1
Introduction
Ideally, all people who become pregnant and desire to remain pregnant would have healthy pregnancies, birth healthy babies, and have the ability to provide human milk to their children. However, some pregnant people get sick, and some sick people become pregnant. To ensure the health and well-being of pregnant and lactating women and their fetuses and newborns, evidence is needed on the safety, effectiveness, and proper dosage of medical products that these individuals may need to take during the perinatal period. Sufficient data on safety and effectiveness allow health care providers and patients to make informed decisions about an intervention’s potential benefits and risks. In the face of insufficient evidence, a health care provider and a patient are in a difficult position: A decision to forgo an intervention may result in harm from an untreated or unprevented condition, while a decision to use an intervention puts the patient, the fetus, and the child at an uncertain risk of harm for an uncertain benefit.
That is precisely the situation that commonly confronts pregnant and lactating women when making decisions about therapeutic or preventive interventions. Although pregnancy and lactation are physiologically unique, pregnant and lactating patients and their clinicians must usually rely on data derived from clinical studies in nonpregnant and nonlactating adults, and preclinical studies in pregnant and lactating animals (Byrne et al., 2020). On an individual level, the evidence gap leads to avoidable harm to pregnant and lactating women and their offspring when a medication’s dosage makes it ineffective, when its harm
outweighs its expected benefits, or when the lack of safety data leads a patient to reject a medication that would have been helpful. On a population level, the evidence gap affects pregnant and lactating women’s access to safe, effective, and timely therapeutic and preventive measures, reduces the ability to develop responsive policies to identify and address health priorities in pregnant and lactating women and their children, and exacerbates existing health inequities.
Society benefits from the knowledge generated through clinical research. Data gathered through clinical research enable the development of safer and more effective therapies and vaccines, promote safer and more effective use of those medical products, and improve human health and health equity. Conducting clinical research with pregnant and lactating women allows these populations to experience the same benefits afforded to other populations who have data available on the dosage, safety, and efficacy of medical products. Because of the direct link between the health and well-being of pregnant and lactating women and that of their fetuses and children (Harris, 2000), children also stand to benefit from clinical research conducted with pregnant and lactating women. To improve maternal health, as well as newborn health and survival, it is imperative that pregnant and lactating women be included in clinical research.
This chapter begins with a discussion of the social benefits of research involving pregnant and lactating women and is followed by an exploration of the human cost of inadequate data, explores the sources of the inadequate data, provides a background to the study, and ends with the committee’s approach to their charge.
THE HUMAN COSTS OF INADEQUATE DATA
Pregnant and lactating women with acute or chronic conditions must make difficult decisions about their health every day. These difficult decisions are compounded by a widespread lack of evidence on the dosage, safety, and efficacy of medical products in these populations, leaving health care providers and the more than 3.5 million patients who give birth each year and the more than 3 million patients who breastfeed in the United States without the critical evidence needed to make informed treatment decisions (Osterman, 2023). These issues are further complicated for racially minoritized pregnant and lactating women, specifically Black and American Indian and Alaska Native populations, who, owing to systemic and structural factors such as racism, bias, and inequitable access to health care, experience higher rates of maternal mortality and morbidity (Hill et al., 2022) and lower rates of breastfeeding initiation, duration, and exclusivity (Jones et al., 2015).
Inadequate data harm pregnant and lactating women, who have different physiological states, as well as the fetuses and breastfeeding children who are not only affected by drug exposure, but also the health of the pregnant or lactating woman. Although the committee briefly mentions women of reproductive age who could potentially become pregnant to appreciate the scope of the problem, pregnant women and lactating women are the focus of this report.
The Preconception Period
The preconception period includes women of reproductive age who may either have an unplanned pregnancy or who are preparing to become pregnant sometime in the future. Data reported from 2018 identify close to 73 million U.S. women of reproductive age (Guttmacher Institute, 2021).1 Although many of these individuals are not intending to become pregnant, some are either seeking to become pregnant or may have an unplanned pregnancy. Many are taking medications before they become or know they are pregnant, often for chronic conditions. More than half of American adults have at least one chronic condition (Boersma et al., 2020), and most, if not all, individuals affected by chronic conditions require some type of medication or treatment, with adherence to the treatment being essential for optimal health (Unni, 2023).
While it would be inappropriate to treat all women of reproductive age as being potentially pregnant, clinicians treating potentially pregnant women face challenges prescribing medications to these individuals without data on their safe use during early pregnancy. Early pregnancy is a time of physiological changes in the pregnant woman and the start of fetal development. Without human data on medication use during this critical period, clinicians must make treatment decisions for their patients without knowing how medication use during this period may affect any potential future pregnancies. However, only 11 percent of drugs approved between 2010 and 2019 included human data to guide prescribing for pregnant women (Byrne et al., 2020), which makes preconception prescribing difficult.
Further challenges arise for unintended pregnancies, which make up over 40 percent of all pregnancies in the United States (CDC, 2023c). Teenagers and women in their early 20s are groups with higher proportions of unintended pregnancy. Unintended pregnancies are associated with a higher risk of exposure to teratogenic substances—a substance capable of causing congenital malformations (Han et al., 2005). A recent study
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1 Article defines reproductive age as 15–44 years.
found that 1 in 16 women took a known or potentially teratogenic agent during pregnancy, with elevated risk of prenatal exposure in teenagers and women 45 and over (Sarayani et al., 2022). Without human data on the effects of medical products in early pregnancy, clinicians are unable to provide the best health care and cannot address potential harm in treating women who are intending to or may become pregnant.
Pregnancy
More than 3.5 million women give birth annually in the United States (CDC, 2023a), and as of 2019, there were an estimated 5.5 million pregnancies each year (HHS et al., 2023). Ninety percent of pregnant women reportedly take some type of medication during pregnancy, with 70 percent taking a prescription medication (Mitchell et al., 2011). It is not uncommon for pregnant women to take multiple medications—13 percent report taking five or more prescription medications (Haas et al., 2018). The medications taken by pregnant women may be for a preexisting condition or for a condition related to pregnancy (see Box 1-1).
Pregnancy leads to a number of physiological changes across all three trimesters that can affect how the body handles and responds to medications, including changes in the cardiovascular, respiratory, gastrointestinal, metabolic, and renal systems (Kepley et al., 2023). Box 1-2 describes these physiological changes throughout different trimesters in greater detail. Despite these physiological changes, very few medications approved by the U.S. Food and Drug Administration (FDA) have human pregnancy data available, though most (90–93 percent) have pregnancy safety data from animal models (Byrne et al., 2020; Mazer-Amirshahi et al., 2014). From 2010 to 2019, only 11 percent of approved medications had human pregnancy data available (Bryne et al., 2020). Moreover, there is insufficient development of treatments for conditions specific to pregnancy, such as gestational diabetes and preeclampsia (Caritis and Venkataramanan, 2021).
