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FDA Should Look to Past Precedents When Applying Flexibility to Approvals to Maintain Public Trust, Study Says

September 21, 2021

Though the U.S. Food and Drug Administration has flexibility in its approval criteria for drugs to treat life-threatening diseases with unmet needs, it lacks a way of weighing past decisions to provide a consistent standard for what constitutes adequate evidence in these cases, a new study finds.  

Researchers at FDA and Stanford University conducted the study, which appeared in the Annals of Internal Medicine in September. It comes in the wake of the controversy over the agency’s approval of Biogen’s Alzheimer’s drug Aduhelm despite the fact that 10 of the 11 advisory committee members voted against recommending approval with one voting “uncertain” because of a lack of evidence of the drug was effective.

The FDA has had a long-established statutory requirement that there must be “substantial evidence” of a drug’s effectiveness for it to approve its use. While there have been pathways and designations introduced to shorten drug development and the FDA approval process, largely in response to patients with unmet needs for life-threatening or rare diseases (orphan drug designation, fast track, accelerated approval pathway, priority review, and breakthrough therapy designation), the researchers note none of these designations or pathways formally change the “substantial evidence” requirement.

The FDA approved Aduhelm under the accelerated approval pathway on the basis of a surrogate endpoint, but the advisory committee felt the company failed to provide evidence of the endpoint’s validity as a predictor of the drug’s effectiveness.

In the study, the researchers sought to understand the FDA’s evidentiary standards when flexible criteria are employed.

The researchers looked at applications submitted between 2013 and 2018 that went through multiple review cycles because the evidence for clinical efficacy was initially deemed insufficient. Of 912 applications reviewed, 117 went through multiple review cycles. Of those, only 22 faced additional review primarily because of issues related to clinical efficacy.

Concerns about the endpoint, the clinical meaningfulness of the observed effect, and inconsistent results were common bases for initial rejection. In 7 of the 22 cases, the approval did not require new evidence but rather new interpretations.

The researchers found that the FDA has no mechanism to find, or tradition to cite, similar cases when weighing evidence for approvals. As a result, these decisions become standalone. In fact, the researchers found that the FDA uses highly variable criteria for “substantial evidence” when flexible evidential criteria are used.

The authors said the FDA has weak structures to support institutional memory, particularly one that crosses FDA therapeutic areas, offices, or centers. Much of it depends on staff memories and is lost with turnover. “This balkanization and fragility of institutional knowledge,” they wrote, “diminishes institutional efficiency and consistency.”

“A precedential tradition and suitable information system are required for the FDA to improve institutional memory and build upon past decisions,” the authors wrote. “These would increase the FDA’s decisional transparency, consistency, and predictability, which are critical to preserving the FDA’s most valuable asset, the public’s trust.”

Author: Rare Daily Staff

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