The US Food and Drug Administration (FDA) aimed to address some of the criticisms of its accelerated approval program with new draft guidance that expresses a preference for using randomized controlled trials (RCTs) to support the approval of oncology drugs in the program. But in public comments, stakeholders asked for more details on when it is appropriate to pursue a single-arm design.
Commenters also called on the agency to provide more specifics on surrogate endpoints and the use of real-world data and evidence.
The draft guidance, issued in March 2023, outlines the recommended designs of oncology trials for accelerated approval. Under the draft, sponsors can conduct a single RCT that would support both accelerated approval and verify clinical benefit, or run separate trials aimed at supporting approval and confirming benefit.
RCTs and surrogate endpoints
The Association for Clinical Oncology, which is the advocacy arm of the American Society of Clinical Oncology (ASCO), noted that while the use of RCTs should be encouraged, single-arm trials “may be of value in the context of rare disease populations or when patients have suboptimal standard treatment options.”
The Leukemia & Lymphoma Society (LLS), which funds cancer research and advocates on behalf of patients with blood cancers, commented that RCTs can be especially challenging to conduct in hematologic malignancies. For instance, as researchers are able to genomically classify patients with blood cancer, the subsets of patients available for enrollments in an RCT will get smaller, LLS wrote. Trial enrollment is also complicated by the FDA’s preference for long-term endpoints, which increases the length of the trial and the number of tests. The development of appropriate surrogate endpoints will be important to encourage the use of RCTs in the future, wrote Bethany Lilly, executive director of public policy at LLS.
The National Organization for Rare Disorders (NORD) also stressed the importance of surrogate or intermediate endpoint validation in its comments on the draft guidance. NORD called on FDA to expand the discussion of new endpoints in the draft guidance and to provide greater clarity about how the draft guidance intersects with the Rare Disease Endpoint Advancement (RDEA) Pilot Program that the agency is tasked with establishing under the Food and Drug Omnibus Reform Act of 2022 (FDORA).
The Biotechnology Innovation Organization (BIO) also requested more information on specific surrogate or intermediate clinical endpoints, beyond the RECIST-based response rate. BIO also noted the lack of inclusion of patient-report outcomes (PROs) in the draft guidance. “Given the clear importance of PROs to patients and the potential for PROs to measure clinically meaningful effects on how patients feel and function, we urge the FDA to include considerations for how PROs might inform safety or efficacy assessments and verification of clinical benefit. This is particularly important in early disease settings where there may be few [overall survival] events, or in which it may not be feasible or ethical to rigorously assess [overall survival],” wrote Leslie Harden, PharmD, director of science and regulatory at BIO.
Single-arm trials
The draft guidance highlights the limitations of single-arm trials, including difficulties in identifying rare adverse events and in predicting clinical benefit, but states that they can be used in some circumstances. Friends of Cancer Research called on FDA to provide examples to help sponsors determine when to employ a single-arm trial versus an RCT.
Friends of Cancer Research also pointed out that the limitations that have been attributed to single-arm trials may have less to do with the design itself and more to do with limitations of external control arms and the appropriateness of employing the single-arm trial design in a given situation. “Including considerations in the guidance for when data from a single-arm trial alone may be sufficient to support an accelerated approval versus a single-arm trial with an external control arm can help distinguish the limitations of a single-arm trial from those of external control arms,” wrote Mark Stewart, vice president for science policy at Friends of Cancer Research.
NORD asked FDA to provide more information on the use of external controls as part of single-arm trials support accelerated approval. Specifically, the group asked FDA to acknowledge its recently released draft guidance on the use of external controls in the accelerated approval guidance and to provide details on how these guidance documents relate to each other.
The Pharmaceutical Research and Manufacturers of America (PhRMA) highlighted the potential to use real-world data (RWD) and real-world evidence (RWE) as part of a single-arm trial to support accelerated approval and suggested that FDA address considerations for when to use RWD to verify clinical benefit. “Maintaining a flexible approach to demonstrating and confirming the safety and efficacy of oncology drugs through the accelerated approval pathway will help avoid delays in the availability of new treatment options for patients in need,” PhRMA commented.
One trial vs. two
Friends of Cancer Research cautioned that use of a single trial to support approval and confirm clinical benefit is a risk for sponsors. “Sponsors may be hesitant to invest resources to conduct a single trial due to the large number of patients required to be appropriately powered. This approach holds greater risk and higher investment up front than a two-trial approach and may be more appropriate for certain indications due to availability of supportive clinical data (e.g., supplementary versus first-in-class original application),” wrote Stewart.
BIO applauded the agency for pursuing the “one trial” approach, which promotes treatment investigations in earlier lines of therapy. However, the group raised concerns that the language in the draft guidance is unclear about whether crossover to subsequent therapies is permitted and if unblinding is allowed for interim analyses.
Product withdrawals
The Association for Clinical Oncology also called on FDA to include more details in the final guidance on confirmatory trials, the agency’s plans for setting target dates to complete confirmatory studies, and the process for expediting withdrawals of drugs that do not have a confirmed benefit.
“It will be beneficial for the public and sponsors to clearly understand the rigorous process and considerations for the withdrawal of an indication or therapy from the market,” wrote Lori J. Pierce, MD, chair of the board of the Association for Clinical Oncology.
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