Evaluation of Drug Labels Following the 2015 Pregnancy and Lactation Labeling Rule

IMPORTANCE The US Food and Drug Administration (FDA) Pregnancy and Lactation Labeling Rule (PLLR), implemented in 2015, includes information on pregnancy, lactation, and women and men with reproductive potential. OBJECTIVES To identify the drugs that have adhered to the new PLLR format; to shed light on the continued need for implementation of pregnancy, lactation, and reproduction into clinical studies; and to evaluate how many new therapeutic products have human and animal data specific to pregnancy and lactation. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study of 290 new therapeutic drugs reviewed labeling data for newly FDA-approved therapeutic products from January 2010 to December 2019. Therapeutic products submitted on or after June 30, 2015, were required to be in PLLR format; those approved from June 30, 2007, to June 29, 2015, had until June 30, 2019, to be in PLLR format. Approval data and subsequent labeling revision were evaluated for pregnancy and lactation data (human and animal), pregnancy registry, black-box warnings, and inclusion of PLLR labeling format. EXPOSURES Date of new drug approval by FDA. MAIN OUTCOMES AND MEASURES Compliance with PLLR; presence of animal or human data; presence of pregnancy registries; and presence of information regarding female and male reproductive potential. RESULTS A total of 290 new molecular entities or therapeutic products were approved by the FDA between 2010 and 2019 in 19 categories. Black-box warnings occurred in 89 drugs (30.7%; 95% CI, 25.4%-36.3%), with 3 (3.4%; 95% CI, 0.7%-9.5%) involving pregnancy. All products submitted after June 30, 2015, were in PLLR format; however, of the 138 submitted between 2010 and that date, 45 (32.6%; 95% CI, 24.9%-41.1%) were not in PLLR format by June 30, 2019. During the 10 years of data analyzed, significantly more were in PLLR format (P for trend < .001). Most approved therapeutic products have pregnancy data derived from animal studies (260 products; 89.7%; 95% CI, 85.6%92.9%) but only 31 (10.7%; 95% CI, 7.4%-14.8%) derived data from human studies. Only 148 therapeutic products (51.0%; 95% CI, 45.1%-56.9%) had any data associated with lactation, 143 (49.3%; 95% CI, 43.4%-55.2%) originating from animal studies and 8 (2.8%; 95% CI, 1.2%-5.4%) from human studies. CONCLUSIONS AND RELEVANCE The results of this study show that with the implementation of PLLR in the last decade, new therapeutic products were in compliance with the new rules; however, (continued) Key Points Question What is the current state of US Food and Drug Administration labeling of medications in relation to pregnancy and lactation? Findings In this cross-sectional study of 290 newly approved medications from January 2010 to December 2019, all products submitted after June 20, 2015, were in compliance with the Pregnancy and Lactation Labeling Rule (PLLR); however, of those submitted between 2010 and 2015, 32.6% were not in PLLR format by the designated date of June 30, 2019. Human data on pregnancy and lactation were available in less than 20% of new product labeling. Meaning This study found that with the implementation of PLLR in the last decade, new therapeutic products are in compliance with the new rule; however, more than one-third of labels remain out of PLLR compliance. Author affiliations and article information are listed at the end of this article. Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(8):e2015094. doi:10.1001/jamanetworkopen.2020.15094 (Reprinted) August 31, 2020 1/8 Abstract (continued)continued) more than one-third of labels remain out of PLLR compliance. Human data on pregnancy and lactation are available in less than 20% of new product labeling. JAMA Network Open. 2020;3(8):e2015094. doi:10.1001/jamanetworkopen.2020.15094 Introduction Most women will take at least 1 medication during pregnancy, delivery, or the postpartum period.1,2 To inform patients on the safety and efficacy of these therapies used during pregnancy and postpartum, obstetrical care professionals rely on available information. The criterion standard for this information is the US Food and Drug Administration (FDA) drug label. The FDA evaluates new and existing medications and provides recommendations regarding safety, specifically during pregnancy and lactation. These recommendations were initially provided in the late 1970s, with the development of the alphabetic risk stratification system (ie, A, B, C, D or X, with A indicating adequate and well-controlled studies have proven safety in pregnancy and X indicating that studies have shown human fetal risk if ingested during pregnancy).3,4 This approach was designed to convey the type and amount of data that were available at the time. However, this design led clinicians to misinterpret the recommendations as a grading system of risk and not a categorization of available data. Nearly 2 decades later in 1994, the FDA established the Pregnancy Labeling Task Force in an attempt to provide a more thorough risk assessment of medications’ effects on pregnancy.5 This attempt to risk stratify medications for pregnancy was further heightened with the establishment of pregnancy registries in 2002 to promote clinical trials examining use of new medications by pregnant women.6 The introduction of a new FDA labeling requirement was posted in the Federal Register in 2008, which would eventually become the implementation of the Pregnancy and Lactation Labeling Rule (PLLR) in 2015.4,5 The change in the labeling process transitioned from the initial letter grade pregnancy category to a more structured approach. The goal was to aid prescribers and patients in obtaining a greater understanding of the nuances of the available data that exist. The new PPLR format includes available data summaries as well as the strength of these data. Furthermore, the data provided include information on pregnancy, lactation, and exposure registries, along with a new subsection for women and men with reproductive potential. The subsection on women and men with reproductive potential includes information regarding pregnancy testing, contraception, and infertility as it relates to the drugs, when necessary.4 The implementation schedule of the new PLLR categorization required that FDA drug submissions on or after June 30, 2015, be in the new PLLR format. The drugs that were approved between June 30, 2007, and June 29, 2015, were to have transitioned to the new PLLR format by June 30, 2019.7 Additionally, the applications approved before June 30, 2001, that were in the previous labeling format were not required to transition to the PLLR format. However, they were required to remove the pregnancy letter category by June 29, 2018. The consequences of the PLLR initiative has yet to be determined. Specifically, it is not known how many new and preexisting FDA drug labels have been transitioned to the PLLR format nor the quality of the data that exist for pregnancy, lactation, and reproductive potential. We have 3 aims in this study, as follows: (1) to identify the drugs that have adhered to the new PLLR format; (2) to shed light on the continued need for implementation of pregnancy, lactation, and reproduction in clinical studies; and (3) to evaluate how many new therapeutic products have human and animal data specific to pregnancy and lactation. We hypothesized that all new products submitted after June 30, 2015, would be in compliance with the PLLR format and that less than half of new products would have human data specific to pregnancy and lactation. JAMA Network Open | Obstetrics and Gynecology Drug Labels Following the 2015 Pregnancy and Lactation Labeling Rule JAMA Network Open. 2020;3(8):e2015094. doi:10.1001/jamanetworkopen.2020.15094 (Reprinted) August 31, 2020 2/8