This lack of human data has serious consequences for pregnant women and their fetuses. Without data on proper dosage, safety, and efficacy on medication use in pregnant women, health care providers and their patients must make difficult decisions about whether to use a medication to manage health without safety information or discontinue a medication and potentially put the pregnant woman’s health and the health of the fetus at risk. In a patient story submitted to the committee, one patient with rheumatoid arthritis (RA) described this difficult decision:
For my second pregnancy, which began in 2013, I was also advised to stop all of the medications that I had been using to control my RA. Unfortunately, this time my RA flared badly during pregnancy. By the time
BOX 1-1
Common Conditions and Treatments in Pregnancy
The Centers for Disease Control and Prevention (CDC) identified the most common complications during pregnancy; they are anemia, anxiety, depression, diabetes (including gestational diabetes), heart conditions, high blood pressure (including preeclampsia), nausea and vomiting, and infections (CDC, n.d.). Each of these conditions may require therapeutic interventions. Pregnant women are at least as susceptible to conditions and diseases as the general population, but when compared to nonpregnant women, pregnant women are more likely to be severely affected by infections. Examples include the influenza virus, hepatitis E virus (HEV), herpes simplex virus (HSV), and malaria parasites (Kourtis et al., 2014). Additionally, pregnant women were hospitalized for COVID-19 infections at a higher rate than nonpregnant women (Ellington et al., 2020).
In addition to infectious diseases, pregnant women are also at higher risk of developing or worsening chronic conditions during pregnancy. A study of 8.1 million hospital deliveries in the United States found that over 600,000 pregnant women (7 percent) had at least one common chronic condition (Admon et al., 2017). For example, from 2013 to 2014 the rate of asthma was 40 cases per 1,000 hospital deliveries, 23.6 cases per 1,000 for chronic hypertension, and 10.3 cases per 1,000 for preexisting diabetes. The prevalence of multiple chronic conditions in pregnancy was 8.1 per 1,000 hospital deliveries (Admon et al., 2017).
According to Medicaid prescription data, the most commonly dispensed medications during pregnancy were for infections, including nitrofurantoin (21.6 percent), metronidazole (19.4 percent), amoxicillin (18 percent), azithromycin (16.9 percent), and promethazine (13.5 percent) (Palmsten et al., 2015). Of the previously listed drugs, only amoxicillin has controlled human data in pregnancy and lactation (FDA, 2006). Animal studies have been completed for the others, two of which have documented adverse effects on animal fetuses (promethazine, nitrofurantoin) (FDA, n.d., 2009). The FDA Office of Women’s Health is currently funding research to describe the drugs that pregnant and lactating women commonly use, and changes in use trends over time (FDA, 2021).
I hit my third trimester, I was struggling so significantly that my doctors advised me the uncontrolled inflammation in my body was more of a risk to my baby than restarting my RA medications would be. Based on pretty limited data, I ended up restarting the same biologic I had been advised to avoid during my first pregnancy. This was a very uncomfortable and difficult decision to make.
Because evidence in humans has not been generated on the safety, efficacy, and dosing for medical products during pregnancy, some individuals will decide to forgo use of a medical product that would benefit their health and support the development of a healthy fetus. Others may decide to continue use of a medical product and find that the dose that they used prior to becoming pregnant is no longer providing effective treatment (Little and Wickremsinhe, 2017).
Box 1-2
Physiological Changes and the Implications for Use of Medications
During pregnancy and lactation, there are dramatic changes in the body’s physiological processes, and these changes have implications for how medical products are absorbed, metabolized, distributed, and eliminated by the body. These changes occur during and throughout the stages of pregnancy and during the postpartum period. Thus, it is critical that pregnant and lactating women be included in clinical research to better understand how medications may affect pregnant and lactating women and women who are not pregnant and lactating differently and to help guide clinical decision making.
Physiological Changes During Pregnancy
Physiological changes begin immediately upon fertilization and affect nearly all systems in the body, including the endocrine, cardiovascular, respiratory, hematologic, renal, and gastrointestinal systems (Kepley et al., 2023). These changes include the following:
Endocrine: Rising levels of hCG stimulate the production of progesterone and estrogen and prevent further ovulation, while other hormones also rise, including thyroid-stimulating hormone for brain development, and prolactin to stimulate milk production. Increased levels of relaxin allow connective tissues to soften, and the body produces mores endorphins to counteract labor pain.
Cardiovascular: Changes in the cardiovascular system include increased heart rate, stroke volume, cardiac output, and decreased vascular resistance. Increased cardiac output directs blood to the uterus, placenta, kidneys, skin, and extremities; the increase in blood flow contributes to a rise in skin temperature.
Respiratory: Increased pressure from the enlarging uterus decreases residual volume and expiratory reserve volume, but an increase in inspiratory reserve volume keeps vital capacity the same as prepregnancy levels. Respiration is stimulated by higher levels of progesterone and can lead to hyperventilation.
Hematologic: Blood volume increases by around 1.5 liters during pregnancy, and red blood cell mass increases by approximately 30 percent; these changes help deliver oxygen to the fetus but increase the need for iron. As pregnancy progresses, elevated levels of clotting factors increase the risk of deep vein thrombosis.
Renal: Increased blood flow to the kidneys during pregnancy results in increased glomerular filtration rate (GFR) and renal plasma flow. Increases in progesterone and relaxin lead to dilation of the urinary collecting system, increasing the risk of urinary tract infections and pyelonephritis with asymptomatic bacteriuria.
Gastrointestinal: Multiple factors present in pregnancy—including delayed gastric emptying, increased small bowel transit time, reduced muscle tone of the lower esophageal sphincter, and compression attributable to uterine growth—make gastroesophageal reflux disease common in pregnant women.
Implications for Medication Use
These changes and many others that occur during pregnancy have implications for the safety and efficacy of medications, owing to changes in the absorption, metabolism,
distribution, and elimination of drugs (Eke et al., 2023). The implications are too numerous to list here; the following includes selected examples:
Absorption: Drug absorption can be affected by pregnancy-related physiological changes, and these effects vary by route of administration. For example, increased blood flow may affect the absorption of injected drugs (Eke et al., 2023). Delayed gastric emptying may affect orally administered medications, while the absorption of inhaled medications is enhanced owing to increased blood flow (Eke et al., 2023).
