpartum (Hebert et al., 2008), indicating that drugs metabolized by CYP3A4 would be more quickly cleared and doses reduced. The study also found there were no adverse reactions or maternal sedation and no changes in fetal heart rate in response to midazolam as given, and that mean plasma concentrations were very many times lower than those used therapeutically for sedation in adults or adolescents.

The study was not approved by the IRB on initial submission or after additional justification was provided. Wisner said the vote was mixed and the disagreement about whether to approve was not about the use of midazolam, but about the definition of minimal risk. The definition used for minimal risk was that “the probability and magnitude of physical or psychological harm anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life, or in routine medical, dental, or psychological examinations.” The IRB struggled to apply this definition to pregnancy, and they were not able to provide Wisner with an answer to what dose would qualify under this definition. A problem for investigators, she said, is where to go next for additional help and review, especially if the IRB did not have obstetric or pharmacologic expertise.

PERSPECTIVES ON EVIDENCE GENERATION

Research Perspective

Geeta Swamy, Duke University, shared observations as a researcher in maternal immunization, infectious diseases, and perinatal disease. First, she encouraged participants to consider how they can contribute to solutions. She currently oversees the IRB at Duke Health. She noted that the former chair of the Duke Health IRB was a pediatric oncologist, a perspective that allowed the IRB to become more streamlined and efficient in addressing issues for higher risk populations in general.

Accountability for Enabling Evidence Generation

Swamy emphasized the need for those who care for pregnant and lactating persons to respectfully demand accountability from those who oversee research with these populations. While discussing case studies and articles about clinical studies that have been done is informative, what is needed is for those who treat pregnant and lactating persons to say, “Tell me what I should tell my patient, because I don’t have something to offer them, because you won’t let me do this study,” she said. They need to understand the perspective of providers who do not have the data they need for treatment decisions.

Training Investigators to be Successful at Inclusion

Although there are many researchers studying issues specific to pregnancy, Swamy observed that there are few researchers conducting studies in pregnant persons for conditions that are not associated with pregnancy. She suggested creating a training pipeline to build the expertise needed to navigate the regulations and review processes associated with including pregnant persons in clinical studies of conditions that are not pregnancy specific. As an example, she noted that clinical trials funded by the National Institutes of Health of a vaccine for pandemic H1N1 influenza were halted three times over a 4-week period owing to preterm births because the investigators were primarily adult infectious disease physicians who assumed that outcomes had to be vaccine associated. Instead of halting studies, the approach should be to have researchers with expertise in pregnancy involved so they can be consulted about occurrences of adverse outcomes in pregnant trial participants (such as the frequency of preterm birth in the general pregnant population).

Industry Perspective

Iona Munjal, senior director of clinical research and development for Pfizer Vaccines and assistant professor of pediatrics at Albert Einstein College of Medicine and Montefiore Medical Center, discussed some of the aspects of developing vaccines to be used by pregnant persons.² Pfizer is currently conducting a phase 3 clinical trial of a maternal vaccine for RSV³ and a phase 2 trial of a maternal vaccine for group B Streptococcus (GBS),⁴ and has other bacterial and viral vaccines in development for this

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² Munjal noted that the opinions expressed are her own and do not necessarily represent an official position of Pfizer.

³ See https://clinicaltrials.gov/ct2/show/NCT04424316 (accessed September 12, 2022).

⁴ See https://clinicaltrials.gov/ct2/show/NCT03765073 (accessed September 12, 2022).

population. Munjal noted that if the regulatory submission for the RSV vaccine is successful, “It would be the first RSV vaccine licensed for the maternal population.”⁵ Because RSV affects children worldwide, Pfizer is conducting the study in 18 countries, including low- and middle-income countries. She added that, on approval, both the RSV and GBS vaccines will be available at a cost acceptable to Gavi-eligible countries.

Recruitment and Retention

Recruitment for the phase 3 RSV vaccine trial began in June 2020 and was affected by the ongoing COVID-19 pandemic (e.g., pregnant persons were having less frequent obstetrical visits, there were increasing public anxieties about vaccination). However, the studies were successfully launched and Munjal discussed several of the key factors to recruiting pregnant persons.

First, in addition to convening a panel of scientific advisors to assess the study protocol, Pfizer also engages potential pregnant participants and their partners to gather feedback about how elements of the study design might affect them, whether the protocol was acceptable to them, and whether their partners would be supportive of them participating in the trial. Their input was used to refine the protocol, addressing issues such as the duration a pregnant participant would need to sit in the clinic for a particular procedure. Other design elements included adapting the inclusion criteria to widen the gestational age and to allow for participants with controlled gestational diabetes and gestational hypertension, which Munjal noted are common in pregnancy.

Pfizer is intentional about diversity in the trial population, Munjal said, and recruitment materials were designed to enroll a trial population that reflected the communities where the trials were being conducted. Social media helps potential participants in target zip codes be aware of available trials, and community-based champions serve to mentor research teams at clinical sites to help them achieve a representative enrollment.

