Skip to content

Pink Sheet — FDA Panel To Consider Strategies For Timely Completion Of Accelerated Approval Confirmatory Trials

Pink Sheet — FDA Panel To Consider Strategies For Timely Completion Of Accelerated Approval Confirmatory Trials

A US Food and Drug Administration advisory committee review of two Acrotech Biopharma LLC accelerated approval drugs with long-overdue confirmatory trial requirements may provide the clearest insight yet into how the Oncology Center of Excellence interprets the “due diligence” requirement for such studies and how sponsors’ planning and implementation strategies may factor into this determination.

The Oncologic Drugs Advisory Committee on 16 November will not only review Acrotech’s current confirmatory trial plan for the peripheral T-cell lymphoma drugs Folotyn (pralatrexate) and Beleodaq (belinostat), but it also will discuss issues contributing to delayed confirmatory trials in general and proactive steps sponsors should take to ensure such studies are completed in a timely matter.

Over the past three years, OCE has been focused on cleaning up ongoing accelerated approvals that lack confirmation of clinical benefit, either for “dangling” approvals when confirmatory trials fail or “delinquent” approvals where confirmatory trials are delayed or never completed.

With the ODAC meeting on pralatrexate and belinostat, OCE is now shifting the focus to what it means to conduct a confirmatory trial with due diligence.

This issue has taken on heightened attention with a provision in the Food and Drug Omnibus Reform Act signed into law in December 2022. Under FDORA, failure to conduct an accelerated approval postmarketing study with due diligence is a new prohibited act under the Food, Drug and Cosmetic Act.  (Also see “Accelerated Approval Drug Promotions Run Risk Of Overstating Efficacy, Understating Safety” – Pink Sheet, 13 Nov, 2023.)

Target Completion Time 2-4 Years After Approval

The time from accelerated approval to verification of clinical benefit or withdrawal “represents a potentially vulnerable period during which drugs that may eventually not prove to provide adequate clinical benefit to patients remain on the market,” the FDA said in a briefing document for the ODAC meeting. “Reducing this time to verification or refutation of clinical benefit through timely completion of confirmatory trials can reduce the risk and exposure to such drugs.”

The agency has regulatory authority to require that confirmatory trials for accelerated approval products be completed with due diligence. “FDA has interpreted this due diligence requirement to mean that sponsors must conduct the trial(s) intended to verify the clinical benefit promptly to facilitate determination, as soon as possible, of whether the drug provides the expected clinical benefit.”

“In oncology, the median time to completion of confirmatory trials that have verified benefit has been 3.1 years. Thus an appropriate target completion date for oncology products would ideally be no later than two to four years after accelerated approval is granted.” – FDA

OCE Director Richard Pazdur has said he defines due diligence as committing the same resources and effort to a confirmatory trial that a company would dedicate to a pivotal trial for registration.  (Also see “Accelerated Approval: US FDA Wants Comprehensive Development Plan From Oncology Sponsors” – Pink Sheet, 21 Sep, 2021.)

“Overall, the time to verification or refutation of clinical benefit for oncology accelerated approvals has improved since the program was first implemented,” the briefing document states. Currently, the median times from accelerated approval to either subsequent traditional approval or withdrawal are 3.1 years and 4.1 years, respectively.

The oncology review office is relying upon these median timeframes for the target length of time that confirmatory trials for anti-cancer accelerated approval drugs should take.

“In oncology, the median time to completion of confirmatory trials that have verified benefit has been 3.1 years,” the agency said. “Thus an appropriate target completion date for oncology products would ideally be no later than two to four years after accelerated approval is granted.”

Sponsors should select a target completion date that is appropriate for the clinical context and unmet need at issue, balancing the potential benefit of earlier availability with the potential risk that a product fails to verify clinical benefit, the agency said.

The proposed target completion date should be informed by the following factors:

  • Natural history of the disease;
  • Disease setting and therapeutic need;
  • Projected rate of site activation/sites planned, including locations in and outside the US;
  • Accrual projections for before and after the anticipated accelerated approval;
  • Expected event rate for the outcomes of interest; and
  • Projected timeline for primary efficacy analyses.

FDORA Reforms Will Help …

The accelerated approval reforms in FDORA are expected to help promote the timely completion of confirmatory trials, the FDA said.  (Also see “Accelerated Approval Reforms Give US FDA More Power And Flexibility – With Some Gaps” – Pink Sheet, 20 Dec, 2022.)

For example, the agency now has the authority to require that confirmatory studies be ongoing at the time of approval. At a recent Friends of Cancer Research meeting, Pazdur said the agency is developing a guidance that defines “ongoing” in this context. (See sidebar for story.)

Accelerated approvals with the confirmatory trial ongoing at the time of approval have been associated with a shorter time to traditional approval or withdrawal (median 3.1 years) than if the confirmatory trial were not ongoing at the time of approval (median 7.3 years), the briefing document states.

“Granting FDA the ability to require that postmarketing studies be ongoing at the time of accelerated approval may reduce the period of uncertainty between accelerated approval and verification or refutation of clinical benefit,” the agency said.

