Preclinical Development Studies

The goal of preclinical development studies is to serve as a bridge between initial laboratory findings that hold promise for a therapeutic target and use of the experimental product in a clinical setting. Preclinical studies include the development of animal models that are predictive of the pharmaceutical agent’s activity, toxicokinetic and nonclinical pharmacokinetic studies, identification of biomarkers that quantify the activity of interest and potential safety parameters of the therapy, establishment of a dose–response relationship for the product, construction of an initial dosing schedule for human pharmacokinetics and pharmacodynamics (PK/PD) studies, and optimization of the dosing regimen, including route of administration. This section explores three broad areas of preclinical studies. This section applies to most medical products in development, although FDA does have product-specific guidance for vaccines for infectious diseases and for oncology products.¹

Developmental and Reproductive Toxicology (DART) Studies

DART studies identify the experimental product’s adverse effects seen in animal species that may portend the types of toxicities that could occur in humans, including evaluation for teratogenicity. The results of these preclinical studies aid in selecting an initial starting dose and a potential dose titration schedule, and the results aid in estimating the probable highest safe dose for human clinical trials, while also initially characterizing potential adverse effects that might occur in humans (ICH, n.d.). DART studies are categorized into three segments according to the stage of development during which the experimental product is administered (Table 3-1). A fourth category (Juvenile) provides data on the experimental product’s potential effect in the pediatric population.

TABLE 3-1

Developmental and Reproductive Toxicology (DART) Studies.

Clinical Development Studies

Prior to the initiation of a clinical study of a new investigational product in humans, the sponsor must submit an Investigational New Drug Application (IND) to FDA (FDA, 2018e). In the application, the clinical investigator includes PK/PD and toxicology data from the preclinical animal studies, manufacturing information, clinical protocols for intended studies to be conducted in humans, data from any prior human research, and information about the investigator. This section provides a description of the phases of drug development and in following sections specifies the FDA guidance and special considerations for research with pregnant and lactating populations.

Phase I Studies

Once the sponsor completes preclinical studies that demonstrate the product is anticipated to be generally safe when used in humans, development can proceed to Phase I studies in human volunteers. The standard approach to Phase I studies begins with a single-dose escalation study (Figure 3-1). Usually, these studies begin by dosing three to five volunteers, at a dose anticipated to have no observable effect, determined during preclinical studies. The amount of the single dose is gradually increased over days or weeks, noting gradual changes in symptoms, physical exams, and laboratory values. This dose escalation schedule continues until a critical value of tolerance is reached, identified as the dose-limiting toxicity. Thereafter, the next lower dose level is identified as the maximum tolerated dose.

FIGURE 3-1

Phase 1: Dose escalation. SOURCE: Adapted from Beninger, 2024.

The range of the dose amounts between those associated with the first onset of observable effects and the maximum tolerated dose is known as the therapeutic window, which serves as the range of doses to be evaluated during Phase II studies. Analysis of the PK/PD assists in narrowing the dose range of interest, setting the dosing interval, helping to estimate the duration of dosing for later studies when appropriate, and proposing the features of the safety profile. Multidose studies generally follow with a separate cohort of volunteers, based on the now available human PK parameters.

Phase II and Phase III Studies

Phase II studies generally begin in volunteers either with, or at risk for, the disease of interest. The goal is dose selection, the process is dose finding, and the numbers generally range from 100 to 300 volunteers (Table 3-2). Depending on whether treatment is anticipated to be time limited (e.g., for treatments in oncology and infectious diseases) or indefinite (e.g., for cardiovascular diseases and diabetes mellitus), the dosing schedule of amount and duration considers the effects on the markers of benefit and the accompanying safety profile. The Phase II studies may include two or more dose amounts and are often conducted with control arms for placebos or active comparators.²

TABLE 3-2

Common Parameters of Studies Conducted DuringClinical Development.

Phase III studies are conducted in thousands of patients with the doses (amount and schedule) expected to be marketed, guided by the results of the Phase II studies. These studies are conducted to collect the quantitative statistical data that will support the commercial sponsor’s New Drug Application (NDA). Phase III is also commonly a time to conduct the increasingly important pharmacogenomic studies (FDA, 2021), as well as expected drug–drug interaction studies.

Product Review and Approval

Once the phased studies are complete, the commercial sponsor then submits an NDA or a Biologics License Application (BLA) to FDA, the approval of which is required before marketing the product is permitted. FDA is the regulatory agency with the statutory authority and the responsibility for determining whether an NDA or BLA provides substantial evidence to support the safety and effectiveness of the therapeutic product under consideration. FDA approval means that the data on the use of the therapeutic product is determined to provide benefits that outweigh its known and potential risks for the intended population (FDA, 2018b, 2022).

