In October, FDA issued a draft guidance titled “Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act,” which will replace a similar April 2011 draft guidance once finalized. This new draft guidance reflects a significant expansion of FDA’s authority to require postmarketing studies. FDA is now permitted to establish postmarket requirements (PMRs) to study efficacy in addition to safety.
This expansion of FDA’s PMR authority is the result of section 3041 of the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT Act). While the SUPPORT Act is generally focused on opioid drugs and treatments for opioid addiction, section 3041 on PMRs is not limited to any particular drug class.
Section 3041 of the SUPPORT Act revised the definition of “adverse drug experience” at section 505-1(b)(1)(E) of the Federal Food, Drug, and Cosmetic Act (FDC Act) to include “reduced effectiveness under the conditions of use prescribed in the labeling of [a] drug.” The purpose of a PMR is to assess a known serious risk, assess signals of a serious risk, or identify an unexpected serious risk when data indicate the potential for a serious risk. Id. § 505(o)(3)(C). A “serious risk” is a risk of a “serious adverse drug experience.” Id. § 505-1(b)(5). Because adverse drug experience now includes reduced effectiveness, FDA can issue a PMR for an efficacy study.
After a drug is approved, FDA can require an additional study on the basis of “new safety information.” Id. § 505(o)(3)(C). “New safety information” includes information derived from adverse events. Thus, if FDA finds that there is reduced effectiveness under the conditions of use prescribed in the labeling once a drug is already on the market, it can require a new efficacy study even if that study was not listed as a PMR at the time of approval.
Notably, the SUPPORT Act also expanded FDA’s authority to require labeling changes under the safety labeling change notification process (id. § 505(o)(4)). Now, FDA can require labeling changes due to new effectiveness information in addition to new safety information (e.g., if FDA determines that the results of an efficacy PMR warrant a change to the drug’s approved labeling).
The SUPPORT Act required FDA to issue guidance “regarding the circumstances under which [FDA] may require postmarket studies or clinical trials to assess the potential reduction in effectiveness of a drug and how such reduction in effectiveness could result in a change to the benefits of the drug and the risks to the patient” within one year of the date of enactment (Oct. 24, 2018). This draft guidance was issued about one week before the one-year deadline.
The draft guidance clarifies how the SUPPORT Act’s amendment to FDA’s definition of “adverse drug experience” affects FDA’s PMR authority: “In some cases, when a serious risk relates to failure of expected pharmacological action, including reduced effectiveness, the trial might be designed with an efficacy endpoint, for example, to further assess whether a failure of expected pharmacological action, including reduced effectiveness, may result in a serious adverse drug experience.”
The draft guidance provides several examples of clinical trials intended to assess reduced effectiveness, including studies for:
- Determining whether treatment duration of an antiviral drug should be extended;
- Evaluating a newly identified drug-drug interaction that could reduce systemic exposure;
- Evaluating a newly identified antibody response to a biologic; and
- Evaluating a new signal that a subgroup of patients with a life-threatening cancer may not respond to an approved drug.
The draft guidance makes clear that FDA can order labeling changes due to the results of an effectiveness PMR. The draft guidance states, regarding both safety and efficacy endpoints in PMRs: “FDA will review the data and/or information obtained under a PMR and assess its effect on the benefit-risk profile of the drug in the context of a serious risk being evaluated. This may result, for example in labeling changes under section 505(o)(4) of the [FDC Act].”
These labeling changes could consist of additional warning statements, but they could also consist of significant changes to the indications for use. For example, if an efficacy study found that a subgroup of patients (e.g., a gender, ethnicity, or age subgroup) demonstrates reduced effectiveness, FDA could require changes to a drug’s indications for use statement.
Comments on the draft guidance are due January 17, 2020. However, this expansion of FDA’s PMR authority cannot be meaningfully changed through revisions to the guidance. Because issuance of the draft guidance was mandated by Congress through the SUPPORT Act, any adjustment to FDA’s new authority to issue effectiveness PMRs will have to be addressed through a legislative fix. It remains to be seen how this new authority will play out in practice, but industry groups may eventually be motivated to seek a legislative change.