Introduction
Most women will take at least 1 medication during pregnancy, delivery, or the postpartum period. 1,2 To inform patients on the safety and efficacy of these therapies used during pregnancy and postpartum, obstetrical care professionals rely on available information. The criterion standard for this information is the US Food and Drug Administration (FDA) drug label. The FDA evaluates new and existing medications and provides recommendations regarding safety, specifically during pregnancy and lactation. These recommendations were initially provided in the late 1970s, with the development of the alphabetic risk stratification system (ie, A, B, C, D or X, with A indicating adequate and well-controlled studies have proven safety in pregnancy and X indicating that studies have shown human fetal risk if ingested during pregnancy). 3,4 This approach was designed to convey the type and amount of data that were available at the time. However, this design led clinicians to misinterpret the recommendations as a grading system of risk and not a categorization of available data. Nearly 2 decades later in 1994, the FDA established the Pregnancy Labeling Task Force in an attempt to provide a more thorough risk assessment of medications' effects on pregnancy. 5 This attempt to risk stratify medications for pregnancy was further heightened with the establishment of pregnancy registries in 2002 to promote clinical trials examining use of new medications by pregnant women. 6 The introduction of a new FDA labeling requirement was posted in the Federal Register in 2008, which would eventually become the implementation of the Pregnancy and Lactation Labeling Rule (PLLR) in 2015. 4,5 The change in the labeling process transitioned from the initial letter grade pregnancy category to a more structured approach. The goal was to aid prescribers and patients in obtaining a greater understanding of the nuances of the available data that exist. The new PPLR format includes available data summaries as well as the strength of these data. Furthermore, the data provided include information on pregnancy, lactation, and exposure registries, along with a new subsection for women and men with reproductive potential. The subsection on women and men with reproductive potential includes information regarding pregnancy testing, contraception, and infertility as it relates to the drugs, when necessary. 4 The implementation schedule of the new PLLR categorization required that FDA drug submissions on or after June 30, 2015, be in the new PLLR format. The drugs that were approved between June 30, 2007, and June 29, 2015, were to have transitioned to the new PLLR format by June 30, 2019. 7 Additionally, the applications approved before June 30, 2001, that were in the previous labeling format were not required to transition to the PLLR format. However, they were required to remove the pregnancy letter category by June 29, 2018. The consequences of the PLLR initiative has yet to be determined. Specifically, it is not known how many new and preexisting FDA drug labels have been transitioned to the PLLR format nor the quality of the data that exist for pregnancy, lactation, and reproductive potential. We have 3 aims in this study, as follows: (1) to identify the drugs that have adhered to the new PLLR format; (2) to shed light on the continued need for implementation of pregnancy, lactation, and reproduction in clinical studies; and (3) to evaluate how many new therapeutic products have human and animal data specific to pregnancy and lactation. We hypothesized that all new products submitted after June 30, 2015, would be in compliance with the PLLR format and that less than half of new products would have human data specific to pregnancy and lactation.  The sources of the breastfeeding data and pregnancy data were recorded. This included origin of data (ie, human data, animal data, or extrapolation from other sources, including similar mechanism of action). The presence of pregnancy registries was evaluated as well as whether this information was specific to the agent or a general drug registry for specific syndromes. Additionally, the presence of fast-track drug approval status was evaluated. 9