Prescription labeling represents what FDA determines to be the relevant experimental evidence that supports the safety and effectiveness of the use of the agent in patients with diseases, conditions, or circumstances indicated for prophylactic use, organized and presented in a standardized format. Labeling for prescription medicines is required for all FDA-approved prescription drugs and biological products and contains a summary of the essential scientific information needed for the safe and effective use of the medicine.³

When a prescription product is approved for use in adults, the product is also approved for use in pregnant and lactating women by default unless there is a clear contraindication or warnings against the product’s use during pregnancy or lactation, which must then be included on the product label. This is because pregnant and lactating women are considered a subpopulation of the adult population and, therefore, absent a contraindication or warnings against the product’s use during pregnancy or lactation, they are not excluded from the approved population when a drug or biological product is approved for use in adults.

FDA Guidance on Preclinical Studies for Pregnant Women and Potentially Pregnant Women

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) strives to have better regulatory harmonization worldwide to ensure safe and effective development of medications. FDA is a founding member of ICH and plays a major role in the development of ICH guidelines, which FDA then adopts and issues as guidance to industry.

As mentioned above, genetic toxicity studies are critical for examining the potential for a product to cause gene changes in mammalian cells. According to ICH guidelines, all preclinical female reproduction toxicity studies and standard genotoxicity tests should be completed before the inclusion of potentially pregnant women not using highly effective birth control in any clinical trial (ICH, n.d.).

Highly relevant to the participation of women who are pregnant and potentially pregnant is the completion of DART studies. ICH recommends conducting DART studies to characterize the risk of the experimental product and take appropriate precautions during exposure of potentially pregnant women in clinical trials, or to limit the risk by taking precautions to prevent pregnancy during clinical trials (ICH, n.d.). In the United States, embryo-fetal development studies (Segment II) for most products can be deferred until the initiation of Phase III trials, the final phase of clinical research prior to submitting marketing applications if precautions are taken to prevent pregnancy in potentially pregnant women (exceptions exist for oncology products to treat advanced cancer). FDA does not require that pre- and postnatal development studies (Segment III) be submitted until the sponsor seeks approval of the product.

If DART studies were conducted earlier in the product development pathway, it could provide an opportunity to begin clinical phases of research with pregnant women sooner (Sewell et al., 2022). Earlier DART studies could shorten the time that pregnant patients and their health care providers must wait for high-quality evidence generated in later stages of clinical research. Further, earlier completion of DART studies would allow for earlier detection of potential harmful pharmaceutical and biopharmaceutical products for pregnant and lactating women and their offspring. Timely conduct of DART studies could also enable women who become pregnant over the course of a clinical trial to remain in the trial once pregnant, which would provide critical information about the use of the product in early pregnancy.

A critique of conducting DART studies earlier in the clinical development process is that doing so before having defined the dose in the general human population could increase the cost of research and delay timelines for approval of the product (Sewell et al., 2022). Although this is a valid concern, waiting to conduct relevant DART studies can delay later stages of research by requiring sponsors to update protocols according to DART study results. Additionally, DART studies can feasibly be conducted without delaying product approval by beginning to conduct DART studies as soon as the dose to be used in Phase III studies for the general population is determined.

Preclinical studies, in general, may not be highly predictive of human responses. For a study of 108 oncology drugs, animal toxicity did not show a strong predictive correlation with human toxicity; the median positive predictive value was 0.65 and the negative predictive value was 0.50 (Atkins et al., 2020). It is not known how well DART studies predict potential outcomes in humans, nor are DART studies routinely designed to capture specific outcomes that may be relevant to later studies in humans. For example, in utero fetal exposure to products may affect immune system development, higher-order learning and memory, and endocrine functioning, but fetal exposure concentrations of drugs are not typically assessed in DART studies (Sewell et al., 2022); yet, such data are critically important to further demonstrate the safety of a product in pregnant women and can only be captured in specially designed studies. Thus, investigators must be attentive to, and discerning with, the results from DART studies. One potential way to exercise greater care in the conduct of these studies is with the selective use of data safety monitoring boards (DSMBs) during the conduct of Phase I studies (see Box 3-1). While few adverse events may be detected during Phase I studies owing to the small number of enrolled participants, use of a DSMB could rapidly evaluate adverse events that do arise during this early stage of clinical development and halt exposure of the product to additional participants if necessary.

