Pregnancy And Lactation Labeling Rule Research Articles

Characterization of the US Food and Drug Administration Post-Marketing Commitments and Requirements for Pregnancy and Lactation.

Enactment of the US Food and Drug Administration Amendments Act (FDAAA) in 2007 and the Pregnancy and Lactation Labeling Rule (PLLR) in 2015 are important milestones giving the FDA the authority to request studies in pregnant and lactating women. Our objective was to characterize trends of pregnancy and lactation-related postmarketing commitments (PMCs) and postmarketing requirements (PMRs) for new molecular entities approved by the FDA between 2000 and 2022. Approval letters of original New Drug Applications (NDAs, N = 488) for new molecular entities were obtained from the FDA website. NDAs with pregnancy and lactation-based PMCs/PMRs were identified, and data extracted. Data included: PMC/PMR timelines and attributes of requested study(ies) (type, design elements, and outcomes) when available. Fifty-nine NDAs included 92 PMCs/PMRs related to pregnancy and lactation. Forty-one NDAs had pregnancy-related PMRs/PMCs, 4 had lactation-related PMRs, and 14 had both. Most PMRs/PMCs were for nervous system medications (N = 33). Forty-seven NDAs specified safety data collection in infants in at least the first year of life. All pregnancy-related PMRs were issued after 2008, most PMCs (N = 8) were issued before 2008. Only one PMC requested a pharmacokinetic study in pregnant women. All lactation-related PMRs (N = 18) requested measurement of drug concentrations in breast milk with one also requiring measurement of maternal blood concentrations. Eighty-nine percent of lactation-related PMRs were requested after 2015. There was a steady increase in pregnancy and lactation-related PMRs following enactment of FDAAA and PLLR. Additions involved information collection pertaining to safety of the medication in pregnant and lactating women and children exposed to medications during pregnancy and breastfeeding.

Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2020 and 2021.

103 novel drugs were approved by the FDA in 2020–2021. Embryofetal development (EFD) studies were conducted for 76 % of these approvals. For the majority of drugs, EFD studies were conducted in rats and rabbits. Both species were equally sensitive to developmental toxicity, but the rabbit was slightly more sensitive to maternal toxicity at the same systemic exposure level. Nonetheless, 68 % of drugs showed more than a 2-fold difference in the low adverse effect level for developmental toxicity between the rat and rabbit. Previous reviews in this series compiled information on EFD studies for all small molecule pharmaceuticals approved since 2014 and for all therapeutic monoclonal antibodies approved to date. The use of non-human primates for the developmental toxicity testing of biopharmaceuticals has fallen over recent years (22 % of biologics license applications (BLAs) for 2020–2021, compared with 62 % for 2002–2015), with more biopharmaceuticals now tested in rodents (37 % of BLAs for 2020–2021). While the Pregnancy and Lactation Labeling Rule (PLLR), adopted in 2014, has brought consistency to the presentation of EFD data in drug labels, prescribers complain that the pregnancy section of current drug labels is neither concise nor clear. The FDA has pledged to address the concerns of clinicians in a future revision of the PLLR rule. The recommendations on risk assessment in the recently revised ICHS5(R3) guideline could be incorporated into the PLLR rule to remove extraneous nonclinical details from the label with the aim of facilitating rapid understanding by the practitioner.

Evaluation of knowledge of the new Pregnancy and Lactation Labeling Rule among pharmacists and physicians

ObjectiveThis study aimed to assess and evaluate knowledge and application of the Food and Drug Administration (FDA) Pregnancy and Lactation Labeling Rule (PLLR) among pharmacists and physicians. Design, Setting, and ParticipantsA cross-sectional study was conducted to evaluate the knowledge of and attitudes toward the new FDA PLLR among pharmacists and physicians. The primary outcome for this study was knowledge of the FDA PLLR. Descriptive statistical analysis was conducted for all study variables, and linear regression analyses were conducted to assess predictive factors of knowledge of the FDA PLLR. SPSS version 25 was used, and all analyses were conducted at an alpha value of 0.05. ResultsIn a cross-sectional study that included 167 pharmacists and physicians, majority were pharmacists (78.4%), and the rest were physicians (21.6%). The overall knowledge score was low with the average number of items answered correctly being 3.03 out of 7. Of all explored predictors, only gender (P < 0.01) and pregnancy letter category knowledge score (P < 0.05) were significant predictors of PLLR knowledge, adjusting for the other factors. ConclusionThe study’s findings showed several gaps in the knowledge of the new PLLR among physicians and pharmacists, thus demonstrating a need to have concerted continuing pharmacy and medical education efforts. Increasing knowledge in this area will lead to better risk communication and quality of care for expectant and nonexpectant women of reproductive age.

The Importance of Clinical Research in Pregnant Women to Inform Prescription Drug Labeling.

