Challenges in Conducting Clinical Research Studies in Pregnant Women

Abstract

Maternal mortality and morbidity continue to rise in the United States. Despite these trends there are limited novel interventions to investigate and improve these metrics, partly due to research protocol limitations which restrict participation of pregnant women. Inclusion of pregnant women in research studies is integral to the process of obtaining important information regarding the safety and efficacy of therapeutics or interventions to improve maternal health and pregnancy outcomes. While significant changes in research practices have resulted in an increase of female participants, there remains a paucity of research trials directly targeting pregnant and lactating women. This article provides an overview of issues surrounding inclusion of pregnant or breastfeeding women in research studies, and includes historical perspectives, navigating concerns over safety profile, considerations for appropriate development, and future perspectives.

Introduction

Despite the rise in maternal morbidity and mortality, the changing demographics and unique physiologic characteristics of women during pregnancy, pregnant and lactating women remain therapeutic orphans as they have been historically excluded from clinical drug development and research trials. The exclusion of pregnant women from clinical research was secondary to hesitancy from clinicians and researchers due to “ethical” concerns regarding possible drug-related injuries to a “vulnerable population”. In addition, exclusion of reproductive aged women by pharmaceutical companies was as much related to fears of litigation, smaller market share and limited return on investment. All of these coupled with the logistical and operational challenges in conducting research in pregnancy including recruitment hurdles, lack of healthy volunteers, the need for long-term follow-up to assess safety,¹ and the lack of regulatory support rendered has resulted in pregnant women being systematically excluded from medical interventions and therapeutics offered to non-pregnant counterparts.^2,3

Historical Perspective: Exclusion Provides a Cautionary Tale

In the 1950s, women were excluded from research studies, and data on drugs’ efficacy, safety, and pregnancy toxicity profiles were based off animal model studies.⁴ The discovery of the association between exposure to certain chemicals during gestation and birth defects led to a heightened awareness of the potential teratogenic risk from medications used in pregnancy. One of the earlier examples was diethylstilbestrol (DES). DES was taken by pregnant women at risk of miscarriages, and was later identified as a cause of reproductive tract anomalies and clear cell vaginal carcinoma in women who were exposed to it in utero.⁵ Concern regarding the risk of drug exposure in-utero was further amplified with thalidomide. Thalidomide was prescribed in the 1960’s for pregnant women with nausea and vomiting early in pregnancy. The drug’s animal testing in a chicken model did not show any teratogenic effects, however, its use in humans was later found to be associated with multiple anomalies, specifically phocomelia.⁶ The drug was banned in March 1962, and the tragedy associated around thalidomide usage served as a catalyst for the 1962 Kefauver-Harris Drug Amendment Act, which enacted stringent pharmaceutical approval and surveillance programs in the United States.

Secondary to these examples and other concerns, the 1977 guidelines on “General Considerations for the Clinical Evaluation of Drugs” set forth by the United States Food and Drug Administration (FDA), prohibited reproductive aged women and those less than eighteen years of age from participation in Phase 1 and early Phase 2 clinical research studies.^7,8 Additionally, the guidelines required pre-marketing animal testing in two different species. This was followed in 1979, by the introduction of the pregnancy category labeling system, which was implemented to provide guidance on the safety of pharmaceuticals in pregnancy, based on availability of nonclinical and clinical information. Medications were classified into five safety categories (A, B, C, D, and X) based on known or suspected concerns for toxicity risk. ^8,9

However, the unintended consequences of the purposeful exclusion of pregnant women in safety and efficacy trials resulted in the assignment of pregnancy risk categories from information gathered only from studies on animal reproductive models or men. Once the pharmaceutical agent was available for use on the market, post-marketing survey analyses were performed to reassess maternal-fetal (albeit largely fetal) risks of drug exposure in pregnancy. While often providing useful data, the process of risk characterization using post-marketing analysis to ascertain risks after the drug exposure occurred was not without fault and subject to significant bias and confounding.¹⁰

