Clinical Researcher—November 2021 (Volume 35, Issue 8)

SPECIAL FEATURE

Tara Coffin, PhD, MEd; Sharad Adekar, MD, PhD, CIP

 

Clinical research facilitates medical advances, improving treatment options for a multitude of health conditions. In fact, the sole act of participating in a research study has been demonstrated to improve health outcomes for individual research participants and patients alike.{1} However, the benefits rendered from research results and participation are limited to the groups and sometimes communities that are represented in the research setting, leaving underrepresented groups less likely to benefit clinically.{2} For example, Black and Indigenous People of Color{2,3} and pregnant people{4,5} are critically underrepresented in the clinical research setting, and care options available to these groups, along with adjacent health outcomes, suffer as a result.

This discussion will focus on the inclusion of pregnant people in clinical trials.

The Problem with Underrepresentation

By excluding pregnant people from research, health professionals are effectively disregarding the fact that these patients fall ill, and that people who are sick give birth.{6} As a result, there are relatively few “on label” medications and medical devices available for pregnant people.{6,7}

For example, a pregnant person seeking treatment for gestational diabetes is often limited to “off label” treatment options—medications or medical devices that have not been formally tested in a prospective interventional study with pregnant participants. Without adequate research data, such treatments are often not approved for use in this population. That doesn’t mean they are inherently unsafe, it just means that the safety profile is unclear for pregnant individuals, simply due to the lack of data.{7} Real-world evidence may be available, but when investigations are forced out of the research setting and into the “real world,” we effectively move an element of risk out of a well-controlled environment and into the clinical setting, where there may be fewer safeguards.

Why are These Groups Underrepresented?

Underrepresentation of pregnant participants, as well as persons of childbearing capacity, is frequently attributed to safety concerns about parental and fetal exposure, associated liability with risks, response from regulatory authorities, and finally preferences of the pharmaceutical industry. This may be the case even when there is possible benefit to the pregnant person and fetus/newborn. In essence, pregnant participants are treated like a vulnerable population{8} as part of a conservative approach fueled by the thalidomide tragedy.

In the late 1950s, thalidomide was touted as an anti-morning sickness drug and was widely used in Europe and the United Kingdom. It didn’t take long for concerns to emerge, as parents who took thalidomide during pregnancy gave birth to children with limb differences and other medical problems. Use of thalidomide (which had never been approved for use in the United States) was severely restricted and significant changes were made to the U.S. Food and Drug Administration drug approval process in response, but the issue made a lasting impression.{9}

Animal studies which seek to describe potential teratogenicity inconsistently predict teratogenic effects in humans, leaving many researchers poised to exclude pregnant participants out of concern for unknown risks to the pregnant participant and the fetus.{10} This conservative approach also extends to lactating individuals.

Research teams may also be concerned that the inclusion of pregnant participants may confound the interpretation of study data. Pharmacokinetics may be influenced by the normal physiologic changes that take place during pregnancy, including changes to binding proteins, the increase in blood volume observed in a pregnant body, metabolic changes, changes in body weight, and other issues that impact the bioavailability and metabolism of drugs.{6,11} The physiologic changes (and signs and symptoms) that occur with pregnancy may be difficult to distinguish from adverse events possibly related to the study interventions. Pregnancy-related tests and interventions that may need to occur to monitor and protect the health of the pregnant person and the fetus may conflict with study procedures or impact the assessment of study outcomes.

Complicating the situation further, there are ambiguous guidelines concerning the inclusion of pregnant people in clinical research.{12,13} With these concerns in mind, additional guidance and acceptance are needed to better understand when and how to include pregnant participants in research studies, addressing representation while maximizing potential benefits and minimizing risks.{7}

Improving Representation of Pregnant Persons

Currently, there are a few ways in which pregnant participants are included in research, including the following:

• Minimal risk research, when research procedures pose no additional risk (to the pregnant participant and the fetus) outside what the participant would encounter in daily life.
• In some cases, a participant of childbearing potential may become pregnant while enrolled in a research study that excludes pregnant people. Depending on the nature of the research, the investigator may determine that it is still in the participant’s best interest to receive the study treatment, or the study treatment may be stopped, but the participant and infant(s) may be followed to assess outcomes.
• A pregnant participant may be enrolled in a study evaluating treatment for a condition that exclusively impacts pregnant people. Depending on the investigational treatment, inclusion of pregnant participants in this case would typically occur after safety and efficacy has been demonstrated in healthy adults.
• Finally, there may be situations when a pregnant participant is enrolled in a study evaluating a treatment for a condition that is not exclusive to pregnant people, but that may benefit the pregnant person or fetus. Even though the compassionate use programs are not considered as research studies, we have seen some change during the COVID-19 pandemic where pregnant patients received treatment under compassionate use programs. The overall representation of pregnant participants in clinical studies including vaccine studies is still low—even in the current COVID-19 pandemic.