Statistical Analysis
Statistical analysis was performed using χ 2 and Mantel-Haenszel test for trend as appropriate.
Analysis was conducted in SAS statistical software version 9.4 (SAS Institute), with a 2-tailed P < .05 considered significant.
Notably, all new molecular entities and therapeutic products submitted after June 30, 2015, were in the PLLR format (Figure 1)    Human data (lactation) The amount of human and animal data for pregnancy and breastfeeding ranged from year to year. The amount of pregnancy and lactation-specific data derived from human research ranged from 0% to 28% and 0% to 8%, respectively. The amount of pregnancy and lactation-specific data derived from animal research ranged from 79% to 100% and 39% to 68%, respectively. The Pregnancy and Lactation Labeling Rule (PLLR) was implemented June 30, 2015. and post-PLLR periods; however, the amount of data derived from animal studies decreased after institution of the PLLR rule (P for trend = .01).
The PLLR final rule includes a subsection 8.3, female and male reproductive potential, to include information for populations when recommendations for pregnancy testing or contraception related to the therapy are needed or there are data suggesting the therapy affects fertility or preimplantation loss. This subsection was incorporated in 115 of 290 labels (39.7%; 95% CI, 34.0%-45.5%) of all approved therapeutic products (Figure 3), and 110 of 245 (44.9%) of those that transitioned to the PLLR format by June 30, 2019. Lastly, pregnancy registries were noted in 40 newly approved therapeutic products (13.8%) ( Table 2).

Discussion
There were 2 primary observations from the analysis. in study period exists between our study and theirs, there was no change in the amount of data associated with lactation, with 48% of drugs with no associated data in their cohort and ours. Most lactation-specific data in both studies were found to arise from research on animals. Interestingly, there were more lactation-specific data derived from animal studies prior to PLLR; however, it is unlikely to be caused by the implementation of PLLR. Lastly, animal lactation data typically do not reliably estimate levels in human milk because of species-specific differences in lactation physiology. 15 Similar to lactation-associated data, Mazer-Amirshahi and colleagues 10 showed that most approved drugs had pregnancy-associated data arising from animal studies (93% in Mazer-Amirshahi et al vs 90% in our study) but few with data arising from human studies. It must be mentioned that the FDA actively encourages the inclusion of pregnant women in clinical trials. 16 Unfortunately, these findings reveal that the trend of the few clinical trials involving pregnant women continues.

Limitations and Strengths
This study should be interpreted in the context of its limitations. This is a cross-sectional study; therefore, it only evaluates the data at 2 distinct points. The FDA maintains this database, and although most drugs are updated frequently, there can be a lag time between new data generation and the creation of a label update. In addition, several of the drugs were approved for conditions that only pertain to men (ie, prostate cancer). The strength of the study is that it evaluated a large database of newly approved prescription drugs, which require screening by the FDA before