Metabolism: The actions of drug metabolizing enzymes, including cytochrome P450, UGT1A4, and CBR1, have been shown to change during pregnancy, with some increasing in activity and others decreasing (Tasnif et al., 2016). CYP450 enzymes are responsible for metabolizing around 75 percent of all drugs in current clinical use (Zanger and Schwab, 2013), so understanding the action of these enzymes is critical for the safe and effective use of medication in pregnant and lactating women.
Distribution: Increases in body weight, fat stores, and blood volume affect how drugs are distributed throughout the body. For example, there are substantial differences between pregnant and nonpregnant women in the distribution of buprenorphine, a lipophilic partial opioid agonist used to treat individuals with substance use disorders (Eke et al., 2023).
Elimination: Many systems are involved in drug excretion, but kidneys are the primary organ for elimination. During pregnancy, the increase in renal blood flow, plasma flow, and GFR increases the excretion of most drugs (Eke et al. 2023). The increase in renal clearance can lead to subtherapeutic levels of renally eliminated drugs (Kepley, 2023).
Lactation and Medication
The safety and effectiveness of medications are affected by the physiology of lactating women and their children, as well as the properties of human milk. Lactating women undergo physiological changes such as increased blood flow to the breasts; increased bone loss; and changes to the intestinal, renal, metabolic, and hormonal systems (Canul-Medina and Fernandez-Mejia, 2019). These changes may affect drug metabolism and distribution. However, the major concern during lactation is the transfer of medication into the breast milk and subsequently into the infant. Whether and how much medication transfers to the infant depends on maternal serum concentration and the pharmacologic properties of the medication (Spencer et al., 2022). The effect of drug exposure on the infant is largely dependent on age and size; neonates in particular have physiological differences that affect drug absorption, metabolism, and elimination (Alcorn and McNamara, 2002). However, approximately 90 percent of marketed drugs are considered safe for breastfeeding given the dose received by infants in human milk (Newton and Hale, 2015).
Lactation
According to the Centers for Disease Control and Prevention’s (CDC) Breastfeeding Report Card, 2022, of those infants born in 2019, 83 percent started out receiving human milk, with almost 79 percent receiving any human milk at 1 month and 56 percent at 6 months (CDC, 2022b). A small U.S. study from 2007 found that nearly all the breastfeeding women enrolled in the study used at least one medication (Stultz et al., 2007). Larger studies conducted abroad suggest that at least 50 percent of breastfeeding women take at least one medication (Saha et al., 2015). Many of these women are concerned about taking medications while breastfeeding and the effects it can have on their child (Etzel and Ambizas, 2022). For the vast majority of drugs, the amount of medication that enters human milk does not reach a level that is dangerous for the breastfeeding child (Halesmeds, 2022; Medsafe, 2015). However, the challenge is to determine which ones may be hazardous. Drugs are primarily transferred into human milk through passive diffusion, but other factors can also affect the maternal plasma-to-breast drug transfer, including maternal concentration of a drug and human milk fat content, as well as a drug’s half-life, acidity, molecular weight, lipid solubility, degree of protein binding, and other physiochemical properties (see Box 1-2 for details). The exposure to medications in human milk vary over the course of the phase of lactation and infant feeding, with exposure decreasing as babies wean off human milk.
Those who are lactating may be taking medications for preexisting or lactation-specific conditions. However, similar to pregnancy, very few medications have human lactation data. From 2010 to 2019, 48 percent of approved medications had labels with no data on lactation, 49 percent had animal data, and less than 5 percent had human data (Byrne et al., 2020). Without human safety data in lactation, many lactating women may choose to cease lactation to take a medical product for their health or continue lactation and delay treatment of their health condition.
These decisions have consequences for both the health of the lactating mother and their breastfeeding child. A predictive model estimates that breastfeeding for less than the recommended first 6 months of a child’s life produces excess maternal and infant mortality and increased health care costs (Bartick et al., 2017). Human milk provides the baby protection against critical infections and inflammation while contributing to improved infant immune response, gut microbiota, and organ development. For the lactating mother, breastfeeding can reduce the mother’s risk of breast and ovarian cancer, type 2 diabetes, and high blood pressure (CDC, 2023b). Further, some conditions left untreated because of fear of medication use while breastfeeding can negatively affect the child as well as the mother. For example, untreated postpartum depression can affect the development of the child and can cause delays in language development, learning problems, increased crying or agitation, and behavioral problems (Stein et al.,
2014). Without evidence from clinical studies in humans on the safety of medication use during lactation, health care providers and their patients are not able to make informed decisions on their health.
CIRCUMSTANCES THAT HAVE LED TO INADEQUATE DATA TO GUIDE MEDICAL DECISION MAKING
There is growing recognition that multiple populations, such as older adults, people living with multiple chronic conditions, and pregnant and lactating women, are unjustifiably excluded from clinical studies (Shore et al., 2024). Inadequate data to inform the treatment of pregnant and lactating women is not a problem unique to the United States, as countries around the world are similarly struggling with limited data for these populations (Manningham-Buller and Brocklehurst, 2022; Thurin et al., 2022). There is a growing international consensus that the responsible and ethical conduct of clinical research with pregnant and lactating women is essential to generate reliable scientific data on dosage, safety, and efficacy. Public calls for inclusion have come from groups ranging from the World Health Organization, the Pan American Health Organization, and the Council for International Organizations of Medical Sciences, to the American College of Obstetrics and Gynecology (CIOMS and WHO, 2016; NICHD, 2018; PAHO and WHO, 2016; WHO, 2023b).
In the United States, researchers and advocacy groups—including the Zika and Beyond: Pregnancy, Research, and Public Health Ethics (PREVENT) and Pregnancy + HIV/AIDS Seeking Equitable Study (PHASES) projects of the Second Wave Initiative, (UNC, 2017), and the Coalition to Advance Maternal Therapeutics (CAMT)—have called for the inclusion of pregnant women in clinical research. In fact, both PREVENT and PHASES offer guidance on how to achieve ethical inclusion of pregnant women in clinical research. The exclusion of pregnant and lactating women from clinical studies has resulted in a dearth of evidence on the safety, efficacy, and dosing of medical products that are used or could be used by these populations. Without sufficient evidence generated through clinical research, pregnant and lactating patients and their clinicians must make decisions about treatment with medical products while not being able to fully assess the benefits and risks of treatment for their own health or that of their fetus or child.
For much of the latter half of the twentieth century, clinical research failed to adequately include women generally, and women of childbearing potential specifically (Merkatz, 1998). Following the revelations of the in utero harms from thalidomide use (see Chapter 2), research involving women of childbearing potential was deemed to be too risky for fear of harming developing fetuses if the research participant were to become pregnant during the study. In 1977, FDA issued guidance recommending
against including women of childbearing potential in early phases of clinical research (FDA, 1977). However, in the years that followed, scientific and public concern grew that using data from clinical research conducted in White males lacked scientific validity for the diverse populations that would go on to use the medical products after approval (IOM, 1994b).
