‘On-And Off-Ramps’ For Cancer Accelerated Approvals: FDA Suggests Earlier Randomized Trials
Executive Summary
Leaders of FDA’s oncology center say sponsors could initiate a single randomized trial prior to receiving accelerated approval or conduct a single-group AA study concurrently with a randomized trial. FDA and sponsor could agree in advance on criteria for approval and withdrawal.
Leaders of the US Food and Drug Administration’s Oncology Center of Excellence say sponsors can more readily obtain evidence to confirm or refute the clinical benefit of drugs granted accelerated approval by conducting a randomized trial prior to obtaining approval.
In a New England Journal of Medicine perspective piece published on 21 September, they note that oncology drug sponsors have typically conducted a single-group study to support accelerated approval (AA) and subsequently conducted a randomized, controlled trial evaluating a long-term outcome, such as survival, to verify clinical benefit.
“Although the FDA has recommended that confirmatory trials be well under way, if not fully enrolled, at the time of the AA, sponsors frequently delay initiating these trials until the single-group study is completed or AA has been granted,” they state. “Rather than waiting to initiate the trial after AA, sponsors could pursue a single randomized trial, potentially in an earlier treatment setting, that could both support AA and subsequently verify clinical benefit.”
Alternatively, the agency officials say sponsors could conduct two concurrent studies: a single-group AA study examining the overall response rate in patients without other available therapies, and a randomized trial with the potential to demonstrate clinical benefit in patients who have received fewer treatments.
“If these studies enrolled patients around the same time, an interim analysis of safety and overall response rate in the confirmatory trial could provide supportive evidence and greater confidence for the AA based on the single-group study,” they state. “A clinically meaningful effect on overall response rate in this interim or a subsequent analysis could support an additional AA indication for the randomized trial population.”
In this scenario, they say, the FDA and the sponsor would agree in advance on the criteria for attaining AA and for withdrawing the indication.
Elements Of A Comprehensive Strategy
The piece, “The On- and Off-Ramps of Oncology Accelerated Approval,” was written by lead author Lola Fashoyin-Aje, OCE deputy division director and associate director of science and policy; Gautam Mehta, medical officer in the OCE Division of Oncology 2; Julia Beaver, OCE chief of medical oncology; and OCE Director Richard Pazdur. They note the need to have a comprehensive strategy for accelerated approval that equally looks at the “on-ramp” and “off-ramp” considerations for AA.
The on-ramp considerations include trial design, endpoints, study population, and timelines for obtaining data to support the AA and to confirm clinical benefit. The off-ramp considerations include confirmation of clinical benefit leading to granting of traditional approval and removal of indications if clinical benefit is not verified.
The commentary clarifies OCE’s views on the accelerated approval pathway, which has gotten increased scrutiny since the agency began cracking down on accelerated approvals that have not confirmed clinical benefit. (Also see "‘Dangling’ Accelerated Approvals: US FDA Flags Concerns About ‘Marginal’ Response Rates" - Pink Sheet, 22 Apr, 2021.) and (Also see "‘Dangling’ Cancer Indications In US: New Year Brings New Withdrawals Of Accelerated Approvals" - Pink Sheet, 18 Jan, 2022.)
Pazdur has previously discussed the benefit of sponsors conducting the accelerated approval study at the same time that they conduct the confirmatory study. Last year, he noted that the agency had begun asking sponsors to adopt a comprehensive accelerated approval development plan approach with concurrent rather than sequential studies. (Also see "Accelerated Approval: US FDA Wants Comprehensive Development Plan From Oncology Sponsors" - Pink Sheet, 21 Sep, 2021.)
At the American Society of Clinical Oncology’s annual meeting in June, Pazdur said he and his colleagues were in the process of writing papers on a two-stage approach where sponsors would simultaneously conduct a smaller-arm study and a randomized study that the agency could review at the same time.
Pazdur said one could envision having two accelerated approvals, one on the basis of the randomized trials and the earlier disease setting, and then an approval on the single-arm study in the later disease-setting. (Also see "Cancer And Accelerated Approval: FDA To Crack Down On Single-Arm Trials, Refractory Disease Focus" - Pink Sheet, 10 Jun, 2022.)
Time To Off-Ramp
The NEJM piece also addresses the length of time between accelerated approval and verification or refutation of clinical benefit. The authors note that among oncology indications that have been granted AAs, the median time to off-ramp action was longer if the confirmatory trial was initiated after the approval.
The difference was most striking among withdrawn indications, where the median time to withdrawal was 3.8 years if the confirmatory trial was ongoing at the time of AA and 7.3 years if the trial had not been initiated.
OCE’s “Project Confirm” found that conversion to a regular approval takes an average of three years versus 4.9 years if a confirmatory trial has not commenced at the time of initial accelerated approval. (Also see "Accelerated Approvals Convert Much Faster If Confirmatory Trial Already Underway, FDA Cancer Data Shows" - Pink Sheet, 14 Jul, 2022.)
The authors say the pathway’s success should be measured in part by the length of time between accelerated approval and a determination of clinical benefit.
They note that withdrawing an AA indication when confirmatory trials have failed to demonstrate clinical benefit, and when sponsors do not voluntarily remove the indication, involves a complicated hearing process. They observe that this process has been used only once in oncology to withdraw the metastatic breast cancer indication for Genentech, Inc.’s Avastin (bevacizumab), and took 16 months from the time the agency’s Oncologic Drugs Advisory Committee recommended removal of the indication.
The two-day hearing on withdrawal of Avastin’s accelerated approval took place in June 2011. Internal emails show the hearing was taxing for FDA employees, who had to deal with a number of novel issues. (Also see "Avastin Withdrawal Showed Accelerated Approval Hearing Process No Easy Task For US FDA" - Pink Sheet, 19 Jan, 2022.)