BOX 3-1

Data Safety Monitoring Boards.

FDA Guidance on the Inclusion of Pregnant and Potentially Pregnant Women in Clinical Studies

For sponsors who plan to include pregnant women in clinical trials of their investigational drug, biological product, or medical device, FDA recommends that sponsors be prepared to discuss such plans with the appropriate FDA review division early in the development phase, and such discussions should involve FDA experts in bioethics and maternal health (FDA, 2018c). However, these discussions are sponsor initiated and not required when pregnant women are not included in the clinical trial.

At the time of IND application submission for products to treat conditions that are not specific to pregnancy, there is rarely any information or consideration of the dosing, efficacy, or safety of the investigational therapeutic agent in pregnant women at this stage. However, according to FDA’s draft guidance for drug developers, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” pre-IND and later clinical-stage meetings between FDA and sponsors may include discussion of trial populations as well as design plans (FDA, 2023d). Therefore, these meetings could provide opportunities for sponsors to discuss plans for involving pregnant and lactating women in their clinical development programs.

FDA’s draft guidance, “Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials,” published in 2018, provides the most expansive current guidance to industry on how and when to include pregnant women in clinical trials for drugs and biological products. This guidance discusses both the scientific and ethical issues that sponsors should address when considering the inclusion of pregnant women in clinical trials.

This 2018 draft guidance states that pregnant women may be enrolled in clinical trials that involve greater than minimal risk to the fetuses. When a trial offers the potential for direct clinical benefit to the enrolled pregnant women and/or their fetuses, it can be acceptable to expose a fetus to greater than minimal risk. FDA provides examples of when such exposure would be acceptable, which include when a trial offers a needed but otherwise unavailable therapy or when a drug or biological product being studied reduces the risk of acquiring a serious health condition (FDA, 2018c). However, the guidance does not define “greater than minimal risk” clearly or provide many examples, which can cause confusion in interpreting the guidance for sponsors and IRBs.

The 2018 draft guidance also includes information on the timing of enrollment for involving pregnant women in clinical trials. According to the draft guidance, Phase I and Phase II clinical trials in nonpregnant women, including potentially pregnant women, should be completed before enrolling pregnant women into later phases. The guidance also lists situations that might affect the decision of when to enroll pregnant women in a trial, including if there are other approved treatments available, if there are limited therapeutic options, or if safety data are available for a drug that has been studied for other indications or for use in other populations (FDA, 2018c).

However, current guidance does not set clear expectations for when pregnant women should ideally be included in clinical studies, other than what studies must be completed in nonpregnant women first. The lack of clear expectations results in most sponsors never conducting studies with pregnant women. Further, FDA does not provide guidance on conducting clinical studies for conditions specific to pregnancy, particularly when the study is for a new product without human safety data. These studies pose a different set of considerations from products to treat general conditions and warrant a specific discussion in guidance documents, especially for study design.

FDA Guidance on Conducting Clinical Studies with Pregnant Women

FDA Guidance Addressing Lactating Women in Clinical Research

Drug exposure and risks during the lactation period are generally lower than pregnancy and depend on whether the child is breastfeeding; the transfer of the drug into human milk; and the absorption, metabolism, and elimination of the drug by the breastfed child (Newton and Hale, 2015). In 2019, FDA updated its draft guidance, “Clinical Lactation Studies: Considerations for Study Design,” which provides recommendations for sponsors conducting pre- or postmarketing clinical lactation studies. The guidance clarifies that although FDA has required lactation studies under Section 505(o)(3) of the FD&C Act under certain circumstances to inform breastfeeding with drug use recommendations included in the “Lactation” subsection of labeling, the guidance states that FDA “is considering additional circumstances in which lactation studies may be required” (FDA, 2019a).

According to FDA guidance, lactating women may participate in clinical lactation studies if they are prescribed a medically necessary drug in the postapproval setting as part of standard clinical care and are allowed to continue breastfeeding while taking the drug. For new investigational drugs, lactating women who are administered an investigational drug for a disorder or condition must discontinue breastfeeding because of the potential or unknown risk to the infant and milk must be discarded for a duration depending on the half-life of the medication. For healthy volunteers who participate in a trial of an investigational drug for research, breastfeeding must be discontinued for the duration of the study.

There are three main types of study designs for clinical lactation studies:

1.

Lactating women (milk only) study: Human milk is collected, and drug concentrations determined. These may be used to estimate drug transfer to the milk to determine whether there are clinically relevant concentrations in human milk, and to evaluate effects of the drug on milk production. Most published studies are in this category.

2.

Lactating women (milk and plasma) study: Milk and plasma are collected from lactating women, and pharmacokinetic data is gathered as well as data regarding any effects on milk production. These are conducted when there may be concern for drug accumulation (i.e., long half-life).

3.

Mother–infant pair: Mother and infant provide blood to determine drug concentrations and pharmacokinetics in the lactating woman and infant as well as drug excretion in human milk. These studies can also include an assessment of the drug effects in the infants. These studies are typically done if there is evidence that there is substantial drug transfer into human milk, placing the infant at risk.

FDA’s clinical lactation studies guidance encourages sponsors to consider conducting clinical lactation studies even when not required, such as

1.

when a drug under review for approval is expected to be used by women of reproductive age,

2.

use of a drug in lactating women becomes evident after approval,

3.

the sponsor is seeking a new indication for an approved drug and provides evidence of use or anticipated use of the drug by lactating women, and

4.

when marketed medications are commonly used by women of reproductive age (FDA, 2019a).

Although the lactation guidance is relatively thorough in outlining research considerations for types of lactation studies and ethical considerations for the participation of lactating women in clinical studies, the guidance falls short in many of the same ways the pregnancy guidance does. First, although lactation studies are encouraged, FDA guidance does not set clear expectations or timelines for when these studies should be completed. Further, as with the guidance on pregnancy, FDA guidance on lactation recommends follow-up examination and testing of the breastfed infant in clinical studies of approved medications postmarket, but it does not provide details on expectations for the duration of follow-up and what types of outcomes should be measured. Nor does it provide guidance on the continuum of care from pregnancy to lactation and consideration for breastfeeding if enrolled in a clinical trial while pregnant.

For studies of new investigational products, FDA guidance on lactation dissuades lactating women from continuing to breastfeed, which could have detrimental health effects on the children receiving human milk, could affect their milk supply, maternal–infant bonding, and could be considered a harm in and of itself. While the mother may express milk to maintain her milk supply, particularly for a short-term study, the discontinuation of breastfeeding presents a major barrier for studies of medications to treat conditions not specific to breastfeeding as well as breastfeeding conditions, such as mastitis, low milk supply, or breastfeeding-associated pain. Discontinuation of breastfeeding and the resultant increased risk of infectious disease and other morbidities may outweigh the potential (and likely low) risk of the investigational product. Human milk transfers beneficial bacteria, immune cells, and nutrients to the nursing child that improve the immunological health of the child (Camacho-Morales et al., 2021).

Patients seeking treatment for breastfeeding conditions typically want to continue breastfeeding. In most cases, requirements to discontinue breastfeeding are not scientifically justified. One common method for estimating the risk of drug exposure to the child is the estimate of the relative infant dose (RID), which standardizes the exposure by weight. A RID of less than 10 percent is generally considered safe for use in lactation and safe for breastfeeding the healthy child (Newton and Hale, 2015). Currently, approximately 90 percent of marketed drugs have a RID in the “acceptable” range considered safe for breastfeeding (less than 10 percent). Therefore, these restrictions present sometimes overly burdensome barriers for participants in these studies and create challenges with recruitment for these studies, as suspending breastfeeding to participate in a study may dissuade many potential research participants from enrolling.

Further, when the study protocol calls for the cessation of breastfeeding, there is no requirement to provide participants with any alternatives or remuneration (i.e., pumping supplies, free formula for supplementation) to offset the monetary and potential emotional costs of discontinuation requirements. This may place an undue burden and greater barriers to entry for low-income populations. Lastly, FDA guidance on lactation suggests sponsors consider conducting an assessment on the effect of the product on milk production, which may include both volume and composition. However, the guidance provides few details on how this assessment might be conducted or how this assessment may take into account the different stages of breastfeeding.

FDA Rule on Labeling for Pregnancy and Lactation

In 2014, FDA amended its regulations through the finalization of its Pregnancy and Lactation Labeling Rule (the PLLR) (initially proposed in 2008), which created a consistent format for providing information about the risks and benefits of prescription drug and biological product use during pregnancy and lactation and by females and males of reproductive potential. For human prescription drug and biological products approved on or after June 30, 2001, the PLLR required that the labeling be revised to include

1.

a summary of the risks of using a drug during pregnancy (Section 8.1 of the labeling) or lactation (Section 8.2 of the labeling), and for females and males of reproductive potential (Section 8.3 of the labeling);

2.

a discussion of the data supporting that summary; and

3.

relevant information to provide health care providers and patients with the best available evidence to make informed decisions regarding the use of medications during pregnancy and lactation.

