Objective
Over the past decades, there have been significant efforts in the United States to improve pharmaceutical labeling pertaining to pregnancy. The goal of this study was to describe trends in pregnancy labeling at the time of drug approval and over time.
Study Design
The labeling data of 213 new pharmaceutical approvals between January 2003 and December 2012 were systematically reviewed. Initial approval data and subsequent labeling revisions were evaluated for pregnancy category, source of pregnancy and breast-feeding data, data in labor and delivery, presence of a registry, black-box warnings, and utilization of the new labeling format.
Results
The most commonly approved pregnancy category was C (51.6%). Most pharmaceuticals (92.9%) had pregnancy data based on animal studies and 5.2% had human pregnancy data. For breast-feeding, there were no data in 47.9% of labels, animal data in 42.7%, and human data in 4.7%. There were no labor and delivery data in 85.9% of labels. Only 2.8% of medications had human data, with the remainder having animal data. The majority of medications (85%) did not have a pregnancy registry. Of those that had a registry, 68.7% were by therapeutic category, not agent specific. Seven medications had black-box warnings related to teratogenicity. Since the new labeling recommendations, 4.7% of medications incorporated the new format into the labeling, primarily approvals that occurred in 2012.
Conclusion
Despite significant efforts to improve drug labeling for pregnancy and lactation, there remains a paucity of human data in this understudied population.
It is estimated that 90% of women will take at least 1 medication during their pregnancy. Moreover, 80% of pregnant women report taking medication during the first trimester, when vital organs and bodily structures are being formed. In addition, the percentage of women taking pharmaceuticals during pregnancy is expected to increase because women are able to bear children later in life and older pregnant women are more likely to require medications for acute and chronic illness. Exposure to pharmaceuticals during pregnancy can also be unintentional. Women may not be aware of early pregnancy and may continue to take current medications because an estimated 50% of pregnancies in the United States are unplanned.
Despite the relatively widespread use of pharmaceuticals during pregnancy, there is a paucity of data regarding the safety of medications in the developing fetus. Several medications have demonstrated adverse effects on the developing fetus, including severe deformity, developmental delay, and even death. On the other hand, failure to treat medical comorbidities during pregnancy can have adverse effects on both the mother and fetus. As such, it is crucial that drug therapy during pregnancy be optimized.
Although initial labeling efforts were stimulated in response to the thalidomide disaster of the 1950s, it was not until 1979 that the current pregnancy category system was established. Current pregnancy and lactation data available in pharmaceutical labeling are often limited, providing little guidance to prescribers in assessing the fetal risk.
Recent efforts have sought to promote change in US Food and Drug Administration (FDA) pregnancy labeling for pharmaceuticals. In 1996, the FDA Pregnancy Labeling Task Force was established and made recommendations to include a more narrative discussion because the risk assessment of a drug to be used in pregnancy was more complex than a simple letter designation. The task force also recommended drug labeling to address fertility and lactation issues.
In 2002, the FDA recommended the establishment of pregnancy registries and issued guidance for industry to establish such registries, improve pregnancy labeling, and promote clinical trials in pregnant women. These efforts culminated with a public hearing, and in 2008, new labeling requirements were posted in the Federal Register for comment ( Table 1 ).
| General information |
| General statement about background risk |
| Contact information for pregnancy registry if available |
| Fetal risk summary |
| Based on all available data, this section characterizes the likelihood that the drug increases the risk of developmental abnormalities in humans and other relevant risks. |
| More than 1 risk conclusion may be needed. |
| For drugs that are systemically absorbed: |
| When there are human data, a statement describes the likelihood of increased risk based on these data. This statement is followed by a brief description of the findings. |
| A standard statement describes the likelihood of increased risk based on animal data. |
| For drugs that are not systemically absorbed: |
| A standard statement that maternal use is not expected to result in fetal exposure to drug. |
| Clinical considerations |
| This section provides information on the following topics: |
| Inadvertent exposure: |
| Known or predicted risk to the fetus from inadvertent exposure to drug before pregnancy is known |
| Prescribing decisions for pregnant women: |
| Describe any known risk to the pregnant woman and fetus from the disease or condition the drug is intended to treat |
| Information about dosing adjustments during pregnancy |
| Maternal adverse reactions unique to pregnancy or increased in pregnancy |
| Effects of dose, timing, and duration of exposure to drug during pregnancy |
| Potential neonatal complications and needed interventions |
| Drug effects during labor and delivery |
| Data |
| Human and animal data are presented separately, with human data presented first. |
| Describes study type, exposure information (dose, duration, timing), and any identified fetal developmental abnormality or other adverse effects |
| For human data, includes positive and negative experiences, number of subjects, and duration of study |
| For animal data, includes species studied and describes doses in terms of human dose equivalents (provide basis for calculation) |
The proposed rule was revised based on public comments and FDA review, and the final rule is currently moving through clearance. The impact of these labeling initiatives has yet to be determined. The goal of this study was to describe trends in US pregnancy labeling for pharmaceuticals at the time of drug approval and over time.
