Update: June 26, 2018: This article was updated with additional context and examples.
- Food and Drug Administration Commissioner Scott Gottlieb, already known for his desire to speed drugs to patients, aims to push the agency toward greater acceptance of more flexible trial designs and intermediate measures of efficacy in deciding whether to approve new cancer medicines.
- Citing recent advances in cancer therapy, Gottlieb laid out in a speech Monday the agency's rationale for relying more heavily on these measures, known more commonly as surrogate endpoints.
- In the coming weeks, the FDA plans to publish a list of surrogate endpoints used by the agency to OK cancer drugs. The hope is to make more transparent how the regulator is balancing between traditional requirements for proving a survival benefit and giving patients access to promising new treatments.
In his speech, Gottlieb made a full-throated case for why treatment progress should prompt fresh consideration of whether overall survival should be the principal gauge of whether a cancer drug is approved or not.
"We needed to adjust our approach for the era we're in today," he said, speaking at a policy summit of The National Comprehensive Cancer Network in Washington, D.C.
Certainly, the rapid emergence of immuno-oncology, coupled with improvements in tumor sequencing and targeted therapies, has shifted standards of care for some cancers.
And, as Gottlieb notes, better enrichment of trials with patients most likely to benefit could mean detection of earlier signals of efficacy than was previously possible.
But it's a controversial position, and one that remains a subject of debate in the field. Surrogate endpoints like overall response rate or progression-free survival can show whether a drug is having an effect on a patient's tumor. That doesn't always mean, however, that patients will end up living longer.
A 2015 analysis from Vinay Prasad, a well-known critic of less stringent clinical measures, and the National Cancer Institute's Chul Kim, for example, found little correlation between surrogate endpoints and improved overall survival.
Even for potent new drugs like checkpoint inhibitors, early signs of benefit don't always translate. Earlier this year, the FDA warned of signs that bladder cancer patients treated first with either Roche's Tecentriq (atezolizumab) or Merck & Co.'s Keytruda (pembrolizumab) were dying sooner than those given platinum-based chemotherapy.
Both drugs had been approved for first-line treatment of bladder cancer on an accelerated basis from initial signs of efficacy. This week, the FDA announced it had changed the drug's label to limit first-line use only to those patients with high levels of a biomarker known as PD-L1.
In his speech, Gottlieb noted that more effective treatments can make proving an overall survival benefit difficult, as patients "cross over" from the control arm to treatment arm of a trial.
"If we were only approving drugs for serious and life threatening diseases based on an overall survival benefit, and then denying patients the ability to crossover to the experimental arms in confirmatory trials, we would literally be asking patients to die so that we could achieve a lower "p" value," Gottlieb said, referring to a statistical measure used in clinical trials.
But some believe the divergent outcomes are more due to trial design and patient crossover than the drugs themselves. To Gottlieb's point, clear signs of early benefit could make it challenging to keep patients on the placebo arm from leaving the trial and receiving an approved drug like Opdivo or Keytruda off-label.
Gottlieb also brought up the example of Novartis' standard-shifting Gleevec (imatinib), which was approved for chronic myeloid leukemia based on cytogenic response rate. Statistical proof of a survival benefit came more than a decade later, long after the drug had established itself as cornerstone treatment for the blood cancer.
Gleevec, it could be argued however, is an outlier, a clear case of benefit that quickly changed how CML was treated. On Twitter, Prasad likened the example to using Lebron James, Albert Einstein and Joyce Carol Oates as case studies for after-school children's programs.
In addition to the list of surrogate endpoints, Gottlieb also previewed forthcoming guidance on how the FDA will accept so-called "Type C" meetings with drugmakers earlier in the development process.
"Both of these efforts will help give the research community and innovators greater clarity about how the FDA utilizes endpoints, and how we expect product developers to carefully evaluate biomarkers as surrogate endpoints, in a given disease state," he said.