During her second pregnancy, a mother tested positive for cytomegalovirus (CMV). The CMV virus can cross through the placenta and infect a developing fetus, potentially causing birth defects or other long-term health problems. This mother was contacted and presented with the opportunity to participate in a clinical trial where she would be infused with a drug that would potentially mitigate the risks of her child developing congenital CMV.
The mother reports that because her child was already at risk, she saw participating in the trial as something she could do to avoid the risk of potential health problems.
The process of participating was relatively simple considering her work-from-home arrangement and having reliable child care for her older child.
At last, her daughter was born healthy and continues to thrive.
This mother reports that, until recently, she hadn’t considered what she would have done if something had gone wrong as a consequence of participating in the trial. She said that she’s unsure what kind of compensation might make up for a hypothetical injury to her child who was unable to consent to the trial. She emphasized that parents dedicate themselves to making the right decisions for their children, so the stress of raising a child with special needs coupled with the guilt of having made the “wrong” decision, could be shattering.
The inclusion of pregnant and lactating people in clinical trials is part of an evolving national and international conversation.
Earlier this spring, the Committee on Developing a Framework to Address Legal, Ethical, Regulatory, and Policy Issues for Research Specific to Pregnant and Lactating Persons held a workshop to discuss how institutions make risk-benefit decisions regarding the inclusion and exclusion of pregnant and lactating persons in clinical research, and the role of liability, risk management, and trial insurance in those decisions as well as reviewed existing compensation schemes for research-related injuries and potential to scale these models to serve the needs of research participants.
Historically, pregnant and breastfeeding women have been excluded from clinical trials, due to concerns about the real or perceived potential risks to the fetus or child. [FDA Voices, 2021] Namely, the thalidomide crisis in the 1950s largely shaped the culture around risk aversion and clinical testing on the pregnant population.
“A 2011 study on all medications approved by the FDA from 1980 to 2010 found that 91 percent of the medications approved for use by adults did not have sufficient data on safety, efficacy and fetal risk of medication taken during pregnancy,” the authors of Fair inclusion of pregnant women in clinical trials: an integrated scientific and ethical approach write. “At the same time, the number of pregnant women who take medications, as well as the number of medications that these pregnant women take, has increased.”
Today, health advocates are pushing for the inclusion of this population in clinical research on the basis that patients should have solid evidence in order to make informed decisions about their health.
“Not having this evidence can result in unfairness in the distribution of benefits and burdens (injustice) and can curtail the autonomy in making informed choice,” Catriona Waitt writes in Clinical trials and pregnancy. “This may make it impossible to provide the best treatment, undermining the principle of beneficence, and risking increasing harm.”
Speakers at the workshop cited several roadblocks to the inclusion of pregnant and lactating people in clinical research.
Institutional Review Boards (IRBs) are charged with keeping patients safe, so they often take a very conservative approach. [White, 2021] Elisa A. Hurley, PhD, executive director of Public Responsibility in Medicine and Research (PRIM&R) explained that the current framework does not encourage or assess the risk of not doing research on this population, and that the culture needs to shift from exclusion to inclusion as the default. Dr. Hurley cited the University of Washington where there’s been a shift to require justification to exclude pregnant and lactating populations.
Lorien Urban, Ph.D., Senior Medical Director Clinical Development at Ferring Pharmaceuticals pointed out that IRBs tend not to acknowledge a distinction between pregnancy and lactation when reviewing trials. In fact, while the placental barrier can be sensitive, there are very few drugs that pass through to mothers’ milk. [InfantRisk Center]
Metin Gülmezoğlu, M.D., Executive Director at the Concept Foundation argued that pregnant and lactating women should demand to be included in research, and that governments should react accordingly, assuming responsibility and taking action.
Gülmezoğlu’s project AIM responds to the created culture of risk aversion in the field. Gülmezoğlu said that risk aversion doesn’t get rid of risk; instead it shifts risk to another person: either the care provider or the pregnant person themself.
Risk is of primary concern for companies and organizations conducting research in these populations.
Sara E. Dyson, M.P.H., C.P.C.U.,Vice President of Underwriting Operations & Risk Management at Medmarc laid out the ways in which institutions can make their trials less risky and more attractive to underwriters:
- demonstrate for the potential risk,
- conduct significant bench testing,
- conduct informed consent on video,
- ensure compensation is reasonable and cannot be construed as coercion
- consult with reputable IRB (multiple IRBs in some cases),
- select a trial site (for instance an institution with specialty in high risk pregnancy)
Niranjan Bhat, M.D., M.H.S., Senior Medical Officer at PATH, shared that PATH’s global umbrella policy which covers any adverse event during participation of the study is a key research enabler.
Michelle Mello, J.D., Ph.D., Professor of Law and Health Policy at Stanford University and Renée J. Gentry, Esq., one of the leading experts on vaccine injury litigation in the National Vaccine Injury Compensation Program (NVICP), laid out the ways in which tort versus private compensation programs can be successful or unsuccessful in compensating injured clinical trial participants. In either case, proving causation tends to be the primary difficulty on the battleground for product liability.
The tort system is capacious enough to handle injury claims, Dr. Bello began. However, using Winston Churchill’s metaphor for democracy– “Democracy is the worst form of government – except for all the others that have been tried.”– it tends to favor the wealthy, is laborious in terms of time, and presents high volatility in terms of settled amounts.
Perhaps not a solid alternative, a system like NVICP, is at a “breaking point”, according to Gentry. The program started with eight special masters when it began in the 1980s; today this number remains. Set up to cover six vaccines, the program now covers 16 vaccines; as such the number of complaints have quadrupled in the past decade. People are waiting two to three years to have their trials scheduled. In fact, some seniors have died waiting for their trials.
Gentry advises that when considering the creation of a compensation system, there should be flexibility built in to include the modification of staffing levels and scheme.
In a private system, like the UW-Washington Human Subjects Compensation Program, this flexibility is a positive attribute; however, speakers pointed out that private systems do not address two major points:
- A private system does not get around addressing causation difficulties.
- A private system does not necessarily address equity and has the potential to lead to a patchwork of compensation of different solutions at different levels of generosity.
As health professionals, consumers and other individuals and organizations work to shape the legal, ethical and policy frameworks that affect research on the pregnant and lactating population, you might consider consulting the following readings and resources.
A Comparison of FDA and EMA Pregnancy and Lactation Labeling
FDA’s Pregnancy and Lactation Labeling (Drugs) Final Rule (2014)
FDA Updates: Pregnant Women Subjects and Medical Device Investigations (2018)
Current resources for pregnant and lactating individuals and care providers
The Trash the Pump and Dump (TPD) app encompasses medical conditions, medications and substances of concern during lactation.
Drugs and Lactation Database (LactMed®)
E-lactancia: comprehensive medication and herbal medicine database in Spain, available in English and Spanish
Organization of Teratology Information Specialists
Brigham and Women’s Hospital Drugs, Herbs, and Supplements during lactation