Policy and legislative changes

The need for inclusive studies to investigate treatments in premenopausal women was not formally acknowledged until the National Institute of Health Revitalization Act in 1993.¹¹ The Revitalization Act was an attempt to allow for the inclusion of women in drug sponsored trials. Overcoming the prior 1977 FDA restrictions, recommendations for the inclusion of these populations were revised to state “(1) exclusion of women from early trials is not medically necessary because the risk of fetal exposure can be minimized by patient behavior and laboratory testing and (2) initial determinations about whether that risk is adequately addressed are properly left to patient, physicians, local IRBs and sponsors, with appropriate review and guidance by the FDA.”¹² Shortly after, the FDA acknowledged the need for clinical data regarding the use of drugs in women and published the “Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs”,⁷ the Office of Women’s Health (OWH) was created within the FDA to further facilitate these efforts. In 1998, the FDA established a Pregnancy Labeling Taskforce, to reassess and improve the pregnancy category labeling system;¹³ and in 2008, released a proposal for labeling requirements,¹³ which was implemented in 2015. The final guideline, called the “Pregnancy and Lactation Labeling Rule” or PLLR, eliminated the 5 letter classification system, and required the following: a descriptive listing of the risks of using a medication during pregnancy and lactation, providing the data from human and animal studies along with the corresponding clinical considerations, and providing information about the use of drugs during breastfeeding.¹⁴ In addition, the NIH now mandates inclusion of women and minority populations in all NIH-funded research proposals “unless a clear and compelling rationale and justification establishes to the satisfaction of the relevant Institute/Center Director that inclusion is inappropriate with respect to the health of the participants or the purpose of the research.”³

Despite the updated guidelines, set forth by the National Institutes of Health (NIH) and FDA since 1993, which aimed for the inclusion of women in clinical trials, there remains a paucity of trials, particularly early phase 1 and phase 2 clinical trials, to determine safety and dose response for medications used in pregnancy and during lactation.^15,16 Though some restrictions have been eased, additional changes are needed to address remaining limitations to that inclusion of women in research, such as the burdensome contraceptive requirements and definitive exclusion and/or removal in event of pregnancy.³ (Details on guidance in the European Union are discussed elsewhere)^17,18

Current state of affairs

Over the past four decades, the use of medications in pregnancy continues to increase,^15,19,20 with almost half of pregnant women currently reporting use of 4 or more medications, over-the-counter products, or supplements at any time during their pregnancy.^20,21 Additionally, there is significant increase in the use of medications in the first trimester of pregnancy, with a recent study showing that the average number of medications used is 2.6 and that at least one third of pregnant women use at least four medications in the first trimester.^15,20 With many women unaware of their pregnancy status, and with the first trimester being a crucial period for fetal organ and placental development, this trend is concerning. While many women try to avoid using drugs during pregnancy and lactation, approximately 25% of women enter pregnancy with a preexisting medical condition (e.g. asthma, hypertension, diabetes, seizures, depression, cancer etc), or develop a pregnancy-specific morbidity such as hyperemesis, gestational diabetes, or preeclampsia that may require drug therapy.^2,15,20,22

Despite the above, pregnant women are still considered therapeutic orphans as the majority of current accepted therapies for medical conditions were never studied in pregnancy. When reviewing labeling and manufacturing information for current medications, most do not include adequate information regarding their use in pregnancy or during lactation. The number of pharmacokinetic studies aimed at studying dose response and safety in pregnant woman has remained very low, representing approximately 1.29% of registered studies despite the overall increase of pharmacokinetic studies registered from the 1960s to 2013 in the US.^15,16 The limited pharmacokinetic and safety studies for therapeutics in pregnancy show most drugs introduced into the market are not studied within the pregnant population prior to obtaining authorization from the FDA. From 2000 to 2010, 97.7% of medications approved for usage by the US FDA included insufficient evidence regarding teratogenic risk, and 73.3% provided no data supporting their usage in pregnancy.²³ In addition, a review of the labeling data of 213 new FDA approved therapeutics showed that only 5% of them included human data in their pregnancy section, and almost half did not have any breastfeeding data.²⁴ As the majority of medications lack data supporting their use in pregnancy, providers are relying on efficacy and safety data from research studies performed in men and non-pregnant women and assuming generalizability of the results to pregnant women. The assumption of generalizability raises concerns for safety and of disparities related to pregnant women not receiving the same level of evidence-based care as other populations.^2,15

