Jacob M. Appel, M.D., J.D.
Sometimes it takes one injustice to shed light upon another. That is the case with recent attention being paid to the exclusion of pregnant and breastfeeding individuals from vaccine trials for COVID-19. In the United States, where the FDA has included these individuals in the emergency use authorizations, the immediate consequence was that pregnant women had to choose whether or not to accept the vaccine without meaningful data to guide them. In Great Britain, regulators initially encouraged them not to get vaccinated at all. Only recently has Pfizer started recruiting for a trial in pregnant populations, while evidence mounts that vaccines afford protection to newborns without significant risk to their mothers.
One consequence of excluding pregnant women from early COVID-19 vaccine studies has been increased attention to the larger problem of omitting these individuals from clinical trials more broadly. The practice has been fostered by misguided federal regulations that define pregnant women as a “vulnerable” population because “research may pose additional and/or unknown risks to pregnant women, human fetuses and neonates” and rules that impose “additional safeguards in research,” which are often burdensome. (The Ethics Committee of the American College of Obstetricians and Gynecologists has long argued that pregnant subjects should be reclassified as “scientifically complex”.) Rather than protecting pregnant women and fetuses, the result of these exclusions has been increased off-label uses of medications whose safety in pregnancy remains uncertain.
A second, related issue has received far less attention: namely, the exclusion of pregnant women from some compassionate use protocols. Situations often arise where a pharmaceutical is already known to be effective, but for a range of logistical reasons, does not have authorization from the Food and Drug Administration. For instance, a manufacturer may believe a drug works but is not economically viable, so they withdraw their request for approval—in essence stranding any subjects in research protocols who are benefitting from the treatment. Or a product may not be ready for market for reasons unrelated to efficacy or safety. In these circumstances, drug makers and clinicians can design research protocols, approved by institutional review boards, to arrange for access on compassionate use grounds for small numbers of patients.
Unfortunately, it has become routine to exclude pregnant women from such compassionate use protocols. No hard data exists to document the frequency of this practice, but it is widespread and familiar to most clinicians. It is also far more ethically troublesome than the generally higher safeguards applied to pregnant subjects—rules which are themselves problematic. In traditional research, the presence of equipoise means that excluding pregnant women from studies does not deny them treatments of known efficacy. In contrast, exclusion from compassionate use prevents them from receiving interventions that are safe, effective and potentially life-saving. It makes no sense to prevent a woman from taking a drug out of concern for her health, or that of the fetus, when the alternative is a high likelihood of death.
So why are pregnant women excluded? A benign explanation is that these exclusions have become so routine that they are now boilerplate. A more skeptical critic might suggest that drug makers do not want to risk tarnishing their image if negative outcomes do occur. Better a few women die, the theory goes, than the company risk another Thalidomide or Diethylstilbestrol. Fears of liability, such as so-called “wrongful life” lawsuits by children who claim to have been injured by such treatments in utero, also likely shape these decisions.
Nobody suggests that pregnant women automatically be enrolled in such compassionate use trials, anymore than any other patients are. Rather, these should be clinical decisions between a woman and her physicians. What is disturbing is when these tools are taken away from doctors and pregnant women in advance without reflection or exception.
Individual hospitals have little power to push back against such policies. Imagine a life saving salvage drug to be used in ICUs that a pharmaceutical company makes available to hospitals from compassionate use, pending FDA approval—but excluding pregnant women. Let us also assume no indication exists that the life-saving drug is dangerous in pregnancy or to fetuses; in essence, the exclusion is as irrational as excluding patients from particular racial or religious backgrounds. The hospital now faces a Hobson’s choice: They can either reject the offered treatment on principle, demanding changes to the protocol—and likely lose an opportunity to save the lives of some non-pregnant patients. Or they can accept the discriminatory protocol, but at the expense of pregnant women who are ineligible.
The solution is a blanket rule that prevents drug makers from excluding pregnant women from compassionate uses studies unless there is specific evidence or reason to believe that these particular drugs are dangerous during pregnancy and that the harm of using them convincingly outweighs the benefit. If all hospitals joined together in such a bright-line approach, this collective action would likely change manufacturers’ policies, for while it is easy to imagine drug makers pulling a compassionate use offer from one hospital, it is almost impossible to imagine them abandoning compassionate use entirely. The public would not tolerate it. Most likely, if the public understood that pregnant women are currently being denied life-saving treatments for optical and liability reasons, they would demand change—and rightly so.