Pregnant women have historically been an understudied population and have been excluded from clinical trials. Recent efforts by stakeholders have raised awareness of the importance of clinical research in pregnant women to inform prescribing decisions. The Food and Drug Administration continues working to improve the format and content of prescription drug labeling for pregnant and lactating women, as demonstrated with the Pregnancy and Lactation Labeling Rule (PLLR), effective in 2015. The pregnancy labeling subsection now includes a subheading dedicated to the inclusion of pharmacokinetic (PK) data that inform the need for dose adjustments during pregnancy and the postpartum period. In addition, the PLLR also requires prescription drug labeling to be updated when important pregnancy information becomes available. Although PLLR improved the presentation of pregnancy-related information in labeling, there is a need to increase the quality and quantity of human data on the use of prescription drugs during pregnancy. PK studies in pregnant women should be incorporated into drug development programs and prioritized to obtain important information about safe and appropriate doses of a drug when used during pregnancy. In addition, opportunistic PK studies, postapproval pregnancy safety studies, ex vivo studies, and in silico modeling can be leveraged to better inform the risks and benefits of using a drug during pregnancy to inform study design and to further understand various mechanisms impacting pharmacokinetic/pharmacodynamic of drugs during pregnancy. It is important to address the significant existing data gaps and better inform the safety and dosing of prescription drugs for pregnant women.

The Influence of the Food and Drug Administration Pregnancy and Lactation Labeling Rule on Drug Information Resources.

Drug information resources are commonly used by health-care providers answering pregnancy-related medication questions. In 2015, the United States Food and Drug Administration approved a new pregnancy and lactation medication labeling content and format, removing the pregnancy category, and using a narrative. Despite labeling requirements changing, it is unknown if drug information resources updated monographs to reflect these changes. The primary objective was to evaluate if commonly used drug information resources provide pregnancy information listed similar to the requirements of the Pregnancy and Lactation Labeling Rule (PLLR). Secondary analyses included evaluating the references and inclusion of the pregnancy category rating. Pregnancy recommendations for 23 medications were evaluated in 9 drug information resources (Clinical Pharmacology, Drugs in Pregnancy and Lactation, Epocrates®, First Databank, LexiComp® Online, LexiComp® Online Pregnancy & Lactation, In-Depth, Medi-Span®, Micromedex®, and Multum®). The number of references per drug monograph and most recent reference publication year was obtained. LexiComp® Online Pregnancy & Lactation, In-Depth mimics the new PLLR structure and consistently had the highest number of and most recent references when the medication was included. Drugs in Pregnancy and Lactation was the next most similar in content with the PLLR and second in most references per monograph; however, the most recent reference was the textbook publication year. LexiComp® Online Pregnancy & Lactation, In-Depth and Drugs in Pregnancy and Lactation provided pregnancy information in a format most similar to the PLLR. However, several drug information resources contained pregnancy categories ratings that were to be removed from medication labeling per the PLLR.

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

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. 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. 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. Date of new drug approval by FDA. Compliance with PLLR; presence of animal or human data; presence of pregnancy registries; and presence of information regarding female and male reproductive potential. 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. 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, 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.

Clinicians' Perspective of the New Pregnancy and Lactation Labeling Rule (PLLR): Results from an AAAAI/FDA Survey

On June 30, 2015, the US Food and Drug Administration (FDA) began implementation of the Pregnancy and Lactation Labeling Rule (PLLR), which replaced the pregnancy letter category system (A, B, C, D, and X) with integrated narrative summaries of the risks of using a drug or biological product during pregnancy and lactation. The letter category system, first established in 1979, was regarded as overly simplistic and misinterpreted as a grading system. The PLLR labeling format was created to improve the presentation of available data on use of the drug during pregnancy and/or lactation. To survey clinician awareness, assessment, and use of this new labeling format. In January 2018, an online survey, developed in collaboration between the American Academy of Allergy, Asthma & Immunology and the FDA, was sent to a random sample of the US membership of the American Academy of Allergy, Asthma & Immunology. The survey content consisted of questions addressing the following: demographic characteristics, awareness and use of the PLLR, and value and understanding of the PLLR format on the basis of an example of the "Pregnancy" subsection of labeling. Of the 1500 members who received the survey via an email, 184 (12%) completed the survey. Respondents had a mean age of 56 years and treated on average 2 pregnant women per month. Less than half (46%) of the respondents were aware that the pregnancy letter category system was replaced with a narrative summary. After reading the example, most of the respondents (68%) did not feel that the narrative summary was concise. However, 71% of the respondents found the background risk and disease-associated risk information helpful. Most of the respondents (95%) continued to use the pregnancy letter category system to make prescribing decisions. These survey results suggest that the PLLR format was not known by most prescribers and that the pregnancy letter category format is continuing to be used despite significant flaws in the old system. However, the survey did not address why prescribers were continuing to rely on the pregnancy letter category system. Whether this is due to the PLLR format itself or the lack of quality data to inform the safe use of medications in pregnancy cannot be determined from these survey results. The FDA will use these survey results to refine the communication of pregnancy safety information in labeling and will expand outreach efforts to educate health care providers in the new labeling system.

