Pregnancy Study Guidance Shows How Safety Data Reach Drug Labels

The Food and Drug Administration on May 8 issued a final guidance for industry, Postapproval Pregnancy Safety Studies, setting out methods companies can use to study the safety of drugs and biological products taken during pregnancy once those products are on the market. The guidance page says the document finalizes a draft of the same name issued on May 9, 2019.

FDA said the reason for the guidance is a gap at approval: "often there is limited or no human data available about how these products affect pregnancy at the time they are approved." The guidance explains how that gap is filled afterward, and how the results are meant to end up in a product's labeling.

Why the evidence usually comes after approval

Pregnant women are historically excluded from pre-approval clinical trials, so FDA often requires postmarketing studies to identify potential risks to the mother or the developing fetus, Contemporary OB/GYN reported in its summary of the document. The outlet noted the guidance's figures of about 3.6 million births a year in the United States and 41.6% of pregnancies being unintended in 2019, meaning many patients are exposed to medical products either inadvertently or by necessity.

Tracy Beth Hoeg, acting director of FDA's Center for Drug Evaluation and Research, said in the agency's announcement that "data from the clinical trials used for FDA approval were insufficient to assess safety during pregnancy" for many products that health care providers may recommend to pregnant women.

Three ways to collect the data

The guidance describes three general approaches. The first is case reports and case series, which can help identify signals of rare outcomes; spontaneous reporting has limitations such as underreporting, but well-documented cases help detect distinctive patterns of congenital malformations, according to Contemporary OB/GYN. The second is pregnancy registries, prospective observational studies that enroll women before the pregnancy outcome is known, which reduces recall bias and allows detailed data collection, including examination of the newborn. The third is complementary studies that use electronic health data, such as insurance claims and health records, to look at outcomes in larger populations and to test safety signals.

The guidance also recommends concurrent internal comparison groups, meaning pregnant women with the same disease who were not exposed to the drug, and outlines three windows for collecting data: exposure before pregnancy, exposure during pregnancy and postpartum monitoring, the outlet reported. FDA said it recommends using the guidance alongside best practices for observational research, "since many pregnancy studies are non-randomized," and other FDA guidance on real-world data, pharmacovigilance and postmarket requirements. Like all FDA guidance, it describes the agency's current thinking and does not create legally enforceable requirements.

Where the results go: the Pregnancy subsection

The goal, FDA said, is information that can be included in drug labeling. The label's structure for that information comes from the Pregnancy and Lactation Labeling Rule, which FDA published in December 2014. According to FDA's labeling resources page, the rule removed the pregnancy letter categories A, B, C, D and X and requires a label to be updated when its information becomes outdated.

Under the rule, the Pregnancy subsection, numbered 8.1, contains a risk summary, clinical considerations and data, and includes information about a pregnancy exposure registry for the drug when one is available. FDA describes those registries as collecting and maintaining data on the effects of approved drugs that are prescribed to and used by pregnant women. The rule also renamed the Nursing mothers subsection as Lactation (8.2) and added a Females and Males of Reproductive Potential subsection (8.3) covering pregnancy testing, contraception and infertility where relevant. The format took effect on June 30, 2015, for new prescription drug and biologic submissions, with older labels phased in; over-the-counter medicines are not covered.