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Can the FDA Require Post-Market Efficacy Studies?

Can the FDA Require Post-Market Efficacy Studies?

A recent FDA draft guidance significantly expands FDA authority regarding post-marketing studies -- in particular, the authority to require new efficacy studies and label modifications.

Until now, the FDA guidance on postmarketing studies and clinical trials has primarily focused on drug safety, requiring sponsors of approved drugs to conduct additional studies based on “adverse drug experience” information in order to:

  • Assess a known serious risk (“adverse drug experience”) related to the use of the drug,
  • Assess signals of serious risk related to the use of the drug, and/or
  • Identify an unexpected serious risk when available data indicate the potential for a serious risk.

However, Congress’ adoption of the Substance Use-Disorder Prevention That Promotes Opioid Recovery and Treatment For Patients and Communities Act (SUPPORT Act) in October 2018 has prompted the FDA to add efficacy studies to its postmarketing research (PMR) guidance.

Prior to the SUPPORT Act, section 505-1(b)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) defined “adverse drug experience” as including:

  • An adverse event occurring in the course of the use of the drug in professional practice;
  • An adverse event occurring from an overdose of the drug, whether accidental or intentional;
  • An adverse event occurring from abuse of the drug;
  • An adverse event occurring from the withdrawal of the drug.

Section 3041 of the SUPPORT Act, added a fifth condition under the definition of “adverse drug experience” in the FD&C Act:

  • Any failure of expected pharmacological action of the drug, 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.

Despite the SUPPORT Act’s focus on opioid drugs and opioid addiction treatments, this expanded definition of “adverse drug experience” in the FD&C Act applies to all drug classes. Therefore, the new FDA draft guidance on post-marketing studies and clinical trials expands the FDA’s authority to require post-market efficacy studies or clinical trials should the drug show reduced effectiveness once entering the market.

Importantly, the FDA may request additional PMR efficacy studies based on “new safety information” – regardless of whether efficacy studies were requested at the time of approval.

Examples of FDA PMR Efficacy Studies 

According to the new draft guidance, “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 potential failure of expected pharmacological action, including reduced effectiveness, may result in a serious adverse drug experience.”

The new FDA draft guidance offers examples of clinical trials that may be required to examine reduced effectiveness, including trials to:

  • Evaluate a newly identified antidrug-antibody response involving a biological drug product approved to treat a serious disease, when data suggests the antibody could reduce drug effectiveness by altering pharmacokinetics or binding functional drug domains.
  • Evaluate a sign that certain patients being exposed to toxicity with less prospect for benefit – i.e., a new signal that a terminal cancer patient subgroup (race, age, biomarker, gender) may not respond to a drug approved based on its clinically meaningful effect in the overall population with that cancer.
  • Determine whether extending antiviral drug treatment duration (targeting a serious viral infection) mitigates the risk for relapse after treatment course completion.
  • Evaluate a newly identified potential drug-drug interaction that may reduce the systemic exposure of a drug approved to reduce the risk of cardiovascular events.

FDA Can Require Post-Market Labeling Changes 

In addition, the added condition under the FD&C Act’s “adverse drug experience” definition grants the FDA authorization to require labeling changes – including changes to indications for use or warnings - if postmarketing efficacy studies indicate reduced effectiveness.

According to the draft guidance, “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 the serious risk being evaluated. This may result, for example, in labeling changes under section 505(o)(4) of the FD&C Act.”

The new FDA draft guidance released in October 2019 acts to update the previous April 2011 FDA guidance on post-market studies and clinical trials.


Gregory J. Glover MD JD is a patent attorney and non-practicing physician. A noted expert on developments and emerging conflicts in the pharmaceutical industry, Greg is an expert on regulatory IP issues.

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