In response, Congress passed the National Institutes of Health (NIH) Revitalization Act in 1993, which required that women and racial and ethnic minority populations be included in clinical research supported by NIH.2 Progress has been slow and unequal. Though the representation of White women in clinical research has improved, other groups, such as racial and ethnic minority groups, older adults, and pregnant and lactating women are still underrepresented in clinical research (NASEM, 2022).
In 2016, Congress addressed the lack of human data on medical products used during pregnancy and lactation when it established the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC Task Force) in the 21st Century Cures Act (Public Law 114-255). This task force was asked to identify gaps in research and knowledge, examine ethical issues, and make recommendations for the safe and effective use of medical therapies in pregnant and lactating women. The PRGLAC Task Force recommended that “this trajectory of exclusion be altered to include and integrate pregnant women and lactating women in the clinical research agenda” and presented 15 recommendations for conducting this research. Further, several international health groups, outlined in Box 1-3, have ongoing efforts to establish broader inclusion of pregnant and lactating women in clinical research.
One reason there is a lack of research involving pregnant populations is concern about fetal safety that reinforces decisions not to include pregnant women in clinical research. For example, the lack of human data on the safety of medical products in pregnancy creates anxiety about the unknown risks to the fetus, which causes sponsors and researchers to be hesitant about conducting research involving pregnant women, and ultimately leads to the continued dearth of dosing, safety, and efficacy data of medical products in pregnant women (Santye, 2016). However, the ethical concerns and potential risk of harms for lactating women are far less than for pregnant women, since the overwhelming majority of on-market products pose little risk to breastfeeding children, given their low concentrations in the breast milk (see Chapter 3 for further discussion).
A number of groups have now examined the ethics of conducting research involving pregnant and lactating women, and they have concluded that there is an ethical requirement to responsibly include pregnant and lactating women in research (Baylis and Ballantyne, 2016; IOM, 1994a; Krubiner et al., 2021; Lyerly et al., 2021; NASEM, 2023; NICHD,
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2 Public Health Service Act., Public Law 103-43, 103d Cong. (June 10, 1993).
BOX 1-3
Global Efforts for Broader Inclusion of Pregnant and Lactating Women in Research
There are growing efforts globally to address the health needs of pregnant and lactating women through research. Although this is not an exhaustive list, it is meant to show the growing international consensus that involving pregnant and lactating women in research is essential.
Council for International Organizations of Medical Sciences (CIOMS): In 2002, CIOMS released updated guidelines that stated that pregnant women should be eligible for participation in research (CIOMS, 2002). Their 2016 guidelines, prepared in collaboration with WHO, states that “Research designed to obtain knowledge relevant to the health needs of the pregnant and breastfeeding woman must be promoted” (CIOMS and WHO, 2016).
World Health Organization (WHO): In 2022, the World Health Assembly adopted resolution 75.8, which notes that “clinical trials on new health interventions are likely to produce the clearest result when carried out in diverse settings, including all major population groups the intervention is intended to benefit, with a particular focus on underrepresented populations.”
In a supplementary report on the resolution, WHO notes that this includes “in particular pregnant and lactating women.” WHO is now moving forward with a series of meetings focused on implementation strategies for this resolution (WHO, 2023b).
International Council on Harmonization (ICH): Inclusion of pregnant and breastfeeding individuals in clinical trials (E21) was endorsed as a topic by the ICH assembly in 2022. The goal of this guideline working group is to “provide a globally accepted framework and best practices to enable inclusion and/or retention of pregnant and breastfeeding individuals in clinical trials.” This working group will put out a technical document in late 2024. FDA is a member of ICH and is involved in the development of the guidelines (ICH, n.d.).
Global Forum on Bioethics in Research (GFBR): Research in pregnancy was chosen as a topic for the 2016 GFBR meeting, given the 2016 Zika outbreak. One of the consensus themes that emerged from this meeting was that pregnant women should not be excluded by default and “should be included in research unless there are valid reasons specifically to exclude them” (Hunt et al., 2017).
2018; van der Graaf et al., 2018). Expanding clinical research to include pregnant and lactating women and developing the necessary data for treating these populations have clear benefits for pregnant and lactating patients and their health care providers, and the benefits of conducting this research expand beyond the pregnant and lactating population.
THE SOCIAL VALUE OF CLINICAL RESEARCH
The potential for societal value—the provision of benefit to society through innovative technologies and medications that improve health—is the primary commitment of biomedical and scientific research (NASEM, 2019). Promoting societal value implies not only direct health benefits for
some but also potential improvements in health equity. Health equity is defined as all people having the opportunity to achieve the highest level of optimal health and well-being (CDC, 2022a; WHO, 2023a). Clinical research is a means through which society understands human health and works toward achieving health equity. The generalizable evidence gained through biomedical discovery, development, and clinical research leads to new medical products that detect disease, reduce human suffering, improve well-being, and save lives. Ultimately, to justify exposing people to potential harms through clinical research, research must have some societal value or benefit (Emanuel et al., 2000).
Including pregnant and lactating women in clinical research allows for these populations to experience the benefits of clinical research that are currently available to other populations who are included in clinical studies and for whom rigorous safety and efficacy data are available. Since 1962, all drugs entering the market must provide evidence of safety and efficacy for “conditions prescribed, recommended, or suggested in the proposed labeling.”3 Since 1998, FDA New Drug Application (NDA) regulations have required human safety and effectiveness data to report on demographic subgroups, including age, gender, and race, as well as other subgroups likely to use the medication.4,5 In 2012, Congress expanded those requirements to include an action plan that prioritizes better completeness and quality of subgroup data, identification of barriers to subgroup enrollment in clinical trials, and making those data more available and transparent.6 However, pregnant and lactating women were not specifically referenced in this legislation. Although considerable work is needed to ensure more data are available for all population subgroups, very little progress has been made on research involving pregnant and lactating women. As recent efforts have highlighted in other population subgroups, prioritizing research needs in pregnant and lactating women helps prevent harm to these women and their offspring.
Pregnant and lactating patients and their clinicians must currently make decisions regarding medications during pregnancy and lactation without the benefit of high-quality evidence on their dosage, safety, and efficacy. That lack of evidence in humans may prompt pregnant and lactating women to forgo medications that are necessary for their and their fetus’s or child’s health or to be treated with ineffective dosing or inappropriate medication. This problem is especially highlighted for pregnant women, since pregnant women who need access to medications
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3 Amendment, the Federal Food, Drug, and Cosmetic Act, Public Law 87-781 (Oct. 10, 1962).
