The US Food and Drug Administration (FDA) on Friday published draft guidance calling for the “judicious inclusion of pregnant women in clinical trials,” with “careful attention to potential fetal risk.”
The 14-page draft guideline notes that trial sponsors should consider including an ethicist in planning and to meet with the appropriate FDA review division, including experts in bioethics and maternal health, early on to discuss when and how to include pregnant women in a development plan.
“There may be circumstances in which a clinical trial can potentially expose a fetus to greater than minimal risk,” the draft says. “Pregnant women can be enrolled in clinical trials that involve greater than minimal risk to the fetuses if the trials offer the potential for direct clinical benefit to the enrolled pregnant women and/or their fetuses. For example, this benefit may result from access to: (1) a needed but otherwise unavailable therapy (e.g., a new anti-tuberculosis drug for multidrug resistant disease); or (2) a drug or biologic that reduces the risk for acquiring a serious health condition (e.g., a vaginal microbicide that reduces transmission of HIV and herpes simplex virus).”
The guidance also discusses when risks are not research-related and when they are independent of the study and not associated with a trial intervention or protocol requirements.
“In other words, when a study collects data about drug treatment during pregnancy but the drug was prescribed before study enrollment by the patient’s HCP, then the risks associated with the drug use are not research related risks. For example, in a study in which the investigator plans to assess the pharmacokinetics of a particular selective serotonin reuptake inhibitor (SSRI) during pregnancy, the investigator enrolls pregnant women with a history of major depression who are currently managed on this drug,” the draft explains. “In this study the SSRI does not create research-related risk, because the patients are already using the SSRI (as previously prescribed by their HCPs) to manage their medical conditions. The only risks of the study are those associated with study specific procedures (e.g., blood sample collection), and potential loss of confidentiality or privacy.”
In terms of the timing of enrollment, the draft says that in general, phase 1 and phase 2 clinical trials in a nonpregnant population that include females of reproductive potential should take place prior to enrolling pregnant women in later trial phases.
The draft also notes what to consider when determining when to enroll pregnant women, including, “If there are limited safety data or other approved (i.e., safe and effective) treatments are available,” if there are limited therapeutic options and if there are safety data for a drug that has been studied previously for other indications or populations.
Situations where it would be appropriate to stop a randomized, controlled clinical trial that is enrolling pregnant women, according to the draft, include: “An appropriately planned interim analysis demonstrates superior efficacy of the control or active comparator arm” or there are “documented serious maternal or fetal adverse events that can be reasonably attributed to drug exposure and are deemed to exceed the potential benefits of drug treatment.”
Draft Guidance for Industry: Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials