Nonefficacy Benefits: Research Evaluates What Companies and FDA Say

Regulatory NewsRegulatory News | 05 March 2019 |  By 

An analysis of new molecular entities (NMEs) approved on the basis of noninferiority trials found that sponsors generally named nonefficacy benefits, while the US Food and Drug Administration (FDA) did so in a minority of cases, according to research letter published Monday in JAMA Internal Medicine.

The authors, from the University of Maryland School of Pharmacy in Baltimore and the George Washington University School of Medicine, said their findings are “concerning because potential nonefficacy benefits form the ethical and scientific justification for choosing noninferiority hypotheses, which allow potential loss of efficacy relative to older effective, often less expensive therapies.”

The researchers evaluated, between January 2011 and September 2017, FDA approvals of 262 indications for 238 NMEs. But they excluded 242 indications (220 NMEs) that were not approved exclusively on noninferiority pivotal trials, leaving 20 indications (18 NMEs) for analysis.

Overall, the analysis found that 15 (75%) of FDA or sponsor communications mentioned a nonefficacy benefit, which can include decreased adverse events, less invasiveness, more convenient formulation and reduced costs, among others.

“Sponsors mentioned nonefficacy benefits more often (n = 15; 75%) than the FDA (n = 6; 30%). The most common nonefficacy benefits mentioned by FDA were decreased adverse events (n = 3; 15%) and simpler dosing/administration (n = 3; 15%). Sponsors most often mentioned simpler dosing/administration (n = 10; 50%), reduced nondrug health care cost (n = 6; 30%), and decreased adverse events (n = 6; 30%),” the analysis found.

The researchers also took issue with the fact that “new treatment option” was the most common expression, appearing in 19 (95%) sponsor and 14 (70%) FDA communications.

“All NMEs are by definition new treatment options. Novelty alone carries no intrinsic therapeutic value, is known before initiation of studies, and neither explains added benefits for patients of new interventions nor justifies harms to participants enrolled in trials. We found that some nonefficacy benefits were based on assumptions not evaluated in trials themselves (eg, reduced nondrug costs),” they wrote.

In addition, a treatment course with the NME was less expensive in eight (35%) comparisons and more expensive than the active control in 13 (57%) comparisons.

“Future noninferiority trials should present potential nonefficacy benefits in protocols and consent forms,” they wrote. “Potential nonefficacy benefits that can be formally studied, such as decreased adverse effects, should be required by regulators to be evaluated in trials and clearly communicated in study results.”

JAMA Internal Medicine


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