Pregnancy Registries Are Insufficient To Assess Drug Safety, US FDA Says

Draft guidance recommends complementary studies to evaluate effects of drug use during pregnancy; FDA may require lactation studies more frequently.

The US Food and Drug Administration wants sponsors to conduct additional studies to evaluate the safety of drugs in pregnant women rather than rely solely on data from patient registries.

"Pregnancy registries remain an important tool for safety data collection in the postmarketing setting because of the prospective design and the ability to collect detailed patient level data," an FDA draft guidance states. "However, because of the recurring challenges of achieving sufficient enrollment, pregnancy registries generally are not sufficient by themselves to assess the safety of products during pregnancy."

Therefore, the agency says, other study methods capable of assessing the occurrence of specific major congenital malformations and other pregnancy outcomes are needed. FDA suggests conducting studies that use electronic data sources, population-based surveillance and national registries, and population-based control studies.

FDA issued the draft guidance, Postapproval Pregnancy Safety Studies, on 8 April. At the same time, it released a draft guidance on clinical lactation studies.

In a joint statement on the guidances, FDA Principal Deputy Commissioner Amy Abernathy and Center for Drug Evaluation and Research Director Janet Woodcock said the documents were designed to increase the availability of high-quality safety information in drugs used during pregnancy and lactation.

Three Approaches

The postapproval pregnancy safety studies draft guidance replaces a guidance FDA issued in 2002, Establishing Pregnancy Exposure Registries.

In a Federal Register notice announcing the new guidance, FDA says it reflects the input the agency received from a two-day public meeting in 2014 and agency reviews of pregnancy registries.

At the public meeting, stakeholders said registries were not large enough to detect an adverse event and recommended additional postmarket approaches. Industry representatives also expressed support for conducting clinical trials in pregnant women in some circumstances. (Also see "Beyond Pregnancy Registries: Complementary Post-Marketing Approaches" - Pink Sheet, 7 Jul, 2014.)

The draft guidance specifies three general approaches to evaluate drug or biological product safety during pregnancy: pharmacovigilance, pregnancy registries, and complementary data sources.

Sources for pharmacovigilance can include spontaneous reports submitted to the sponsor and FDA, case reports from the medical literature, or clinical studies. FDA notes that it has occasionally considered cases reports and case series to be adequate for establishing a causal association for a human teratogenic exposure, such as with isotretinoin, or a severe adverse event, such as oligohydramnios with trastuzumab.

The guidance says routine pharmacovigilance usually will be insufficient for a conclusive assessment of the potential risk of an exposure during pregnancy because of the inability to quantify risk.

Regarding complementary studies, the guidance says they complement data obtained from pregnancy registries and other sources and can be implemented to better understand the specific effects of using a product during pregnancy and to more precisely quantify the magnitude of an association between a pregnancy exposure and a specific outcome.

Such studies can be retrospective in design and use data collected for other purposes than to assess the safety of one specific product. The guidance notes that sources for these studies can include electronic administrative claims databases and electronic health record databases, population-based birth defect surveillance registries, and case-control study designs.

Multiproduct Pregnancy Registries

Nearly half of the guidance is devoted to discussing pregnancy registries. FDA notes that strengths of these registries include their ability to start to accrue real-time data as soon as a product becomes commercially available, and their potential to obtain accurate information about whether and when exposure occurred.

"We encourage sponsors to work together directly or through consortiums to develop or support multiproduct registries." – FDA

As for their limitations, the guidance says analyses of data collected from the registries may have minimal statistical power to detect associations for rare pregnancy outcomes. It also notes that patient recruitment and retention are often challenging and identification of an appropriate comparator group may not always be feasible.

FDA recommends that sponsors use multiproduct pregnancy registries.

"To prevent overburdening patients, physicians, and health delivery systems with multiple requests to participate in individual studies, we encourage sponsors to work together directly or through consortiums to develop or support multiproduct registries," the guidance states.

FDA notes that multiproduct registries have advantages over single-product registries in their efficiency and economy and in having readily available comparison groups of pregnant women unexposed to the product of interest.

FDA May Require More Lactation Studies

The agency's second pregnancy-related draft guidance, Clinical Lactation Studies: Considerations for Study Design, replaces draft guidance issued in February 2005.

FDA says the recommendations in the new document reflect discussions from a 2007 pediatric advisory committee meeting and a 2017 lactation workshop, which considered how data from clinical lactation studies can inform the safety of a drug when used during lactation.

The guidance notes that there is a paucity of human data on drug use during lactation and women and health care providers often must make decisions without quality human data in labeling. It says that for them to make decisions about drug treatment and continuation of breastfeeding during therapy they would need, at a minimum, information on the amount of drug in human milk, the effect of the drug on milk production, and an understanding of the risks posed by the drug on the breastfed infant based on expected levels of exposure and adverse drug event data.

The agency indicated that it may require lactation studies more frequently.

FDA has required these studies "under some circumstances and is considering additional circumstances in which lactation studies may be required," the guidance states.

The agency cites situations in which a sponsor may consider whether conducting a clinical lactation study would be appropriate. They include when a drug under review for approval is expected to be used by women of reproductive age; use of a drug in lactating women becomes evident after approval; a new indication is sought for which the product is expected to be used in lactating women; and medications that are commonly used by women of reproductive age, such as antidepressants, antihypertensives, anti-infectives, diabetic and pain medications.

Comments on both draft guidances are due in 60 days.