Skip to content

Pink Sheet — Accelerated Approval: US FDA Writing Guidance On What ‘Ongoing’ Means For Confirmatory Trials

Pink Sheet — Accelerated Approval: US FDA Writing Guidance On What ‘Ongoing’ Means For Confirmatory Trials

Oncology sponsors soon will better understand the meaning of “ongoing” in the context of a confirmatory trial and the potential barrier it presents to accelerated approval.

OCE Director Richard Pazdur said 14 November that guidance on the meaning of “ongoing” is in development – and he also emphasized that without an ongoing confirmatory trial, an oncology product will not receive accelerated approval.

“We really want to send a clear message that these trials need to be ongoing,” Pazdur said during the Friends of Cancer Research Annual Meeting. “We’re writing guidance at the present time on what ongoing means, but let me tell you folks it’s not just one patient on the trial when the trial has been activated at sites.”

OCE would not elaborate on when the guidance will be released. “At this early stage we can’t discuss the specific content,” a spokesperson said.

Sponsors’ alternate interpretations of the word likely helped push the agency to develop a guidance.

“There have been instances of disagreement between the FDA and sponsors on the meaning of ‘ongoing,’” an OCE spokesperson told the Pink Sheet. “The purpose of the guidance is to bring clarity to the legislation’s intention to ensure that confirmatory trials are ongoing at the time of the accelerated approval.”

Pazdur added during the conference that sponsors will be expected to discuss confirmatory study plans with the agency early in development.

“We really want companies to come before they begin any trials to discuss agreed upon timelines [for] both of the accelerated approval study plus the confirmatory trial,” he said. “The days of doing a single arm trial of 100 patients with X response rate and saying ‘well we’ll get to the confirmatory trial someday,’ those days are over.”

The defined timelines are necessary in part because the treatment landscape can change quickly. Pazdur also wants to minimize the time between accelerated approval and confirmatory trial completion, which reduces the risk of using the pathway.  (Also see “Accelerated Approval: US FDA Wants Comprehensive Development Plan From Oncology Sponsors” – Pink Sheet, 21 Sep, 2021.)

Pazdur’s comments at the conference were timely, as the Oncologic Drugs Advisory Committee will meet 16 November to discuss Acrotech Biopharma LLC’s Folotyn (pralatrexate) and Beleodaq (belinostat), whose confirmatory studies are years behind schedule. The current timeline envisions completion in 2030, which would be a 21- and 16-year delay, respectively. (See sidebar.)

The FDA believes a confirmatory trial for an oncology accelerated approval should be completed in two to four years. (See sidebar below.)

OCE increased its focus on products that received accelerated approvals and now have overdue confirmatory trials as part of its Project Confirm. So far, 26 oncology indications have been withdrawn, including nine that resulted in products leaving the market.  (Also see “‘Dangling’ Cancer Indications In US: New Year Brings New Withdrawals Of Accelerated Approvals” – Pink Sheet, 18 Jan, 2022.)

Oncology Community Support Needed For Accelerated Approval Stance, Pazdur Says

Pazdur also warned during the conference that OCE’s approach to accelerated approval could result in delays for promising products. He said reiterated there will be a period of “tough love” for sponsors.

“This is going to require some support of the community,” he said. “We may have an application that has demonstrated safety and efficacy, but will we approve the drug if the confirmatory trial is not underway? And the answer to that is no.”

“That’s the intent of the legislation,” Pazdur added. “And I have the support of all of the leadership of the FDA on this point of view.”

The 2022 Consolidated Appropriations Act added to the accelerated approval statute that the FDA “may require, as appropriate, a study or studies to be underway prior to approval or within a specified time period after the date of approval.”  (Also see “Accelerated Approval Reforms Give US FDA More Power And Flexibility – With Some Gaps” – Pink Sheet, 20 Dec, 2022.)

Pazdur said there will be some “flexibility that we will have” with confirmatory trials, “but the general approach of we’re not starting the trial until we get the accelerated approval, that ain’t happening anymore.”

“We want to have these early discussions: what’s the confirmatory trial, what’s the accelerated approval [study],” he said. “We’ll actually work with you on that with the numbers of patients that you might need for accelerated approval, earlier looks at randomized trials to give us additional information at the time of the accelerated approval.”

Experts told the National Academies of Sciences, Engineering and Medicine that the default expectation should be that confirmatory trials be underway at the time of accelerated approval and that the FDA should explain when an exception is allowed.  (Also see “Accelerated Approval: US FDA Should Explain Why An Ongoing Trial Is Not Required” – Pink Sheet, 1 Feb, 2023.)

Will The Rest Of FDA Embrace Pazdur’s Perspective?

The more forceful approach to confirmatory studies and accelerated approval may not be shared across the FDA. Many senior leaders seem to prefer a flexible policy.

Rare disease sponsors already worry that a blanket confirmatory study policy could hinder product development.  (Also see “Confirmatory Studies For Rare Diseases Shouldn’t Need To Start Before Accelerated Approval, Stakeholders Argue” – Pink Sheet, 26 Jun, 2023.)

Nicole Verdun, director of the Center for Biologics Evaluation and Research’s Office of Therapeutic Products, which regulates gene therapies, also has said that while the preference is that confirmatory trials be underway at the time of an accelerated approval, there will be exceptions.  (Also see “FDA Gene Therapy Office Chief Prefers Flexibility With Accelerated Approval Confirmatory Trials” – Pink Sheet, 23 Sep, 2023.)

CBER already has a difficult decision pending on the accelerated approval of Sarepta Therapeutics, Inc.’s Duchenne muscular dystrophy gene therapy Elevidys (delandistrogene moxeparvovec-rokl).

The product received an accelerated approval in June, but the confirmatory trial did not meet its primary endpoint. Sarepta argued that secondary endpoints sufficiently prove the product is effective and that a traditional approval should be granted.  (Also see “Elevidys And The EMBARK Trial: Is Another Advisory Committee Meeting Coming?” – Pink Sheet, 31 Oct, 2023.)

Center for Drug Evaluation and Research Director Patrizia Cavazzoni also has said confirmatory studies should be planned early in development.

But the center has granted exceptions, most notably for Biogen, Inc.’s Alzheimer’s treatment Aduhelm (aducanumab-avwa), which received a surprising accelerated approval in 2021. Accelerated approval was not considered until late in the product’s assessment cycle and a confirmatory trial had not been planned. The FDA gave the company nine years to design and conduct the study.  (Also see “Accelerated Approval: Mid-Review Decisions ‘Not The Norm’ But Will Continue, FDA’s Cavazzoni says” – Pink Sheet, 20 Jul, 2022.)