Munjal also emphasized the contribution of the data monitoring committee to the success of the trials. Pfizer’s data monitoring committee for the RSV trial included experts in obstetrics, maternal health, pediatrics, and pulmonary medicine. Conducting clinical trials with pregnant persons

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⁵ After the workshop, Pfizer released interim data that showed the vaccine was effective in preventing severe illness due to RSV in infants, and expected to submit a regulatory appliction by the end of 2022. For more information, see https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-positive-top-line-data-phase-3-global (accessed November 6, 2022).

is “a very emotional scientific endeavor,” she said, and the data monitoring committee brings “a calm and a scientific rationality” as they review data from the ongoing trial and provide guidance to the sponsor on addressing issues of safety that might occur.

Pfizer is also committed to empowering clinical trial participants by providing them with their clinical data at the end of the study. Another lesson from the COVID-19 vaccine trials that Pfizer is also applying, Munjal said, is the need to keep trial participants informed of any changes to the ongoing study.

Munjal also discussed the challenges of recruiting for clinical trials of products that are already approved for adult populations and available to pregnant and lactating persons. It becomes challenging to enroll patients in a placebo-controlled trial when they know they can receive the actual product from their health care provider, she said. This is what happened when pregnant persons began receiving the approved COVID-19 vaccine from their provider, despite the lack of studies in pregnant persons. After consultation with FDA, the pathway that was pursued in this case was to discontinue the placebo-controlled trial with pregnant persons and instead submit descriptive data from the COVID-19 vaccine trial. She suggested that a framework is needed for conducting trials with pregnant and lactating persons for products that are already approved for use in adult populations.

Advocacy Perspective

Kathryn Schubert, president and chief executive officer of the Society of Women’s Health Research (SWHR), described efforts by the Coalition to Advance Maternal Therapeutics (CAMT) to increase the inclusion of pregnant and lactating persons in clinical research.⁶ CAMT was established in 2014 and is overseen by a steering committee that includes the Society for Maternal-Fetal Medicine, March of Dimes, ACOG, and American Academy of Pediatrics, with SWHR joining the steering committee later. Advancing maternal therapeutics is a priority for each of these groups, Schubert said, because of the lack of data on the use of medications during pregnancy. In the absence of these data, individuals have been advised to stop taking medications for chronic conditions after becoming pregnant, or to stop breastfeeding if taking a medication, or even to avoid becoming pregnant if continuing a medication will be needed. Discussions with providers revealed that they prescribe drugs they believe to be safe for pregnant or lactating persons based on their experience in practicing medicine, and that product labeling regarding

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⁶ See https://www.smfm.org/advocacy/camt (accessed September 12, 2022).

use during pregnancy or lactation can be confusing to both patients and providers.

Schubert said that CAMT did consider pursuing a “best pharmaceuticals for pregnant people act” modeled on the Best Pharmaceuticals for Children Act. However, after assessing what is known about the use of drug products by pregnant and lactating persons and what data were needed, CAMT advocated for the creation of the PRGLAC Task Force. She noted that the PRGLAC Task Force became written into law relatively quickly, by the end of 2016, which she credited to putting forth a logical proposal and securing the support of bipartisan congressional champions.

ADDITIONAL LESSONS

Working with IRBs

Participants continued the discussion of working with IRBs. One of the barriers that studies encounter, Munjal said, is the time it takes to get through the various review processes. For the IRB review process, she noted that the length of review is often extended by rounds of challenges and comments from the IRB related to the inclusion of pregnant persons that the sponsor must address (as demonstrated in Wisner’s case example). To enable faster review, she suggested that IRBs and others who review sponsor applications need increased resources to improve their infrastructure and expand their capacity, which includes adding expertise in pregnancy and lactation.

Thomas Hale, Texas Tech University School of Medicine, agreed that IRB approval can be a particular challenge. He said that those who serve on IRBs should have an understanding of the importance of conducting studies with pregnant and lactating persons, and he suggested there is a role for government in ensuring this. Schubert said the expertise needed on IRBs might not necessarily need to be legislated, but there does need to be increased awareness. Swamy agreed that government support would be helpful, and she suggested that the Secretary’s Advisory Committee on Human Research Protections in the Office for Human Research Protections might be the appropriate office to approach on this issue. She noted that the expertise needed might vary, and that adding someone with OBGYN expertise does not necessarily mean they have experience conducting research with pregnant and lactating persons.

Swamy reiterated the point made throughout the workshop that pregnant and lactating persons are distinct populations. Lynne Yao, U.S. Food and Drug Administration (FDA), said that building in the right blend of knowledge and experience across IRBs could help improve the acceptability of including pregnant and lactating persons in studies.

Swamy suggested documenting the IRBs rationale for approval of a study in a format that a sponsor or study coordinator can then share with investigators and other IRBs to use as a framework for their decisions. Wisner suggested that cases such as the two she presented could be developed into exercises to dissect the decision-making process and understand why an IRB made the decision it did, and then develop strategies to help investigators and IRBs better manage these types of decisions.

