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.