10 ways to reform the FDA's accelerated approval pathway: ICER and MSKCC offer options
The FDA’s top cancer doctor Rick Pazdur recently called the FDA’s accelerated approval pathway “under attack,” and three top drug pricing experts from Memorial Sloan Kettering Cancer Center and ICER are now calling the pathway “in flux, and many would say, in crisis.”
As the alarm bells sound, Pazdur’s Oncology Center for Excellence initiated a review of the accelerated approval pathway about a year ago, while more recently, HHS’ Inspector General said it also will review the pathway, following a quick accelerated OK for Biogen Alzheimer’s drug Aduhelm. The latter review came in the face of conflicting data over whether the drug could actually slow patients’ mental decline.
“There’s two major issues here: How do we remove these drugs if their accelerated approval studies do not pan out, and the other one is how the legislation is written,” Pazdur said in a Prevision Policy webinar earlier this summer. At the time, he noted some disappointments from the recent multi-day ODAC meeting in April on so-called “dangling” accelerated approvals, where a drug that fails a confirmatory trial stays on the market.
The other major issue is what should be considered confirmatory studies, Pazdur said, questioning if it should just be additional information from an ongoing, single-arm trial, or something more.
“We’re caught in the middle many times with oncology products of a suboptimal development program yet a terrific unmet need,” Pazdur said. Overall, however, the accelerated pathway has “been very, very successful,” he added, noting, “but that doesn’t mean there isn’t room for improvement.”
Taking that cue on what improvements can be made, Anna Kaltenboeck, health economist and policy researcher at Memorial Sloan Kettering Cancer Center, and ICER’s Amanda Mehlman and Steven Pearson published an article in the Journal of Comparative Effectiveness Research on Wednesday outlining 10 possible ways to reform the accelerated approval pathway.
The researchers point to seven policy reforms that the FDA could make and another three for payers and the life science industry.
For the FDA, ICER and MSKCC, authors point to reforms in the premarket space, such as by strengthening the selection and use of surrogate endpoints, developing standardized review templates and requiring greater use of randomized controlled trials, as well as other recommendations in the postmarket space, such as creating a new label alert for accelerated drugs and better enforcing the completion of confirmatory trials.
On surrogate endpoints, the researchers call for FDA to release for public comment a preliminary justification for why such an endpoint could be used, including what criteria FDA has already established to support that endpoint. The public comment period could allow clinical experts and other stakeholders with expertise in a particular area to see the FDA’s thinking and contribute to the final decision on using that endpoint.
While RCTs are infeasible in some situations, such as with some very rare diseases, Kaltenboeck, Mehlman and Pearson also say FDA “should adopt a formal shift in posture toward requiring randomized controlled trials.” This approach could do more of the work upfront, ahead of an accelerated approval, relying less on the confirmatory work.
Once a drug is marketed under the accelerated pathway, the researchers say FDA could help patients understand the unconfirmed benefits of the drug by including a new visual for its label, such as a yellow triangle or a gray box.
On increasing the FDA’s enforcement of companies that have dragged their feet in completing confirmatory trials, the researchers echo what Pazdur mentioned about how the pathway only works if the FDA has the ability to pull drugs when the follow-ups are moving too slow or fail. One of the major issues with more enforcement, however, is that it’s likely to trigger pushback from industry and patient groups, raising the risk that Congress would lean on the FDA to cool its jets on enforcement, as it did with the Right to Try legislation.
The researchers also propose two more ideas that might require Congressional action and are further removed from the status quo: Sunsetting accelerated approvals that lack confirmatory evidence and creating a separate “safety-only” approval pathway, which could potentially put patients at even more risk, especially if it waives public or private insurance coverage requirements.
They write:
A law or regulation could be changed to automatically withdraw marketing authorization for an accelerated approval drug should its confirmatory evidence not be available for the FDA review by a predetermined date set at the time of approval. This kind of formal ‘sunset’ policy would give the clearest signal to industry of what is required, and protect the FDA from pressure to change decisions when it makes them at its discretion.
As far as policies for life science companies and payers, the MSKCC and ICER researchers call to increase mandatory federal rebate levels until a drug shifts from accelerated to full approval, use pricing to incentivize completion of confirmatory trials, and require payments under Medicare and Medicaid for accelerated approval drugs to be based on outcomes-based contracts.
For instance, the Medicaid Drug Rebate Program could be modified for drugs with accelerated approval, they note, to require a higher rebate during the time between accelerated and full approval. The Medicaid and CHIP Payment and Access Commission recently voted 16-1 to recommend to Congress that they increase Medicaid rebates for accelerated approval drugs before confirmatory trials are completed.
