This concept paper has been developed by the FDA Pregnancy Labeling Taskforce to serve several purposes beginning with summarization of concerns that have been raised about current regulations that guide labeling of new drugs and biologic products for use in pregnancy [CRF 312. 57 (f)(6)]. Second, it outlines recommendations to FDA from multiple stockholders at a Part 15 public hearing held in September 1997. Third, this concept paper describes a (draft) model for pregnancy labeling that begins to address the concerns and recommendations.
It outlines a format with general content designed to facilitate discussion. Within the text of this concept paper, “issues” are highlighted. These are placed in close proximity to parts of the draft model to provide “food for though,” for the reader. Some are statements and other issues are posed as questions. PREGNANCY LABELING ISSUES Under current FDA regulations, unless a drug is not absorbed systemically and is not known to have a potential for indirect harm to the fetus, its labeling must include a “Pregnancy subsection.
” The Pregnancy subsection must contain information on the drug’s teratogenic effects and other effects on reproduction and pregnancy. When relevant, effects on later growth, development, and functional maturation of the child (21 CFR 201. 57(f)(6) must also be included. The regulation requires that each product be classified under one of five letter categories (A, B, C, D, or X) on the basis of risk of reproductive and developmental adverse effects or, for certain categories, on the basis of such risk weighed against potential benefit. (See Appendix A). Concerns with Current Pregnancy Labeling Requirements.
Clinicians who treat pregnant women and women of childbearing potential, academic and specialty medical organizations, women’s health organizations, and others have expressed concerns about the usefulness of pregnancy labeling. They maintain that information contained in the typical pregnancy labeling subsection, and the way it is presented under current regulations, is not sufficient for practitioners and patients to make informed decisions about drug therapy in pregnant women. Further, most pregnancy sections of existing labels are not informative in facilitating decisions about what to do in the event of inadvertent fetal drug exposure.
The pregnancy categories are considered a significant part of the problem. There have been two major criticisms of the categories. First, they convey the incorrect impression that reproductive risk increases from category A to B to C to D to X. This confusion occurs because the criteria for inclusion in categories A, B, and to a certain extent C, may reflect increasing risk from A to C, while criteria for inclusion in categories D, X, and to a certain extent C, are based on risk weighed against potential benefit.
Thus, drugs in categories D, X, and in some cases C, may pose similar risk, but be categorized differently on the basis of different risk/benefit considerations. Second, the categories create the impression, often mistaken, that the drugs within a given category present similar reproductive risks. For drugs with identified risks, existing inclusion criteria may permit, in the same category, drugs that vary in the type, degree, or extent of risk. The category inclusion criteria may also place drugs with known risks and drugs for which there are no known risks in the same category.
For example, category C may include drugs with demonstrated adverse reproductive effects in animals and drugs for which no animal studies have been performed. Category B may include drugs which have no demonstrated adverse reproductive or developmental effects in animals and for which there are no adequate and well-controlled data in humans. Category B may also include drugs that have demonstrated adverse reproductive or developmental effects in animals but did not demonstrate adverse effects in adequate and well-controlled trials in humans.
Public Hearing on the Pregnancy Labeling Categories In September of 1997, the agency held a public hearing on the current category requirements for pregnancy labeling (62 FR 41061, July 31, 1997) to obtain comment on the practical utility, effects and problems associated with the categories. The agency also sought input on ways to address these problems, including possible alternatives to the categories for communicating information on reproductive and developmental toxicity. The following are the specific issues the agency sought comment on and summaries of the comments received: 1.
The extent to which the category designations are relied upon in making decisions about drug therapy in pregnant women and women of childbearing potential and decisions about inadvertent fetal exposure, the extent to which such reliance may be misplaced, and the extent to which such reliance may have untoward public health consequences: There was consensus that, because the category designations appear to provide a simple, convenient measure of risk, they are routinely relied upon by clinicians and others in making decisions about drug therapy in pregnant women and women of childbearing potential.
