Dr. Suhasini Sharma

Pregnancy Exposure Registries & The New FDA Pregnancy & Lactation Labeling Rule (PLLR)

Dr. Suhasini Sharma

[This post discusses the importance/benefits of pregnancy registries; and the new labeling rule – PLLR – proposed by the FDA/EMA for pharmaceutical and biological products used by Pregnant and Lactating women.]

Women of childbearing potential form a sizable proportion of the population receiving prescription pharmaceutical and biological products. Of these, pregnant and lactating women are the most vulnerable as their exposure to drugs entails unwarranted exposure of the fetus or the breastfeeding infant which may lead to serious consequences. Unfortunately, these are the groups most often excluded from clinical trials during drug development, and a proper guidance on the use of drugs in pregnant and lactating women is often lacking when the drug is marketed. Currently, drugs are labeled by a series of lettered categories — A, B, C, D and X –which give an overly simplistic view of product risks. Clinicians and patients also commonly think that drugs in the same category have the same level of risk, or that there is a similar quantity and quality of information to support that risk category. In addition, the categories do not always distinguish between risks based on human versus animal data or between differences in frequency, severity, and type of fetal developmental toxicities.

Hence, in order to give women and their health care providers clearer information on the risks and benefits of prescription medicines when taken during pregnancy and breast-feeding, the US FDA has finalized a new rule modifying the structure and content of pregnancy and lactation information in product labels. The new Pregnancy & Lactation Labeling Rule (PLLR), to be effective from 30th June 2015, replaces the current product letter categories – A, B, C, D and X –with three detailed subsections titled “Pregnancy,” “Lactation” and “Females and Males of Reproductive Potential” that must provide details about use of the drug or biological product in these populations including a summary of the risks, a discussion of the data supporting the summary and relevant information to help healthcare providers make prescribing and counseling decisions.

The data in these sections could come from various sources, including well-conducted studies published in medical literature. Companies will be required to include clinically relevant information from such published studies in the labeling and to update existing information when new information becomes available. Another source of data could be from pregnancy exposure registries, which are conducted by some companies to collect information on the effects of their approved drugs used by pregnant women.

The European Medicines Agency (EMA) and the Food and Drug Administration in the USA (FDA), based on certain criteria, recommend pharmaceutical companies consider developing a pregnancy exposure registry for products that may be used during pregnancy to treat new or chronic conditions and for products frequently used by women of childbearing age where the likelihood of inadvertent exposure during pregnancy is high. For example, there are registries for a number of drug products, for cancer, epilepsy, arthritis, diabetes and psychiatric conditions. Pregnancy registries collect health information from women who take prescription drugs or vaccines while they are pregnant, and follow them till delivery and for some time thereafter, to monitor the possible adverse consequences of drug exposure on pregnancy outcomes or on babies born to exposed mothers.The primary objective of a pregnancy registry is to estimate the overall risk of all major congenital malformations. Information on live births, stillbirths, induced terminations and spontaneous abortions are also captured. Some registries may extend the length of infant follow-up in order to evaluate any evidence of an association between maternal drug exposure and developmental delay in the offspring. Pregnancy exposure registries can also be hypothesis-generating by detecting adverse pregnancy outcomes that may warrant further investigation. To reduce the likelihood of selection bias, analysis of data collected by pregnancy exposure registries tends to focus on those pregnancies that were prospectively enrolled when knowledge of the pregnancy outcome was not known, though pregnancies reported to registries retrospectively, following the diagnosis of a major congenital malformation, are still reviewed and analyzed. Information from pregnancy registries can form a valuable source of label information.

Pregnancy exposure registries are often constrained by low levels of enrollment. The new PLLR may help overcome this shortcoming by facilitating increased reporting of pregnancy exposures.The PLLR requires that details of the pregnancy exposure registry, if available, to be included in the label, and the contact information for the registry be prominently listed. This provision, which is mandatory, will help improve reporting of pregnancy exposures by healthcare professionals and even consumers, allowing better data collection and systematic detection of safety signals in this risk population. However, to ensure maximum impact, the registry information needs to be effectively communicated in the label through wordings that will motivate HCPs to report pregnancy exposures readily and convey to patients the importance and benefits of reporting pregnancy and getting enrolled in the registry should they become pregnant while taking the drug. There is no detailed guidance in the final rule on the exact wording to be used.

We, as stakeholders could discuss how we can use the PLLR to improve enrollment in pregnancy registries and could dialogue and suggest an appropriate wording to enhance the effectiveness of this important measure.