Obstetrical healthcare providers frequently field questions about the safety of medications recommended or prescribed to their pregnant patients. Most women use as least 1 medication during pregnancy; however, there is little information about the safety or appropriate dosing of many medications during this phase of life. In addition, the development of drugs for use in pregnant women trails behind the development of drugs intended for other sectors of the population. Our goal is to inform the obstetrics community about the US Food and Drug Administration authority and their role in approving drugs for marketing. We begin with the statutes that led to the creation of the Food and Drug Administration and its current organization. We then cover drug development and the Food and Drug Administration review process, including the role of the advisory committee. The different types of drug approvals are discussed, with some specific examples. Finally, we enumerate the drugs specifically approved for use in obstetrics and contrast them with drugs commonly used by pregnant women and drugs used “off-label” during pregnancy. The Food and Drug Administration is committed to protecting and advancing the public health of pregnant women by guiding the development and ensuring the availability of effective and safe therapeutics for obstetrical indications and for medical conditions during pregnancy. We hope this review will inspire more research addressing drug use during pregnancy.
Introduction
No other relationship is as fundamental to human development as that of the mother-fetus dyad. The 9 months a fetus spends in utero lays the foundation for the next 90 years of its life. A 2011 study using data from 2 large birth defect studies found that about 90% of women took at least 1 medication during pregnancy, with 70% taking at least 1 prescription medication. About 50% of postpartum women—whether breastfeeding or not—take at least 1 medication. However, the development of drugs for use by pregnant women trails behind the development of drugs intended for other sectors of the population. As part of the compendium of articles presenting multiple perspectives about fostering collaboration during the development of medical therapies for use in pregnancy, our goal is to inform the obstetrics community about the US Food and Drug Administration (FDA)’s authority and role in approving drugs for marketing in the United States. The FDA’s role in monitoring the safety of drugs after approval is beyond the scope of this article.
Background of the Food and Drug Administration
Creation of the Food and Drug Administration
Several incidents in the late 19th century and early 20th century incited public concern about the unregulated nature of marketed food and drugs. Manufacturers were not required to list the ingredients in product labeling and made unsubstantiated claims about their drug products. For example, the manufacturer of “Mrs Winslow’s Soothing Syrup” claimed that the syrup would greatly facilitate the process of teething, alleviate pain, and regulate the bowels. Because the syrup contained morphine and alcohol, many infants suffered addiction and withdrawal, became comatose, or died from a morphine overdose. Upton Sinclair’s description of food adulteration and unsanitary conditions in meat packing plants in “The Jungle” shocked the American public . The outrage ensuing after exposing these conditions prompted the passage of the Pure Food and Drug Act of 1906, the first federal consumer protection law. The Pure Food and Drug Act aimed to foster consumer safety by requiring that products be accurately labeled with ingredients and dosage. This legislation laid the foundation for creation of the nation’s first federal consumer protection agency, the FDA.
Over time it became clear that drugs should be demonstrated to be safe and effective before approval, leading to the following 2 legislative enactments that together form the FDA’s modern legal authority:
- (1)
The 1938 Federal Food, Drug, and Cosmetic (FD&C) Act required drug sponsors to establish safety before the marketing of new drugs and required submission of a new drug application to the FDA before marketing. The FD&C Act was spurred by the sulfanilamide tragedy, an antimicrobial agent that was dissolved in a sweet-tasting liquid targeted to pediatric patients. The drug sponsor did not conduct toxicity testing on the sweet solvent, which contained ethylene glycol (antifreeze), and it caused over 100 deaths, including that of many children.
- (2)
The 1962-Kefauver-Harris Amendments required drug sponsors to establish the efficacy of new drugs, in addition to safety, and required that the FDA give positive approval before new drugs could be marketed. Thanks to Dr Frances O. Kelsey’s careful review of the safety of thalidomide, a sedative for pregnant women that was highly teratogenic, this drug was never marketed in the United States, averting the clusters of rare, severe birth defects in thousands of babies seen in other countries. The avoidance of a near disaster propelled passage of these amendments and fundamentally changed drug regulation.
