From the Journals

Studies cast doubt on FDA’s accelerated cancer drug pathway



Two recent studies that assess the Food and Drug Administration’s accelerated approval process for cancer drugs suggest the agency is using inadequate measures to determine clinical value for patients.

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In the first study, lead investigator Emerson Y. Chen, MD, of Oregon Health & Science University, Portland, and colleagues conducted a retrospective analysis of all drugs approved by the FDA on the basis of response rate – the percentage of patients who experience tumor shrinkage – from Jan. 1, 2006, to Sept. 30, 2018. The data set consisted of 59 oncology drugs with 85 unique indications approved by the FDA for advanced-stage metastatic cancer on the basis of a response rate (RR) endpoint during the study period.

Of the 85 indications, 32 were granted regular approval immediately with limited postmarketing efficacy requirements and 53 (62%) were granted accelerated approval. Of the accelerated approvals, 29 (55%) were later converted to regular approval.

The median RR for the 85 indications was 41%, and the median sample size of such RR trials was 117 patients, according to the analysis published in JAMA Internal Medicine.

Among all approvals, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%.

Most approved drugs had an RR ranging from 20% to 59%, the study found. Of 81 available indications, the median complete response rate – defined as the percentage of patients with no visible disease and normalization of lymph nodes – was 6%. (Complete response data were not reported for four drug indications.)

The investigators found that many of the drugs studied have remained on the market for years without subsequent confirmatory data. For example, when the accelerated approvals based on RR were converted to full approval, 23 of 29 were made on the basis of surrogate endpoints (progression-free survival or RR), 7 of 29 were made on the basis of RR, and just 6 of 29 were made on the basis of overall survival (OS).

The findings suggest that most cancer drugs approved by the FDA based on RR have less than transformational response rates, and that such indications do not have confirmed clinical benefit, the study authors wrote.

While in some settings, a response can equal prognostic value regarding overall survival, the authors wrote that “the ability of RR to serve as a validated surrogate for OS varies among cancer types and is generally poor.”

In the second study, researchers found that confirmatory trials for only one-fifth of cancer drug indications approved via the FDA’s accelerated approval route demonstrated improvements in overall patient survival.

Lead investigator Bishal Gyawali, MD, PhD, of Queen’s University, Kingston, Ont., and colleagues examined FDA data on recent drugs and indications that received accelerated approval and were later granted full approval.

For their analysis, the investigators reviewed the FDA’s database of postmarketing requirements and commitments, as well as PubMed, to determine the current status of postmarket trials for indications labeled as “ongoing” in the original FDA data.

Of 93 cancer drug indications for which accelerated approval was granted from Dec. 11, 1992, to May 31, 2017, the FDA reported clinical benefit was adequately confirmed in 51 indications. Of these confirmations, 15 demonstrated improvement in overall survival.

In their updated analysis, the investigators determined that confirmatory trials for 19 of the 93 (20%) cancer drug approvals reported an improvement in OS, 19 trials (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 trials (21%) reported improvement in a different surrogate, according to the study, also published in JAMA Internal Medicine.

Additionally, results showed that 5 confirmatory trials were delayed, 10 trials were pending, and 9 trials were ongoing.

For three recent accelerated approvals, the primary endpoints were not met in the confirmatory trials, but one of the indications still received full approval.

The findings raise several concerns about the accelerated cancer drug pathway, including whether the same surrogate efficacy measure should be used as verification of drug benefit, according to the investigators. Conversely, using a different surrogate endpoint than the original measure can cause confusion among physicians and patients about whether the cancer drug improves survival or quality of life, information that is essential in the benefit-risk evaluation for clinical decision making.

That a number of the confirmatory trials examined were delayed or pending emphasize the considerable time that can elapse between drug approval and confirmatory trial completion, they added.

“Timely planning and completion of postmarketing trials is necessary for proper implementation of the accelerated approval pathway, and the FDA should minimize the period during which patients and physicians are using drugs approved through accelerated pathways without rigorous data on their ultimate clinical benefit,” the authors wrote in the analysis.

Dr. Chen, lead author of the RR study, said both studies call into question what criteria is optimal when assessing cancer drug value, while ensuring such measurements are not too high to achieve – preventing useful drugs to market – but also not too low – allowing drugs with marginal benefit into the market.

“There has been tremendous drug development within the oncology space, and it is always important to look back to reassess and see if the process [matches] the original vision so that we can correct any misuse or concerns,” Dr. Chen said in an interview.

Dr. Chen said his study indicates the RR endpoint has been misused in scenarios with low response rate, common cancer, and/or situations with already available therapies. In the study by Dr. Gyawali, the results suggest many drugs approved on the basis of a surrogate endpoint (RR or progression-free survival) ultimately do not demonstrate survival benefit confirmation or patient-reported benefit, Dr. Chen said.

“We hope that readers of these JAMA IM studies and the accompanying commentaries will recognize that there could be a set of guidance criteria from regulatory agencies or oncology organizations to recommend use of surrogate endpoints in special situations: high response rate of the drug, very rare cancer, or highly innovative therapy not yet seen before,” he said. “The use of surrogate endpoints to justify these therapies must also have postmarketing confirmation of survival or patient-reported benefit.”

The study led by Dr. Chen was supported by the Laura and John Arnold Foundation. Dr Chen reported receiving lecture honorarium from Horizon CME; another coauthor reported receiving honorarium from universities, medical centers, and publishers. The study led by Dr. Gyawali was supported by the Arnold Ventures; one of the coauthors reported receiving grant support from the Harvard-MIT Center for Regulatory Science and the Engelberg Foundation, as well as unrelated research funding from the FDA.

SOURCES: Chen EY et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0583; Gyawali B et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0462.

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