FACTORS THAT AFFECT INCLUSION
Social and Cultural Considerations
“Pregnant people should have the opportunity to choose whether or not they want to participate in clinical trials,” Zsakeba Henderson, March of Dimes, said. From an ethical perspective, denying them this opportunity prohibits them from exercising autonomy in making informed health care decisions. The ability to exercise that autonomy also requires providing them with the necessary information and support for decision-making.
A host of factors can influence the recruitment and retention of pregnant and lactating participants for clinical trials. Beyond outright exclusion by design, pregnant patients and their providers may be unaware of opportunities to enroll in clinical trials. For pregnant and lactating persons who might be aware, access to and understanding of information about a clinical trial and completing the informed consent process have been identified as barriers to recruitment and retention, Henderson said. Studies have found that having information delivered by someone the patient trusts and ensuring that patient priorities have been incorporated into the trial design can help to facilitate participation.
A pregnant or lactating person’s perceptions of the risks and benefits of participation in a clinical trial are also a factor. Henderson said that many people are hesitant to participate for fear of how it will affect their pregnancy and their baby. There are community- and social-level factors that affect recruitment and retention. For example, people are more receptive to participation when their provider shares the information and promotes participation. The pregnant or lactating person’s social network also influences their participation, including information they get from spouses, family, the community, and “the grapevine” about the risks and benefits of participating in trials.
Personal factors play a significant role in the decision to enroll, especially the accessibility and affordability of participation. Henderson repeated the point that pregnant people are just like nonpregnant people in that they have duties and responsibilities and other life issues that
affect their ability to participate (e.g., jobs they cannot take time off from, children who would need childcare, medical conditions they deal with). Veronica Gillispie-Bell, Oschner Health System and Louisiana Department of Health, and Henderson emphasized the importance of having the patient voice represented when designing a clinical trial so patients’ priorities and lived experience are taking into consideration.
Another personal factor that Henderson identified as affecting trial recruitment and retention is the relationship the enrollee has with the study team. Participants need to feel a sense of trust that the information they are being given is true, and they need to perceive benefit in their participation, Henderson said. Gillispie-Bell and Henderson discussed how diversity in the trial population is enabled by having diverse people involved in the design and conduct of the trial. Gillispie-Bell added that, in her experience, patients are often willing to participate in a trial when they know they are contributing to the body of scientific evidence that will help other people who look like them. As an example, she described a recent clinical trial involving a uterine fibroid treatment. Although Black women have a higher burden of disease (80 percent of Black women will have fibroids by age 50) (Baird et al., 2003) and their symptoms are much worse than other populations, data in this population is lacking because Black women are underrepresented in these clinical trials. This lack of applicable data leaves providers at a disadvantage when trying to counsel patients on the best treatment for them. In the recent trial, Gillispie-Bell said that 68 percent of participants identified as Black or African American. She attributed this to the fact that, by design, the principal investigators chosen for the trial reflected the patient population that was most appropriate for trial enrollment.
Brittany Bettendorf, University of Iowa, also reviewed some of the factors that affect the recruitment and retention of pregnant and lactating persons in clinical trials. At an individual level these factors can include patient demographics (e.g., age, income, education), existing pregnancy-related health problems, perceived relevance of the study to the patient’s condition, the time commitment to participate in the trial, and fears. A recent systematic review of pregnant patients’ reasons for participating in clinical research included:
- altruism (a desire to help others and/or contribute to science);
- collateral benefits of participation such as services provided (e.g., vaccination, free ultrasound, enhanced care);
- financial reimbursements or incentives;
- the opportunity to learn more about their condition;
- direct benefits of the intervention for the mother or fetus (i.e., access to an otherwise unavailable drug or a procedure);
- influence of their health care provider, family, friends, or community networks; and
- ease of participation (van der Zande et al., 2018).
While access to an investigational product can be a potential benefit of trial participation, Bettendorf said that patients should not be compelled into trial participation to obtain treatment they could not otherwise afford or access.