Under the PLLR, both the pregnancy and lactation sections of a drug or biological product’s labeling must include summaries of the pertinent available evidence providing information about the safety and use of the drug in pregnancy and lactation. Information on pregnancy exposure registries, if available, including how to enroll or to obtain more information, must also be included. A risk summary is also required that provides, as a narrative summary, a statement of background risk if there are data demonstrating that the product is systemically absorbed or if there are data on the product’s presence in human milk. This includes a separate summary based on human data, animal data, and pharmacologic data that describes the risk of adverse developmental outcomes, if such data are available (FDA, 2018b).

Additionally, the PLLR requires statements acknowledging when data on any of the labeling requirements are not available or do not establish the presence or absence of drug- or vaccine-associated risk.⁵ Lastly, the PLLR requires the label to be updated to include clinically relevant information as it becomes available to prevent the label from becoming “inaccurate, false, or misleading.”⁶

Although the PLLR was designed to provide more relevant summary information for health care providers and patients, there still is not much information in product labels about their use during pregnancy or while lactating. A cross-sectional labeling analysis of 290 newly FDA-approved medications from January 2010 to December 2019 indicated that

All products submitted after June 20, 2015, were in compliance with the Pregnancy and Lactation Labeling Rule (PLLR); however, of those submitted between 2010 and 2015, 32.6 percent were not in PLLR format by the designated date of June 30, 2019. Human data on pregnancy and lactation were available in less than 20 percent of new product labeling. (Byrne et al., 2020)

Postmarketing Commitments and Requirements

Phase IV postmarketing studies are commonly required by FDA (2016). These are clinical studies, epidemiologic studies, and registries that focus on specific questions of safety and/or effectiveness for various related conditions of the disease of interest for related demographic populations, such as pediatrics (FDA, 2023c), related diseases, special populations, safety issues, and long-term use. These studies are known as postmarketing commitments or postmarketing requirements. Postmarketing commitments involve preclinical studies or clinical trials that a sponsor agrees to conduct postapproval but are not legally required to be performed (FDA, 2016). Postmarketing requirements, however, are preclinical studies or clinical trials that a sponsor is required to conduct in order to comply with certain laws and/or regulations, or to assess a known serious risk related to the use of the drug, assess signals of serious risk related to the use of a drug, or identify an unexpected serious risk when available data indicate the potential for a serious risk (FDA, 2016). FDA may also impose postmarketing requirements on manufacturers of certain Class II or Class III medical devices that are approved by FDA.

Data for these types of studies can come from institutional electronic medical records, health insurance claim data, and registries. These observational studies may aid in (1) assessing the relative risk of a serious adverse event occurring with the use of a particular drug or biologic; (2) identifying certain risk factors that make the occurrence of a serious adverse event among a particular patient population more likely; and (3) obtaining data over a significant period of time, which may help identify rare serious adverse events, among others (FDA, 2011). Observational studies of pregnancy may aid in informing pregnancy or child outcomes following drug exposure, in comparison to a group that has not been exposed to the drug product (FDA, 2011).

FDA has the authority to require postmarketing studies and clinical trials to (1) “assess a known serious risk related to the use of the drug,” (2) “assess signals of serious risk related to the use of the drug,” and (3) “identify an unexpected serious risk when available data indicate the potential for a serious risk.”⁷ FDA also has the authority to require postapproval studies or trials if it becomes aware of new safety information (FDA, 2011). However, if human pregnancy or lactation data has not been collected at the time of FDA approval, FDA may not have the information required to determine whether there are potential risks to pregnant and lactating women to evaluate through postmarketing studies. Expanding FDA’s authority to request postmarketing studies could help fill important clinical knowledge gaps on the safety and efficacy of products in pregnant and lactating women, particularly to better identify long-term effects of a product.

Section 505(o)(3)(E)(ii) of the FD&C Act requires a sponsor to “periodically report,” and in any event at least annually, on the status of preclinical studies or clinical trials, regardless of whether or not the sponsor was required to conduct a clinical trial or study as part of a postmarketing requirement or voluntarily chose to do so. A sponsor must report on the preclinical study or clinical trial’s status to comply with this section.⁸ The status report must include a timetable for the completion of specific target goals, along with a status update of the study or trial (FDA, 2011). Unfortunately, the annual reports do not provide details on the ongoing status of the trial such as enrollment updates, any adverse events reported to FDA, or any information that might assist health care providers make prescribing decisions, although any adverse events that inform the labelling should be reflected in the label under FDA requirements.

