With a new draft guidance document, the Food and Drug Administration (FDA) is addressing what at least one observer describes as a Catch-22 of research: determining the safety of drugs during pregnancy. The FDA’s draft guidance “Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials” was released in late March and is open for public comment. If adopted, it could build a framework for learning more about what treatments are safe during pregnancy.
Medical research involving pregnant women has long presented a conundrum for ethicists, researchers, and clinicians. The possible consequences to both the fetus and mother are deeply concerning, and researchers are understandably reluctant to risk testing new treatments on these vulnerable parties. However, FDA approvals require studying how drugs affect a particular population. Without research data or FDA approval, practicing physicians hesitate to start or continue a particular treatment during pregnancy. A reluctance to prescribe treatments during pregnancy creates a further dearth of observational data about efficacy or side effects. These factors compound to form a long list of uncertainties and a short list of actual medical treatments approved for pregnant women.
Meanwhile, the specter of thalidomide hovers over any discussion about drug treatments and pregnancy. The FDA never approved thalidomide’s use for morning sickness, but the drug was a popular treatment in Europe and elsewhere in the 1950s and 1960s. Thalidomide proved to be a teratogen, causing thousands of cases of birth defects. The regulatory and ethical legacy of that experience has been decades of caution when researching or prescribing treatments during pregnancy.
The FDA’s new set of proposals aims to ease the research community toward widening the scope of research in pregnant women. In the words of the draft guidance document’s introduction, the FDA supports “judicious inclusion of pregnant women in clinical trials and careful attention to potential fetal risk.” The guidance document suggests steps to move carefully away from the ethical and research strategy of exclusion as a default to considering when and how studies can include pregnant participants.
Using the OHRP Playbook
In approaching pregnancy and medical research, the FDA in part borrows rules from its fellow research regulator, the Office for Human Research Protections (OHRP). For research on pregnant women and fetuses, the FDA draws on language that already appears in the Health and Human Services regulations “Research involving pregnant women or fetuses” at 45 CFR 46.204, a part of the regulations known as Subpart B. From those regulations, the FDA draft guidance imports 10 requirements:
- Where scientifically appropriate, nonclinical studies, including studies on pregnant animals, and clinical studies, including studies on nonpregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses;
- The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means;
- Any risk is the least possible for achieving the objectives of the research;
- The pregnant woman’s consent is obtained in accord with the informed consent provisions of 45 CFR part 46, subpart A;
- If the research holds out the prospect of direct benefit solely to the fetus then the consent of the pregnant woman and the father is obtained in accord with the informed consent provisions of 45 CFR part 46, subpart A, except that the father’s consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest;
- Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate;
- For children as defined in § 46.402(a) who are pregnant, assent and permission are obtained in accord with the provisions of 45 CFR part 46, subpart D;
- No inducements, monetary or otherwise, will be offered to terminate a pregnancy; Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; and Individuals engaged in the research will have no part in determining the viability of a neonate.
Including Pregnant Women in Research
The FDA’s draft policy presents a set of “ethically justifiable” circumstances for including pregnant women in research. The guidelines call for adequate preclinical studies (such as in pregnant animals) and research data about women who are not pregnant. Safety concerns also play a role for the FDA—that is, there should be no other way to assess drug safety than involving pregnant women. In considering premarketing settings, the FDA wants to require that participation in research presents a prospect of unique, direct benefit to the parent or fetus.
The guidance also proposes guidelines about the risks and benefits of including pregnant women in research, the timing of enrolling pregnant women, safety reporting in such studies, and when to end a study with pregnant women.
Some Implications for IRB Review
This FDA draft guidance presents some specific issues for institutional review board (IRB) consideration. For one, it states that IRBs reviewing research involving pregnant women should include a board member with adequate expertise. On the topic of informed consent, the guidance document endorses a re-consenting process for anyone that becomes pregnant in the course of a study. This represents a new concept and process for protocol writers and for IRBs that more often exclude pregnant women than consider how to include them in research.
This new guidance document aims toward resolution of a longstanding dilemma in research. By focusing on cautious inclusion, FDA’s guidance could offer novel routes to improving care during pregnancies.