4 Investigational New Drug Application, 21 C.F.R. 312.33.
5 Applications for FDA Approval to Market a New Drug, 21 C.F.R. 314.50 (Feb. 22, 1985).
6 FDA Safety and Innovation Act, 126 Stat. 993, 1092-94 (July 9, 2012).
do not have an alternative other than to forgo necessary medications or potentially risk harming their fetus. Although it is important for both the lactating mother and their child to have the option to breastfeed, lactating women do have the option to cease breastfeeding and use formula or donor milk for their child, should a lactating woman need to take a medication without available safety data.
Insufficient data on the use of medical products in pregnancy and lactation has implications for health equity. Maternal mortality and severe maternal morbidity continue to be some of the most serious public health crises in the United States, particularly among Black women, American Indian and Alaska Native (AIAN) women, and low socioeconomic status communities (Chinn et al., 2020; Kozhimannil et al., 2020). In fact, the United States has the highest maternal mortality rate in high-income countries, and that rate is more than twice that of 10 other wealthy countries (Chakhtoura et al., 2019; White et al., 2022). Since sufficient evidence on medical products is also not available to pregnant women in other countries with lower maternal mortality rates, the high rate of U.S. maternal mortality cannot fully be explained by the lack of high-quality data to guide treatment decisions. However, common causes of maternal mortality in the United States, such as preeclampsia (Joseph et al., 2021), have no currently available treatment options. Rates of maternal mortality in the United States have sharply risen from 2018 to 2021 with stark racial and ethnic disparities, and substantially higher rates exist among non-Hispanic Black women (69.9/100,000), compared to 28.0/100,000 among Hispanic, and 26.6/100,000 births for non-Hispanic White women (CDC, 2021).
Maternal mortality is linked closely to maternal morbidities, and racial/ethnic disparities are apparent for conditions including preeclampsia and postpartum hemorrhage, as well as adverse birth outcomes (preterm birth and low birth weight). These adverse birth outcomes lead to a life cycle of inequity linked to higher rates of infant mortality. A report from CDC showed that infant deaths have risen for the first time in 20 years—up 3 percent from the previous year (CDC, 2016). Although the report does not provide a cause for this increase in death in the first year of life, maternal health and access to human milk are closely linked to newborn survival and health. Infant mortality rates are also approximately two times higher in children born to Black and AIAN individuals compared to children born to White individuals (Hill et al., 2022). Thus, generating sufficient data on safety, efficacy, and dosage, along with increased access to and appropriate prescribing of medications to treat maternal illness in pregnancy and lactation, is a key strategy to address and reduce health disparities in the United States.
Chronic conditions, such as hypertension and cardiovascular disease, diabetes, and mental health conditions, increase the risk of adverse maternal outcomes (Brown et al., 2020). Additionally, a woman with multiple chronic conditions has 3.8 times the rate of severe maternal morbidity and mortality compared to people without chronic conditions (Admon et al., 2018). Addressing these serious scientific gaps and promoting maternal and infant health will require research that centers pregnant and lactating women and also addresses the social and structural determinants of health (Crear-Perry et al., 2021). Beyond the personal and emotional cost of this issue, maternal mortality has serious social and economic consequences for the United States generally (White et al., 2022).
The burden of chronic disease is disproportionately experienced by racially minoritized groups in this nation as a result of structured inequities and discrimination (Geronimus et al., 2006). This means that pregnant women of color, who are more likely to enter pregnancy with comorbid conditions and end pregnancy having experienced adverse health events, are disproportionately disadvantaged by the exclusion of pregnant women from clinical studies and the resultant lack of sufficient data to inform optimal care of their conditions. Further, because racially minoritized populations have historically been excluded and are currently underrepresented in clinical research and the burden of disease is compounded at the “intersection” of pregnant and lactating women of color (NASEM, 2022), research studies that include pregnant and lactating women will need to be intentional about using an intersectional framework during the recruitment and retention of racially minoritized populations to truly maximize societal value and improve health equity.
To reduce harm to pregnant women and their fetuses and allow pregnant women to benefit from the knowledge generated in clinical research, it is imperative to “shift from an emphasis on protecting pregnant people from research to protecting them through research” (Lyerly et al., 2021). The same is true for promoting the health of lactating women and their children; clinical research must be conducted to protect lactating women and their children from the harms of breastfeeding cessation, untreated disease, and insufficiently studied medical products.
STUDY BACKGROUND
A number of domestic and international committees, working groups, and task forces have written important reports with recommendations to advance research in pregnant and lactating women (CIOMS and WHO, 2016; Hunt et al., 2017; IOM, 1994a; Manningham-Buller and Brocklehurst, 2022; NICHD, 2018; PHASES, 2020; PREVENT, 2018). Despite these
efforts and other remedies tried, such as calls for more registries, an information vacuum on dosage, safety, and efficacy of medical products in pregnant and lactating women remains. However, every report listed has recognized that legal liability and the legal context are an underexamined but potentially significant factor contributing to the reticence to move forward in this area.
In 2020, as a follow-up to its 2018 report, the PRGLAC Task Force released the PRGLAC Report Implementation Plan, which provided an update on the implementation of the recommendations in the PRGLAC report and provided guidance for making progress on the recommendations. The implementation plan called for the following:
Convene a panel with specific legal, regulatory, and policy expertise to develop a framework for addressing liability issues when planning or conducting research with pregnant women and lactating women. Specifically, this panel should include individuals with legal expertise at the federal and state levels, regulatory expertise, plaintiffs’ attorneys, pharmaceutical representatives with tort liability and research expertise, insurance industry representatives, federally funded researchers who work with pregnant and lactating women, and health policy experts. With agency support, the National Academies of Sciences, Engineering, and Medicine could be considered as a convenor of such a panel. (PRGLAC, 2020)
In the 2022 appropriations process, Congress mandated that NIH fund a consensus study committee “with specific legal, ethical, regulatory, and policy expertise to develop a framework for addressing medicolegal and liability issues when planning or conducting research specific to pregnant people and lactating people.”7
COMMITTEE TASK AND APPROACH
Under the congressional mandate, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) requested that the National Academies of Sciences, Engineering, and Medicine convene an ad hoc committee of experts to conduct a study on the state of real and perceived liability around research conducted with pregnant and lactating women. The committee’s statement of task is presented in Box 1-4. The committee was asked to present within this report its findings, conclusions, and recommendations for including pregnant and lactating women in clinical research while mitigating liability. The committee’s findings are not identified as such and are
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7 Consolidated Appropriations Act of 2022, Public Law 117-103, 117th Congress (March 15, 2022).