PRACTICAL SUGGESTIONS
Creating an End-to-End Product Development Framework
Ajoke Sobanjo-ter Meulen, Icosavax, suggested that an end-to-end product development framework for pregnant and lactating persons is needed. She said this would include, for example, appropriate preclinical animal models, a platform approach to safety data that could use available safety data from similar drugs, and linkage of pregnancy surveillance to pharmacovigilance and disease surveillance. Examples of linked surveillance include the Centers for Disease Control and Prevention’s (CDC’s) V-safe registry of postvaccination health information that links with the CDC COVID-19 pregnancy registry,1 and the UK-wide Obstetric Surveillance System (UKOSS), which is linked to clinical trials and clinical research.2 Standardized protocols and harmonized regulatory guidelines across companies, platforms, and countries could help facilitate regulatory approval and recommendation for use across regions. Regulatory incentives could encourage manufacturers to include pregnant and lactating persons in clinical trials. However, she cautioned that some requirements might actually create barriers or disincentives for companies to undertake clinical research in pregnancy (especially smaller companies with fewer resources). Ultimately, the goal would be for studies to include pregnant and lactating persons by default where appropriate, except when there is scientific or ethical reason not to do so, she said. Translation of clinical trial data from research to practice is also needed, including communications to ensure that both patients and their providers understand the benefits and risks of drugs they might take during pregnancy and lactation.
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1 See https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html (accessed September 12, 2022).
2 See https://www.npeu.ox.ac.uk/ukoss (accessed September 12, 2022).
Mobilizing Advocates and Champions
Mobilizing advocates and champions across different institutions is also essential for progress because equitable inclusion of pregnant and lactating persons needs to be adopted not only by the clinical research enterprise, but also by policy institutions, regulators, academia, and patient advocacy groups, Sobanjo-ter Meulen said. Partnership and collaboration between the maternal health community and drug developers, as well as public–private partnerships supporting research are needed. As an example, she mentioned that the Gates Foundation has long invested in global maternal health and awards grants to support clinical research in pregnancy.
She also encouraged a global approach to the inclusion of pregnant and lactating persons in clinical trials because half of the pregnancies worldwide occur in low- and middle-income countries where access to medicines can be limited.
Disseminating Information to Stakeholders
Information for Clinicians
Disseminating information about the safety and efficacy of drugs in pregnancy and lactation and about associated clinical trials was a key topic of discussion. Gillispie-Bell said that effective ways to reach obstetricians/gynecologists (OBGYNs) with new information are through the literature from the American College of Obstetrics and Gynecology (ACOG) and through the American Board of Obstetrics and Gynecology (ABOG) maintenance-of-certification process, which includes updates on changes to practices. Gillispie-Bell and Bettendorf also discussed the importance of bidirectional communication among all the providers on the patient’s care team (not just obstetrics) to ensure the safe use of appropriate drugs during pregnancy as well as to share information about clinical trials that might be appropriate for the patient.
Information for Pregnant and Lactating Persons and Support Teams
Henderson said that patients are also seeking information about how treatments might affect their pregnancy and that patient advocacy and community-based organizations are good resources. The March of Dimes, for example, provides information directly to patients on its website as well as through programs and community-based partnerships.
Geeta Swamy, Duke University, noted the need to focus on reproductive health planning so people can choose when to conceive and carry a
pregnancy, and clinicians can work with them to optimize their medications before they conceive. She observed that many pregnancies in the United States are mistimed or unplanned. When people have not had adequate counseling or preparation the reaction is to stop any medications without considering any available evidence or looking for a trial to enroll in. Henderson agreed that preconception care and planning are important but added that 54 percent of counties in the United States have inadequate access to maternal care, 35 percent of which are “maternity care deserts,” leaving a significant proportion of reproductive-age women without access to maternity care providers or facilities in their county (March of Dimes, 2020).
To foster trust, Ebony Boyce Carter, Washington University School of Medicine, and Bettendorf said that practitioners need to be honest with patients about the available evidence about a drug and the gaps in knowledge on the use of the drug during pregnancy or lactation. Carter said she makes clear that she is giving her opinion based on her knowledge of pregnancy and on what is known and what is not about the drug, giving patients a balanced argument. Bettendorf said that in shared decision-making, providers are accountable for sharing their knowledge with the patient and the patient is accountable for sharing their personal values and preferences with the provider.
Bettendorf suggested the need to promote “an informed culture of research in pregnancy” by making general information about the importance of this research readily available at family medicine clinics, obstetrics clinics, and midwifery practices. Patients who obtain such materials in the waiting room might be inspired to ask their provider about clinical trials that might be relevant to them. Ciarra Covin, Well Project, (via prerecorded video) said that patients can also contribute to raising awareness of the availability of clinical trials or ongoing research. Communication, storytelling, and actions by pregnant persons can influence others. “If we have the information, if we’ve been told, then that…opens the networks of people who are able to receive this information,” she said.
