COVID Elucidates the Need for Pregnancy Safety Studies
While there has been growing attention in health care on the need for safety studies in pregnant women, COVID-19 brought a heightened awareness of this issue over the past year and a half. In this blog, Kristin Veley, senior research scientist for Evidera, discusses insights on how to incorporate pregnant and lactating women into product development planning.
Despite a recent, positive trend of increased regulatory rigor for including pregnant and lactating women in product safety studies in the United States and Europe, more work is needed to ensure that this group is not forgotten or underrepresented. The potential implications of exclusion or underrepresentation can have lifelong consequences for mothers, future mothers and their children. As the global health care community raced to discover efficacious vaccines to slow the spread of COVID-19, we also learned that COVID-19 puts pregnant women at greater risk for serious illness or death than their nonpregnant counterparts. This served as an important reminder that this population should be prioritized by conducting robust and thorough pregnancy safety studies to ensure that products are safe for exposure and to reduce adverse outcomes both now and in the future.
COVID-19 risk factors for pregnant women include higher rates of severe illness and death, as well as preterm birth. The American College of Obstetricians and Gynecologists recommends that vaccines be available and administered to pregnant women who wish to be vaccinated, stressing that women should be free to make autonomous decisions and not be denied due to pregnancy status alone. The Centers for Disease Control (CDC) and the European Medicines Agency (EMA) have both identified pregnant women as a population of interest and have issued plans and recommendations for further research.
Both the U.S. and the European Union are utilizing existing safety surveillance systems to monitor vaccine safety in pregnant women. In the U.S., the CDC is utilizing the Vaccine Adverse Event Reporting System (VAERS), a passive reporting system to detect safety issues in U.S.-licensed vaccines, co-managed by the U.S. Food and Drug Administration (FDA) and CDC; Vaccine Safety Datalink (VSD), a collaboration between the CDC’s Immunization Safety Office (ISO) and nine health care organizations in the U.S., which has published 14 studies related to pregnancy and vaccination and prioritizes vaccine safety in pregnant women; and V-SAFE, a new, smartphone-based program for COVID-19 vaccine recipients that conducts health checks via text message and email and responds to adverse event reports with telephone follow-up and VAERS reporting.
In the EU, CONSIGN (COVID-19 infection and medicines in pregnancy) is a collaboration between eight European countries and is funded by the EMA to provide adequate data on the impact of COVID-19 in pregnancy to further guide decision-making. The EU also leverages the International COVID-19 and Pregnancy Registry (COVI-PREG), which is an international network of antenatal clinics around the world, to launch prospective data collection to allow future research projects to better characterize the risks of infection in pregnancy. The International Network of Obstetric Survey Systems (INOSS) is another multinational collaboration of organizations that conducts prospective studies about pregnancy, childbirth and infants.
The FDA has instituted post-marketing requirements for all three U.S. vaccines that received Emergency Use Authorization to conduct observational studies in several populations of interest — including pregnant women — and further specified that these studies should be conducted in large-scale databases with active comparator groups.
Beyond COVID-19, draft guidance released by the FDA in May 2019 significantly increased the rigor of pregnancy safety studies in general. For products that are expected to be used by a substantial number of pregnant women, the FDA may require sponsors to conduct both prospective and retrospective studies comparing the maternal, fetal and infant outcomes of women exposed to the product during pregnancy contrasted against an unexposed comparator population. Adverse outcomes will be assessed throughout pregnancy and the first year of life for live-born infants. For products that are expected to have rare pregnancy exposures, the FDA may require sponsors to conduct a worldwide descriptive study that collects prospective and retrospective data for pregnant women exposed to the product to assess maternal, fetal and infant outcomes.
In the EU, for products with anticipated use in women who are pregnant or may become pregnant, the EMA may require post-authorization safety studies in addition to the standard risk management plan. These studies are more likely to be required if a product cannot be discontinued due to the disease it treats, when a disorder arises during pregnancy that necessitates treatment or when changes in treatment during pregnancy are associated with a risk to a pregnant woman or fetus.
In recent years, we have seen an encouraging upward trend in the number of pregnancy safety requirements mandated by the FDA for new drug applications and biologics license applications. Between 2015 and 2019, the proportion of product approvals that required a pregnancy registry grew from 11% to 27%, and the proportion that required a paired complementary study (with a case-control or retrospective design) increased from 0% to 17%.
All of this is great news toward ensuring the safety of products that may be administered or exposed to pregnant women, but what more can be done to ensure earlier and/or better detection of adverse outcomes? The two most common pregnancy study designs are prospective and retrospective studies. Prospective studies require that eligible women be recruited after they become aware of their pregnancies and require consent and medical releases for health care providers to submit data to the registry. Only data routinely documented in a patient’s chart as part of usual care are collected. Data are typically collected at enrollment, at the end of the second trimester and immediately after their pregnancy outcome. For live-born infants, data collection typically continues post-delivery at four and 12 months of age. One of the biggest challenges of this type of study is in recruitment. Creating awareness is of paramount importance, and it can be difficult to encourage enrollment, particularly in cases of a novel disease where vaccine administration is not explicitly indicated in pregnancy.
Retrospective study designs leverage secondary data, which are collected in the usual course of medical care and accessed through de-identified databases that represent large populations of patients. An advantage of these studies is that they can typically be conducted with reduced timelines and budget compared to prospective studies. However, retrospective designs also present their fair share of challenges. It is necessary to use a database in which mother and infant records can be linked and study outcomes such as birth defects can be validated. Low sample sizes and the inability to assess certain outcomes are also common, particularly for novel vaccines or medications that have just been approved.
A potentially more robust approach to pregnancy studies is an ambispective pregnancy study design. It is essentially a hybrid approach that uses both prospective and retrospective study methodologies and mitigates many of the challenges of these designs when used separately. Ambispective studies use data from large, integrated delivery networks to identify eligible patients and collect data via electronic health records. These data can be captured from multiple sources (different health care providers within the network providing care to a particular patient) without the need to communicate directly with the source, and if necessary, these data can be supplemented with data collected prospectively from the patient and/or her heath care providers.
COVID-19 provided a timely reminder that the population of pregnant women and future pregnant women around the world must be prioritized, as major congenital malformations, fetal losses, pregnancy complications, preterm births, growth deficiencies, developmental delays and other health risks may be able to be mitigated with a comprehensive and thorough approach that is mandated by regulatory bodies and implemented throughout the entire product life cycle.