BOX 1-4
Statement of Task
An ad hoc committee of the National Academies of Sciences, Engineering, and Medicine will conduct a study on the state of real and perceived liability around research conducted in pregnant and lactating persons which lays out a framework for addressing medicolegal and liability issues when planning or conducting research specific to pregnant and lactating persons.
The committee, as a first step, will conduct data collection and analysis of the myriad of state laws and regulations governing liability for conducting research, including informed consent provisions, and to which populations they apply.
The committee will generate a matrix of the relative liability for (1) currently on-market and off-patent therapeutics and vaccines, (2) currently on-market and on-patent therapeutics and vaccines, and (3) new therapeutics and vaccines under development. This liability assessment is to address real and perceived risks to (1) private companies (e.g., vaccine manufacturers, biotech, pharmaceutical companies), (2) individual researchers and their institutions, and (3) the government for conducting research specifically on therapeutics and vaccines, including associated medical devices (e.g., diagnostic devices, drug delivery systems), for medical conditions experienced by pregnant and lactating persons. The committee will distinguish liability issues between pregnant persons and lactating persons because their liability profiles likely differ.
Based on its review of the information and other expert input, the committee will develop a report with its findings, conclusions, and recommendations for safely and ethically including pregnant and lactating persons in clinical research that substantially mitigates or avoids incurring liability (absent negligence or malfeasance). These recommendations may include:
- pre-clinical studies (e.g., reproductive toxicology studies), and different types of study design and methodologies to generate relevant evidence for decision-making;
- considerations for the treatment of obstetric/lactation conditions (e.g., preeclampsia, pre-term labor, mastitis) and conditions experienced during pregnancy (e.g., asthma, chronic pain);
- considerations and implications for trial participants of reproductive age who may become pregnant while enrolled in a study;
- ways to maximize the use of informed consent procedures with consideration of shared decision-making, provider-patient communication, and health literacy of trial participants; and
- potential policy changes that would address disparities in state laws and regulations while protecting research participants’ legal rights and providing researchers with protection against liability.
instead woven into the narrative of this report. Conclusions represent the committee’s interpretation of the available evidence and are presented at the end of Chapters 2 through 5. The committee’s recommendations, which build on its findings and conclusions, are discussed in Chapter 6.
The Committee’s Interpretation of the Charge
Although there are many important issues to explore in the area of research involving pregnant and lactating women, it was necessary for the committee to restrict the scope of the report owing to space and time limitations. This report primarily focuses on liability and regulatory concerns, rather than biomedical issues, issues of recruitment and retention, or communication strategies to raise the national consciousness of the issue given the charge of the statement of task. These are critical issues worth examination, and some of these topics have been addressed by the PRGLAC Task Force (NICHD, 2018), but they are outside of the scope of this committee’s charge.
The committee interpreted the statement of task as asking for recommendations directly tied to liability and asking for some elements, such as different study designs, as going beyond liability. Therefore, the committee interpreted its task as examining liability and medicolegal liability issues that go beyond the narrow scope of liability. For example, Chapter 5 of the report provides an overview of factors beyond liability that prevent broader inclusion of pregnant and lactating women in clinical research. These factors are not directly tied to liability but may often get conflated with liability and are considered alongside liability in decisions whether to include pregnant and lactating women in clinical research.
The committee emphasizes the need for research on drugs and vaccines, rather than over-the-counter products. The committee also did not focus on medical devices, as examining four different regulatory and development systems (drugs, vaccines, devices, and over-the-counter products) was untenable in the given time frame.
The committee focused on liability for clinical research on general conditions that affect pregnant and lactating women. However, the committee describes in Box 1-5 its considerations for conditions that are specific to pregnant and lactating women.
The statement of task asks the committee to “generate a matrix of relative liability.” The committee spent a great deal of time attempting to create such a matrix and ultimately concluded that any matrix of relative liability created would be subjective rather than based on empirical analysis, as quantifying relative liability is not possible. The committee has provided a thorough analysis of the evidence on real and perceived risks to different stakeholders; however, after careful consideration, the committee was unable to generate a matrix on relative liability. Instead, the committee did a survey of actual liability and the laws and regulations applicable to liability, all of which help to minimize harm and mitigate liability.
The statement of task charges the committee with developing recommendations “for safely and ethically including pregnant and lactating
BOX 1-5
Medical Product Development for Conditions Specific to Pregnancy and Lactation
A variety of medical conditions may arise because a woman is pregnant, including preeclampsia, gestational diabetes, severe nausea and vomiting, and preterm labor. Similarly, conditions such as mastitis and low-milk supply may present in a woman because she is lactating. Yet, there has been little to no development of medical products to treat many of these conditions (Bahmanyar et al., 2021; Spatz, 2022).
The report primarily focuses on liability in clinical research for conditions experienced in the general population and in women during pregnancy and lactation. However, the liability considerations for research on conditions specific to pregnancy or lactation, while parallel, are distinct and compounded. First, whereas many general conditions have existing, evidence-based treatments, there is a poor understanding of the basic pathophysiology of many pregnancy- and lactation-specific conditions (Ahmed et al., 2017; Jin et al., 2024; Plows et al., 2018). Furthermore, there is no alternative to conducting clinical studies in pregnant and lactating women for products designed to exclusively serve these populations. Clinical studies must be conducted in pregnant and/or lactating women if pregnancy- or lactation-specific medical products are to get to market. However, the basic science research, the pool of obstetrical/lactation clinical investigators, and the infrastructural support that are uniquely focused on the potential problems associated with pregnancy and lactation are in short supply (Longo and Jaffe, 2008). Therefore, the forces that disincentivize clinical research in these populations effectively result in almost nonexistent innovation in this space. Only two new medications for pregnancy-specific conditions have been brought to market since 2000, and one has since been withdrawn from the market (Appendix D). No new medications for lactation-specific conditions have been developed in that time.
Another important consideration that is likely to weigh on decisions regarding perceived liability is the potential market size for conditions specific to pregnancy and lactation. Pregnancy and lactation are temporary states, which, despite provisions made for orphan drugs, may still dissuade medical product developers from investing in treatments specific to pregnancy and lactation (Caritis and Venkataramanan, 2021).
While the focus of the report and recommendations are on addressing the lack of human data for general conditions experienced during pregnancy and lactation, the committee’s recommendations also aim to address the paucity of medical products for pregnancy- and lactation-specific conditions. Careful consideration of the unique aspects of product development for these conditions is important to promote research policy and investment in this area.
persons in clinical research that substantially mitigates or avoids incurring liability (absent negligence or malfeasance).” However, negligence and malfeasance are critical components of liability, particularly in a finding of causation of a personal injury claim in a clinical trial. Therefore, the committee was not able to examine liability without consideration of negligence or malfeasance.
