National Center for Health Research: June 8, 2018
National Center for Health Research Comments on
Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials;
Draft Guidance; Availability
[FDA-2018-D-1201]
Thank you for the opportunity to provide comments on FDA’s draft guidance for inclusion of pregnant women in clinical trials. The National Center for Health Research (NCHR) is a nonprofit research center focused on research, policies, and programs that affect public health. Our Center analyzes scientific and medical data and provides objective health information to patients, providers, and policymakers. We do not accept funding from companies that make medical products, so we have no conflicts of interest.
We commend the FDA in its efforts to provide guidance on the inclusion of pregnant women in clinical trials. Currently, there is limited information regarding benefits and risks of drugs in pregnant women, including potential benefits and risks to the fetus. Pregnancy represents a critical period for counseling, health promotion, and health maintenance. Providers and patients must engage in informed discussions of benefits, risks, and alternatives in order to achieve shared-decision making. However, that is not possible when so little scientific information is available.
Since clinical trials have historically excluded pregnant patients and/or patients who become pregnant, this presents unique clinical challenges. In order to provide pregnant women with more evidence-based, patient-centered, and ethical care, we need to close these knowledge gaps.
We generally support the recommendations and guidelines in the draft document. We will focus our remarks on the following:
#1. We agree that the ethical implications of including pregnant women as human research subjects are complex. We support the FDA’s recommendation that sponsors consult with bioethics experts in program planning and development. The ethicists should also play an active role on the data monitoring committee to ensure the protection of human subjects (both mother and baby) enrolled in the trial.
When a woman becomes pregnant during a trial, we agree that a process must be put in place to provide her with additional informed consent. Understandably, this will involve unblinding, which creates both practical and ethical challenges. In order to maintain trial integrity, the person who conducts this second consent should be kept separate from the data analysis team. The ethicist should provide oversight in these cases to ensure that safeguards are in place to protect a woman’s autonomy and prevent coercion.
We appreciate the importance of protecting research subjects, including women who are pregnant or who may become pregnant. We agree with the National Task Force on Research Specific to Pregnant Women and Lactating Women, which strongly recommends that pregnant women be removed as example of vulnerable population in the common rule.[1] Doing so will enable a shift from exclusion to inclusion and will encourage research to be conducted as early in the fetal development process as possible. In addition, it will preclude investigators from needing a father’s consent in cases where an investigational therapy provides benefit only to the fetus. We agree with The American College of Obstetricians and Gynecologists’ (ACOG) position on the guidance and their own guidance that a father’s consent (except in a few scenarios) is not justified.[2],[3]
#2. We agree that the scientific study of pregnancy and fetal development is complex and raises additional issues for research study design. We agree with the FDA that when designing clinical trials, sponsors should consider disease-related factors, pregnancy-related factors, pharmacokinetics, and the availability of treatment alternatives. We suggest that the FDA provide further clarification on the following: selection of an appropriate control group and comparator, maintaining integrity of data in the face of potential unblinding, and collection and reporting of safety data.
Well-designed randomized controlled trials can provide us the best evidence regarding whether a drug works and is safe. For pregnancy, it is important to identify a control population and comparator drug that are both scientifically and ethically appropriate. For instance, a placebo control may not always be the practical or ethical choice. Pregnancy is also biologically dynamic, so it will be important for sponsors to account for differences in pregnancy trimester, gravidity and parity, gestational weight and weight gain, and other factors.
#3. Last, we encourage the FDA to provide additional clarification on its recommendations for stopping a clinical trial. We agree that sponsors should include a plan to monitor data, including interim data analysis. We also agree with the examples provided in the guidance document. Stopping a trial early is warranted when harms exceed benefits or when the ratio of benefits to harms are so significantly greater in one group compared to the other that it would not be ethical to continue the study. We agree that the risk-benefit evaluation should consider the risks of not treating a given condition to both mother and baby and the availability of alternative treatments. However, the risk of stopping a trial of an apparently beneficial drug before long-term risks are established must be seriously considered as well.
We encourage the FDA to work with sponsors to develop appropriate stopping guidelines, including consideration of statistical thresholds and clinically meaningful results. It is also important to recognize that stopping a trial because of the apparent benefit of a treatment may have unintended negative consequences, including overestimation of a treatment effect, overinterpretation of short-term effects, and underestimation of long-term safety. It is therefore important that the FDA work with sponsors to develop appropriate follow-up studies and/or drug registries in order to capture adequate and accurate data.
The study of new drugs in a pregnant population is largely uncharted territory, which raises additional complexities and challenges. A large number of new drugs are being approved by the FDA on the basis of one pivotal trial instead of two, on the basis of biomarkers rather than clinically meaningful outcomes, and on the basis of smaller numbers of patients. All these efforts to streamline the approval process make it difficult to judge the benefit-risk ratio in nonpregnant patients, and even more difficult to predict the benefits and risks for pregnant women and fetuses. It will be important to have more robust evidence of safety and efficacy for new drugs before they should be studied in pregnant women. It will be necessary to have ethical oversight, informed consent, as well as preparation through clinical trial design and procedures to appropriately deal with any concerns that arise.
Thank you for the opportunity to share our perspective.
References
- NICHD – Eunice Kennedy Shriver National Institute of Child Health and Human Development. Task Force on Research Specific to Pregnant Women and Lactating Women. May 14-15, 2018. Web Cast and Materials Available: https://www.nichd.nih.gov/about/meetings/2018/051418-agenda#51418
- Joyce Frieden, News Editor, MedPage Today. Pregnancy Not a Bar to Trial Participation, FDA Says Draft guidance met mostly with praise. April 09, 2018. Available: https://www.medpagetoday.com/obgyn/pregnancy/72229
- ACOG. Ethical Considerations for Including Women as Research Participants. Available: https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Ethics/Ethical-Considerations-for-Including-Women-as-Research-Participants