Many cancer patients and oncologists may turn to the US Food and Drug Administration’s accelerated approval program, which provides access to new cancer drugs faster – especially when a life-threatening cancer needs swift treatment or relief.
Yet a new study questions the clinical benefit of some drugs in the program and suggests ways in which the program could be improved.
The FDA recently facilitated the use of what’s called “surrogate endpoints” when studying a new drug for approval or accelerated approval.
A surrogate endpoint serves as a way to measure the impact of a drug without waiting to collect real clinical data on outcomes such as survival.
So a patient might not necessarily live longer, and their symptoms might not appear to be improving, but that surrogate endpoint – such as how many patients saw their tumors shrink – may be an easier or earlier measurement to assess.
The new study, published in the medical journal JAMA Internal Medicine on Tuesday, found that among cancer drugs that received accelerated approval from the FDA using surrogate endpoints or other measures, only one-fifth ended up improving overall survival rates in later confirmatory trials.
“We recommend that the success of accelerated approval pathway lies in the fact that confirmatory studies are duly conducted in time, and use clinical endpoints such as overall survival or quality of life to actually confirm benefit rather than test another surrogate measure,” said Dr. Bishal Gyawali, a medical oncologist and assistant professor at Queen’s University in Canada, who was first author of the study.
“Our study’s objective is not to criticize the FDA but to provide important suggestions how accelerated approval can better serve the cancer patients,” he said. “Cancer patients need cancer drugs faster, and accelerated approval helps expedite the process but patients don’t need just any cancer drugs, they need cancer drugs that help them have a longer and-or better lives.”
In response, “the FDA only approves drugs when the data received in a drug application demonstrate a favorable risk-benefit profile,” according to a written statement that FDA spokeswoman Amanda Turney emailed to CNN on Monday.
“Patients with refractory diseases often have few or no therapeutic options and we take that into account when examining the risk-benefit profile of these drugs. We have had multiple discussions over a number of years within the global scientific and patient community, including with the Oncologic Drugs Advisory Committee, regarding the use of progression-free survival, response rate, and other endpoints to support approval of drugs that treat cancer. It has been widely accepted that benefit can be demonstrated by a number of endpoints, not just overall survival,” the statement said.
Finding left researchers ‘surprised’
For the study, researchers reviewed 93 cancer drug uses for which accelerated approval was granted between 1992 and 2017. They also took a close look at data on surrogate endpoints used in preapproval and confirmatory trials of those drugs.
The researchers found that only 19 of those drug uses ended up demonstrating improvements in overall patient survival in subsequent confirmatory trials.
Some recent cancer drug uses that received accelerated approval from the FDA but failed to improve the primary endpoint of overall survival in their post-approval trials were bevacizumab for glioblastoma; atezolizumab for urothelial; nivolumab after ipilimumab or BRAF-inhibitor in melanoma and pembrolizumab for head and neck cancer, according to the new study.
“We were surprised by our results because we found that most of those drugs were actually improving only a surrogate measure even in confirmatory trials – and often times, it was the same surrogate endpoint tested in confirmatory trial that was used for accelerated approval,” Gyawali said.
“So the confirmatory trials were not confirming clinical benefit but actually confirming benefit in a surrogate endpoint,” he said. “The major takeaway is that for drugs approved on the basis of accelerated approval pathway, only a minority have proven clinical benefit and most drugs just demonstrate benefit in surrogate endpoints in the confirmatory trials.”
He added that for the accelerated approval pathway to function effectively, when the drugs receiving accelerated approval fail to prove clinical benefit in confirmatory trials, “prompt action should be taken to withdraw the approval.”
The study had some limitations, including that the status of confirmatory trials were continually changing, such as changing from a pending to ongoing to completed status, during the course of the study.
Also, the researchers did not evaluate the methodology trials, relying mostly on the reported results, and the researchers evaluated only publicly available FDA data.
The study could have missed data on drugs that over time have proven to be beneficial to patients or may have shown to work in combination with other drugs, said Dr. Leonard Lichtenfeld, interim chief medical officer at the American Cancer Society, who was not involved in the study.
Therefore the study findings may be slanted, he said.
The questions raised in the study surrounding the FDA’s accelerated approval program are not new and have been deliberated ever since the program was created in 1992.
“There really have been two major camps regarding this particular question,” Lichtenfeld said. One camp argues that the FDA has an obligation to provide access to promising drugs for patients, even on an expedited basis. Another camp argues that time should be taken to more closely evaluate drugs before they are provided to patients.
Although “not every drug is going to be a life-saving blockbuster drug,” but the drug might provide some comfort to a patient in need, Lichtenfeld said.
“From our perspective, and I’m comfortable in saying on behalf of the American Cancer Society, we respect and admire the work done by the FDA,” he said.
An ongoing debate over cancer drugs
“Surrogate endpoints typically have to do with whether tumors shrink or grow beyond arbitrary thresholds,” said Dr. Vinay Prasad, an oncologist and associate professor of medicine at Oregon Health and Science University in Portland, who was not involved in the new study.
Prasad was one of the authors of a separate study that also published in JAMA Internal Medicine on Tuesday. That study suggests that many drugs are approved on the basis of low or modest surrogate endpoints in place of clinical trial outcomes.
The study involved reviewing data on 85 FDA-approved uses of 59 drugs to treat cancer. The drugs were approved between 2006 and 2018.
The data showed that 32, or 38%, of the drugs received regular approval, and 53, or 62%, of the drugs were granted accelerated approval.
The researchers took a close look at the percentage of cancer patients whose tumors appeared to shrink when treated with the drugs receiving regular approval versus those granted accelerated approval pending confirmation. That tumor measurement was a surrogate endpoint.
The researchers found that among patients who were treated with drugs granted accelerated approval that was pending confirmation, an average of 28% showed a surrogate endpoint compared with 42% among the drugs that obtained regular approval.
In general, 41% among all drug uses total showed a surrogate endpoint.
“Cancer drugs come to market with too much uncertainty,” Prasad said.
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Richard Lehman, a professor at the University of Birmingham in the United Kingdom, and Dr. Cary Gross, a professor at the Yale School of Public Health in New Haven, Connecticut, coauthored an editorial that published alongside the two new studies in JAMA Internal Medicine on Tuesday.
“In the past, progress in our understanding of cancer and how to treat it has been frustratingly slow. Now that the pace of the science has accelerated, there is a natural tendency to impatience,” Lehman and Gross wrote in the editorial.
“Yet these studies remind us that most new cancer drugs are of marginal benefit at best, despite their immense cost. Rigorous postmarketing studies with meaningful end points are expensive, requiring substantive infrastructure and oversight,” they wrote. “One might ask, ‘How can we afford to increase the rigor, and hence the cost, of assessing new cancer therapies after initial approval?’ The real question is: how can we afford not to?”