Even in situations when there is the potential for benefit, research teams may be reluctant to include pregnant participants for many of the reasons detailed above. However, this conservative route quickly becomes a justice issue, with underrepresentation contributing to existing health disparities. The Double Effect Doctrine offers guidance for when pregnant patients may be included in research,{4} providing another view of the Belmont Report’s principle of beneficence.

The Double Effect Doctrine explains that an act, such as exposure to an investigational treatment during pregnancy, 1) must have good intention, 2) must exclude any intentional harm, 3) must ensure that the benefit is a product of the treatment, rather than a product of the harm, and 4) the benefit must be desirable enough that it “makes up” for any harm experienced on the way.{4} Importantly, the research team should consider how the investigational treatment stacks up against currently available treatments. In other words, how does the risk-benefit ratio of the investigational treatment compare to the risk-benefit ratio of the standard of care pregnant patients would receive outside the study?

Such guidance may assist research teams in addressing a situation when a pregnant participant may otherwise be eligible for participation in a research study that could benefit them or the fetus, but also may pose a potential risk. From a regulatory perspective, inclusion of pregnant participants is ethically permissible, if it meets the criteria for approval under the 45 CFR 46 Subpart B of the Code of Federal Regulations.{14} These regulations are what the institutional review board will adhere to and capture in the careful risk-benefit analysis.

Delivering the Data

While the above considerations offer guidance for when it is ethical to include pregnant participants, what about the practical consideration of data interpretation? As mentioned earlier, pregnancy introduces biological changes that may confound research results.

With this issue in mind, research teams may consider including pregnant participants as a separate cohort when the risk-benefit ratio is favorable. Interpretation of these data would take into account the physiological changes that take place during pregnancy. This will also facilitate additional pregnancy-specific safeguards unique to the research setting. These accommodations could be built into a protocol and drive enrollment.

Alternatively, these plans could be written into the protocol with the intent of creating a pregnancy-specific cohort if a participant becomes pregnant while participating in a study, and the study doctor and the patient determine that it is in the patient’s best interest to continue receiving the investigational treatment. Small cohorts of this sort would likely lack statistical power, but could generate hypotheses and help build upon existing safety profiles.

Conclusion

Safety will always be paramount, but as long as pregnant people get sick (and sick people get pregnant), there will be situations where healthcare can be improved by including pregnant participants in the clinical research setting. By including pregnant participants when the risk-benefit ratio is favorable, researchers create opportunities to improve resources for on-label treatment options for pregnant people, but also effectively move the “risk” associated with using new therapies out of the clinical setting and into the research setting.

With appropriate safeguards in place and with a critical look at the risk-benefit ratio, pregnant participants can be included in the research setting, without facing another thalidomide disaster. In essence, if safety is truly at the heart of this issue, there are times when the safest option may be to include pregnant people in research.

References

1. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.14528
2. https://www.frontiersin.org/articles/10.3389/fcell.2019.00074/full
3. https://extramural-diversity.nih.gov/diversity-matters/underrepresented-groups
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303058/
5. https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-017-2402-9
6. http://www.gfbr.global/wp-content/uploads/2017/04/GFBR-2016-report-ethics-of-research-in-pregnancy-FINAL.pdf
7. https://peh-med.biomedcentral.com/articles/10.1186/s13010-019-0081-8
8. https://link.springer.com/chapter/10.1007/978-3-319-26512-4_3
9. https://www.sciencemuseum.org.uk/objects-and-stories/medicine/thalidomide
10. https://www.jacc.org/doi/full/10.1016/j.jacbts.2019.10.008
11. https://muse.jhu.edu/article/245708
12. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.13899
13. https://care.diabetesjournals.org/content/39/6/1004
14. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/common-rule-subpart-b/index.html

 

Tara Coffin, PhD, MEd, is IRB Chair/Vice Chair at WCG IRB, which conducts ethical reviews of clinical research protocols and studies and has more than 200 members on boards accredited by the Association for the Accreditation of Human Research Protection Programs, Inc.

Sharad Adekar, MD, PhD, CIP, is Medical Chair at WCG IRB.