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Two new studies call into question the FDA's use of the accelerated approval pathway and surrogate endpoints in the approval of new cancer-directed therapies.

Of the 93 cancer drugs granted accelerated approval from 1992 to 2017, only 20% of the postmarket confirmatory trials demonstrated an improvement in overall survival, reported Bishal Gyawali, MD, PhD, of Brigham and Women's Hospital in Boston, and colleagues in .

The remainder of the drugs granted accelerated approval had confirmatory studies that used surrogate endpoints that were either different from its preapproval studies (21%) or the same as those used in the preapproval studies (20%), or the trials did not confirm clinical benefit (9%), were delayed (5%), pending (11%), ongoing (10%), terminated, or not required.

A by Emerson Y. Chen, MD, of Oregon Health & Science University, examined cancer drug approvals given on the often-used surrogate endpoint of response rate. The median response rate among the 85 indications for 59 cancer drugs approved from 2006 to 2018 was 41%, with a median complete response rate of 6%.

"In the past, progress in our understanding of cancer and how to treat it has been frustratingly slow," Richard Lehman, MRCGP, BM, of the University of Birmingham in England, and Cary Gross, MD, of the Yale School of Public Health in New Haven, Connecticut, wrote in an accompanying the articles. "Now that the pace of the science has accelerated, there is a natural tendency to impatience. Yet these studies remind us that most new cancer drugs are of marginal benefit at best, despite their immense cost."

In , Sarah S.P. DiMagno, BA, of the University of Pennsylvania, and colleagues added that the FDA has no good reason to "rely so heavily on accelerated approval using response rates or other unreliable surrogate endpoints," noting that because many cancer drugs approved under the accelerate pathway "are being studied in patients with advanced or metastatic disease, randomized clinical trials with meaningful endpoints are likely feasible on relatively short timelines."

Proving Clinical Benefit

Drugs granted accelerated approval can be approved by demonstrating benefit on a surrogate measure such as progression-free survival or response rate. Drugs approved via this pathway are often required to undergo post-approval confirmatory trials to evaluate their clinical benefits.

According to a of accelerated approval, the pathway has been successful because only 5% of accelerated drug approvals were withdrawn or revoked since the launch of the program.

For their study, Gyawali's group wanted to update the outcomes reported in this 2018 assessment. They examined the required post-approval confirmatory trials for 93 cancer drug indications given accelerated approval from December 1992 to May 2017. They compared endpoints used in preapproval trials with endpoints used in the confirmatory trials and grouped trials in one of three categories:

• Trials that used overall survival or quality-of-life endpoint
• Trials that used a surrogate measure different from the preapproval trial
• Trials that used the same surrogate measure used in the preapproval trial

In addition to the updated data showing that only 20% of cancer drug indications approved through accelerated approval had shown improved overall survival in postmarketing studies, the researchers pointed to examples of the FDA approving drugs where no substantial benefit on meaningful endpoints was shown.

For example, olaparib (Lynparza) and rucaparib (Rubraca) were given accelerated approval based on response rates, and were required to show progression-free and overall survival benefits in confirmatory trials. However, the FDA granted each full approval based on a confirmatory trial showing improved progression-free survival alone. In another example, bevacizumab (Avastin) received accelerated approval for progressive glioblastoma based on response rates in a phase II trial. Despite the fact that a confirmatory phase III trial showed no improvement in overall survival or quality of life, the FDA granted full approval for this indication.

These types of approvals have consequences, according to DiMagno and colleagues. First, drugs with "unproven effectiveness sell false hope to desperate patients, who are likely paying thousands of dollars out of pocket for them."

In addition, these approvals crowd out innovation, they wrote. "Once a drug has been approved for a certain indication, other companies and researchers might not invest resources in treatments related to the condition, believing that there is no market."

Response Rates

The FDA may grant a drug accelerated or full approval based on response rate in cases where drugs have demonstrated "unprecedented activity in early clinical development in cancers with few effective options." According to Chen and colleagues, about one-third of cancer drugs are approved based on response rate.

They conducted a retrospective review and identified 85 indications for 59 cancer drugs that received approval based on response rate from 2006 to 2018. Of these, 38% received regular approval and 62% received accelerated approval.

More than half (55%) of the accelerated approvals were converted to a regular approval, where again only about 20% showed an overall survival benefit. The remaining converted approvals were based on either progression-free survival benefit (55%) or continued use of response rate (24%).

Among the drugs approved based on response rate, 16% had a response rate of less than 20%; 33% had a response rate of less than 30%; and 47% had a response rate of less than 40%.

"Many cancer drugs come to market based on single-arm studies with modest response rates," Chen's group wrote. "Our findings suggest greater room for the role of randomization in the assessment of novel anticancer drugs that exhibit low levels of innovation or treat common cancer types."

Lack of Clarity

Lehman and Gross pointed out that clinical trials are supposed to provide patients and physicians with evidence about a drug's benefits and harms, and inform about the uncertainties of treatment choices.

"By accident or design, the current system seems to achieve the exact opposite -- a maximum of perplexity and confusion -- and this results in a decisional and often catastrophic financial burden for those in the worst position to shoulder it: people with cancer that has spread and is likely to cut short their lives," they wrote. "Regulatory authorities therefore have a duty to ensure that the evidence supporting the use of new treatments combines clarity and timeliness and that areas of uncertainty are clearly identified and addressed by further trials that address patient-centered outcomes."