Sharing information with the patient’s chosen support team was also discussed. Bettendorf suggested planning in advance for discussions with patients about clinical trials. Specifically, providers can alert patients, through a phone call or their health care portal, that they plan to discuss clinical trial opportunities at their next visit and ask if there is someone they would like to bring with them. In addition, providers can leverage telemedicine or phone calls as needed to include the patient’s support person. Gillispie-Bell raised a concern that doulas are often not considered to be part of a patient’s care team, and during the height of the COVID-19 pandemic they were often not allowed into care settings. She said that doulas should be considered an extension of the care team, serving as birth
workers and perinatal care workers, as well as community advocates who can encourage patients to receive recommended treatment (e.g., a vaccine).
Recruiting Clinical Investigators
Anup Challa from AstraZeneca highlighted the challenges of engaging obstetric providers who are interested in and knowledgeable about serving as clinical investigators for trials that enroll pregnant patients, especially OBGYNs who work in community practices outside of an academic health system. He noted that biases can be introduced when participants are recruited solely from academic sites and said there is a need to promote better awareness among practicing OBGYNs of how clinical trials are conducted.
Gillispie-Bell said her personal interest in fibroids led to her becoming a clinical investigator. From the academic side, she suggested that researchers work with practicing clinicians to identify their areas of interest and pursue funding opportunities and develop clinical studies aligned with those interests. For community physicians, she suggested developing models of care that demonstrate how they can incorporate clinical trials into their community without taking up their limited time or adding costs.
Henderson said that better networks of communication are needed between academic centers and satellite or community-based practices to share information about clinical trials that are enrolling and the benefits of participation for the provider as investigator, for the patient, and for the community.
Recruitment and Retention of Trial Participants
Bettendorf discussed strategies to address individual-level logistical barriers to recruitment and retention, including selecting study locations that promote equitable participation (e.g., near public transportation stops); having clinical research staff travel to communities; using community-based partners to reach potential participants who do not routinely access prenatal care (e.g., not-for-profit social and health organizations that work with patients in low-resource settings); and using mobile technology to send study reminders, questionnaires, or other key study information.
Patients may be apprehensive about taking medications during pregnancy, and Bettendorf discussed the concept of risk distortion, where a patient overinterprets the risk of taking a drug in pregnancy relative to the risk of taking no action. Addressing these concerns requires shared decision-making and an individualized and unrushed informed consent process. Studies also suggest that the opinion of the pregnant person’s
spouse or partner weighs heavily in their decision to participate in a trial, which, as discussed above, highlights the importance of engaging all stakeholders in informed conversations about trial participation.
As discussed, lack of trust of the health system and the clinical trials enterprise is a key barrier to trial participation. Bettendorf said that community-based efforts have been effective in promoting pregnancy-related interventions such as infant nutrition and breastfeeding, and there is an opportunity to engage community health providers and community-based organizations as partners in recruitment for clinical trials. These partners can help to develop culturally competent promotional materials and trial designs. Focus groups with pregnant and lactating persons can also help to inform the understanding of the barriers and facilitators of participation in a population.
Bettendorf noted that progress has been made in addressing barriers to recruitment at the regulatory level and that promoting the presumption of inclusion is a critical aspect for continuing this progress.
At the community and social level, Bettendorf said that providers are “a direct conduit for study promotion and effective recruitment.” Clinicians can be advocates for enrollment and can help improve the diversity of the trial population. Study teams need to reach out to community partners and clinicians and ensure they are aware of current clinical trials and have the information needed to discuss trials with their patients, she said.
Carter emphasized the importance of establishing trusting relationships with communities long before approaching them about trial enrollment. She described how the local community health centers from which she recruits pregnant patients were part of the trial development process from its inception, helping to write and then review the grant application. Instead of being fearful of the research, they were excited for it to begin. She said it is important to establish how the research will serve the community and enhance the mission of the community health center, and to ensure they have the resources needed to participate (e.g., staffing) so that the study is not a burden. Henderson acknowledged that this approach is time-consuming and intensive but has allowed them to recruit successfully from these community health centers where other studies have failed.
Danielle Askin emphasized the importance of going to where people are to recruit for trials. She said “people are on the Internet” and that she and her friends found information on clinical studies they participated in through social media. She added that not all communities have a community health center and people with insurance must see providers that their plan will cover.