In 2019, FDA issued its draft guidance, “Postapproval Pregnancy Safety Studies.” This guidance describes three postapproval approaches to assessing drug safety in pregnant women who have been exposed to a drug or biological product: (1) pharmacovigilance, (2) pregnancy registries, and (3) complementary data sources (FDA, 2019b).⁹ Based on an approach’s relative strengths and limitations and its potential application to a particular drug or biological product, FDA may recommend or require a particular approach or combination of approaches to be used by a sponsor for a particular drug or biologic product (FDA, 2019b).

Complementary Database Studies

FDA guidance on postmarketing studies also discusses complementary studies that may be conducted alongside pregnancy registries to address the “specific effects” of a drug or biological product during pregnancy (FDA, 2019b). These studies may be retrospective in their design and use secondary data sources, such as electronic health records, population-based surveillance, and national registries or registers.

For studies that use electronic health care data, FDA provides recommendations for identifying pregnancies in health care records and acknowledges the challenges of identifying pregnancies that do not result in a live birth. The ability to link the records of the pregnant woman to the offspring is critical to evaluating fetal outcomes related to in utero exposure (Johnson et al., 2013). These linkages can be developed through a number of records, including birth certificates, health record identifiers, and congenital malformation surveillance registries. The guidance also describes methods for estimating gestational age to understand the window during which a fetus would have been exposed to a medical product used by a pregnant woman.

Another form of complementary studies is the case-control study, which can be useful for obtaining additional information or long-term follow-up once a safety signal has been identified. While the guidance notes that these studies can be affected by recall bias from self-reported outcomes, case-control studies have the benefit of being able to capture detailed exposure and outcome assessments through follow-up interviews with the pregnant individual and to collect biospecimens. FDA guidance outlines the necessary considerations and the existing challenges for selecting and validating cases and matched controls to be included in the analysis. FDA goes on to note that it is important for cases and controls to be from the same disease population whenever possible to facilitate comparisons.

In addition, FDA has made a number of commitments in the Prescription Drug User Fee Act (PDUFA) VII Commitment Letter that focuses on pregnancy postmarketing requirements. As described in Box 3-2, these initiatives will result in updated guidance for sponsors conducting postmarketing studies with pregnant women.

BOX 3-2

FDA’s PDUFA VII Commitments.

Office for Human Research Protections (OHRP)

The HHS Office for Human Research Protections (OHRP) was established in 2000 to oversee HHS efforts to protect human research participants in clinical research and to provide leadership for all federal agencies that support human subjects research under the Common Rule (HHS, 2020). OHRP’s core functions include providing regulatory guidance and clarity, developing educational materials, administering IRB registration programs, and maintaining regulatory oversight of IRBs. OHRP’s guidance documents are not legally binding but help to inform and guide IRBs. OHRP has several guidance documents addressing populations mentioned in HHS regulations for the protection of the rights and welfare of human participants in research, including children and prisoners, but it has not issued any guidance on pregnant and lactating women as research subjects.

OHRP could develop guidance focused on pregnant and lactating women, including guidance to IRBs on the interpretation of Subpart B for clinical research including pregnant women and the applicability of Subpart D for clinical research including lactating women in which the child is exposed to human milk. Various research institutions have developed guidance and standard operating procedures specific to clinical research including pregnant women (CU Denver, 2022; MCW, 2023; Purdue, 2019; University of Utah, n.d.; UW, 2021, 2023). A study at the University of Washington found that such materials facilitated research that includes pregnant women at the institution (Mastroianni et al., 2020). OHRP guidance applicable to the inclusion of pregnant and lactating women in clinical research could help IRBs provide feedback to protocols and ultimately approve more protocols for human subject research involving pregnant and lactating women.

SACHRP was created in 2003 to “provide expert advice and recommendations to the Secretary [of Health and Human Services], through the Assistant Secretary for Health, on issues and topics pertaining to or associated with the protection of human research subjects” (HHS, 2022b). SACHRP is composed of appointed experts and heads of various HHS agencies. As a committee, it provides advice on improving protections for research participants. SACHRP occasionally establishes subcommittees that are formed of experts on special topics of interest to the committee (HHS, 2016). For example, in the early 2000s, SACHRP created a subcommittee to provide advice on pediatric research “to help ensure that children who participate in research are neither underprotected nor overprotected” (HHS, 2016). To date, there is no record that SACHRP has provided advice on the inclusion of pregnant and lactating women in clinical trials. It does have the authority to establish a subcommittee focused on research with pregnant and lactating women and to request recommendations for HHS to ensure that pregnant and lactating women included in research are similarly neither underprotected nor overprotected.