There was concern that, because such decisions are more complex than the category designations suggest, such reliance may often be inappropriate. 2. The extent to which current pregnancy labeling (category designation and ccompanying narrative text) is effective in communicating risk of reproductive and developmental toxicity: There was consensus that the current category system is confusing and overly simplistic and, therefore, not adequate to effectively communicate risk of reproductive and developmental toxicity.
There was concern that, because each category includes under a single letter designation a wide range of products used in a wide range of potential clinical situations, the category designation erroneously suggests that drugs within a category present quite similar risks or risk-benefit considerations.
3. The extent to which current pregnancy labeling may not adequately address the range of issues that bear on decisions about drug therapy in pregnant women and women of childbearing potential and decisions about inadvertent fetal exposure (e. g., indication-specific concerns, pregnancy status, magnitude of exposure, incidental exposure, chronic exposure, timing of exposure):
There was consensus that current pregnancy labeling does not adequately address the range of clinical situations in which information about drug exposure in pregnancy is needed. There was concern that current pregnancy labeling focuses almost entirely on prospective consideration of whether to prescribe a drug for a pregnant woman, or a woman who may become pregnant, and usually does not address inadvertent exposure (where a woman is taking a drug and discovers she is pregnant).
Because a majority of pregnancies are unplanned and, therefore, there is significant potential for inadvertent exposure to a drug before a pregnancy is detected, there was strong support for addressing inadvertent exposure issues in pregnancy labeling. 4. Additional information (data or interpretation of data) that could be included in pregnancy labeling to better address the range of issues that bear on decisions about drug therapy in pregnant women and women of childbearing potential and decisions about inadvertent fetal exposure:
There was consensus that current pregnancy labeling does not adequately address the full range of potential developmental toxicities–fetal death, structural malformations, perturbations of fetal growth, and functional deficits. There was also concern that current labeling does not present enough of the evidentiary basis for the category designation or adequately discuss the potential relevance of animal data to humans. FDA was urged to implement a mechanism to routinely update the pregnancy section of labeling after a drug is marketed to include human exposure information, as it becomes available.
FDA was also encouraged to incorporate discussions of a product’s effects on fertility, pregnancy, and lactation issues into a single labeling subsection. 5. Options to improve communication of reproductive and developmental risk in labeling, which could include alternatives to the categories (both content and format options) or efforts to make the current category scheme and accompanying narrative text more consistent and informative: There was consensus that the current letter categories should be replaced.
There was considerable support for replacing the categories with a concise narrative summarizing a product’s risks to pregnant women and women of childbearing potential, and a separate statement discussing the clinical implications of such risks. To aid comprehension and facilitate evaluation of therapeutic options, it was recommended that the narratives contain common core elements. Some comments also supported providing a conclusive statement or recommendation about clinical use.
FDA was also encouraged to take steps to better understand how language used to communicate risk (terms and statements) is perceived by potential users of pregnancy labeling. Principle Recommendations from the Public Hearing From the hearing testimony and comments, FDA’s Pregnancy Labeling Taskforce has identified five major recommendations for changes in the format and content of pregnancy labeling. 1. The current pregnancy letter category designations and accompanying text should be replaced by narrative text that is more informative and less prone to misinterpretation or misapplication.
2. The narrative text should provide more detailed clinical management advice than it presently does, including advice relevant to inadvertent fetal exposure. This advice should more specifically address the unique situations presented by a product and its indication(s), but have a structure that is similar enough from drug to drug to allow users to readily find information and to compare therapeutic alternatives. 3. The labeling should provide a concise summary of risks associated with a product, including the settings in which the relevant toxicities occurred. 4.
The labeling should contain a broader and more meaningful discussion of the data, animal and human, that underlie the evaluation of risks associated with a product. 5. Fertility, pregnancy, and lactation are a clinical continuum, therefore it would be logical and useful to address these situations in the same section of the labeling. Draft Model Labeling: Content and Format To illustrate possible applications of these recommendations the Taskforce has developed a model labeling format. The Taskforce has also applied the format to two fictitious drug products (Appendices B and C).
