Understanding the Data required to meet the US FDA Pregnancy and Lactation Labeling Rule (PLLR)

Virginia Hogan and Dr. Suhasini Sharma

Recently we attended the 4th Annual Pharmaceutical Labeling event hosted by Marcus Evans in Boston, MA. Among the several interesting presentations, there was one related to the pregnancy and lactation labeling rule. The PLLR which came into effect on 30th June 2015 requires changes to the content and format of information presented in prescription drug labeling so as to adhere to the Physician Labeling Rule (PLR) format. This will assist health care providers in assessing benefit versus risk and in subsequent counseling of pregnant women and nursing mothers who need to take the medication, thus allowing them to make informed and educated decisions for themselves and their children. While the rule and its intention is a significant step in the right direction, the presenter’s assessment of 64 US labels showed that pharmaceutical companies may not have enough data today to support a label which includes the information on whether to breast-feed while taking a drug.

According to Delinda Kindig, Manager Global Labeling Department at Eli Lilly who gave an excellent presentation on “Pregnancy and Lactation Labeling Rule – Overview of the PLLR and Assessment of sections 8.1-8.3 of 64 US labels”, it is estimated that annually approximately 6 million pregnant women in the United States take an average of three to five prescription medications for various reasons. Currently the FDA has a ranking system of medications for use in pregnancy dating back to 1979 (A, B, C, D and X), which classifies the drug products according to risks posed to the fetus. Some rankings are based on risks posed to the fetus; some are based on a comparison of possible risk and benefit. A single category, “C”, was allowed for a broad spectrum of risk and assigned to almost 2/3rd of all categorized drugs. This category included drugs demonstrated to have no risk for harm, to drugs that might have a significant risk for harm to humans and all drugs in the category are seen as “okay” to use by some clinicians.

This outdated ranking does not provide information regarding risks in relation to dose, duration of use, or gestational age at time of exposure. Nor does it distinguish fetal developmental toxicities according to severity, incidence or type; or consider the maternal disease being treated or its impact on the fetus.

The PLLR removes pregnancy “letter” categories – A, B, C, D and X. The PLLR also requires the label to be updated when information becomes outdated1. Below is a comparison of the current prescription drug labeling with the new PLLR labeling requirements.

Current pharmaceutical product labeling compared to the new PLLR requirements.

The new PLLR rule provides more details about registries, risks, clinical considerations and supporting evidence which forms the basis of risk information in the label. It also requires acknowledgment of lack of data or data that does not establish risk potential.

The current 8.1 – Pregnancy and 8.2 – Labor and Delivery will be combined into 8.1 – Pregnancy, includes Labor and Delivery. The current 8.3 – Nursing Mothers will be the new 8.2 – Lactation, includes Nursing Mothers. The Females and Males of Reproductive Potential subsection (8.3), new to the labeling, will include information about the need for pregnancy testing, contraception recommendations, and information about infertility, when necessary.

Companies will not be required to conduct new studies to meet the new PLLR requirements, but will evaluate medical literature and most of the information will come from post-marketing studies. The sources will include human data from pregnancy registry findings, previously identified or potential risks, animal data from toxicology studies, relevant toxicology literature and a thorough review of potential impact of the mechanism of action and relevant ADME (Absorption, Distribution, Metabolism, Excretion) data.

In conclusion, implementing the PLLR rule will provide an analysis of risk and clinical considerations that will assist prescribers and pregnant women when making decisions regarding drug use during pregnancy. The label will also include information to reduce the risk of exposure during pregnancy and information regarding the risk of infertility. However, at this time there is not enough data to support labeling that will enable prescribers and patients make informed decisions on whether to breast-feed while taking a drug. To obtain this critical data, pharmaceutical companies can look at post-approval support studies, or PRO studies or any new data that becomes available.

1) Pregnancy and Lactation Labeling (Drugs) Final Rule