Materials and Methods
This study is a review of prescribing data for original new drug approvals by the FDA between Jan. 1, 2003, and Dec. 31, 2012. The FDA maintains a publicly available online database of drug approvals that includes the initial labeling information and subsequent revisions. Labeling information for recently approved pharmaceuticals was obtained from the FDA database ( www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm ; accessed Feb. 25, 2014).
Approval reports by month were analyzed in reverse chronological order, searching for original new drug approvals. Original new drug approvals included new molecular entities and selected new biologicals. Biologicals included in the analysis were listed on the FDA web site under new drug approvals. Biologicals used for research purposes, tissues, gene therapies, and vaccines were not included. Generic approvals, new formulations, abbreviated new drug approvals, and supplemental applications were excluded because these medications were already on the market. A total of 10 years of approval data was reviewed, yielding a sample size of 213.
The initial approval label and any supplemental data were reviewed as well as subsequent labeling revisions. Data extracted included month and year of approval, therapeutic category, pregnancy category, source of pregnancy data, presence of a pregnancy registry, and labor and delivery and breast-feeding data. Utilization of the new labeling format was recorded. Data regarding teratogenicity, carcinogenicity, mutagenicity, and reproductive toxicology were collected as potential markers of fetal toxicity. The presence of black box warnings regarding fetal toxicity was also noted.
The therapeutic category was determined by the drug’s primary indication and mechanism of action. The pregnancy category was based on the current FDA lettering scheme: A, B, C, D, and X ( Appendix ; Supplementary Table ). The source of the pregnancy data was categorized by whether there were human data, animal data, both, or none available. The presence of a pregnancy registry was noted and if present, it was determined whether the registry was specific to that agent or whether it was a general registry for multiple products (such as the antiepileptic drug pregnancy registry).
Package inserts were scanned for a specific section that addressed use in labor and delivery. If there was a section present, the content was further categorized as to whether there were human data, animal data, or no data at all. If breast-feeding data were present, it was determined whether these were human data, animal data, or extrapolated from other sources, such as drugs in the same therapeutic class. The presence of approval data pertaining to teratogenicity, reproductive toxicology, mutagenicity, and carcinogenicity were also evaluated because toxicity noted in animal studies can also but not always be indicators of human toxicity. Label revisions were then analyzed searching for updates regarding pregnancy labeling.
Data were collected in Microsoft Excel 2010 (Microsoft, Richmond, WA). Statistical analysis was performed using SAS version 9.2 (SAS Institute Inc, Cary, NC). The FDA database does not contain patient information and is publicly available and therefore is not considered human subjects research.
Results
General characteristics
Over the 10-year study period, there were 213 new drug approvals; however, the number of approved medications varied between study years. The largest number of drugs (n = 33) were approved in 2012 and the least (n = 14) in 2010. The most common therapeutic categories for newly approved pharmaceuticals were oncology (19.3%, n = 41), infectious disease (16.4%, n = 35), and endocrine/metabolic disorders (12.7%, n = 27) ( Table 2 ).
| Therapeutic category | Number of approvals | Percentage |
|---|---|---|
| Allergy/immunology | 4 | 2 |
| Anesthesia/analgesia | 3 | 1 |
| Cardiology | 10 | 5 |
| Dermatology | 6 | 3 |
| Diagnostic imaging | 9 | 4 |
| Endocrine/metabolic | 27 | 13 |
| Gastrointestinal | 11 | 5 |
| Hematology | 7 | 3 |
| Infectious disease | 35 | 16 |
| Nephrology | 2 | 1 |
| Neurology | 17 | 8 |
| Obstetrics/gynecology | 2 | 1 |
| Oncology | 41 | 19 |
| Ophthalmology | 6 | 3 |
| Psychiatry | 12 | 6 |
| Pulmonary | 6 | 3 |
| Rheumatology | 2 | 1 |
| Toxicology | 3 | 1 |
| Urology | 10 | 5 |
| Total | 213 | 100 |
Approvals by pregnancy category
The most commonly approved pregnancy category was C (51.6%, n = 110). There were no medications approved during the study period classified as category A. A significant number of medications (25.4%, n = 54) were deemed potentially harmful to the fetus, being categorized as D or X. The majority of drugs that had a category X designation (68.8%, n = 11) were approved during the second half of the study period.
The therapeutic categories that were most likely to carry a pregnancy category X designation were endocrine/metabolic (n = 6) and oncology drugs (n = 5), followed by cardiology (n = 2) and obstetrics/gynecology medications (n = 2). Six drugs had changes in their pregnancy labeling based on new data that became available after approval.
Of the medications that had changes in their pregnancy category since approval, 4 (aliskiren, azilsartan, darunavir, and deferasirox) were moved to a category with more warnings in pregnancy, either from category C to D or from B to C. Two medications (anidulafungin and insulin detamir) changed from category C on approval to category B when more data were available.
