The Need for Flexible Pregnancy Safety Studies

The EU:
European Medicines Agency (EMA) Requirements

Risk Management Plans (RMPs)

In the EU, every authorized product requires a risk management plan (RMP). RMPs should reflect the measures considered necessary to identify, characterize, and minimize a medicinal product’s important risks. For products with anticipated use in women who are or who may become pregnant, the RMP should also include current understanding of safety in pregnancy and/or breastfeeding, along with the likelihood of use of the medicine in women of child-bearing potential, or who are pregnant or breastfeeding.

Post-Authorization Safety Studies (PASS)

Additional pharmacovigilance activities in the form of PASS should be used if/when:

• The use of a product cannot be discontinued due to the disease being treated, when a disorder arises during pregnancy that necessitates treatment, or when changes in treatment during pregnancy are associated with risks for the pregnant woman and/or fetus.
• A potential risk to the child has been suggested by non-clinical data, a signal, or based on the chemical or pharmacological properties of the medicine.
• The medicine is used to treat conditions that commonly occur in women of child-bearing potential.
• Measuring compliance with risk minimization measures (RMM) regarding pregnancy or breastfeeding.

There is an encouraging upward trend in the number of pregnancy safety studies conducted in both the US and the EU.

A search of the FDA listing of post-marketing commitments (PMCs)² revealed a significant increase, from 2015 to 2019, in the number of pregnancy safety requirements mandated by the Center for Drug Evaluation and Research (CDER) for New Drug Applications (NDA) and Biologics License Applications (BLA). This trend applied for both pregnancy registries and complementary studies (e.g., retrospective database studies) (See Figure 1). By 2019, more than 25 percent of approvals required a pregnancy registry, and nearly 20 percent required a complementary study. Complementary studies were always paired with registry studies unless an existing registry (for example, for the class of medications or disease) was already in progress. Pregnancy post-marketing commitments varied by therapeutic area, with products treating autoimmune disorders being most likely to need a pregnancy safety study and oncology and infectious disease products being least likely.

Figure 1. Frequency of Pregnancy Registry PMCs by Year

The recently approved COVID-19 vaccines present a timely and compelling opportunity to design flexible pregnancy safety studies. Evidence has accumulated from a variety of sources indicating that pregnant women are at higher risk of severe COVID-19 infection compared to non-pregnant adults.

A study published in the American Journal of Obstetrics and Gynecology in January of 2021³ found that pregnant women are in fact at higher risk of severe disease and mortality compared to non-pregnant adults. This multi-center retrospective cohort study in Washington state compared case fatality rates between pregnant women and similarly aged, non-pregnant adults; maternal and neonatal outcomes were also compared by trimester of infection and disease severity at the time of delivery. The study found that hospitalization and case fatality rates were significantly higher in pregnant women, and that pregnant women with severe COVID-19 infections were at higher risk of pre-term delivery than women who recovered or had mild infections.

The Centers for Disease Control (CDC) and other institutions have published similar findings related to COVID-19 and pregnancy. Based on the accumulation of data, the American College of Obstetricians and Gynecologists (ACOG) recommends that COVID-19 vaccines should be available and administered to pregnant women who wish to be vaccinated, that pregnant women should be free to make their own decision regarding vaccination, and that women should not be denied a vaccine due to their pregnancy status alone.⁴

The CDC and the EMA have both identified pregnant women as a population of interest relative to COVID-19 vaccinations, and have issued plans and recommendations for further research in this population. Both the US and the EU plan to utilize existing safety surveillance systems to monitor COVID-19 vaccine safety in pregnant women In the US, the CDC plans to leverage Vaccine Adverse Event Reporting System (VAERS), Vaccine Safety Datalink (VSD), and V-SAFE; in the EU, the EMA encourages collaboration with COVID-19 infectiOn aNd medicineS In preGNancy (CONSIGN), International COVID-19 and Pregnancy Registry (COVI-PREG), and the International Network of Obstetric Survey Systems (INOSS).

Some of these systems existed prior to COVID-19, including VAERS, VSD, Vaccines and Medications in Pregnancy Surveillance System (VAMPSS), and INOSS, while others are COVID-19-specific. V-SAFE is a new, smartphone-based active surveillance program in the US that conducts health checks of vaccine recipients via text message or email. If an important adverse event is reported, a telephone follow-up and a report are completed if appropriate. COVI-PREG and CONSIGN are also COVID-19-specific initiatives. Figure 3 outlines the existing surveillance systems that can be leveraged to monitor COVID-19 vaccine safety in pregnancy.

A flexible approach to pregnancy study design encourages participation and facilitates data collection, resulting in greater sample sizes and a more thorough assessment of safety. We’ll consider the common challenges presented by prospective, retrospective, and ambispective pregnancy study designs, and offer practical solutions. There are multiple factors to consider when selecting a study design (See Figure 4).

Figure 4. Pregnancy Study Design Decision Tree

Retrospective study designs utilize secondary data, which are collected in the usual course of medical care and accessed through de-identified databases that represent large populations of patients. The data are historical and analyses are typically iterative, in which interim analyses are repeated until the set of final analyses. Subsequent analyses can include women who newly qualify for the study based on drug exposure, as well as additional follow-up data on infants. Twelve-month infant follow-up is typically required because not all congenital malformations—which are the standard primary outcome of interest—are diagnosed at birth. The baseline period is used to characterize patients based on demographic and clinical characteristics, as well as healthcare resource utilization, and the pregnancy period is estimated based on gestational age information within diagnosis codes recorded during the pregnancy.

Ambispective Pregnancy Registry Design 

An ambispective registry design implements some of the features of both retrospective and prospective registries. The term hybrid is sometimes used to describe this design, but ambispective is more accurate. Ambispective studies use data from large integrated delivery networks (IDNs). Patients are identified via EHRs, which can be supplemented with prospective data collection if needed. The greatest benefit is that data can be captured from multiple sources without having to go directly to that source or site. Because patients who are insured by the IDN are typically incentivized to visit IDN-owned facilities, there is typically reliable identification of care across various healthcare settings.

Ambispective registries can mitigate many of the challenges associated with retrospective and prospective study designs. For example, potentially eligible patients can be identified directly from the EHR data to mitigate recruitment challenges, and data that are not available or poorly captured in the EHRs may be collected directly from patients.

Regardless of the type of pregnancy safety study, it is critical to design flexible models that encourage patient enrollment. Solutions may include hybrid models with both in-person and remote enrollment, as well as flexible recruitment methods that utilize advertising, social media, and advocacy groups. Streamlined data collection relieves the burden on the patient and the HCP. For example, home health nurses can be used in lactation and/or placental transfer studies, allowing data collection to occur without the patient ever leaving home and without undue burden at the healthcare facility. Patient reimbursement can also increase enrollment and retention.