FDA’s ODAC Confronts Issues With Accelerated Approval Program

The FDA’s Oncologic Drugs Advisory Committee (ODAC) met to discuss delays in post-approval confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq) in peripheral T-cell lymphoma (PTCL), as well as strategies to promote timely completion of post-marketing requirement (PMR) confirmatory trials in oncologic drugs.¹

The specific discussion topics were the delays in post-approval confirmatory trials for pralatrexate and belinostat and whether the current plan to verify the clinical benefit was reasonable. Strategies to promote timely completion of the confirmatory trials as well as insights from this experience that could facilitate future accelerated approvals were also discussed during the meeting.

About the FDA Accelerated Approval Program

The FDA accelerated approval program provides patients with early access to drugs based on early clinical end points that are considered reasonably likely to predict clinical benefits, including overall response rate (ORR) and progression-free survival (PFS). These approvals are balanced against some level of uncertainty that the drug may not provide clinical benefit. The clinical benefit, usually measured in overall survival (OS), is established in PMRs. Since the program’s initiation in 1992, 60% of the FDA’s accelerated approvals have been granted in oncology.

PMRs either result in a traditional acceptance if clinical benefit is established or withdrawal if the product fails to verify a benefit or shows evidence that the product is unsafe. The decision to withdraw an accelerated approval is not automatic if the confirmatory trials do not meet their primary end point. Rather, the FDA considers the available confirmatory trial results, a current benefit-risk analysis, available therapies, and potential safety advantages.

The delay between the granting of an accelerated approval and a final report from the confirmatory trial creates a “period of vulnerability,” according to Gautam Mehta, MD, acting cross-disciplinary team leader with the Division of Oncology Products 2, Office of Oncologic Diseases, Office of New Drugs, FDA. That delay is the time that patients may be exposed to a therapy that does not end up showing clinical benefit.

The average time between an accelerated approval and a drug being granted traditional approval is 3.1 years, while the average between an accelerated approval and a drug’s withdrawal from the market is 4.1 years. This latter delay is the target of the ODAC’s discussion, according to Mehta.

“The risk of accelerated approval is the risk that clinical benefit is not verified multiplied by the time the product is on the market,” Mehta said.

Four main factors affect the delays of confirmatory trials. These include if the confirmatory trial is underway at the time of accelerated approval, the effect of the accelerated approval itself limiting how many patients enroll in the confirmatory trial, the effect of new available therapies, and the change of incidence in disease.

Lymphomas: © immimagery - stock.adobe.com

About the Confirmatory Trials of Pralatrexate and Belinostat

Pralatrexate and belinostat have the 2 oldest ongoing accelerated approvals at 14 years and 9 years, respectively. Pralatrexate, a dihydrofolate reductase inhibitor, was granted accelerated approval in March 2009 based on an ORR of 27% (95% CI, 16-36) and an estimated duration of response (DOR) of 9.4 months in a single-arm trial. Two post-marketing trials were agreed upon with the FDA.

Belinostat, a histone deacetylase (HDAC) inhibitor was granted accelerated approval in July 2014 based on an ORR of 26% (95% CI, 18-35) and an estimated median DOR of 8.4 months. With this approval, a new phase 3 design was agreed upon for both pralatrexate and belinostat.

In 2016, the belinostat, cyclophosphamide, hydroxydaunomycin, vincristine sulfate (Oncovin), and prednisone (CHOP) dose-finding study was completed. The study of pralatrexate and CHOP was delayed and ultimately not completed by its estimated study completion date of April 2018.

In 2019, Acrotech acquired both agents and became the drugs’ sponsor. The pralatrexate and CHOP dose-finding study was completed in 2021. The sponsor sent the final phase 3 protocol to the FDA in 2022, and the final revised phase 3 protocol, including an optimal dose-finding part, was determined in 2023. The first part was initiated in October 2023, and trial completion with 2-year follow-up is expected in February 2030, which will be 21 years after the approval of pralatrexate and 16 years after the approval of belinostat.

The factors contributing to the delayed confirmatory trials for pralatrexate and belinostat are threefold: the confirmatory trials were not underway at the time of accelerated approval, a combination dose was not established, and the drug sponsor changed in 2019.

The current design of the confirmatory trial is a randomized (1:1:1) trial of patients with previously untreated PTCL who will receive either pralatrexate and chemotherapy, belinostat and chemotherapy, or chemotherapy alone. The primary end point is PFS, and the secondary end points are OS and ORR.

Strategies to Minimize Delays

Mehta presented several general strategies to minimize the time of verification of benefit during his presentation. A comprehensive development plan would involve a pre-specified pathway to verification of clinical benefit, as well as timing of the confirmatory trials and rational timelines for trial completion.