Current Food and Drug Administration organization
Today, the FDA regulates and ensures the safety and effectiveness of products that account for 20% of all consumer expenditures in the United States, worth over a trillion dollars per year. The FDA is part of the Department of Health and Human Services within the Executive branch of government. This branch implements the pertinent laws enacted by the legislative branch. Therefore, the FDA executes, but does not create laws related to drug regulation.
The FDA consists of individual centers, each dedicated to the evaluation of different products as indicated by their names. For example, the Center for Drug Evaluation and Research (CDER) ensures that safe and effective drugs are available to improve the health of people in the United States, whereas the Center for Biologics Evaluation and Research ensures biological products (eg, vaccines and blood products) are safe and effective for those who need them. Similarly, the Center for Devices and Radiological Health ensures that patients and providers have timely and continued access to safe, effective, and high-quality medical devices and safe radiation-emitting products.
For this article, we focused on the work of the CDER, which ensures that safe and effective prescription, nonprescription, and generic drugs are available to the American people in a timely manner. The CDER fulfills this mission by regulating drug research and the development, manufacture, and marketing of drugs. The CDER personnel review the clinical and scientific evidence to determine if the evidence supports marketing approval of the proposed new drugs or new indications (new uses for already approved drugs for patients with specific diseases or conditions); monitor drug safety after approval; and ensure that drug labeling, drug information for patients, and drug promotional materials are truthful, helpful, and not misleading.
Drug development and the Food and Drug Administration drug review process
Drug development occurs in the following 2 ways: a new chemical entity or biological product is created, or a new indication is developed for an already approved drug to cure or palliate a certain disease or condition.
The CDER regulates but does not develop drugs or conduct clinical studies; drug sponsors are responsible for these activities, with important contributions from the academic and other research centers. Within the CDER’s Office of New Drugs, 2 divisions–the Division of Urology, Obstetrics, and Gynecology and the Division of Pediatrics and Maternal Health–are dedicated to overseeing therapeutics in obstetrics and activities related to maternal health, respectively, in collaboration with other groups within the FDA.
Nonclinical studies
Nonclinical evaluation, which includes in vitro and animal studies, is the first step toward investigating the efficacy and safety during drug development. Drug sponsors do not need to notify the FDA or obtain the FDA’s approval before conducting these nonclinical studies. The FDA requires nonclinical studies to be conducted to characterize the pharmacology and toxic effects of a drug product with respect to the target and nontarget organs, dose dependence, and relationship to exposure, which can guide and support the investigative use of drugs in human clinical trials. , The results of these studies aid in determining a safe starting dose for initial human clinical trials, dose titration, and the highest safe dose, while also characterizing potential adverse effects that might occur or that would need to be monitored during clinical trials (if applicable). As human clinical trials progress and become more complex in their type and duration, additional nonclinical studies provide supportive data to allow these clinical studies to proceed. There is a standard, nonclinical safety assessment that is necessary before a drug sponsor seeks FDA approval for their product, which includes evaluation of the general toxicity, pharmacology, absorption, distribution, metabolism and elimination, safety pharmacology, pharmacokinetics and toxicokinetics, reproductive toxicity, genotoxicity, and carcinogenicity. Additional studies may be warranted if the drug has certain biological properties, targets a unique study population based on age or gender, or has safety concerns.
With some exceptions, when adult men and women, especially those of childbearing potential, are to be enrolled in clinical trials, nonclinical reproductive and developmental toxicity studies are conducted to evaluate the effects of a drug product on fertility and early embryonic development, embryofetal development, and pre- and postnatal development. , Often these reproductive and developmental toxicology data are the only evidence informing the safety of drug use during pregnancy, especially for newer drugs.
Nonclinical reproductive toxicity assessments include the following:
- (1)
Male and female fertility: damage to reproductive organs, alterations in endocrine regulation or function, effects on sperm count, motility, or morphology, mating behavior or the ability to mate, reduction in fertility, and effects on estrous cycling;
- (2)
Parturition: abnormal or difficult delivery (dystocia) or changes in the onset and duration of parturition;
- (3)
Lactation: concentration of the drug in breast milk through sampling; effects on the quantity and quality of milk would manifest as abnormal growth and development of the offspring.