Study Approach
The committee comprised 14 members with expertise in obstetrics, maternal fetal medicine, pediatrics, nursing, public health, clinical research, pharmacy, law, policy, pharmacovigilance, and bioethics. Two fellows of the National Academy of Medicine also contributed to the committee’s deliberations and report. The committee met six times over the course of the study to discuss and analyze the available evidence and to develop the recommendations presented in this report.
As part of its work, the committee reviewed relevant peer-reviewed literature, with the assistance of the National Academies’ Research Center staff, that fell under the statement of task. Additionally, committee members submitted peer-review journal articles to study staff and the committee for consideration. While examining the literature, the committee found a robust literature on the ethics, liability, and other factors surrounding the inclusion of pregnant women in clinical research. However, the committee found substantially less literature on the inclusion of lactating women in clinical research. Therefore, the committee refers to pregnant and lactating women where the literature supports the inclusion of lactating women, but there are places in the report where the committee refers only to pregnant women. This is not to minimize the importance of including lactating women in clinical research but a result of limitations of the literature.
The committee held a public workshop in March 2020 that examined risk mitigation and liability. During this workshop, the committee heard from a defense attorney, clinical trial insurers, academic medical center counsel, an expert in institutional review boards, research participants, lawyers with expertise in tort law and compensation programs, and researchers who have experience conducting clinical studies involving pregnant and lactating women. The agenda for this workshop and the committee’s other public meetings are available in Appendix A. The committee also worked with a patient advocate to collect stories of individuals’ lived experience being pregnant and lactating while living with a chronic illness.
The committee contracted with law firm Hogan Lovells US LLP to conduct a review of the legal landscape of tort liability for injuries related to pregnant and lactating populations’ participation in clinical trials and/or use of products regulated by FDA. This legal assessment was critical to responding to the statement of task and is referenced throughout the report; it can be found in full in Appendix B. The committee also commissioned a series of papers to inform its work. The first commissioned paper is a table of state statutes that may affect research conducting with pregnant and lactating women, which was authored by Taleena Nadkarni and Amelia Nell, law students at the University of Virginia. The full table
and their methodology can be found in Appendix C.8 The second commissioned paper is a review of FDA regulations, guidance, and policies related to conducting research with pregnant and lactating women and was conducted by Sarah Wicks, Julie Tibbets, Elizabeth Caruso, Emily Tribulski, and Elizabeth Mulkey at the law firm Goodwin Proctor LLP. This paper heavily informed Chapter 3 of this report and can be found in full in Appendix D.9 The third commissioned paper was an examination of the effect that the recent Supreme Court decision Dobbs v. Jackson Women’s Health Organization may have on the legal landscape to include pregnant and lactating populations in clinical research. This paper was authored by law professor Allison Whelan at Georgia State College of Law and can be found in full in Appendix E.10 The fourth commissioned paper was authored by the Tufts Center for the Study of Drug Development, and it was tasked with examining the successes and challenges of incentive programs and other relevant initiatives in leading to new product approvals or expanded labels for either new populations or uses (Tufts CSDD, 2023).
Defining Key Terminology
The previous work on clinical research involving pregnant and lactating women has not always been consistent in the use of terminology. Therefore, to promote clarity, the sections below provide a list of the committee’s definitions for key terms used throughout the report. In addition to these terms, the committee defines any other important terminology throughout, alongside the relevant discussion. Lastly, clinical research involves many stakeholders that play different roles in developing medical products that are safe and effective for the people who use them. Box 1-6 provides an overview of the key stakeholders that are involved in conducting research with pregnant and lactating women.
Pregnant and Lactating Women
Throughout this report, the committee uses the term pregnant and lactating women to refer to anyone who is gestating a live pregnancy or who produces milk for a child. This terminology differs from what appears in the committee’s statement of task from NICHD and in the committee’s name, where this population is described as “pregnant and lactating
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8 Appendix C can be viewed online at https://nap.nationalacademies.org/catalog/27595.
9 Appendix D can be viewed online at https://nap.nationalacademies.org/catalog/27595.
10 Appendix E can be viewed online at https://nap.nationalacademies.org/catalog/27595.
BOX 1-6
Relevant Stakeholders and Their Roles
Clinical trial insurers: Insurance companies contract with sponsors and/or investigators to insure financial risks associated with liability and medical expenses arising out of clinical trials, such as compensation for research-related injuries to participants.
Data and safety monitoring boards (DSMBs): Independent boards monitor ongoing trials to ensure participant safety and data integrity. They can recommend modifying or stopping a trial if safety concerns arise or if it becomes clear that the intervention is effective.
Food and Drug Administration (FDA): FDA (and similar agencies in other countries) regulates and approves new medical products. FDA approves applications for clinical trials on new medical products (Investigational New Drug Application [IND], Investigational Device Exemption [IDE]), and assesses the safety, efficacy, and quality of products before they can be marketed or used widely. FDA has the authority to require collection of postmarket data for approved products.
Health care providers: Physicians, pharmacists, nurses, and other health care professionals are often involved in recruiting participants, administering treatments, and monitoring patient progress during clinical trials. Their insights and expertise contribute to the trial’s success.
Industry sponsors: The research and development of pharmaceuticals and other medical products is primarily paid for by private industry. Private industry stakeholders—including pharmaceutical companies and medical device companies—conduct trials to evaluate the safety and efficacy of products and collect data to support regulatory approval.
Institutional review boards: These independent groups are responsible for reviewing and approving the ethical and scientific aspects of clinical trials. They ensure that studies protect participants’ rights, safety, and well-being.
National Institutes of Health (NIH): NIH is the primary funder of basic research in biomedical sciences; this research is the foundation for identifying and developing pharmaceuticals and other medical products. NIH also provides funding for preclinical and clinical research, although the vast majority of funding for medical product research and development comes from the private sector.
Nonindustry sponsors: Some clinical trials are sponsored by nonindustry entities, including nonprofit organizations, venture capitalists, universities, and research institutions. These sponsors face some of the same risk factors as industry sponsors, while some are unique to the specific type of stakeholder.
Research participants: The most essential stakeholders are the individuals who participate in clinical trials. Their willingness to volunteer for studies helps advance medical knowledge and treatments. Their safety, informed consent, and overall experience are paramount.
Researchers and principal investigators: These are the scientists, medical professionals, and researchers who design, lead, and conduct clinical trials. They are responsible for ensuring the scientific validity, ethical standards, and safety of the study. Many of the risk factors the sponsor face are also experienced by the investigators. However, there may be unique challenges that individual investigators face when considering research with pregnant and lactating women.
persons.” The latter wording was intended to recognize that not all people who become pregnant or lactate are women, such as transgender men or people who are intersex or identify as nonbinary (Kukura, 2022). People of diverse sexes (biologically determined) and genders (individual’s identity) may become pregnant (Moseson et al., 2021) or produce milk (MacDonald et al., 2016).
