FDA Should Reassess Postmarket Trials for Cancer Drugs Approved via Accelerated Pathway, Researchers Say
Regulatory News | 28 May 2019 |
The US Food and Drug Administration (FDA) may need to reassess how confirmatory trials are conducted after just one-fifth of such trials for cancer drug indications approved via FDA’s accelerated approval pathway have demonstrated improvements in overall survival (OS), researchers reported Tuesday in JAMA Internal Medicine research.
The researchers looked at 93 cancer drug indications granted accelerated approval by FDA from 1992 through May 2017, finding confirmatory trials reported that 20% had improvement in overall survival, 21% had improvement in a different surrogate measure and 20% had improvement in the same surrogate measure used in confirmatory trials and preapproval trials.
“Appropriate use of surrogates for accelerated approval requires an appreciation for how the validity of a surrogate can vary from one indication to another. One strategy for capturing this variability would be to have a continually updated database of strengths of surrogate validation across tumor types as results from newer trials become available,” the researchers from the Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School said.
They also called to adapt FDA’s recently published list of surrogate measures to include the strengths of surrogacy validation. “Confirming the clinical benefit of a cancer drug using the same surrogate measure as the one used in its preapproval trial should be reserved for when the surrogate measure for a given indication has been validated,” they added.
Lead author Bishal Gyawali explained to Focus: "Our recommendation to the FDA is to use clinical endpoints for confirmatory trials. Using same surrogate endpoint in both pre-approval and confirmatory trials is a contradiction because by definition, accelerated approval means the approval is based on a surrogate that should be confirmed in a confirmatory trial. If the same surrogate is enough for confirmation, why mandate confirmatory trials at all?"
In addition, the researchers addressed potential critics who may disagree that it is important to demonstrate an OS benefit to verify a clinical benefit. They use the example of imatinib for chronic myeloid leukemia (CML), which was approved without the need to report OS benefit in trials.
“However, imatinib for CML is an atypical example of a drug with such huge benefits that it is considered lifesaving rather than life prolonging,” they wrote. “Most approved cancer drugs fall into the latter category, and as a result, even impressive effects on surrogate measures may not translate to extended survival benefits. Thus, although improvement in surrogate measures alone may be acceptable for accelerated approval, the confirmatory trials should verify the clinical benefit in terms of benefits in OS, quality of life, or a valid surrogate of either.
“Reassessment of the requirements for confirmatory trials may be necessary to obtain more clinically meaningful information,” they added. “FDA should adopt a consistent approach regarding the results of confirmatory trials to help physicians and patients better understand what constitutes verification of benefit.”
Commentaries
In a commentary accompanying the study and a second study on cancer drugs approved based on response rates, professors from the Perelman School of Medicine at the University of Pennsylvania criticize FDA for calling the accelerated approval process a success because only 5% of confirmatory trials failed.
“FDA is congratulating itself, using its own ‘surrogate’ end points, which it can alter to demonstrate that its policies are succeeding. This low rate of withdrawals is not a valid measure of success. There is no good reason for the FDA to rely so heavily on accelerated approval using response rates or other unreliable surrogate endpoints,” they write.
They also point to three necessary policy changes: “First, the endpoint for confirmatory trials should never be the same surrogate endpoint used in the original study, and a new surrogate endpoint should be used only if there is a proven correlation between that endpoint and overall survival or improved quality of life. Most confirmatory trials should use overall survival and/or quality-of-life endpoints.
“Second, approval of drugs should be rapidly withdrawn when confirmatory trials report serious toxic effects or do not report meaningful clinical improvements. Finally, the confirmatory trials must be conducted promptly, with credible threats of reversed approval. Having more than a quarter of trials incomplete years after accelerated approval is unacceptable,” they add.
Another commentary from a professor at Yale School of Medicine and a professor at the University of Birmingham in the UK explain how the findings from the two studies “build on a growing body of work, which in aggregate, demonstrate a postmarketing evaluation process that is serving neither patients nor society well.”
Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval
An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate
Accelerated Approval of Cancer Drugs—Righting the Ship of the US Food and Drug Administration
An International Perspective on Drugs for Cancer
Editor's note: Article updated with comment from research author Bishal Gyawali.
The researchers looked at 93 cancer drug indications granted accelerated approval by FDA from 1992 through May 2017, finding confirmatory trials reported that 20% had improvement in overall survival, 21% had improvement in a different surrogate measure and 20% had improvement in the same surrogate measure used in confirmatory trials and preapproval trials.
“Appropriate use of surrogates for accelerated approval requires an appreciation for how the validity of a surrogate can vary from one indication to another. One strategy for capturing this variability would be to have a continually updated database of strengths of surrogate validation across tumor types as results from newer trials become available,” the researchers from the Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School said.
They also called to adapt FDA’s recently published list of surrogate measures to include the strengths of surrogacy validation. “Confirming the clinical benefit of a cancer drug using the same surrogate measure as the one used in its preapproval trial should be reserved for when the surrogate measure for a given indication has been validated,” they added.
Lead author Bishal Gyawali explained to Focus: "Our recommendation to the FDA is to use clinical endpoints for confirmatory trials. Using same surrogate endpoint in both pre-approval and confirmatory trials is a contradiction because by definition, accelerated approval means the approval is based on a surrogate that should be confirmed in a confirmatory trial. If the same surrogate is enough for confirmation, why mandate confirmatory trials at all?"
In addition, the researchers addressed potential critics who may disagree that it is important to demonstrate an OS benefit to verify a clinical benefit. They use the example of imatinib for chronic myeloid leukemia (CML), which was approved without the need to report OS benefit in trials.
“However, imatinib for CML is an atypical example of a drug with such huge benefits that it is considered lifesaving rather than life prolonging,” they wrote. “Most approved cancer drugs fall into the latter category, and as a result, even impressive effects on surrogate measures may not translate to extended survival benefits. Thus, although improvement in surrogate measures alone may be acceptable for accelerated approval, the confirmatory trials should verify the clinical benefit in terms of benefits in OS, quality of life, or a valid surrogate of either.
“Reassessment of the requirements for confirmatory trials may be necessary to obtain more clinically meaningful information,” they added. “FDA should adopt a consistent approach regarding the results of confirmatory trials to help physicians and patients better understand what constitutes verification of benefit.”
Commentaries
In a commentary accompanying the study and a second study on cancer drugs approved based on response rates, professors from the Perelman School of Medicine at the University of Pennsylvania criticize FDA for calling the accelerated approval process a success because only 5% of confirmatory trials failed.
“FDA is congratulating itself, using its own ‘surrogate’ end points, which it can alter to demonstrate that its policies are succeeding. This low rate of withdrawals is not a valid measure of success. There is no good reason for the FDA to rely so heavily on accelerated approval using response rates or other unreliable surrogate endpoints,” they write.
They also point to three necessary policy changes: “First, the endpoint for confirmatory trials should never be the same surrogate endpoint used in the original study, and a new surrogate endpoint should be used only if there is a proven correlation between that endpoint and overall survival or improved quality of life. Most confirmatory trials should use overall survival and/or quality-of-life endpoints.
“Second, approval of drugs should be rapidly withdrawn when confirmatory trials report serious toxic effects or do not report meaningful clinical improvements. Finally, the confirmatory trials must be conducted promptly, with credible threats of reversed approval. Having more than a quarter of trials incomplete years after accelerated approval is unacceptable,” they add.
Another commentary from a professor at Yale School of Medicine and a professor at the University of Birmingham in the UK explain how the findings from the two studies “build on a growing body of work, which in aggregate, demonstrate a postmarketing evaluation process that is serving neither patients nor society well.”
Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval
An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate
Accelerated Approval of Cancer Drugs—Righting the Ship of the US Food and Drug Administration
An International Perspective on Drugs for Cancer
Editor's note: Article updated with comment from research author Bishal Gyawali.
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