Nonclinical developmental toxicity assessments include the following:
- (1)
Mortality: pre-or postimplantation loss, early or late resorption, abortion, stillbirth, neonatal death, or postweaning loss;
- (2)
Dysmorphogenesis (structural abnormalities): skeletal or soft tissue malformations or variations in the offspring;
- (3)
Alterations in growth: growth retardation, excessive growth, early maturation (via measurement of body weight, crown-rump length, and anogenital distance);
- (4)
Functional impairment: developmental neurobehavioral effects and reproductive function of offspring as measured through assessments on locomotor activity, learning and memory, reflex development, time to sexual maturation, mating behavior, and fertility.
Juvenile animal studies can also be conducted to identify postnatal developmental toxicities that may not be adequately assessed in reproductive and developmental toxicity assessments. , There are many organ systems that undergo considerable postnatal development in terms of both structure and function between birth and adolescence, including the brain, kidneys, lungs, and immune, skeletal, gastrointestinal, and hepatobiliary systems. If general toxicity studies in adult animals have identified target organ toxicities or pharmacology in organs that are known to markedly mature postnatally, juvenile animal studies can provide key safety information to determine the risk in those organ systems from prenatal or lactational exposure to a drug. These studies can also evaluate the risk across specific developmental stages, such as neonatal, infant, older children, and puberty or adolescence, that may not be captured in mature animal toxicity studies.
The FDA pharmacology and toxicology review team evaluates the totality of the general nonclinical and reproductive and developmental toxicology data to assess the relevance of risk for the proposed human use. This approach integrates a number of factors, such as the relevance of the data and test species to humans (pharmacology, dose, exposure), the observed signals in multiple animal species, multiple positive signals observed in a single species, class alerts for the drug product, signals for related toxicities, dose-response relationship, and evidence of maternal or paternal toxicity, among others. After integrating and collating all the data, the nonclinical team includes in the labeling the information supported by evidence, including positive findings, lack of findings, or no data available.
Clinical trials
Traditionally, there are usually 3 phases of clinical trials in the development of drugs. These phases are not necessarily sequential and can sometimes overlap or be combined and be re-iterative. The number of patients studied will depend on the disease and its prevalence. Completion of these clinical phases can take several years to well over a decade, with many programs failing along the way owing to safety concerns or a lack of efficacy.
Phase 1
These trials usually include 20 to 100 subjects, most likely healthy volunteers, and test mainly the drug’s pharmacokinetics (the body’s effect with regards to the absorption, distribution, metabolism, and elimination of the drug and include the peak drug concentration in the blood and the time it takes to reach the peak concentration after drug intake), pharmacodynamics (the drug’s effect on the body with regards to, for example, changes in vital signs, laboratory values, or other clinical measures), and preliminary safety in humans.
Phase 2
These trials are usually for proof-of-concept and dose-finding purposes and conducted in the target patient population, which are further investigated in phase 3 trials. These trials include up to several hundred patients and provide more preliminary safety and efficacy information.
Phase 3
These trials are intended to establish the safety and effectiveness of a drug and usually include hundreds to thousands of patients. They are designed to provide the necessary clinical data to support a marketing application seeking approval for a drug product for a certain indication in the intended patient population.
Clinical trials evaluating a new drug, or an investigative use of an approved drug for a new indication, are conducted under Investigational New Drugs (INDs). The FDA has federal oversight of trials conducted under INDs, playing an important role along with others (eg, institutional review boards) in protecting the safety of study participants and ensuring that the trials are designed and conducted to meet their objectives. The FDA can place a hold on entire development programs, on specific trials, or on aspects of trials if the investigations raise considerable concerns, such as unreasonable risks to patients. All the points along the drug development process are interactive; the FDA and drug sponsors communicate regularly, usually with formal meetings or via written communications, to facilitate acquisition of the highest quality data and allow timely marketing of needed medications. As a regulatory agency, the FDA sees the full spectrum of drug development processes, including successes, failures, delays, and barriers. We are uniquely positioned to work with drug sponsors to provide the appropriate guidance to obtain the necessary testing needed to establish the efficacy and safety of investigational products and help identify and address the challenges of drug development.