When the frequency of approvals by category was graphed by year, significant fluctuations were noted over the study period. There appeared to be increases in category B, D, and X approvals later in the study period ( Figure 1 ). A complete list of medications by pregnancy category is included in the Appendix .
Quality of pregnancy data
The majority of drugs had some data regarding the use of medication in pregnancy; however, most of these data were based on animal studies. Of the 213 drugs evaluated, 189 (88.7%) had only animal data available at the time of approval. Nine medications had both human and animal data and 2 medications had only human pregnancy data. Of the medications with any human data at approval, the most common therapeutic category was psychiatry (n = 3), followed by neurology and gastrointestinal drugs. There were not any available pregnancy data for 13 medications in the approval label (6.1%).
Labor and delivery
There was no mention of drug use in labor and delivery in the vast majority (73.7%, n = 157) of labels at the time of approval. Whereas 12.2% of labels (n = 26) had a section for drug information pertaining to labor and delivery, they simply reported there were no data. Only 2.8% of medications (n = 6) had human data, with the remainder having animal data. Adverse effects reported during labor and delivery in animals included primarily prolonged parturition and bleeding complications. For those medications with human data, the primary concern was neonatal central nervous system depression. One medication (hyaluronidase) was reported to have been used safely during labor and delivery.
Breast-feeding data
There were no data regarding the safety of medication use while breast-feeding in 47.9% of labels (n = 102). There were animal data present in 42.7% of labels (n = 91). Recommendations for breast-feeding were based on human data in 4.7% of labels (n = 10). The proportion of approved medications with breast-feeding recommendations based on human or animal data did not change significantly over time. Only 1 medication had an update of breast-feeding data during the study period.
Pregnancy registries and new labeling format
The majority of medications (85%, n = 181) did not have a pregnancy registry. Of those that did, 31.3% (n = 10) were agent specific and 68.7% (n = 22) were by therapeutic category. The medications that had registries by therapeutic category were most commonly infectious disease and neurological agents. There were fluctuations in the number of approvals with registries over the course of the study period, reaching a low in 2010 but increasing by 2012.
Since the new labeling recommendations, 4.7% of medications (n = 10) incorporated the new format into the labeling, primarily approvals that occurred in 2012. Prior to 2012, there was only 1 medication that had the new labeling format. Of those medications that used the new narrative format, all of them continued to use the required current letter designation.
Black box warnings
There were a total of 63 drugs (29.6%) that were approved during the study period and had black box warnings either at approval or subsequently added in labeling revisions. Seven medications had black box warnings specifically related to teratogenic effects. One medication had a black box warning for increased death in juvenile animals (linaclotide). No new black box warnings pertaining to fetal toxicity were added during the study period. There was not any therapeutic category noted to have a substantially larger number of black box warnings ( Table 3 ).
| Medication |
|---|
| Aliskiren |
| Ambrisentan |
| Azilsartan |
| Lenalidomide |
| Telavancin |
| Teriflunomide |
| Vismodegib |
Teratogenicity, reproductive toxicology, mutagenicity, and carcinogenicity studies
There were teratogenicity tests performed in the majority of pharmaceuticals (90.4%, n = 193). Reproductive toxicology studies were performed for 87.8% of medications approved during the study period (n = 187). Mutagenicity data were available for 93.9% of approved pharmaceuticals (n = 200). The percentage of medications with carcinogenicity data was lower, with 45.1% (n = 96) without data at the time of approval ( Figure 2 ).
Results
General characteristics
Over the 10-year study period, there were 213 new drug approvals; however, the number of approved medications varied between study years. The largest number of drugs (n = 33) were approved in 2012 and the least (n = 14) in 2010. The most common therapeutic categories for newly approved pharmaceuticals were oncology (19.3%, n = 41), infectious disease (16.4%, n = 35), and endocrine/metabolic disorders (12.7%, n = 27) ( Table 2 ).
| Therapeutic category | Number of approvals | Percentage |
|---|---|---|
| Allergy/immunology | 4 | 2 |
| Anesthesia/analgesia | 3 | 1 |
| Cardiology | 10 | 5 |
| Dermatology | 6 | 3 |
| Diagnostic imaging | 9 | 4 |
| Endocrine/metabolic | 27 | 13 |
| Gastrointestinal | 11 | 5 |
| Hematology | 7 | 3 |
| Infectious disease | 35 | 16 |
| Nephrology | 2 | 1 |
| Neurology | 17 | 8 |
| Obstetrics/gynecology | 2 | 1 |
| Oncology | 41 | 19 |
| Ophthalmology | 6 | 3 |
| Psychiatry | 12 | 6 |
| Pulmonary | 6 | 3 |
| Rheumatology | 2 | 1 |
| Toxicology | 3 | 1 |
| Urology | 10 | 5 |
| Total | 213 | 100 |
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