Researchers call on FDA to get tough on accelerated approval labeling

Regulatory NewsRegulatory News | 06 March 2023 |  By 

"Updated on 8 March 2023 to include comments from PhRMA."
More than 10% of drugs granted accelerated approval by the US Food and Drug Administration (FDA) have not complied with the agency’s 2019 labeling guidance, according to a new study. The study authors wrote that the lack of labeling transparency can affect prescribing habits and call on FDA to ensure regulatory compliance through meetings with manufacturers, warning letters or by levying fines.
FDA’s 2019 guidance on labeling for products with accelerated approval instructs manufacturers to acknowledge that an indication is approved under the accelerated approval pathway and to include a “succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits” when a product was approved based on surrogate or intermediate endpoints. The purpose is to help healthcare providers and patients be better informed about the limitations of the approved drugs so they can make better clinical decisions. (RELATED: FDA Finalizes Accelerated Approval Labeling Guidance, Regulatory Focus 22 January 2019)
Unlike traditionally approved drugs, products approved under FDA’s accelerated approval pathway use surrogate outcome measures that are reasonably likely to offer clinical benefits. When such a product is approved by the agency, regulators say it needs to be clear in the labeling that the drug was approved through the accelerated pathway which means it needs to explain that the pathway uses surrogate markers, and it hasn’t received full approval from the FDA. It must also state what clinical outcomes are being evaluated by the manufacturer in its postapproval commitment trials.  
On 5 March, researchers from Johns Hopkins, the University of South Carolina, and the City of Hope Comprehensive Cancer Center published their findings on labeling of products that have gone through accelerated approval pathway in Pharmacotherapy.
“Although manufacturers are required to complete confirmatory trials and demonstrate clinical benefit before obtaining full approval, many accelerated approval drugs remain on the market for several years without completing such confirmatory trials, with some trials failing to confirm benefit,” the study authors cautioned. “Therefore, there is less certainty around the proven clinical benefit of drugs approved via accelerated approval prior to the drug obtaining full approval.”
The study looked at labels of drugs that have been approved through the FDA’s accelerated approval pathway between 1992 and 2020. The researchers found 146 drugs had been approved through the pathway within that period and of those, 110 indications had not yet received full approval from the agency. While 87% of the products followed the FDA’s labeling requirements, 13% did not fully comply with the agency’s labeling guidance.
“This study found that 12 (11%) accelerated approval drug-indication pairs had labels that failed to describe that approval was obtained via the accelerated approval pathway and failed to describe the surrogate marker(s) that supported the accelerated approval,” the authors said. “An additional two (2%) indications had mentioned accelerated approval, but had no description of the surrogate used to support the accelerated approval. There were no striking common characteristics of drug-indication pairs that failed to follow the FDA guidance. In addition, none of the labels of the 110 drug-indication pairs included information on the clinical outcomes or benefits being evaluated in post-approval commitment trials.”
The researchers argue that accurate labeling is important for prescribers to make informed clinical decisions, and labels that don’t conform to the FDA’s 2019 guidance should be corrected to be more transparent.
“Changes and highlights to the label by the FDA have impacted prescriber habits, with the most direct effect being the FDA’s ability to dictate safety and adverse event warnings, with the most serious or life-threatening side effects or risks receiving a boxed warning, or ‘black box,’” the authors wrote.
“The case of long-acting beta-agonists for the treatment of moderate to severe persistent asthma is an example that illustrates how both specialists and primary care physicians are likely to alter their prescribing habits based on the label black box warnings,” they added. “In a survey evaluating physician awareness of black box warnings on these long-acting beta-agonist, prescribers aware of the labeled warnings indicated they were likely to alter their prescribing habits and also discuss the warnings with their patients.”
The study authors recommended that FDA take more stringent action to ensure manufacturers update their product labels by scheduling meetings to discuss the matter with them, issue warning letters and even levy fines for noncompliance.
“These corrections would immediately enhance clarity and transparency to health care providers prescribing a range of medications,” the researchers added. “Ensuring clear and consistent language in accelerated approval drug labels would help increase transparency and improve the information available to health care practitioners and patients alike.”
The drug lobby group PhRMA pushed back on aspects of the study, telling Focus in emailed comments that the study mischaracterizes confirmatory trials and the accelerated approval pathway. PhRMA noted that there many reasons why confirmatory trials may take longer than originally planned, such as difficulties recruiting enough trial subjects and patients declining to participate in trials. The group added that the FDA understands these limitations and has been flexible with drugmakers regarding their confirmatory trials.
“While we can’t speak to the specifics of any particular product labeling, we note that these researchers appear to be asking the [FDA] to enforce non-binding guidance by way of warning letters and other mechanisms that would be contrary to FDA’s good guidance practice and applicable legal requirements,” Andrew Powaleny, a PhRMA spokesperson said. “Moreover, approval for the vast majority of products identified by name in the article predates the applicable guidance.”
“It is also worth noting that a medicine granted an accelerated approval must meet the same standard of safety and efficacy for approval as medicines awarded traditional approval by FDA,” he added. “When deciding whether a medicine should receive accelerated approval, the FDA carefully considers the scientific data behind the surrogate endpoint and requires substantial evidence for approval, maintaining the same gold standard review and requirements for safety and effectiveness as that used for traditional FDA approval.”



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