The effect of the regulatory bodies on clinical trials in pregnancy
Pregnant women have previously been categorized as a “vulnerable population’ with special consideration enforced by regulatory bodies when including them in research. The American College of Obstetrics and Gynecology instead recommended that pregnant women be categorized under “scientifically complex,” and recently the Common Rule, the federal policy for the protection of human subjects, has been revised in 2019 to remove pregnant women from the vulnerable population category [40]. However, despite that, some institutional review boards (IRB) may still feel reluctant given that there is no practical guide to address the risk and benefits of enrolling pregnant women into clinical trials [41]. Two important steps to curtail this is to involve experts in the field of maternal-fetal medicine and obstetrics pharmacology in board meetings and to require justification for exclusion of pregnant women and that this justification may be questioned during review [42]. IRB interpretation of the regulatory process has some flaws [11], particularly when it comes to the wording of “minimal risk of the fetus.” When submitting to the IRB of the academic institution or other regulatory bodies, researchers may present preclinical and animal studies corroborating the risk to the fetus, but with concern that these studies are evaluated by the IRB regulatory staff and due to the dearth of available data may not be sufficiently supportive or convincing[11]. For that reason, there is wide agreement to clarify regulations for enrolling pregnant women in trials and develop practical guidelines that can be universally implemented [15].
The FDA previously had regulatory rules in place that restricted inclusion of pregnant women in clinical trials, citing that woman should only be included if there is direct benefit to the woman or fetus with minimal risk or if risk is solely related to the intervention in question [43]. In their revised guideline in 2018, they have recommended excluding pregnant women from phase 1 and phase 2 trials and allow enrollment later. Federal regulations require investigators to consider the interest of the pregnant woman and fetus, raising the ethical question of whether the fetus is considered a patient. One argument involves a dependent moral status to be deemed on the fetus, which is based on the expectation of whether the fetus is to achieve the moral status of becoming a child and a person [44]. It is only when the pregnant woman considered the previable fetus a patient and therefore invoke the dependent moral status, then the healthcare provider and patient should have a thorough discussion about the beneficence of protecting the fetus from harm.
Pharmaceutical companies have long feared including pregnant women in clinical trials even during the phase 3 and phase 4 of the process. In response to that, the FDA has issued a guidance for industries to better design clinical trials. It highlights emphasis on pharmacokinetic and pharmacodynamic studies of drugs in pregnant women, particularly if that population is to benefit from the drug. In addition, in 2002, the FDA also issued a guidance on reporting adverse effects of medication in pregnancy and that surveillance should not be limited to the post-marketing phase. The recent events of the COVID-19 pandemic have highlighted the deficiency and reluctance posed on including pregnant women in trials. In a recent analysis, it has been shown that pregnant women have been excluded from the therapeutic clinical trials involving the COVID-19 infection, despite most medications used showing low or non-significant safety concerns, except for remdesivir [45]. This only increases the concerns that despite guidance and call to action initiatives, there is no legal framework to enforce its implementation.