FDA’s accelerated approval program: Is change on the way?

Regulatory NewsRegulatory News | 11 October 2021 |  By 

David Dorsey, Janssen

The U.S. Food and Drug Administration (FDA) launched its accelerated approval program in 1992, offering a pathway to bring life-saving drugs and biologics to the market faster. After nearly 30 years, could substantial reforms be on the way?
At RAPS Convergence 2021, David Dorsey of Janssen R&D, said Congress could choose to make changes to the accelerated approval program through the upcoming reauthorization of the Prescription Drug User Fee Act (PDUFA). Congress has already acted to codify and grant enforcement authority to the FDA through the original act and subsequent reauthorizations, he explained.
“The question is, what will happen in 2022?” asked Dorsey, who is also a former FDA staffer. “I think the real lesson from this brief history is that Congress is well aware of what FDA is doing in this space, has given it consideration and essentially codified and agrees with FDA’s approach to accelerated approval, and has done so over an extended period of time.”
“We don’t know where this will go in the next year, but we expect accelerated approval will be back on the docket for consideration by Congress as it goes into the user fee reauthorizations next year,” Dorsey added.
What is accelerated approval?
The accelerated approval program, which applies to serious or life-threatening diseases or conditions, allows for an earlier submission or approval based on substantial evidence of an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or a clinical endpoint that can be measured earlier than irreversible morbidity or mortality and is reasonably likely to predict clinical benefit. The accelerated approval is tied to the sponsor’s agreement to conduct a post-approval study to confirm the expected benefit.
The program was initially aimed at speeding access to treatment for HIV/AIDS treatments and has recently been dominated by cancer therapies. From 2010-2019, 84% of the agency’s accelerated approvals have been for oncology indications.
There have been “many successes” in the nearly 30 years of the program, said David Whitrap, vice president of communications and outreach at the Institute for Clinical and Economic Review (ICER). Most notably, ICER points to Novartis’ Gleevec (imatinib mesylate). The treatment for chronic myelogenous leukemia was granted accelerated approval and earned full approval two years later after confirmatory studies showed a clear survival benefit.
“The evidence, while not certain upon approval, was ultimately confirmed to be beneficial. Patients are much better off for having this pathway there,” he told Focus. “But there are also several instances where the pathway hasn’t been coupled with the incentives necessary to bring confirmatory evidence forward in a rapid enough manner.”
Whitrap pointed to Sarepta’s Exondys 51 (eteplirsen), a treatment for Duchenne muscular dystrophy granted accelerated approval in 2016. The company did not launch confirmatory studies until 2019 and there are still no results from the trial to confirm the drug’s benefit. Meanwhile, the treatment carries a per-patient price tag of around $1 million a year.
Accelerated approvals under scrutiny
The accelerated approval program has been getting increased attention in 2021. Both ICER and Friends of Cancer Research (FCR) issued white papers earlier this year exploring potential changes to the program, and recently the accelerated approval program came under fire as the mechanism for the controversial approval of Biogen’s human monoclonal antibody Aduhelm (aducanumab) for patients with Alzheimer’s disease. That decision, based on the surrogate endpoint of reduction in amyloid plaque, prompted the U.S. Department of Health and Human Services’ Office of the Inspector General (OIG) to launch a review of the FDA’s policies and procedures related to accelerated approval (RELATED: HHS OIG to review FDA’s use of accelerated approval pathway, Regulatory Focus 04 August 2021).
The FDA has also been revisiting cancer therapy approvals made through the program. In April 2021, the agency convened the Oncologic Drugs Advisory Committee (ODAC) to review six so-called dangling accelerated approvals in which the confirmatory trials had failed but the drug remained on the market. Of the six checkpoint inhibitor indications reviewed, ODAC recommended that four be maintained (RELATED: ODAC recommends pulling 2 of 6 accelerated approvals, Regulatory Focus 30 April 2021).
The committee is scheduled to meet again on 2 December to review dangling accelerated approvals for Farydak (panobinostat) for multiple myeloma and Marqibo (vincristine sulfate liposome injection) for adults with Philadelphia chromosome negative acute lymphoblastic leukemia. Novartis received accelerated approval for the multiple myeloma indication in 2014, and Talon Therapeutics’ Marquibo got its accelerated approval nod in 2012.
Proposals seek transparency, consistency
Both ICER and FCR have outlined changes aimed at increasing transparency and consistency in the agency’s expectations, particularly around surrogate endpoints. For accelerated approvals, the FDA evaluates surrogate endpoints that are reasonably likely to predict clinical benefit, but papers from both groups note that there is a lack of clarity from the agency about the level of evidence needed to establish that a surrogate endpoint meets that threshold.
FCR called for additional guidance on qualitative metrics of surrogate or intermediate endpoints for pivotal studies as well as confirmatory trials. They also asked for more information on how the agency weighs the intermediate endpoint in a benefit-risk assessment. The ICER paper, which outlines the pros and cons of various reform approaches, floats the idea of the FDA publicly posting a “scorecard” that would rate a proposed surrogate endpoint against the agency’s criteria for supporting a “reasonably likely to predict clinical benefit” threshold.
“The FDA could articulate and essentially establish where the goal posts are,” Whitrap said. “Right now, we don’t have that, and it creates a little bit of a guessing game, not just for the FDA adcomm and those members, but for drug makers and for organizations designing the clinical trials earlier in the pipeline. It creates some confusion there.”
Whitrap praised the FDA for convening ODAC to review the dangling accelerated approvals, noting that the action aligns with one of the solutions explored in the ICER white paper – creating either an annual review cycle or a mechanism to sunset accelerated approvals that lack confirmatory evidence. These approaches would create standardization and an incentive for life sciences companies to follow through rapidly with confirmatory evidence, he said. But they have downsides too, as both would be more burdensome for FDA and industry.
Some other proposals explored in the two white papers include:
  • Developing standardized review templates for accelerated approval review (ICER)
  • Requiring greater use of randomized controlled trials (ICER)
  • Creating a new label alert for accelerated approvals (ICER)
  • Increasing enforcement around requirements for confirmatory trials (ICER)
  • Creating a safety-only approval that would waive insurance coverage requirements (ICER)
  • Creating a standardized definition of “available therapy” that is specific to the disease and patient population (FCR)
  • Increasing use of real-world evidence and synthetic controls to provide confirmatory evidence (FCR)
  • Requiring confirmatory trials to have enrolled a pre-determined number of patients at the time of the marketing application (FCR)
Linking cost and clinical benefit
Along with concerns about the strength of evidence and the speed of confirmatory trials, Whitrap said cost is a major issue surrounding accelerated approvals. “These are almost universally oncology or orphan drugs, and sometimes both, and they have, almost across-the-board, very high prices,” he said. “There’s a lot of concern from the payer community and from the patient community and even from providers, that if we don’t know how well these drugs work maybe the prices need to be moderated in some way during this period until we have more confidence in their efficacy.”
Among the proposals explored by ICER is temporarily increasing the mandatory federal rebates paid to the Medicare and Medicaid programs for drugs receiving accelerated approval until the products receive regular approval. The ICER white paper also explores limiting pricing at the time of accelerated approval to the average cost of producing and delivering the drug. The price could rise to market price at the time of full approval and the drug company could receive a bonus payment representing some of the lost revenue during the time between accelerated and full approval. Another cost-based strategy outlined in the ICER paper is an outcomes-based contract that ties some, or all, of the payment to patient benefit from the drug.
Friends of Cancer Research white paper
ICER white paper
ODAC meeting announcement


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