The committee chose to use women to highlight the complex and highly pertinent history of discrimination against women and the impact this continues to have on their health and well-being. Discrimination against women in health care is a systemic issue that encompasses multiple aspects of medical treatment, research, access to care, and patient outcomes (Holdcroft, 2007; Paulsen, 2020). For decades, women, especially racially minoritized women in the United States, including Black, Latinx, Native American, and Asian populations, were excluded from clinical research because they might become pregnant or breastfeed their child (Bierer, 2022). Owing to systemic and structural biases and racism, racially minoritized women have faced even greater challenges with respect to inclusion and representation in clinical research. Recent policy changes have begun to correct the prolonged neglect of women’s particular health conditions and needs but have not yet overcome the failure to focus on finding the appropriate dosage, safety, and efficacy of drugs during pregnancy or lactation.
Using the term women also aligns the report with the language in federal guidance and regulations, such as those on conducting clinical trials during pregnancy or lactation. Given how critical these documents are to the legal questions addressed in this report, linguistic consistency removes a possible source of confusion. Moreover, the analysis of the case law discussed in depth in Chapter 2 and in Appendix B found only cases involving women. When referring to pregnant or lactating women in the context of clinical care or research, the committee also uses terms such as pregnant and lactating patients or pregnant and lactating research participants. There should be no doubt, however, about the relevance and applicability of this report and its recommendations to all individuals who become pregnant or breastfeed their child, regardless of their gender identification.
Lactating
When referring to a woman producing milk for a child, this report uses the terms breastfeeding, chestfeeding, nursing, and lactating. The committee notes that human milk is provided to children in multiple ways: some children suckle directly from the breast or chest of a lactating woman, others drink pumped milk from a bottle or supplemental nursing system, some receive milk from a donor, and some are fed using a combination of human milk and infant formula. Lactation occurs naturally when a woman
has given birth and can also be induced in those who have not been pregnant; for example, some adoptive parents choose to induce lactation in order to provide their child with their own milk. The committee uses child or children throughout the report, unless regulatory guidance states otherwise, because not all breastfeeding children are infants. However, as described in Box 1-2, there are unique risk considerations for neonates and infants compared to children because of their age and size.
Patient
While most pregnant and lactating women visit a health care provider at some point during pregnancy or lactation, the committee notes that pregnant and lactating women spend a majority of their time outside of the direct supervision of a provider and make many care decisions on their own (e.g., over-the-counter medications). Thus, pregnant and lactating women are not patients merely because they are pregnant or lactating. This report generally only refers to pregnant and lactating women as patients when in the context of provider-based health care, or when a cited study refers to pregnant and lactating women in this way.
Clinical Research
Clinical research is a general term that encompasses several different approaches to research. For the purposes of this study, the committee has chosen a broad definition of clinical research, which includes:
- Preclinical research that uses laboratory and/or animal studies to assess safety and efficacy before testing in humans.
- Clinical studies that involve human participants can be divided into four phases:
- Phase I: Small groups, generally of healthy volunteers, are tested to assess pharmacokinetics, pharmacodynamics, dosing, safety and activity.
- Phase II: A larger group, generally of patients, is studied to determine efficacy and to further evaluate safety.
- Phase III: Large-scale studies are conducted to confirm results, monitor side effects, and compare the treatment to standard treatments or placebos.
- Phase IV: After a medical product is approved by regulatory agencies, ongoing studies monitor its long-term effects, safety, and optimal use.
- Observational studies that observe participants without intervening, often to gather information about real-world treatment outcomes, disease patterns, or risk factors.
Liability
Liability is the state of being responsible for something, especially by law. The PRGLAC Task Force report identifies liability as a significant impediment to the acquisition of an evidence base to facilitate the use of medical products by women who are or might become pregnant and by lactating women because of the fear of legal or regulatory risk or obligation for causing harm. This report does not include a definition of liability itself. For this report, the committee chose to focus on a broader concept, legal liability risks, which encompasses not only adverse legal decisions, but also the risks attendant to potential legal actions more generally. Even if a clinical researcher or medical product sponsor believes that it is likely to prevail in a lawsuit, the fear of becoming embroiled in such a lawsuit is likely to affect behavior. Even with favorable results, legal actions entail significant costs, including time, reputational harm, psychological harm, and legal and potential settlement fees. Throughout the report, any mention of the term liability refers to legal liability risks. When referring to perceived liability, the committee refers to it as such. However, addressing legal liability and minimizing harm to research participants helps address perceptions of liability. Therefore, the same strategies that mitigate legal liability also help to reduce perceived liability.
Harm and Liability
Harm and liability are two terms that are often conflated when discussing the factors that affect willingness to conduct research with pregnant and lactating women, but it is important to distinguish the two. Harm refers to injury, liability refers to legal responsibility for causing harm. Pregnant women may be excluded from clinical studies because of the risk of harm to them and/or their fetuses, the risk of liability for causing harm to them and/or their fetuses, or based on other factors described later in this report (see Chapter 5). It is also important to note that decisions are sometimes made based on perceptions of risk, even if those are not well founded in data or experience. In the context of this report, the committee has considered multiple different kinds of harm. There is potential harm to pregnant and lactating women and their offspring (psychological, possibly physical and economic) and harm to clinicians (psychological, possibly reputational and legal) because of the paucity of human data on which to base decisions.
Similarly, society may be harmed by the downstream effects of these injuries. There is also potential harm that may be associated with participation in clinical studies; usually these potential harms are included in informed consent as known and unknown risks. Harm may happen without liability; harms can happen even when no one has done anything
wrong. When something negative occurs, such as harm to a fetus or child, it is human nature to seek an explanation for the negative outcome (Peeters and Czapinski, 1990). That can create liability risk even when all parties have attempted to minimize harm. All of these factors are related to one another, but each must be addressed in order to develop recommendations for improving the representation of pregnant and lactating women in clinical research.
Organization of the Report
This report is organized into six chapters. Chapter 2 provides an introduction to liability, provides an overview of liability for including pregnant and lactating women in clinical studies, explores perceptions of liability, and discusses the relationship between the risk of harm and the risk of liability. Chapter 3 is about reducing the potential for harms from clinical studies with pregnant and lactating women, both through the current regulatory system and through any improvements that can be made to that system to minimize harm. Chapter 4 focuses on the mitigation of liability beyond minimizing harm, and Chapter 5 explores other factors in a medicolegal context that affect stakeholders’ willingness to do research with pregnant and lactating women. Finally, Chapter 6 presents the committee recommendations and the evidence supporting each recommendation.
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