FDA finalizes guidance on designing pregnancy safety studies
The US Food and Drug Administration (FDA) has finalized guidance to assist sponsors in evaluating drug safety during pregnancy after a drug has been approved. The purpose of these safety studies is to gather information that can be included in drug labeling, which will help healthcare providers and patients make informed decisions.
The guidance outlines three different approaches for assessing post-approval safety. These approaches involve using postmarketing or pharmacovigilance data, which includes adverse event reports; pregnancy registries; and other electronic data sources such as medical claims and electronic health records (EHR). The purpose of this guidance is to highlight the strengths and limitations of each method while providing recommendations for planning and conducting various types of pregnancy safety studies.
The guidance includes several changes compared to the draft version that was released on 9 May 2019. (RELATED: Studying Drugs in Pregnant and Nursing Women: FDA Issues Draft Guidances, Regulatory Focus 8 May 2019).
“Currently, collection of safety data in drug and biological products used during pregnancy usually occurs after approval. Pregnancy registries have been used to collect these data. However, in the years since FDA first issued guidance on this topic, scientific methodologies for assessing the safety of drug and biological products used during pregnancy in the postmarketing setting have evolved,” the agency wrote in a Federal Register notice.
“Pregnant women and their healthcare providers need clear, reliable information to make informed treatment decisions. This guidance supports better ways to collect safety data, so clinicians have more useful information when counseling patients during pregnancy,” said FDA Commissioner Marty Makary.
The guidance highlights the benefits and drawbacks of using each approach for these safety studies. For example, it notes that “spontaneous postmarketing reports may be useful, but have limitations such as underreporting, incomplete information, or lack of a denominator (number of exposed patients and timing of exposure). These limitations pose challenges for case analyses and determining whether a causal relationship exists between a product exposure and an adverse pregnancy outcome.”
Pregnancy registries are designed to gather information from patients who have been exposed to a specific drug during pregnancy, along with data on pregnancy and birth outcomes. This information can be used to conduct a prospective observational study, meaning that pregnant women are enrolled before their pregnancy outcomes are known.
These registries rely on the voluntary participation of both pregnant women who have been exposed to the drug in question and those who have not. The data is collected through maternal interviews and documentation from medical records, and it may also include results from clinical examinations of newborns.
The guidance states that sponsors are required to submit their study protocols for FDA review prior to starting a study. To determine if a pregnancy registry will yield safety data that can influence product labeling, sponsors should conduct a feasibility study. Plans to evaluate feasibility should be included in the protocol and should be based on assumptions regarding the anticipated incidence of outcomes, drug usage, and registry enrollment.
Pregnancy registries have several strengths: prospective enrollment allows for accurate tracking of exposure status and timing in relation to gestational age, including dosage, frequency, and duration. However, pregnancy registries also face several limitations, including the challenges in recruitment as it can be difficult to recruit and retain both patients and healthcare providers.
The last approach of using alternative data sources such as electronic health data (EHD) sources to evaluate product safety during pregnancy also poses challenges.
The guidance states that “in the United States, linkages of non-live birth outcomes identified in EHD sources to other data sources are limited. Some states require reporting of fetal deaths (after 20 weeks), and this information may be available to investigators on a case-by-case basis via the state’s vital records department. Information collected by the state is often similar to that collected on a birth certificate, but specific data elements vary by state.”
FDA said it considered the comments received on the draft guidance when finalizing it. Key changes from the draft to the final guidance include: clarification of the section on pregnancy registries, which now includes a subsection on statistical methods; an expansion of the scope in the complementary study methods sections; a more comprehensive discussion on data collection in situations where rare exposure to a drug during pregnancy is expected; and an update in terminology to incorporate descriptive pregnancy safety studies. Additionally, editorial changes were made to enhance clarity.
