FDA Drafts Guidance for Consideration for Inclusion of Pregnant Women in Clinical Trials – Part 2


In Part 1 of our blog series about the Food and Drug Administration (FDA)’s draft guidance on inclusion of pregnant women in clinical trials entitled Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials: Guidance for Industry, we discussed the introduction and background behind the draft guidance. The FDA identified some risk-based ethical considerations for inclusion of pregnant women, including availability of other treatment options, the type and severity of the disease or condition being treated, and the stage of development of the drug (approved or investigational). The FDA recommends the sponsor consult an ethicist to evaluate the trial design, and the sponsor should have discussions with the FDA, including bioethics and maternal health experts, early in the development stage. In any case, the sponsor must follow the regulations for human subject protections.

Human subject protection regulations for pregnant women include:

  • 21 CFR part 56: Institutional Review Boards
    • In order to adequately review clinical trials involving pregnant women, IRBs need to include a member who is knowledgeable about the unique medical needs and vulnerabilities of pregnant women and fetuses. (21 CFR 56.107(a))
    • The IRB should only consider the risks and benefits that the pregnant woman and her fetus would encounter as a direct result of participation in the trial. (21 CFR 56.111(a)(2))
    • The IRB must ensure protections are established and supported for the pregnant woman and fetus during the clinical trial. (21 CFR 56.111(b))
  • 21 CFR part 50 subpart B: Informed Consent of Human Subjects
    • Additional considerations for pregnant minors must be reflected in FDA regulated trials. State law governing legal age of consent for pregnant minors must be followed.
    • If a pregnant child is considered a minor and permitted to enroll or remain on trial, 21 CFR part 50, subpart D, Additional Safeguards for Children in Clinical Investigations must be followed.
  • If the trial is supported by Department of Health and Human Services (HHS), 45 CFR part 46, subpart B, Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research must also be followed. The FDA also suggests that these HHS requirements are followed for FDA regulated trials. Some requirements of note are:
    • Animal laboratory studies and clinical trials on non-pregnant subjects are conducted to contribute to a risk-benefit profile for pregnant women and fetuses.
    • The clinical trial poses minimal risk and the potential knowledge is important and cannot be obtained by other means, or
    • The risk to the fetus is only related to the tests or procedures and there is a potential for direct benefit to the mother and/or fetus.
    • A fully informed consent is obtained from the appropriate consenting parties, including the father of the fetus when required under regulations, and assent and permission are obtained for pregnant minors.
    • No encouragements or enticements will be rendered to the pregnant woman to end a pregnancy.

Risks to the Pregnant Woman and Fetus:

  • Research-related risks are the possibility of harm caused by the exposure to a therapy (marketed or investigational) and/or clinical trial tests and procedures.
  • Interventions or treatments would not be considered research-related if the subject already was undergoing therapy or intervention but then enrolled in a trial that collected information about the therapy or intervention.
  • The level of research-related risk is scaled according to the risk that the subject would ordinarily encounter.
    • A trial is considered minimal risk if the subject would likely be exposed to a similar risk during their usual lives or during routine exams.
  • A clinical trial that includes exposures to interventions that are not research-related would be considered minimal risk to the fetus.
    • For example: pharmacokinetic studies of pregnant women who are currently on a therapy for a preexisting condition.
  • Trials that expose the fetus to greater than minimal risk are permissible if the pregnant woman and/or the fetus may directly benefit.
    • For example: a treatment that may reduce the possibility of transmission of a disease to the fetus from the mother.

Guidelines for Including Pregnant Women in Trials:

The FDA considers including pregnant women in clinical trials to be ethical if they have a disease or condition requiring medical treatment while pregnant and if the following conditions are met:

  • For FDA approved drugs:
    • Animal reproductive toxicity studies have been conducted; and
    • Clinical trials or medical literature indicate the safe use of the drug in women; and
    • Safety data in pregnancy cannot be determined without a clinical trial and/or any other method.
  • For investigational products:
    • Animal reproductive toxicity studies have been conducted; and
    • The investigational product may provide a direct benefit to the pregnant woman and/or the fetus and an equivalent treatment is not otherwise feasible.

Considerations if pregnancy occurs on trial:

  • To determine what fetal exposure occurred, unblinding is advised.
  • A risk-based analysis should be conducted to determine whether continuing or stopping the trial would be beneficial.
  • If the benefits to the pregnant woman and/or fetus outweigh the risks, the woman should be permitted to stay on the trial.
  • If the pregnant woman continues on trial, a new informed consent should be conducted to disclose the increased risk of remaining on treatment.

Join us in Part 3 of “FDA Drafts Guidance for Consideration for Inclusion of Pregnant Women in Clinical Trials” to learn about other considerations prior to designing and enrolling pregnant women in clinical trials.

- The Clinical Pathways Team

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