Marketing application
Here, we focus on marketing applications for drugs that are not generics (a generic is a duplicate of a previously approved drug and is approved by relying on the FDA’s finding that the previously approved drug is safe and effective). A marketing application is a formal application that a drug sponsor submits to the FDA requesting approval to market a new product (drug or biologic) in the United States or for a new indication of an approved product. The marketing application must contain full reports of investigations about the safety and effectiveness of the drug for its intended use. This application may contain thousands of pages and includes information about the drug chemistry, quality, and manufacturing data; safety information from in vitro and animal data; clinical pharmacology data; and clinical trial data. The core review team consists of regulatory project managers, physicians, statisticians, chemists, nonclinical pharmacologists and toxicologists, clinical pharmacologists, experts in drug labeling and medication errors, epidemiologists, and inspection teams for manufacturing and clinical study sites.
Once the FDA receives the marketing application or after the application is considered fileable for review in the case of a new molecular entity, the review clock starts. For a standard review, the FDA completes a thorough review, may hold an advisory committee (AC) meeting (given below), and renders a decision regarding approval within 10 months of the start of the review clock (or within 6 months if it is a priority review). These timelines allow for the FDA’s independent analyses of the data and requests for additional information from the drug sponsor, because more information or clarifications of the existing data may be needed. Concurrent with the review of the efficacy and safety of the marketing application, the FDA also conducts inspections of selected study sites to confirm the data integrity and of manufacturing sites to ensure acceptable product quality.
Benefit and risk assessment in the Food and Drug Administration’s decision making
In deciding whether to approve a marketing application for its proposed use, the FDA determines (1) whether a drug is effective and (2) if its benefits outweigh the risks to patients. Both criteria must be met for approval. In recent years, the FDA has implemented a structured framework used to assess the benefits and risks and which serves as a standard approach for the drug review process and explains the FDA’s decisions. As explained below, this structured approach considers the context of the target condition and the available treatments, the benefits of the drug, its important risks, and strategies to manage these risks.
Analysis of the target condition and available treatment
This analysis provides the foundational context for weighing the drug’s benefits against its risks. For example, certain risks may be acceptable for a life-threatening medical condition for which there is no available therapy, whereas the same risks may be unacceptable for a symptomatic condition or for 1 where there are available therapies without such toxicities.
Assessment of benefits and risks
This assessment is based primarily on the data submitted in the marketing application. The FDA determines whether the findings from the pivotal trials adequately inform the drug’s efficacy. The FDA characterizes the safety profile by evaluating all the available data from nonclinical studies to phase 1 through phase 3 trials and the available postmarketing information (if the drug has been approved in the United States for another indication or elsewhere worldwide). Because clinical trials are conducted in a controlled setting and are limited by size, there are limitations to the available safety data, including the likelihood of not seeing more rare serious side effects or side effects that take a long time (years) to develop. Therefore, the drug’s safety profile is unlikely to be completely characterized at the time of approval. Instead, as a drug is used by many more patients and in more diverse populations postapproval, the FDA’s understanding of its safety profile will be further augmented in the postmarket setting.
Risk mitigation
All drugs have risks. The primary risk management tool is the FDA-approved drug label. The label contains all the information to ensure the safe and effective use of a drug and includes the known and potential risks and available strategies to prevent or reduce the occurrence or severity of those risks. If the drug labeling alone cannot adequately mitigate the risks, the FDA can require the development of a Risk Evaluation and Mitigation Strategy (REMS) to manage certain serious risks and would approve the drug if the REMS can ensure that the benefits of the drug outweigh its risks. In certain cases, however, drug approval is not possible because the serious risks are such that they cannot be sufficiently managed with the strongest warnings on the drug label, such as a “black” boxed warning and a REMS. A hypothetical example of such a risk requiring a boxed warning and a REMS is idiopathic, drug-induced liver failure by a drug that treats a nonserious condition and for which it is not possible to identify potential patients at risk or effective testing methods to prevent the occurrence of liver failure. A real-life example of a black boxed warning can be seen with the labeling for indomethacin, which highlights the risks for serious cardiovascular and gastrointestinal events.
The Figure and a simplified example ( Table ) illustrate the concepts of a benefit-risk assessment for a theoretical drug “Normotensive” for the prevention of recurrent preeclampsia.
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