These labeling examples are being provided solely for the purpose of illustrating the model format and not to generate specific comment on the details of the underlying data. In describing the format and content of the model labeling issues that offer “food for thought” are interspersed, highlighted by italics. These may speak to practicality, controversy, or simply offer challenges for further consideration. The model pregnancy labeling is organized into three major subsections: 6. Clinical Management Statement 7. Summary Risk Assessment 8.
Discussion of Data This format is intended to prominently display important conclusions about risk management in the context of clinical care; provide a summary of the risks that are the basis for the management statement; and place in close proximity more detailed information about the data that are the basis for the risk analysis. In making a clear distinction between the Clinical Management Statement and the Summary Risk Assessment, the intent is to clearly separate the clinical management recommendations and the actual risk information that underlies it.
Consider the practical implications (e. g. , advantages; applicability in the absence of data; length of summaries) of a pregnancy labeling format that includes a Clinical Management Statement, a separate Summary Risk Assessment and a broader Discussion of Data that underlie the risk assessment. Clinical Management Statement In the comments and testimony from the public hearing there was consensus that the currently required management statements are overly general (e. g. , “[name of drug] should be given to pregnant women only if clearly needed”).
The clinical management statement in the labeling model here is intended to provide clinical management advice that is more product-specific and clinically relevant (to the risk-benefit decision to be made) than the information required under the current regulation. Such advice might include discussion of specific clinical settings in which the drug should be avoided, dosage adjustments, necessary monitoring, and, for drugs with multiple indications, management considerations that are unique to certain indications.
There is tension between providing management information that is product-specific and clinically relevant and providing information that is sufficiently structured to ensure that it is informative. Statements should also be reasonably consistent across drug products to allow evaluation of a range of therapeutic alternatives. Consider the types of issues that should routinely be addressed in Clinical Management Statements (e. g. , uncertainties or toxicities that are unique, or of particular concern, to the health of a pregnant woman).
In the examples, the Clinical Management Statement specifically addresses inadvertent exposure (i. e. , exposure that occurs when a woman who is taking a drug becomes pregnant without having previously considered whether to expose the fetus to drug). Current pregnancy labeling focuses primarily on prospective consideration of risk? whether to expose a pregnant woman to a drug or whether to discontinue a drug prior to conception. Such advice may not be helpful in evaluating risks and options after exposure has occurred.
There was considerable agreement among presenters at the public hearing that pregnancy labeling should provide clinical management information that more specifically addresses retrospective consideration of drug exposure. In considering how to address risk relevant to both planned and inadvertent exposure, a range of data quantity and quality is likely. With regard to offering clinical management advice for the patient exposed to a product without knowledge of her pregnancy, consider the types of recommendations that might be included and in how much detail. It will be important to balance informative recommendations with directives.
Summary Risk Assessment The Summary Risk Assessment in this model is intended to distill risk information presented in the Discussion of Data section into a concise overview of specific fetal abnormalities and other potential hazards identified. It includes information about the setting or settings in which hazards occurred (e. g. , relative exposure, gestational stage or stages). The statement is intended to bridge the more detailed Discussion of Data and the Clinical Management Statement derived from that data. Consider the utility of such a summary risk assessment and how to make it most informative. Discussion of Data.
The Discussion of Data subpart in this model provides a comprehensive presentation of the data that contributed to the risk summary. Its role is to describe the risk findings in a way that their potential relevance to clinical decision making can be best understood by the clinician. In order to address the full range of possible reproductive and developmental toxicities, the following subheadings (to the extent relevant to an individual drug) would be included: 9. Structural alteration (or dysmorphogenesis) 10. Embryo-fetal death 11. Growth retardation (irreversible and reversible) 12. Functional toxicities 13. Maternal toxicity.