Institutional Review Boards

Federal regulations require that institutions engaged in clinical research involving human participants must use an IRB (HHS, 2018). IRBs are tasked with determining whether the research protocols before them are ethically justifiable and with ensuring that the researchers involved are not bound to certain interests that might pose a conflict with the ethical conduct of the research (Grady, 2015). Importantly, IRBs also serve a critical role in interpreting federal and state laws and regulations relevant to the protection of human subjects from exploitation and undue risk of harm. As a result, IRB members must be familiar with the Common Rule, FDA, HHS, and other agency and department regulations on human subject protections, as well as OHRP guidance. Given that IRBs are responsible for promoting a favorable balance of risks and benefits to research participants and that there is regulatory ambiguity for the protection of pregnant and lactating participants (van der Zande et al., 2017), clearer guidance from OHRP could help IRBs uphold their duties to minimize harm to pregnant and lactating participants.

For an institution to receive federal support for research involving human subjects, it must register its IRB with OHRP and renew its registration every 3 years to ensure compliance with federal regulations. IRBs that review HHS-supported research must apply the Common Rule and other HHS regulations for the protection of human subjects to that research, including those addressing the inclusion of pregnant research participants. In addition, IRBs that review FDA-regulated research must apply FDA regulations for the protection of human subjects to that research, which are similar but not identical to the Common Rule.

In ensuring compliance with federal regulations, IRBs aim to ensure that the research is conducted ethically, which includes minimizing harm to research participants and balancing risk with commensurate benefit to the research participants or the broader population through the creation of generalizable knowledge. It also ensures that informed consent is adequate and that there is equitable selection of research participants.

Staging of Clinical Research

An important consideration for designing clinical studies that include pregnant and lactating women is the timing of enrollment of these populations. Regulators and sponsors must strike a balance between including pregnant and lactating women in a sufficiently timely manner as to provide quality evidence on the use of the product in these populations, without rushing their inclusion in the absence of adequate safety information or planning. Moreover, a potential form of harm resulting from the inclusion of pregnant and lactating women in clinical research is that FDA approval of a medical product could be delayed, slowing the general population’s access to the product. Delays in regulatory approval could result from more complex data analyses and identification of false-positive safety signals, which are discussed in more detail in Chapter 5. Considering the most appropriate stages of clinical development to include pregnant women and lactating women (likely different for each population, given the differences in risk) could mitigate the risk of this form of harm. Importantly, the committee emphasizes that it is possible to include pregnant and lactating women in clinical research without expanding the risk of harm from delayed product approval, but careful consideration for which staging approach fits the research needs of the project being conducted is important. Nothing in current FDA regulations or the committee’s recommendations would require clinical studies in pregnant and lactating women to be complete before product approval for the general adult population.

A staggered approach to the enrollment of pregnant and lactating women entails conducting PK/PD clinical studies specific to the population of interest concurrently with the conduct of Phase III trials in the general adult population (Eke et al., 2019). Staggered enrollment would allow for the development of study protocols specific to pregnancy and promote the involvement of researchers with expertise in conducting research in these populations (Baylis and Halperin, 2012). Enrollment of pregnant participants could also be tailored to begin recruitment with individuals in their third trimester of pregnancy, when fetal organogenesis is complete, gradually enrolling participants in earlier stages of pregnancy. Lactating women could be included earlier than pregnant women for investigational products, especially since FDA guidance suggests that women cease breastfeeding for investigational products. Therefore, there is no risk to the baby and lactating women could be enrolled earlier in the trial. However, to avoid breastfeeding cessation, single-dose PK studies, where human milk is collected at time intervals until the drug has been excreted from the body, could be done early to determine potential for infant exposure. Once these single-dose PK studies are completed, if the medication is deemed safe for breastfeeding, as is the case for 90 percent of on-market medications, then breastfeeding could continue.

In embedded enrollment, the strategy would involve enhanced safety and pharmacokinetic evaluations in pregnant and lactating women who enroll in Phase III or late Phase II studies for the general adult population (Eke et al., 2019). According to this approach, pregnant and lactating women would be evaluated as subpopulations of the broader adult population enrolled in the clinical trials. Because pregnant and lactating women would be enrolled in Phase II or Phase III trials, researchers would be able to collect data relevant to these phases of research simultaneously with the basic safety data being collected (Baylis and Halperin, 2012). An embedded approach to enrollment would also facilitate comparisons between pregnant or lactating participants and nonpregnant or nonlactating participants enrolled in the same trial.

