The US Food and Drug Administration (FDA) has issued draft guidance for industry regarding the science and ethics of including pregnant women in drug development clinical trials. The guidelines are intended to advance clinical research in pregnant women, while accommodating the complexities of maternal bioethics and fetal health.
The guideline draft asserted that trial design should minimize risk to participants while preserving the research objectives. In choosing the appropriate study population, the FDA recommended that sponsors take into account disease type, severity, and treatment availability; pregnant women with no other therapeutic options may be appropriate candidates for clinical trial enrollment. Regarding the timing of enrollment, the draft suggested that phase 1 and 2 clinical trials in a “nonpregnant population with reproductive potential” should be complete prior to the enrollment of pregnant women. The document also emphasized the physiologic changes associated with pregnancy and noted that pharmacokinetic parameters may change enough to justify dose or dosing regimen changes in trial enrollees.
The guidelines recommend that clinical trials enrolling pregnant women include consultants or investigators with expertise in obstetrics, maternal, and/or fetal medicine to allow for appropriate safety data collection and monitoring during the study period. The FDA also addressed situations in which it would be appropriate to stop a randomized, controlled trial with pregnant enrollees, including: (1) an interim analysis that “demonstrates superior efficacy of the control or active comparator arm,” and (2) serious maternal or fetal adverse events attributable to drug exposure are observed, and “exceed the potential benefits of drug treatment.”
The draft also detailed the circumstances under which it is “ethically justifiable” to include pregnant women in clinical studies in both the postmarketing (ie, FDA-approved drugs) and premarketing setting (ie, investigational drugs).
Guidelines for the postmarketing setting:
- Adequate nonclinical studies must have been completed, including studies involving pregnant animals.
- There must be available safety data regarding use in pregnant women from medical literature or established safety information regarding use in women who are not pregnant.
- Postmarketing studies involving pregnant women are justifiable only if the efficacy and safety of the drug cannot be extrapolated or assessed by other study methods.
Guidelines for the premarketing setting:
- As with the postmarketing setting, adequate nonclinical study data involving pregnant animals must be available.
- Premarketing studies involving pregnant women must involve the prospect of “direct benefit” to the pregnant woman and/or fetus that is unavailable outside the trial setting.
In women who become pregnant while enrolled in a clinical trial, the FDA recommended that unblinding occur to allow investigators to determine the level of fetal exposure to the investigative drug, placebo, or control. Per these guidelines, women who become pregnant while enrolled should receive counseling on the risks and benefits of either continuing or stopping the trial. If a woman chooses to continue the study, she must undergo a second informed consent process to address additional risk-benefit considerations. Regardless of whether or not the mother remains enrolled in the trial, FDA guidelines assert that the trial should assess and report the pregnancy outcome.
By standardizing the care for pregnant women enrolled in clinical trials, these guidelines aim to facilitate the inclusion of pregnant women in research studies and the subsequent development of accessible treatment options for the pregnant population.
Food and Drug Administration. Draft Guideline: Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM603873.pdf. Updated April 2018. Accessed May 25, 2018.