14. Labor and delivery In describing and discussing individual data sources a challenge will be to provide sufficient information to meaningfully inform clinicians while avoiding excessive detail that might make information less accessible. The following are elements that could be addressed in describing an individual study or other data source: 1) Description of data source (e. g. , human, case control study or rat toxicology study) and the specific findings. 2) Specific conditions under which the identified or suspected hazard is present in the study(s) and the nature of the adverse effect seen, which may include discussion of:
1. species 2. dose 3. dose-response 4. exposure/duration 5. timing of effect (e. g. , phase of pregnancy) 6. magnitude of effect (severity) 7. incidence of effect 8. biological plausibility of observed effect 3) Where the hazard is identified in animal data, information that addresses the potential relevance of the hazard to humans. Please consider ways in which the Discussion of Data subsection can meet the goal of being sufficiently comprehensive to be useful to clinicians while avoiding excessive detail.
For example, under what conditions should a data source be described and how comprehensively (keeping in mind that literature references are generally avoided in product labels). Fertility, Pregnancy, and Lactation Information in the Same Section Fertility, pregnancy, and lactation represent a clinical continuum, therefore the labeling examples in the Appendices present these subsections of labeling in contiguous subsections. Also, because fertility and lactation present issues similar to those presented by pregnancy, the model assigns the same internal subsections for Pregnancy as illustrated below:
|Fertility, Pregnancy and Lactation | | | |Fertility | |• Clinical management statement | |• Summary risk assessment | |• Discussion of data | | | |Pregnancy | |• Clinical management statement | |• Summary risk assessment | |• Discussion of data | | | |Lactation | |• Clinical management statement | |• Summary risk assessment | |• Discussion of data | Consider the applicability and usefulness of the overall format, particularly whether having a Clinical Management Statement, Summary Risk Assessment, and Discussion of Data would be useful applied to the Fertility and Lactation discussions in labeling (See Appendices B and C).
Appendix A Pregnancy Categories The regulation specifies the following language for the category designations: “Pregnancy Category A. Studies in pregnant women have not shown that (name of drug) increases the risk of fetal abnormalities if administered during the first (second, third or all) trimester(s) of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote.
Because studies cannot rule out the possibility of harm, however, (name of drug) should be used during pregnancy only if clearly needed. ” “Pregnancy Category B. Reproduction studies have been performed in (kind(s) of animal(s)) at doses up to (x) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to (name of drug). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. ”
Or, if animal studies have shown an adverse effect (other than decrease in fertility), but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters), the labeling shall state: “Pregnancy Category B. Reproduction studies in (kind(s) of animal(s)) have shown (describe findings) at (x) times the human dose.
Studies in pregnant women, however, have not shown that (name of drug) increases the risk of abnormalities when administered during the first (second, third, or all) trimester(s) of pregnancy. Despite the animal findings, it would appear that the possibility of fetal harm is remote, if the drug is used during pregnancy.
Nevertheless, because the studies in humans cannot rule out the possibility of harm, (name of drug) should be used during pregnancy only if clearly needed. ” “Pregnancy Category C. (Name of drug) has been shown to be teratogenic (or to have an embryocidal effect or other adverse effect) in (name(s) of species) when given in doses (x) times the human dose. There are no adequate and well-controlled studies in pregnant women.
(Name of drug) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ” Or, if there are no animal reproduction studies and no adequate and well-controlled studies in humans, “Pregnancy Category C. Animal reproduction studies have not been conducted with (name of drug). It is also not known whether (name of drug) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. (Name of drug) should be given to a pregnant woman only if clearly needed. ” “Pregnancy Category D. See >Warnings’ section.
” Under the “Warnings” section the labeling states: “(Name of drug) can cause fetal harm when administered to a pregnant woman. (Describe the human data and any pertinent animal data). If this drug is used during pregnancy, or if this patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. ” “Pregnancy Category X. See >Contraindications’ section. ” Under “Contraindications,” the labeling shall state: “(Name of drug) may (can) cause fetal harm when administered to a pregnant woman.