A potential concern with this approach is that embedding pregnant and lactating women in the same trials as the general adult population could delay interpretation of overall trial results when there are challenges with the recruitment of pregnant and lactating participants, which could delay drug approval. It may also present risks to pregnant populations, given that there may not be sufficient safety and efficacy data before enrolling them in the trial. Therefore, this approach may be best for lifesaving medications for conditions with no available alternative therapies, but not for non-life-threatening acute and chronic conditions for which alternate therapies are available.

The opportunistic approach to enrollment is a useful way of collecting data on pregnant and lactating women who become pregnant while already enrolled in a trial (Eke et al., 2019). Once the participant is unblinded and reconsented, pharmacokinetic and safety data can be collected for these individuals before therapy is discontinued and potentially throughout all trimesters of pregnancy and postpartum. However, an opportunistic enrollment approach is likely to be slow and may not accomplish recruitment goals while clinical trials are actively being conducted. Such an approach also raises issues of whether the investigators involved in these trials will have sufficient expertise in pregnancy and lactation. Regardless, an opportunistic approach to enrollment can be an effective strategy for collecting data on the use of the product in early stages of pregnancy.

Pragmatic Study Designs

A pragmatic study design, specifically when focusing on pregnant and lactating women as the study population, is pivotal in advancing the understanding of medical products within real-world clinical settings (Eke et al., 2019). At their core, pragmatic study designs aim to evaluate the real-world effect of interventions or strategies that are already part of clinical practice (Patsopoulos, 2011; CU Denver, 2019). Unlike traditional clinical trials with tightly controlled settings, these studies strive to replicate the conditions encountered in routine patient care. This fundamental difference is crucial for gauging how interventions perform when applied to diverse groups of pregnant and lactating women during their specific health care journeys, which can be particularly useful in reducing harm in real-world use of the product (Eke et al., 2019).

One of the defining features of pragmatic trials in this context is the inclusion of a diverse and representative range of participants (Eke et al., 2019). By encompassing such diversity, pragmatic studies can provide valuable insights into how interventions function across different subgroups, considering such factors as age, ethnicity, socioeconomic status, and underlying health conditions, which often influence health care outcomes.

Pragmatic study designs in pregnant and lactating women would be bolstered by encompassing longitudinal data collection. Recognizing that pregnancy and lactation are dynamic processes with evolving needs and experiences, these trials could span extended periods to capture a comprehensive view of the effects of the intervention over time. This longitudinal approach enables researchers to assess not only short-term outcomes but also the sustainability and long-term effect of the intervention. Observing the long-term effects of medical product exposure can facilitate the identification of latent adverse effects. In addition, pragmatic study designs are attuned to minimizing disruptions to routine clinical care (CU, Denver, 2019). This consideration is essential to ensure that both pregnant and lactating patients and health care providers can participate in the study without an undue burden or disruption to their usual health care activities. By integrating seamlessly into clinical practice, pragmatic trials can gather data in a nonintrusive manner that respects the demands of health care delivery.

Opportunistic Studies

Nonrandomized opportunistic studies, a subset of observational research, provide a unique way to study pregnant and lactating women already using specific medical products or interventions (Sheffield et al., 2014). Opportunistic studies thus reduce harm to research participants by only studying the product in individuals who would already be using the product. However, conducting such studies requires careful consideration to ensure ethical and appropriate practices, with informed consent and IRB oversight being ethical cornerstones. Participants must fully understand the research objectives, potential risks, and benefits. An opportunistic study could be a useful study design when it would otherwise be ethically or logistically challenging to conduct an interventional study, such as chemotherapy treatment during pregnancy.

Innovative Methodologies

In striving toward increasing research in pregnant and lactating women earlier in the drug development process, several innovative approaches can be undertaken to conduct and analyze such clinical research safely while lessening the risk of harm to the pregnant woman and developing fetus. Although many of these methods are still evolving, they present novel ways to evaluate the safety and efficacy of medical products before they are used in humans. Further exploration of these methodologies could align with FDA’s Broad Agency Announcement for regulatory science innovation, advancing the ability of FDA regulators to assess clinical studies that use methods to predict exposure to the medical product under evaluation (FDA, 2024a). In fact, FDA recently funded a project studying the use of physiologically based pharmacokinetic models (FDA, n.d.b).