Moreover, careful examination of past studies and historical events including thalidomide exposure, points to the need for more controlled evidence-based considerations in premarket research studies rather than research observations which come after the exposure of large numbers of pregnant women. While fetal safety profile is the most cited reason for the exclusion of pregnant women and those who could become pregnant from research studies, experiences as described above reflect the need for the inclusion of pregnant women; it is therefore unethical to preclude pregnant women from carefully designed clinical therapeutic research studies. It is hypothesized that if appropriate early phase studies of thalidomide had been conducted in pregnant women; the adverse pregnancy outcomes associated with the medication would have been significantly decreased.^2,3,25 In addition, exclusion of pregnant and premenopausal women from clinical research especially as it relates to drug development has created a knowledge void on drugs’ safety and efficacy in pregnant women. Pharmacokinetic and pharmacodynamics properties of drugs differ between not only men and women but are greatly influenced by the physiologic changes during pregnancy and postpartum.²⁶ Thus, there is a need for clinical trials to explore efficacy and safety of drugs specifically in pregnant and lactating women.^3,15 As changes in maternal physiology continue throughout gestation and the fetus is constantly developing, drug studies should ideally include women in all trimesters of pregnancy if clinically applicable, as the efficacy and safety may differ based on the timing of exposure.

Overcoming research obstacles in “vulnerable” populations

Despite significant changes in research design, and pharmaceutical and governmental regulatory practices, knowledge gaps continue due to lack of inclusion of pregnant and breastfeeding women, in premarketing early stage clinical research trials. While no longer medically relevant, the stigma of women especially those who are pregnant or breastfeeding as a “vulnerable population” needing protection from exploitation research studies has hindered progression of care.²⁷

Similar to pregnant women, the pediatric population was challenged by the barriers of obtaining adequate research to garner robust data to drive pharmaceutical therapies. Evaluation of therapeutic agent’s safety profiles, appropriate dosing, and effective response is integral to the treatment of pediatric disorders given known physiologic differences in the pediatric population. Clearly pharmacokinetic trials with men and women will have different results due to the differences in adult size, body composition, metabolism, and developmental differences. Applying results from these studies to the pediatric populations is flawed for the same reasons as the results would not be generalizable.^1,2,28,29

After recognition of the knowledge gaps in pediatric population, the NIH required inclusion of children in clinical, social, and behavioral research in 1994.¹ Federal legislations included the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act.¹ These regulatory changes coupled with innovative research design protocols lead to significant gains in pediatric research over the past fifteen to twenty years.¹ Trial designs for pediatric research studies are notable for using an abundant number of recruitment sites for maximum enrollment, testing multiple treatments within a single protocol as applicable, using innovative pharmacokinetic, pharmacodynamic, modeling and simulation, and sampling techniques. These adaptations have allowed for the timely collection of clinical data while maximizing information obtained from each individual participant. These seemingly small, albeit significant changes in overall research design have led to the development of feasible study protocols, which are gaining acceptance among institutional research approval boards, and parents of study participants. Following the innovations and adaptations outlined in pediatric studies, research protocols for pregnant and breastfeeding women could be adapted to provide similar efficiency and minimal risk models. For example, while conventional pharmacokinetic studies are difficult to perform in pregnancy and during lactation due to logistical and practical issues, pharmacometric approaches such as population pharmacokinetics, simulation, sparse data sampling, or physiologically based pharmacokinetic studies might be alternative study designs.^1,2 Examples of the utility of population pharmacokinetic s in pregnancy are discussed elsewhere.^2,30