(Describe the human data and any pertinent animal data.) (Name of drug) is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if this patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. ”
APPENDIX B Sample Fertility, Pregnancy, and Lactation Labeling Subsection for Fictitious Product ROSELENS Fertility Clinical Management: No specific precautions are indicated when Roselens is used by men or women who are intending to conceive. Summary Risk Assessment: Based on data from animal studies, there are no known concerns or suspected consequences for fertility in persons taking Roselens.
Discussion of Data: There are no human data on the effects of Roselens on male or female fertility. Male and female rats were treated with Roselens at doses of 8 to 13 milligrams (mg)/kilogram (kg) (equivalent to 2 and 4 times the maximum recommended human dose (MRHD) of 80 mg daily when normalized for interspecies differences based on body surface area) for greater than 3 weeks prior to, and throughout, mating. There were no reported adverse effects on mating behavior, fertility, or viability of the conceptus. Pregnancy.
Clinical Management: Use of Roselens should not effect the obstetric or psychiatric management of patients who are in early pregnancy or considering becoming pregnant. Women in the latter months of pregnancy should be evaluated for the need to continue Roselens therapy and, if therapy is to be continued, monitored for appropriate fetal growth. Summary Risk Assessment: Based on studies in animals and limited human data, there is no known concern for malformations or abnormal neurobehavioral function in infants born to mothers treated with Roselens.
There is some concern, based on animal studies, for an increased risk of impaired fetal growth and late fetal and neonatal mortality when Roselens is administered during the third trimester of pregnancy. Discussion of Data: In one epidemiological study, the frequency of congenital anomalies was no greater than expected among the infants of 90 women who took Roselens during the first trimester of pregnancy (Stevens et al. , 1993). In an observational study, six infants from 107 pregnancies in which the mother took Roselens at various times during pregnancy had congenital anomalies.
In at least two of these cases, the malformations developed prior to treatment (Smith et al. , 1992). The frequency of congenital anomalies did not appear unusual among the infants of 59 women who became pregnant while taking part in clinical trials of Roselens or among the children of 485 women who took Roselens for varying amounts of time during pregnancy and voluntarily reported those exposures to the manufacturer. The manufacturer has received a total of 28 reports, from a variety of sources, of infants with major congenital anomalies born to women who had taken Roselens during pregnancy.
No consistent pattern of malformations was apparent (Stevens and Stevens, 1993). Dysmorphogenesis. Pregnant rats and rabbits were treated throughout organogenesis with doses # 12. 5 and 15 mg/kg, respectively (equivalent to 1. 5 and 3. 6 times the MRHD when normalized for interspecies differences based on body surface area). There were no teratogenic effects reported. Mortality. In pregnant rats treated during organogenesis (see Dysmorphogenesis), there was no evidence of fetal loss or resorptions. In rats treated during mid and late gestation and late gestation and lactation at doses of 5 and 7.
5 mg/kg (approximately equivalent to the MRHD when normalized for interspecies differences based on body surface area), there were increases in the number of stillborn pups and reductions in neonatal viability at the higher dose. No effects on mortality were observed at the lower dose. Growth. There were no reductions in body weights in fetuses of rats treated during organogenesis (see Dysmorphogenesis). There were reductions in body weights of rats treated during mid and late gestation or late gestation and lactation (see Mortality). There was no effect on pups when treatment ended at day 16 (of 28) of gestation.
Functional toxicities. In a study in rat pups born to dams treated with 5 and 7. 5 mg/kg (approximately equivalent to the MRHD when normalized for interspecies differences based on body surface area) during mid and late gestation, there was no evidence of developmental neurotoxicity among surviving offspring. Lactation Clinical Management: Breast-feeding while on Roselens is not recommended. If the decision is made to nurse while on Roselens, the infant should be followed for signs of decreased growth, altered feeding behavior, and other potential effects based on the known pharmacology and toxicity profile of Roselens.