The agency also points to measures aimed at expediting the withdrawal process. Those procedures currently are being tested by Oncopeptides AB’s appeal of the Center for Drug Evaluation and Research’s proposed withdrawal of its multiple myeloma drug Pepaxto (melphalan flufenamide).  (Also see “To Save Pepaxto, Oncopeptides Throws Shade At IMiD Use In Elderly Myeloma Patients” – Pink Sheet, 30 Aug, 2023.)

Under FDORA, sponsors are now required to provide confirmatory trial status reports to the agency every six months, which will increase transparency and facilitate study completion, the FDA said. In addition, the agency will convene a new accelerated approval council at least three times a year to discuss issues related to the expedited pathway and make sure the program is applied consistently across the agency.

… But Sponsors Need To Plan Early

Despite these measures, the FDA’s briefing document makes clear that the onus for conducting a study with due diligence rests with the sponsor, and it details various strategies and factors sponsors should take into consideration in ensuring this requirement is met.

First and foremost is the need for a comprehensive drug development strategy that includes plans for a confirmatory trial, including timing of initiation and rationale to support the feasibility of meeting the target milestone dates. These plans should be discussed with the FDA early in a development program and before submission of the initial marketing application for accelerated approval. The plan may consider one or more pathways to verification of clinical benefit.

Since confirmatory trials should be “well underway at the time of marketing application submission with full or near full enrolment at the time of accelerated approval,” sponsors should consider how accelerated approval and wider availability of a drug in the US and other countries will affect study accrual and conduct, the briefing document states. These considerations include:

  • Whether the accelerated approval has been granted for the same indication being studied in the confirmatory trial;
  • Whether the availability of the drug could cause challenges in enrolling or continuing treatment on the control arm of an ongoing study even if fully accrued; and
  • How the accelerated approval will affect the trial’s US accrual rate and plans to mitigate any decreased accrual to ensure the target completion date is met.

12 Cancer Drugs Overdue For Confirmation Of Benefit

The FDA’s decision to convene an ODAC meeting on the Acrotech drugs, and its recommended strategies for sponsors to help ensure timely completion, suggests the agency will be far less tolerant of delays in completing confirmatory trials for oncology accelerated approval drugs going forward.

There currently are 12 ongoing accelerated approval oncology drugs that have yet to confirm clinical benefit even though their confirmatory study completion milestones have passed. (See chart at end of story.) This list includes both dangling and delinquent approvals.

Acrotech’s pralatrexate and belinostat, which were granted accelerated approval in 2009 and 2014, respectively, represent the biggest offenders on the list in terms of interval since approval without confirmation of clinical benefit (14 and nine years, respectively). Acrotech’s current proposal calls for the single confirmatory trial for both drugs to be completed in 2030. (See sidebar for story.)

Aliqopa Withdrawal

The list of 12 drugs unofficially shrunk by one on 13 November when Bayer AG announced plans to voluntarily withdrawing the follicular lymphoma drug Aliqopa (copanlisib) due to failure of the CHRONOS-4 confirmatory trial to meet its progression-free survival endpoint.

Copanlisib received accelerated approval in September 2017 for the treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies.  (Also see “Keeping Track: Biosimilar Submissions Galore (And An Approval), Bayer Gets An Oncology Approval, KemPharm Resubmits Apadaz NDA” – Pink Sheet, 17 Sep, 2017.)

In early 2022, Bayer withdrew applications in the US, EU and several other markets for use of copanlisib in combination with rituximab for treating subtypes of indolent B-cell non-Hodgkin’s lymphoma.  (Also see “Bayer Pulls Aliqopa Combo Filings In EU, US & Other Markets – But May Resubmit” – Pink Sheet, 25 Jan, 2022.)

CHRONOS-4 assessed copanlisib in combination with standard immunochemotherapy versus standard immunochemotherapy in patients with relapsed iNHL who have received between one and three prior lines of treatment.

The drug is a member of the phosphatidylinositol 3-kinase (PI3K) inhibitor class that has been the focus of numerous accelerated approval withdrawals due to never completed or failed confirmatory trials, including studies that suggested a potential detriment in overall survival despite positive progression-free survival results.  (Also see “PI3K Inhibitors: Overall Survival, Adverse Events And Dose Optimization Top US FDA’s Concerns” – Pink Sheet, 19 Apr, 2022.)

Oncology AA Approvals Past Original Projected Completion Date
The FDA’s briefing document for the 16 November Oncologic Drugs Advisory Committee lists 12 anti-cancer agents that represent “dangling” or “delinquent” approvals for which clinical benefit has not yet been verified despite passage of the original milestone date for confirmatory trial completion. The list, which is current as of 13 October 2023, includes AAs for which a supplemental application for verification of clinical benefit is currently under review by the agency.

1 Dangling AA with posmarketing reuqirements released and reissued.2 Sponsor Oncopeptides is challenging the Center for Drug Evaluation and Research’s proposal to withdraw Pepaxto’s AA under the new expedited withdrawal procedures.

3 On 13 November, sponsor Bayer announced plans to voluntarily withdraw Aliqopa because the CHRONOS-4 confirmatory trial failed to meet its primary endpoint.

Sources: FDA, Bayer