Research into 3- and 6-month PFS end points in castrate-resistant prostate cancer, however, has suggested that PFS is a strong and significant predictor of OS.7

Regarding the use of RR as a surrogate, a study found that, among 20 reviewed clinical trials involving patients with acute myeloid leukemia, complete response with incomplete blood recovery or better was a valid surrogate marker for OS.8 In 2015, A US Food and Drug Administration (FDA) review of 14 clinical trials in NSCLC suggested there was a correlation between RR and OS.9

These results do not generalize to all markers, disease types, and varieties of treatment, nor do they confirm or refute the possibility that surrogate markers for hard end points are always valid predictive tools.

Yet it is even open question for some of whether OS itself, as it is experienced in clinical trials, actually corresponds to survival among patients in the real world.5

Given that it is not uncommon for phase 2 trials to show favorable survival benefits, and for phase 3 trials of the same drugs to determine there was no overall survival benefit, it’s reasonable to also consider that making predictions about real-world outcomes based on the results from a controlled, phase 3 clinical trial may also be unjustified.

Research published in 2017 showed, based on data from nearly 40,000 patients receiving at least 1 of 30 treatments across 5 therapeutic areas in oncology, that better OS in clinical studies may be only a slightly better predictor of real-world survival than is PFS or time-to-progression.10

It appears, then, that to claim that surrogate end points are uniformly unreliable would be unjustified — although there remains a clear issue of how to determine whether the selection (and reporting) of any given surrogate is likely to be predictive of OS, and therefore, of the most benefit to patients in the real world.

“We should be careful not to hype new drugs as game-changers based on improvements in unvalidated surrogates alone,” said Dr Gyawali. “Using surrogate end points for accelerated approval is fine, but for regular approval, the benchmark has to be true clinical benefits. All randomized clinical trials with a primary end point of surrogates, such as PFS, must mandatorily demonstrate benefits in QoL.”

The pressure, then, should be equally felt by drug developers — those involved in trial design, and those responsible for overseeing the approval process.

Disclosure: Dr Prasad disclosed payments for various projects and entities with the original JAMA Internal Medicine study. For a full list of disclosures, please refer to the original study.

References

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