Safety assessment of herbal drugs in pregnancy

This contribution consolidates data on international pregnancy rating classifications, including the former US Food and Drug Administration (FDA), Swedish, and Australian classification systems, as well as the evidence-based medicine system, and discusses discrepancies among them. It reviews the new Pregnancy and Lactation Labeling Rule (PLLR) that replaced the former FDA labeling system with narrative-based labeling requirements. PLLR emphasizes on human data and highlights pregnancy exposure registry information. In this context, the review discusses important data on the safety of most medications used in the management of skin disease in pregnancy. There are also discussions of controversies relevant to the safety of certain dermatologic medications during gestation.

Medication Use During Pregnancy and Lactation: Introducing the Pregnancy and Lactation Labeling Rule

On June 30, 2015, the U.S. Food and Drug Administration implemented the Pregnancy and Lactation Labeling Rule (PLLR). The PLLR was issued to address the shortcomings of pregnancy and lactation information in prescription drug and biological product labeling. The new labeling format under PLLR is structured to better help providers communicate important information about the risks and benefits of taking a specific medication to their pregnant or breastfeeding patients.

The 2015 US Food and Drug Administration Pregnancy and Lactation Labeling Rule.

As of 2015, the US Food and Drug Administration (FDA) discontinued the pregnancy risk categories (ABCDX) that had been used to denote the putative safety of drugs for use among pregnant women. The ABCDX system has been replaced by the FDA Pregnancy and Lactation Labeling Rule (PLLR) that requires narrative text to describe risk information, clinical considerations, and background data for the drug. The new rule includes 3 overarching categories: 1) pregnancy, which includes labor and birth; 2) lactation; and 3) females and males of reproductive potential. This article reviews the key components of the PLLR and clinical implications, and provides resources for clinicians who prescribe drugs for women of reproductive age.

Medication use in pregnancy and the pregnancy and lactation labeling rule.

On 30 June 2015, the US Food and Drug Administration Pregnancy and Lactation Labeling Rule (PLLR) took effect. This rule sets new and improved standards for the inclusion of information about the use of prescription drugs and biological products during pregnancy and lactation. The new labeling requirements have important implications for clinical pharmacology as there is a subheading that is dedicated to inclusion of clinical pharmacology information that inform dosing during pregnancy and the postpartum period, if available.

New prescription drug labeling for pregnant or nursing women

New prescription drug labeling for pregnant or nursing women

Drug safety: Pregnancy rating classifications and controversies

This contribution consolidates data on international pregnancy rating classifications, including the former US Food and Drug Administration (FDA), Swedish, and Australian classification systems, as well as the evidence-based medicine system, and discusses discrepancies among them. It reviews the new Pregnancy and Lactation Labeling Rule (PLLR) that replaced the former FDA labeling system with narrative-based labeling requirements. PLLR emphasizes on human data and highlights pregnancy exposure registry information. In this context, the review discusses important data on the safety of most medications used in the management of skin disease in pregnancy. There are also discussions of controversies relevant to the safety of certain dermatologic medications during gestation.

FDA makes changes to medication initiatives

FDA makes changes to medication initiatives

The US FDA pregnancy lactation and labeling rule – Implications for maternal immunization

The FDA has responsibility for ensuring that prescription drug and biological products including vaccines are accompanied by labeling that summarizes scientific information concerning their safe and effective use. As part of a broader effort to improve the content and format of prescription drug labeling FDA published a final rule, the Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling, referred to as the “Pregnancy and Lactation Labeling Rule (PLLR).” The most significant change to be implemented by this Rule is the removal of the letter risk categories A, B, C, D and X from all labeling, replacing them with a narrative summary of the risks of using a drug or biological product including vaccines during pregnancy. The PLLR requires an evaluation of available information about a product's use in pregnancy and provides an opportunity to update labeling when new information about use of a vaccine in pregnancy becomes available. Implementation of the provisions articulated in the PLLR, as they apply to vaccine product labeling, will require close collaboration between FDA and the vaccine manufacturer for both currently licensed vaccines and those in development.

Identification of developmental toxicants by their interference with cardiomyocyte differentiation of embryonic stem cells studied using transcriptomics

Details of embryo-fetal development (EFD) studies were compiled for all FDA drug approvals in 2016–17. Rats and rabbits were used for 63% of small molecule (SM) drugs. The cynomolgus monkey was used for 47% of biopharmaceuticals. Rodent studies using the clinical mAb or animal homologue replaced monkey studies under some circumstances. EFD studies were not required for anti-cancer drugs when the mode of action was associated with known developmental risk. One quarter of SM non-oncology drugs and all tested SM anti-cancer drugs were teratogenic in at least one species. The rat and rabbit were essentially equally sensitive to developmental toxicity. Eighty-nine percent of SM non-cancer drugs induced maternal or fetal toxicity in at least one species at below 25-times human exposure (proposed maximum exposure in the draft revised ICH S5(R3) guideline). The pregnancy and lactation labeling rule (PLLR) has brought consistency to the presentation of EFD data in drug labels.