Prioritizing Data Needs

A participant said that the regulated drug industry cannot separate risk from benefit and all product development includes assessment of risk. She questioned at what stage in the clinical research process the development and reproductive toxicology studies could realistically be expected to be done. She suggested that the broader community needs to be engaged in identifying research priorities, and that new models are needed to make development and reproductive toxicology testing more efficient and to reduce the number of animals needed for testing.

Yao suggested focusing on identifying the specific data needed during pregnancy, rather than on specific studies to be done in pregnant persons, and presenting a plan to collect that data for discussion with regulators. She agreed with the need for prioritization and gave an example from pediatrics. The Research to Accelerate Cures and Equity (RACE) for Children Act amended Pediatric Research Equity Act with regard to conducting pediatric studies for drugs to treat cancer. During the implementation phase of the law, FDA convened public stakeholder meetings to establish priorities areas for clinical research to meet the needs of children with cancer. Prioritization might be done before or in conjunction with a legislative approach. Schubert said that ongoing conversions at SWHR about this issue are, in fact, focusing on how best to get the data needed, not on requiring specific studies. As an advocacy organization, SWHR emphasizes this important distinction, she said. The focus is on issues such as defining the right questions, identifying the data gaps, and improving the infrastructure for collecting and sharing those data, rather than on requiring studies. She also agreed with the need for prioritization but added that it can be challenging to reach agreement and suggested that additional data could help guide prioritization.

Improving Data and Research Infrastructure

Participants discussed further the challenges of conducting clinical studies with pregnant and lactating persons globally, especially studies of vaccines for infectious diseases. Munjal said that, for Pfizer’s maternal

vaccine trials in the United States, 70 percent of the principal investigators are obstetricians. Globally, 30 percent of principal investigators are obstetricians, but every trial site is required to have obstetric and pediatric expertise. She described several approaches to overcoming challenges for the RSV maternal vaccine study. For example, to ensure that literacy was not a barrier to enrollment, audiobooks were available for illiterate patients in the United States and abroad. To eliminate lack of accessibility to prenatal care as a barrier to enrollment there was a 90-day screening period for participants to ensure that their pregnancy was accurately dated and to have an anatomy scan (i.e., ultrasound). Munjal noted that getting the 90-day screening period approved internally and by the IRBs was challenging, but the rationale, she explained, was that adequate prenatal care during this time is necessary to be able to standardize trial populations in the United States with those outside the United States. In contrast, Munjal said that trial startup timelines outside of the United States were a barrier to conducting placebo controlled COVID-19 vaccine trials in many countries. The lesson learned was the need to have the infrastructure already in place to be able to activate trial sites.

Swamy observed that there have been opportunities to learn and apply lessons from prior outbreaks (e.g., Zika, Ebola, avian influenza), but progress has stalled and the same discussions will need to happen again for the next outbreak. “The question becomes, are we ready to be innovative and think about training and infrastructure development so we are ready for whatever is next,” she said. Examples are having standard protocols, consent documents, and training materials ready to go (to enable the inclusion of pregnant and lactating persons). She acknowledged, however, that this takes time, effort, and money, and it is challenging to drum up support for investment in general infrastructure (i.e., not targeted toward a specific product). In addition, she said that maternal and pediatric research are generally low priority. However, this infrastructure could be used in routine practice and then used for pandemic responses. Steven Kern, deputy director of quantitative sciences at the Bill & Melinda Gates Foundation, agreed about the need to “use the ordinary, everyday times to get us ready for the extraordinary.”

Kern also acknowledged the importance of cooperation and collaboration and lamented the lack of data sharing by otherwise well-intentioned researchers. There is a lot of data from experience treating pregnant and lactating persons that needs to be pulled together, he said. Brittany Bettendorf, University of Iowa, agreed that there are many missed opportunities to collect observational data as most pregnant persons take a prescription medication at some point during their pregnancy. She asked whether it might be better to have patients opt out of registry and database participation if desired, rather than the current method

of needing them to actively opt in. Perhaps information gathered from medication data in the patient’s electronic health record (EHR) can be collected and associated with pregnancy outcomes. Schubert agreed that there are opportunities to use EHR data but noted that lack of interoperability across EHR systems presents a barrier. She noted the need to raise clinician awareness of pregnancy exposure registries and the importance of enrolling their patients who are taking a medication. She added, however, that gaining access to the data in registries can be difficult for both researchers and patients. Sabra Anckner, Association of Maternal and Child Health Programs, emphasized the importance of obtaining the patient’s informed consent to use their data for research purposes. “Just because we have data does not mean that it’s ours to use and share,” she said. She cautioned that patients could be harmed if use of their data leads to stigmatization (e.g., based on the drug, diagnosis, or population affected), and it is increasingly difficult to ensure anonymity even when data are anonymized or deidentified, especially when a condition disproportionately affects smaller populations.

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