Why are Post-Approval Pregnancy Studies Post-Marketing Requirements Rather Than Post-Marketing Commitments?January 8, 2024
New Year’s is often associated with baby New Year and with resolutions, which in a convoluted way got us thinking about post-approval pregnancy studies. Lots of us start the new year with a resolution. Is it a commitment, or a requirement, and does the difference matter? For post-approval pregnancy studies, it most certainly does.
A review of FDA’s Postmarketing Requirements and Commitments database reveals that one of the most common reasons FDA requires postmarketing studies is to assess the impact of a drug on maternal and fetal outcomes when taken by pregnant women. These studies typically take the form of a pregnancy “registry,” which passively tracks outcomes in pregnancies followed through the registry, and prospective outcomes studies, which actively recruit and enroll pregnant women exposed to a drug. For many drugs, both a registry and an outcomes study are required.
Post-approval studies can be classified by FDA as a postmarketing requirement (PMR) or a postmarketing commitment (PMC). What distinguishes a PMR from a PMC? A PMR is a study “that sponsors are required to conduct under one or more statutes or regulations,” whereas a PMC is a study “that a sponsor has agreed to conduct, but that are not required by a statute or regulation” (see FDA Webpage, Postmarketing Requirements and Commitments: Introduction). As a result, failure to conduct a PMR would be a violation of the Federal Food, Drug, and Cosmetic Act (FDCA) and/or implementing regulations, subject to enforcement action. Potential enforcement actions can include an FDA Warning Letter, charges under section 505(o)(1) of the FDCA, misbranding charges under section 502(z), or civil monetary penalties. In contrast, failure to conduct a PMC would not be a violation of the FDCA or regulations, and therefore not subject to enforcement action.
To better understand FDA’s approach in classifying postmarketing pregnancy studies as PMRs or PMCs, we reviewed all postmarketing requirements (PMRs) and postmarketing commitments (PMCs) related to maternal and fetal outcomes in FDA’s PMR/PMC database for drugs approved in the ten-year period from January 2014 through December 2023. This review was limited to drugs with approved New Drug Applications (NDAs); biologics and vaccines were excluded. Additionally, this review excluded pharmacokinetic and animal studies.
In that ten-year period, there were 67 drugs approved with a requirement to conduct a postmarketing pregnancy study, and 99 studies. As noted above, many drugs were approved with the requirement to both establish a pregnancy registry and conduct a prospective pregnancy outcomes study, which is why there are more studies than drugs.
Notably, of the 99 postmarketing pregnancy studies in the 10-year period, all but one were PMRs. The only example of a pregnancy PMC is for Paxlovid, for treatment of COVID-19, which is a distinguishable example because the sponsor committed to this study while the drug was still under an Emergency Use Authorization (EUA), not an NDA.
Under Section 505(o) of the FDCA, FDA may only require a PMR for one of the following reasons:
- “To assess a knownserious risk related to the use of the drug involved.”
- “To assess signals of serious risk related to the use of the drug.”
- “To identify an unexpected serious risk when available data indicates the potential for a serious risk.”
(Emphasis added.) PMRs can also be required for confirmatory studies for accelerated approval, deferred pediatric studies, and studies for products approved under the Animal Efficacy Rule, but those categories of PMRs are not relevant here.
In all three bases for a PMR listed above, there must be information indicative of a serious risk or the potential for a serious risk, because that serious risk is “known,” there are “signals” suggesting the serious risk, or “available data” indicating a potential serious risk. Without data or information indicative of a serious risk, FDA does not have authority to require a PMR. FDA’s Draft Guidance on Postapproval Pregnancy Safety Studies states that “pregnancy registries may be required to assess potential serious risks to the pregnancy that may affect the health of the fetus or the woman due to drug or biological product use during pregnancy.” However, the language in the Draft Guidance omits the requirement in Section 505(o) that “available data” must indicate the potential for a serious risk.
It is notable that all but one postmarketing pregnancy study for drugs in this 10-year review were PMRs, and not PMCs, because for the studies to be PMRs, FDA must have identified a basis for the study under the statutory language, requiring data or information indicative of a serious risk. It is difficult to believe that all 99 studies fell within this category, and not one (except perhaps Paxlovid) fell short of the statutory basis for a PMR, instead requiring categorization as a PMC.
In fact, the publicly available review documents for Zavzpret (zavegepant hydrochloride), Sotyktu (deucravacitinib), and Quviviq (daridorexant) do not identify any data (e.g., animal data or pregnancy exposure data from clinical trials) indicating a known or potential serious risk associated with drug exposure during pregnancy. The Quviviq Integrated Review states explicitly: “Animal studies do not suggest an increased risk for embryofetal toxicity.” At least for these few examples, FDA’s basis for requiring a post-approval pregnancy study as a PMR is unclear.
FDA often presents PMRs to applicants as a required condition of drug approval. As a result, applicants often feel compelled to agree to perform the PMR. Given the statutory limitations to FDA’s authority to require a PMR in Section 505(o) of the FDCA, we would encourage applicants faced with the prospect of a pregnancy PMR, where there are no data suggesting a serious risk, to assess whether FDA’s position is justified and whether a PMC is more appropriate.