We should not accept anything less than an approval process that results in drugs that improve or extend lives.
On March 24, 2023, the Food and Drug Administration (FDA) issued draft guidance on clinical trial designs for accelerated approval of oncology drugs. The draft guidance, unfortunately, does not advance a process that will result in drugs that save lives. It perpetuates approval based on the surrogate endpoint, progression-free survival (PFS), instead of prioritizing clinical trial designs that will show overall survival. It also fails to include trained patient advocates in the process.
The National Breast Cancer Coalition (NBCC) opposes the characterization of PFS as a clinically meaningful endpoint as mounting evidence demonstrates that it is often not correlated with true clinical benefit for patients, which would be living longer or better.
On May 26, NBCC submitted a public comment on this draft guidance identifying three key areas that need to be addressed, stopping the persistent use of PFS as a measure of clinical benefit, ensuring that clinical trials enroll enough participants to determine real clinical benefits, and including educated and trained patient advocates in the clinical trial design and implementation process.
The FDA’s accelerated approval pathway was established in 1992 to expedite access to new therapies for patients with serious or life-threatening diseases by allowing surrogate endpoints in clinical trials, so long as confirmatory trials are subsequently conducted that demonstrate clinical benefit.
Accelerated approval was first created as a strategy to rapidly address unmet medical needs during the HIV-AIDS crisis. Now, oncology drugs comprise the largest proportion of accelerated approvals (~65%). The FDA cites the high proportion of drugs converted to regular approval following the completion of confirmatory trials as evidence of the success of the program. However, they fail to mention that the majority of confirmatory trials continue to use surrogate endpoints like PFS to demonstrate “clinical benefit” rather than a true clinical benefit. In one analysis, only 9 of 93 confirmatory trials (~20%) demonstrated improvements in overall survival in confirmatory trials.
NBCC is concerned that accelerated approval is being used largely to help drug manufacturers get their drugs to the market faster when in fact, its sole purpose should be to advance promising drugs that show real clinical benefit to patients with life-threatening conditions—in this case, lethal cancer—where there is an unmet need, and the drugs have the potential to lengthen or improve patients’ lives.
In addition to providing guidance on preferred study designs, NBCC believes the FDA should clearly define “unmet need” and guide drug manufacturers on when the accelerated pathway is appropriate.
PFS is not a measure of clinical benefit for a patient and can mislead the public by virtue of its name. PFS is the average length of time after the start of treatment in which a person is alive, and their cancer does not grow or spread.
PFS is intended to describe what happens to tumors during therapy—not to infer a meaningful benefit from those changes. It does not measure how a patient feels, functions, or survives. In fact, there is little relationship between delay in the progression of a tumor and overall survival or quality of life for patients with advanced cancer.
FDA should only allow the use of PFS as a measure of clinical benefit in the limited cancer-specific scenarios where PFS has been properly justified. Importantly, the FDA should cite and make available to the public evidence supporting the justification of a surrogate endpoint.
Trial Sample Size
Clinical trials should enroll enough participants to detect clinically meaningful improvements in overall survival. The public deserves to know if a drug that is on the market provides real clinical benefit.
Include Educated Patient Advocates in Trial Design and Implementation
The guidance offers no recommendations for sponsors on partnering with educated and trained patient advocates and advocacy groups in their clinical trial design and implementation process. The educated patient voice is imperative to ensuring that trials are being designed to bring new treatments forward that will address patients’ goals and values.
We are all desperate to find interventions that will save lives or significantly prolong lives without reducing the quality of life. We should not accept anything less than real, high-level evidence that approved treatments actually do this. That would be progress. We should not redefine progress to include what is possible in the short term, rather than what is meaningful.