Summary Risk Assessment: Based on human and animal data, there is significant concern for the infant when Roselens is used by the breast-feeding mother. Discussion of Data: Roselens is excreted in human milk and can achieve concentrations in the nursing infant that are equivalent to or exceed therapeutic levels in adults. In one breast milk sample of a mother receiving Roselens, the concentration of the drug was twice the maternal plasma level. No adverse effects in the infant were noted.
In two other cases of infants nursed by mothers on Roselens, the infants’ plasma levels were similar to their mothers’ and the infants developed vomiting and diarrhea. There is no information regarding timing of administration of Roselens and its excretion in breast milk. In rat pups of dams that were administered Roselens postpartum, feeding time was significantly decreased (see Pregnancy–Discussion of Data). Appendix B Sample Fertility, Pregnancy, and Lactation Subsection for Fictitious Product LEURAL Fertility
Clinical Management: Men and women attempting to conceive should be advised of the potential for reduced fertility while taking Leural (also see Pregnancy). Summary Risk Assessment: Based on studies in animals, there is some concern for risk of reduced fertility in persons taking Leural. Discussion of Data: There are no human data addressing the effects of Leural on fertility. In animal reproductive/fertility studies, Leural had no effect on pregnancy rates in rats at oral doses up to 400 mg/kg (systemic exposures equivalent to 8 times (male rats) and 18 times (female rats) that of humans at maximum recommended human dose (MRHD)).
However, reduction in fetal implants was observed at doses of 150 mg/kg and higher (systemic exposure equivalent to 9 times that of humans at MRHD). There was also evidence of testicular atrophy in dogs treated chronically at doses of 15 mg/kg (systemic exposure equivalent to 20 times that of humans at MRHD). Pregnancy Clinical Management: Women who are taking Leural and become pregnant should be advised to consider discontinuing the drug and may warrant evaluation for potential effects on fetal growth and development.
Women who are considering pregnancy should be advised to consider alternative treatments for asthma maintenance when feasible. Summary Risk Assessment: Based on studies in animals, there is some concern for an increased risk of mortality and decreased growth in fetuses exposed to Leural. The time of gestation at which risk may be greatest is unknown. Also, based on animal studies, there is some concern for increased risk of fetal malformations. Discussion of Data: There are no human data addressing the effects of Leural on pregnancy and its outcomes.
In rats, the drug and its metabolites cross the placenta. Leural is also known to alter cellular signal transduction, a function important in embryogenesis (see Clinical Pharmacology). Dysmorphogenesis. In studies in rats at 400 mg/kg (systemic exposure equivalent to 18 times that of humans at MRHD), there was an increased rate of skeletal variation. A greater than expected rate of cleft palate (3 of 118, or 2. 5%) was observed in fetuses of rabbits treated with 100 mg/kg/day (systemic exposure equivalent to that of humans at MRHD). Mortality and Growth.
In a study in rats treated throughout gestation at doses of 70 mg/kg (systemic exposure equivalent to approximately 4 times the recommended dose) and higher, there was an increased rate of stillbirths and, at doses of 400 mg/kg, there were also reduced body weights of fetuses. In a study in rats treated in late gestation through lactation at 400 mg/kg (systemic exposure equivalent to approximately 18 times that of humans at MRHD), there was reduced pup survival and body weight. Functional toxicities. There are no studies that assess infant neurobehavioral effects of Leural related to intrauterine exposure.
Lactation Clinical Management: Women who are breast-feeding should be advised of the potential risk for long term effects to the infant due to exposure to Leural. Summary Risk Assessment: Based on animal carcinogenicity data, there is some concern for the infant who is exposed to Leural. Discussion of Data: There are no human data on the excretion of Leural into human breast milk or on the safety of Leural exposure in infants. Leural and its metabolites are excreted into rat milk (also see Carcinogenicity).