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In October 2019 FDA issued a revised draft guidance entitled: “Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act Guidance for Industry” This is to replace the original guidance of April 2011.

This document was issued as a consequence of the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT Act) which required FDA to change the post marketing study requirements regulations in Section 3041. For the full SUPPORT Act, which is very long and deals primarily with the opiate situation, see: https://www.congress.gov/115/plaws/publ271/PLAW-115publ271.pdf

The SUPPORT Act requires the FDA to add to the definition of “adverse drug experience” (Section 505-355-(1)(E) of the Federal Food and Drug Act:

“…which may include reduced effectiveness under the conditions of use prescribed in the labeling of such drug, but which may not include reduced effectiveness that is in accordance with such labeling’’.

It further states that:

“If the Secretary [of HHS] becomes aware of new information, including any new safety information or information related to reduced effectiveness…that should be included in the labeling of the drug”

The act also requires the FDA to issue a guidance by October 2019 proposing how this will be done.

If FDA determines that there is a “serious risk, the FDA may require a post-marketing safety study. This has been in effect for several years. A “serious risk” is defined in the glossary of the draft guidance as “a risk of a serious adverse drug experience.” The change here is that now the definition of serious adverse event includes “reduced effectiveness” also called “lack of efficacy”. Thus the FDA may now require, under this regulation, a new efficacy study as a Post Marketing Requirement (PMR).

The guidance then states that “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 (SADE).”

So the new, required PMR may be a study with an efficacy endpoint to assess whether the lack of efficacy may result in an SADE.

The revised draft guidance referenced in the first paragraph of this posting, runs 22 pages and covers the definitions and requirements of PMRs, studies, clinical trials, periodic reporting, timetables for completion, missing information, whether reliance on FAERS and VAERS and the Sentinel System and its Active Postmarket Risk Identification and Analysis System (ARIA) are sufficient for safety surveillance of the product.

The guidance also gives examples of postmarketing studies and trials that could be done including animal and pharmacoepidemiologic studies, meta-analyses. These may be post marketing requirements or postmarketing commitments.

Specific examples of possible studies are given on pages 14 and 15 include:

The FDA may then, as a result of the findings of the postmarketing efficacy study, alter the approved labeling of the product. This could include not just new safety information (new adverse events/reactions, warnings, precautions etc.) but also changes or limits to the efficacy statements and indications.

Although comments are requested, it is not really possible to alter the FDA’s new authority to require new efficacy studies as a result of safety information as this is required under the SUPPORT legislation.

Comments: The FDA will have the authority to require a new efficacy study if it feels there is a new risk or signal but also if they feel that the current surveillance methodology in use for that product is insufficient to identify patients who are at risk for new safety problems due to lack of efficacy.

This means that the sponsor must be very careful and meticulous in designing, setting up, tracking and completing such studies. It also means the pharmacovigilance/drug safety group and signaling group must pay attention to lack of efficacy as an AE/SAE.

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