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Review highlights lack of consistency in FDA’s ‘close call’ approvals

Posted 23 September 2021 | By Mary Ellen Schneider 

Review highlights lack of consistency in FDA’s ‘close call’ approvals

The process used by the US Food and Drug Administration to vet new drugs and biologics is inconsistent in borderline cases and fails to rely on evidence standards used in previous decisions, according to findings from a case series that examined the process across 22 "close call" applications in recent years.
The findings, published as a case series in the Annals of Internal Medicine, show that in some cases the agency revised an initial denial based on a reinterpretation of the evidence, but not new evidence. The authors also noted that nowhere in FDA’s approval package did the agency cite reasoning from past decisions.
“We saw multiple instances of evidential requirements changing across review cycles, and some decisions changed not with new evidence but with a change in the division considering the drug. In 2 cases, the applicant’s apprising the FDA of its own past decisions shifted the balance in favor of approval. Although each decision had an explainable internal logic, it was not clear whether the same reasoning applied in other cases; each decision invoked a bespoke rationale,” Perrine Janiaud, PhD, of Stanford University, and colleagues wrote.
The study was a collaboration between researchers at Stanford University and staff at the offices of biostatistics of FDA’s Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research and was primarily funded by FDA. The study notes that the funders had no role in study and that its conclusions are those of the authors and do not necessarily represent the official views of the agency.
Regulatory flexibility
FDA recently came under fire when it granted accelerated approval to Biogen's Alzheimer's drug Aduhelm (aducanumab) against the recommendation of its own advisory committee, drawing criticism for not following its own rules of evidence. The agency quickly revised the label to narrow the indicated population. (RELATED: FDA trims Aduhelm’s indicated population, Regulatory Focus 08 July 2021)
The current study, which examines approvals from 2013 to 2018, seeks to examine how the agency has used the regulatory flexibility it was granted through the 1997 FDA Modernization Act for applications related to life-threatening diseases and unmet therapeutic need.
The researchers reviewed all original new drug applications (NDAs) and biologics license applications (BLAs) approved from 2013 to 2018 that had first been rejected by FDA based on efficacy concerns. They identified 22 drugs and biologics that fit the criteria and analyzed the full approval package, which included clinical, statistical, and summary reviews, as well as the director’s memo, the complete response and approval letters, and in some cases minutes of the advisory committee meeting.
Since each of the 22 applications had initially been rejected, the investigators reviewed FDA’s complete response letter to identify the efficacy weaknesses and then reviewed the approval package to see how problems were ultimately resolved.
One of the most common deficiencies in the applications – seen in eight applications – was a disagreement between FDA and the applicant about the primary end point. In some cases, the applicants used a surrogate end point that was not included in the agency’s Table of Surrogate Endpoints. In other cases, the applicants used an approved end point, but the clinical meaningfulness of the effect was unclear. Other reasons for an initial rejection included inconsistent results across trials or end points, and deficiencies in data integrity such as improper accounting for missing data or poor population descriptions.
In total, 15 of the 22 applicants reviewed in the study resolved efficacy concerns by providing additional data such as new pivotal studies, data corrections, or new subgroup analyses. However, in 7 of the 22 applications, no new information was provided.
Additionally, the researchers could find no references to how past approvals factored into the decision making. “No decisional memos referred to the reasoning used in other approvals, meaning that the FDA does not have a tradition or structure to ensure consistency in its decisions,” the researchers wrote. “In the legal field, consistency of logic and reasoning across cases and jurisdictions is maintained through case law; arguments made by previous judges are used and cited by others, albeit in different contexts and with different evidence – exactly the FDA’s situation.”
While the researchers noted that these are “close calls” are not representative of the large majority of FDA approvals, they called on the agency to make changes to their approval process. Namely, they called on the agency to create a database of its own decisions so that FDA staff can rapidly retrieve similar relevant approvals to include as part of the reasoning for deciding on current applications. “This would enable the FDA to improve institutional memory and learn from its own decisions, thereby increasing the transparency and consistency of its determinations,” they wrote.
In an accompanying editorial, Joel S. Perlmutter, MD, of Washington University in St. Louis School of Medicine, praised the case series as “an important first step in trying to demystify the actions of the FDA.”
Perlmutter also called on FDA to develop prospective rules for transparency and on Congress to break the financial link between FDA and industry by fully funding the agency. “These corrective steps will permit the FDA to regain and maintain community trust,” he wrote. “We need a strong and independent FDA.”
Perlmutter is one of three experts who resigned from FDA’s Peripheral and Central Nervous System Drugs Advisory Committee in protest over the agency’s approval of Aduhelm.
Annals of Internal Medicine case series, Editorial `


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