In the Journals

FDA guidelines for cancer drug approval may need reevaluation

The FDA’s accelerated approval pathway for cancer drugs may need to be reevaluated, according to results from two studies recently published in JAMA Internal Medicine.

For the first study, Bishal Gyawali, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School, and Queen’s University, Ontario, Canada, and colleagues evaluated the FDA’s accelerated approval pathway for investigational cancer drug approval by comparing endpoints in preapproval trials with endpoints in confirmatory trials. They also reviewed the efficacy of surrogate endpoints.

Gyawali and colleagues wrote that the FDA needed a consistent approach for results of confirmatory trials in order to help physicians and patients understand how benefits of certain drugs were verified. Their results showed that confirmatory trial requirements should be reassessed in order to collect more clinically useful information.

In the second study, Emerson Y. Chen, MD, of the division of hematology and medical oncology at the Knight Cancer Institute at Oregon Health & Science University, and colleagues evaluated cancer drugs approved by the FDA based on their response rate, or the percentage of patients who experienced 30% tumor shrinkage. Researchers noted that 30% tumor shrinkage does not necessarily indicate patient improvement.

Chen and colleagues found that a significant number of cancer drugs approved by the FDA based on response rates had numerically low or modest response rates. Specifically, they found that high response rates justified accelerated approval status, as only 21% of drugs had a high response rate. Researchers wrote that the high number of drugs with low and modest response rates showed that response rates were not a good surrogate for overall survival rate.

In an editorial accompanying the studies, Richard Lehman, MRCGP BM, BDh, of the University of Birmingham, England, and Cary Gross, MD, of the Yale School of Medicine, explained that the studies’ findings show that the FDA’s accelerated approval pathway leads to approval of drugs tested in non-randomized trials and/or based on outcome measures that may not be benefit patients. They also explained that both studies indicated that surrogate outcome measures did not provide the outcomes patients wanted, and that most drugs given accelerated approval status did not achieve an increase in overall survival during postmarketing trials.

In another editorial published with the studies, Sarah S. P. DiMagno, BA, of the department of medical ethics and health policy in the Perelman School of Medicine at the University of Pennsylvania, and colleagues explained that although the FDA determined that the accelerated approval pathway was a success in its 25-year review due to only 5% of confirmatory trials resulting in failure and withdrawal of previously approved drugs, the FDA itself was responsible for drug approval withdrawal. DiMagno and colleagues noted that the FDA was reluctant to withdraw approval and was often slow to do so when necessary. Therefore, approval withdrawal was not an accurate measure of the success of the accelerated approval pathway.

“Ultimately, the purpose of clinical trials is to produce evidence that can inform shared understanding between patients and clinicians about the benefits, harms, and uncertainties of critical treatment choices,” Lehman and Gross wrote in the editorial. “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.” – by Erin Michael

References:

Chen EY, et al. JAMA Internal Medicine. 2019;doi: 10.1001/jamainternmed.2019.0583.

DiMagno SSP, et al. JAMA Internal Medicine. 2019;doi: 10.1001/jamainternmed.2019.0584.

Gyawali B, et al. JAMA Internal Medicine. 2019;doi:10.1001/jamainternmed.2019.0462.

Lehman R, Gross C. JAMA Internal Medicine. 2019;doi: 10.1001/jamainternmed.2019.0458.

Disclosures: Chen, Gyawali, Lehman and DiMagno report no relevant financial disclosures. Gross reports grants from Johnson & Johnson and the National Comprehensive Cancer Network/Pfizer, and funding for travel from Flatiron Inc. Please see full studies and editorials for all other authors’ relevant financial disclosures.

The FDA’s accelerated approval pathway for cancer drugs may need to be reevaluated, according to results from two studies recently published in JAMA Internal Medicine.

For the first study, Bishal Gyawali, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School, and Queen’s University, Ontario, Canada, and colleagues evaluated the FDA’s accelerated approval pathway for investigational cancer drug approval by comparing endpoints in preapproval trials with endpoints in confirmatory trials. They also reviewed the efficacy of surrogate endpoints.

Gyawali and colleagues wrote that the FDA needed a consistent approach for results of confirmatory trials in order to help physicians and patients understand how benefits of certain drugs were verified. Their results showed that confirmatory trial requirements should be reassessed in order to collect more clinically useful information.

In the second study, Emerson Y. Chen, MD, of the division of hematology and medical oncology at the Knight Cancer Institute at Oregon Health & Science University, and colleagues evaluated cancer drugs approved by the FDA based on their response rate, or the percentage of patients who experienced 30% tumor shrinkage. Researchers noted that 30% tumor shrinkage does not necessarily indicate patient improvement.

Chen and colleagues found that a significant number of cancer drugs approved by the FDA based on response rates had numerically low or modest response rates. Specifically, they found that high response rates justified accelerated approval status, as only 21% of drugs had a high response rate. Researchers wrote that the high number of drugs with low and modest response rates showed that response rates were not a good surrogate for overall survival rate.

In an editorial accompanying the studies, Richard Lehman, MRCGP BM, BDh, of the University of Birmingham, England, and Cary Gross, MD, of the Yale School of Medicine, explained that the studies’ findings show that the FDA’s accelerated approval pathway leads to approval of drugs tested in non-randomized trials and/or based on outcome measures that may not be benefit patients. They also explained that both studies indicated that surrogate outcome measures did not provide the outcomes patients wanted, and that most drugs given accelerated approval status did not achieve an increase in overall survival during postmarketing trials.

In another editorial published with the studies, Sarah S. P. DiMagno, BA, of the department of medical ethics and health policy in the Perelman School of Medicine at the University of Pennsylvania, and colleagues explained that although the FDA determined that the accelerated approval pathway was a success in its 25-year review due to only 5% of confirmatory trials resulting in failure and withdrawal of previously approved drugs, the FDA itself was responsible for drug approval withdrawal. DiMagno and colleagues noted that the FDA was reluctant to withdraw approval and was often slow to do so when necessary. Therefore, approval withdrawal was not an accurate measure of the success of the accelerated approval pathway.

PAGE BREAK

“Ultimately, the purpose of clinical trials is to produce evidence that can inform shared understanding between patients and clinicians about the benefits, harms, and uncertainties of critical treatment choices,” Lehman and Gross wrote in the editorial. “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.” – by Erin Michael

References:

Chen EY, et al. JAMA Internal Medicine. 2019;doi: 10.1001/jamainternmed.2019.0583.

DiMagno SSP, et al. JAMA Internal Medicine. 2019;doi: 10.1001/jamainternmed.2019.0584.

Gyawali B, et al. JAMA Internal Medicine. 2019;doi:10.1001/jamainternmed.2019.0462.

Lehman R, Gross C. JAMA Internal Medicine. 2019;doi: 10.1001/jamainternmed.2019.0458.

Disclosures: Chen, Gyawali, Lehman and DiMagno report no relevant financial disclosures. Gross reports grants from Johnson & Johnson and the National Comprehensive Cancer Network/Pfizer, and funding for travel from Flatiron Inc. Please see full studies and editorials for all other authors’ relevant financial disclosures.