Integral to ensuring adequate inclusion of pregnant women in studies, the Task Force for Research Specific to Pregnant Women and Lactating Women was convened per the Federal Advisory Committee Act for the sole purpose of providing guidance to the Secretary of Health and Human Services in addition to Congress regarding improving research efforts for this population. In May 2018 the task force, commonly referred to as PRGLAC, held open forums to the public to hear the current state of affairs regarding research in pregnant and lactating women and was responsible for the executive report to the Secretary and Congress with recommendations specific to breastfeeding and pregnant women.^31,32 The PRGLAC developed 15 recommendations based on expert opinion, public commentary, and collateral information gathered from the meetings. Recommendations were centered around the inclusion of pregnant women, removing the barriers, and changing the stigma around research studies for pregnant and lactating women. It also emphasized the importance of improving the scientific knowledge to assess therapeutic safety, dosing, and effectiveness of medications during pregnancy and lactation, in order to improve the overall public health.^31,32

Aligned with the central goal to increase the inclusion of pregnant and breastfeeding women, the Task Force for Research Specific to Pregnant Women and Lactating Women has focused on supporting the removal of this population from the “vulnerable” populations distinction, and promoting a cultural shift within the research community to view this population as more “scientifically complex.”^3,27 Pregnant women should be permitted to determine their eligibility and entry into a research study based off of the principle of informed consent. Excluding pregnant women from research studies under the guise of the “vulnerable populations” label, places a restraint on their right to autonomy. Additionally, this exclusion deprived pregnant woman as a whole from benefiting from research endeavors from which valuable information can be derived.

Assessment of the safety profile while balancing maternal and fetal benefit

A principle of safety is of the utmost importance when it comes to research studies in any population. Given the sensitive nature of pregnancy, it is easy to understand the ethical concerns related to the inclusion of pregnant woman in research studies. An additional challenge is that clinical trials involving pregnant women require long-term follow-up in order to adequately assess not just fetal and neonatal outcomes, but potential effects on childhood health and behavior. When considering the safety profile of medications, it is important to consider a risk benefit approach for both the mother and fetus. While one must consider the safety of a drug in pregnancy, it is equally important to consider the risks of not- or inadequately treating pregnant mothers. It is crucial that the sequelae of lack of treatment be weighed against the risks of treatment.¹² Therefore, a risk-benefit ratio approach needs to be considered, and during pregnancy, the safety profile to both mother and fetus must be considered. Moreover, it is important to differentiate between medications used to treat chronic conditions as opposed to those needed for the acute management of life-threatening conditions.¹²

While maternal and fetal risks are intricately connected during the antenatal period and must be considered for research studies, investigating measures to treat diseases for maternal benefit is of utmost importance, especially that women who are becoming pregnant, are more “medically complex” than in the prior decades. This is related to medical advancements that have prolonged the lives of women with previously considered fatal diseases (e.g. organ transplantation, cystic fibrosis, cancer), increased usage of assisted reproductive therapy, and advanced maternal age as women are delaying childbirth for a myriad of reasons.¹⁵ Therefore, the increased medical complexity of pregnant women, which often lead to increased risk of morbidity and mortality, need to be considered in any discussion about the use of therapeutics in pregnancy, especially that the majority of medications were never tested in pregnant women specifically.^2,3,12,15

Studying Pravastatin for the prevention of preeclampsia

When developing clinical trials involving medications in pregnant and lactating women, preclinical studies ought to be performed to inform the design of the clinical trial.²⁶ Depending on whether the drug is a new compound being developed or an existing one being repurposed, these preclinical studies may include animal embryo-fetal toxicity and toxicokinetic studies, and in-vitro placental transfer studies. In fact, the United States Office for Human Research Protections requires that researcher provide data on potential maternal and fetal risks from preclinical studies that use a pregnant animal model as well as clinical studies in nonpregnant women where “scientifically appropriate” in order to justify inclusion of women and fetuses. The investigation of pravastatin for the prevention of preeclampsia serves as an example.³³