Having the confirmatory trial fully enrolled or near full enrollment would also help to significantly minimize the risk of delays, according to Mehta. This would lessen the number of patients who opted for the approved on-market version of the drug instead of enrolling in the confirmatory trial, as well as prevent administrative delays in trial initiation or opening sites.

Rational, realistic, and data-drive timelines would also be important to confirmatory trials, and patient accrual should be based on disease incidence and natural history, as well as the potential effect of the accelerated approval on accrual. This could be especially relevant in a small and heterogeneous patient population like in PTCL, as noted by Owen O’Connor, MD, PhD, American Cancer Society research professor and director of the Translational Orphan Blood Cancer Research Center at the University of Virginia, during the meeting.

The FDA has already taken steps to minimize delays. In December 2022, the FDA passed the Food and Drug Omnibus Reform act, which requires confirmatory studies be underway prior to approval, sponsors submit biannual progress reports, and a streamlined withdrawal process to drugs that do not verify clinical benefit. The FDA’s Oncology Center for Excellence has also established Project Confirm, an initiative to increase transparency and accountability for accelerated oncology approvals.²

During the discussion portion of the meeting, committee members, including Gita Thanarajasingam, MD, hematologist at Mayo Clinic, and Ashley Rosko, MD, professor, Division of Hematology at The Ohio State University, expressed concerns with how the sponsor would ensure patient accrual.¹

“The protocol has been submitted to all the sites, and 77 sites have agreed to participate, so that is what give us the confidence that they have reviewed the protocol…and [accrual] may not be the most rate-limiting factor as of now,” said Ashish Anvekar, president at Acrotech, during the meeting. “All of these results will be reviewed along with the FDA to see how we can proceed to the next step. We will want to keep them updated with the studies, so we are not in the same place 3 or 4 years down the line…If we are not tracking for any reason, at least have an open conversation with them to see why not.”

“With PTCL, there is an importance to ensure a representation in population at there Is a lot of heterogeneity,” Nicholas Richardson, DO, MPH, deputy director, Division of Hematologic Malignancies 2, said on behalf of the FDA. “We do work with the sponsors to create milestones…those are milestones that are agreed upon between the sponsors and the FDA.”

Richard Pazdur, MD, director of the Oncology Center of Excellence, spoke to the “suboptimal” and “inadequate” development of the drugs and how the sponsor would perform due diligence in continuing to evaluate the progress of the drugs in PTCL, including evaluating the drugs in the relapsed/refractory (R/R) population.

Committee members, including Jorge Nieva, MD, associate professor of Clinical Medicine and section head, Solid Tumors at the Norris Comprehensive Cancer Center, University of Southern California, echoed the question of why the indication could not be expanded to the R/R population.

“The onus is on the sponsor to provide data to the FDA to support that there is verification of clinical benefit. It’s the sponsor’s responsibility to conduct and design trials to confirm clinical benefit,” Richardson said during the meeting. “However, for this situation, we’re in the situation that we’re in, and the sponsor has elected to choose this randomized trial in the first-line setting. We have been open to trials in multiple disease settings…but at the end of the day, it’s the sponsor’s responsibility to conduct these trials.”

“While yes, the onus is on the sponsor to have resolved this, I would also say, very respectfully, that the onus is still on the FDA that we’re at this point…I am still perplexed by keeping [pralatrexate and belinostat] approved for 6 years,” said committee member Daniel Spratt, MD, Vincent K. Smith chair, Department of Radiation Oncology, UH Seidman Cancer Center, Case Western Reserve University, during the meeting. “For a traditional approval, there needs to be some demonstrable benefit in outcome or surrogate to be approved…these end points are not surrogate end points. I do believe there is data that can be used to establish a surrogate threshold response rate.”

Committee member Christopher Lieu, MD, associate professor of medicine and director of Gastrointestinal Medical Oncology Program, University of Colorado, spoke to strategies of how the FDA and the sponsor could continue with the proposed confirmatory trials.

“In this case, I think [the sponsor] should…show an acceptable accrual rate. If the FDA and the sponsor do agree to move forward with the proposed confirmatory study, I think failure to meet certain milestones really should lead to pulling the approval for these agents,” Lieu said.

“At the end of the day, we want to move the field forward and have safe and effective treatments for patients,” Richardson concluded.

REFERENCES:

1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. November 16, 2023. Accessed November 16, 2023. https://tinyurl.com/3xbbw3m2

2. Project Confirm. FDA. Updated April 13, 2023. Accessed November 16, 2023. https://tinyurl.com/aexpau44