Use of surrogate outcomes a poor tradeoff for uncertainty in oncology trials

3 Apr 2019

Use of surrogate outcome measures to hasten oncology trials creates a large amount of uncertainty for only an 11-month advantage in bringing a drug into clinical use, a new US study shows.

An analysis of trials of 107 cancer drugs approved for 188 indications from 2006 to 2017 found that 38% were approved based on surrogate endpoints of tumour shrinkage or delay of tumour growth, while only 28% were approved based on robust outcome measures such as overall survival and patient-reported quality of life. A further 34% were approved based on progression-free survival.

The researchers at Oregon Health & Science University Knight Cancer Institute estimated that if progression-free survival were used instead of overall survival, study duration would be shorter by an average of 11 months. If response rates were used, study duration would be shorter by 19 months.

The small reduction in trial and drug approval times was a poor trade-off for imprecise evidence on drug effectiveness, they asserted.

“That is not a long time to wait for more definite data,” said lead author Dr Emerson Chen, a haematology and medical oncology fellow at OHSU.

Co-author of the paper published in JAMA Internal Medicine, Dr Vinay Prasad, said accelerated approval processes for cancer drugs based on a surrogate endpoint clinical trials only made sense if the surrogate reliably predicted improvements in survival or quality of life or in in rare disease situations with no existing treatment options.

“In short, we find surrogate endpoints are NOT associated with massive time savings (as claimed) instead mostly massive uncertainty,” he tweeted on social media

Safety issues with novel oncology drugs may to be more likely to go undiscovered in clinical trials using surrogate endpoints, he added, as such trials tend to enroll fewer patients and monitor them for a shorter time than trials designed to measure overall survival.

The researchers cited the case of bevacizumab (Avastin) as embodying the problems of relying on surrogate endpoints in oncology trials. It gained an accelerated approval for metastatic breast cancer in 2008 based on dramatic gains in progression-free survival. In subsequent randomised controlled trials, bevacizumab did not help breast cancer patients live longer even as it caused a range of severe side effects, some of them life-threatening. The FDA withdrew its approval for the breast cancer indication in 2011.

“Because manufacturers have an incentive to bring existing drugs to earlier lines of therapy to reach more customers and increase market shares, regulators must institute valid end points for confirming benefit and expanding subsequent indications,” they recommended.

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