Currently, a leading cause of pregnancy related deaths in the U.S. are cardiovascular conditions such as cerebrovascular events, cardiomyopathy, heart failure, and sudd³⁴en cardiac death,³⁵ with hypertension and preeclampsia being a significant factor contributing to increased short- and long-term maternal morbidity and mortality. Preeclampsia complicates 3–5% of pregnancies, and due to its significant impact on maternal and neonatal morbidity and mortality, research investigations for interventions to prevent or treat preeclampsia are crucial. Moreover, preeclampsia and atherosclerotic cardiovascular disease share similar pathophysiologic pathways such endothelial dysfunction, inflammation, and common risk factors.³⁴ Due to the similarities between preeclampsia and adult cardiovascular disease, and the significant benefit of 3-hydroxy-3 methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in preventing cardiovascular morbidity and mortality, through lipid lowering, and pleiotropic actions,^12,36 we and others sought to investigate the utility of statins to prevent preeclampsia in high-risk pregnant women.³⁴

When first introduced in 1987, as a medication class for the treatment of hypercholesterolemia, statins were labelled as pregnancy “category X”. This indicates that “studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risks based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnancy women clearly outweigh potential benefits.”⁸ Given initially to lovastatin, this classification was largely based on the assumption that pregnant woman would not benefit from using statins in pregnancy. Cardiovascular disease is a chronic condition, and it was assumed that there is no harm from stopping statins for the short duration of pregnancy. In addition, there were theoretical concerns regarding cholesterol synthesis, and small case series showing congenital malformations with lipophilic statins.³⁴ However, this classification was never revised for subsequent statins despite increasing data suggesting no increased teratogenic risk with hydrophilic statins.^37–41

Pravastatin, a hydrophilic statin, was demonstrated in various animal models and in-vitro studies to reverse the pathophysiological pathways associated with preeclampsia.^42,43 Moreover, accumulating evidence did not support its teratogenicity or increased risk of maternal harm.^41,44 However, prior to launching large scale studies investigating its role in preeclampsia prevention, mechanistic and in-vitro placental transfer studies ^45,46 were conducted. In addition, studies were conducted to evaluate the long-term neurodevelopmental and metabolic outcomes of pups born to dams exposed to pravastatin.^47–49 Last, pilot phase I and II, dose finding, and escalating studies were conducted to determine the safety and pharmacokinetic profile of the drug in high-risk pregnant women, defined as those with history of preeclampsia in a prior pregnancy that required delivery before 34 weeks. Whereas lowering cholesterol concentrations is a major goal in cardiovascular protection studies, data from murine preeclampsia models and the pathophysiology of preeclampsia suggest other mechanisms of action of pravastatin including reversal of angiogenic imbalance, endothelium protection, and reduction of inflammatory and oxidative stress.³⁴ Data from the pilot trials, including pharmacokinetic and pharmacodynamic outcomes, as well data from other observational studies⁵⁰ helped inform the design of a clinical trial.²⁹ The road to repurpose a medication in pregnancy is full of challenges including logistical hurdles, issues of potential fetal risk, altered maternal-fetal pharmacokinetics and pharmacodynamics, and navigating regulatory guidelines. This systematic evaluation of pravastatin use in pregnancy is an example of an approach involving a multidisciplinary group of experts in basic and clinical pharmacology, research methods, pregnancy physiology and maternal fetal medicine, to address the above challenges.

Conclusion

Due to directed efforts at the government and institutional levels, more women are included in clinical research trials. This resulted in improved health information regarding diseases and treatment outcomes, as they pertain to women. Continued emphasis for the inclusion of pregnant and lactating women, is needed to close the knowledge gap especially in view of the increasing morbidity and mortality in pregnancy. While pregnant women are medically complex, appropriately designed research studies can be conducted in this population. Safe development of new, and repurposing of old pharmaceuticals for use in pregnancy, can safely be achieved with a stepwise investigation of the drug that includes a progression from the research bench, translation studies, early phase, pragmatic clinical trials, and the institution of innovative study designs. Further efforts are needed to continue the intentional recruitment of pregnant women in research studies, and address barriers preventing them.