The FDA Should Listen to Its Own Evidence on Surrogate Markers

Bishal Gyawali, MD, PhD


November 12, 2021

The US Food and Drug Administration (FDA) clearly states that surrogate markers must undergo testing to confirm that they are indeed validated endpoints when used in clinical trials to study a drug's efficacy. The proportion of cancer drugs approvals based on surrogate endpoints, such as objective response rates or progression-free survival, is increasing each year.

Given this, one might assume that the FDA has performed its own research on surrogate markers to justify approval decisions for many cancer drugs. However, that is not necessarily the case. Our research shows that although the FDA published a table of surrogate endpoints that formed the basis for drug approvals, many had limited evidence to support their use. Some surrogates had never been formally tested, whereas others were included despite poor performance as a surrogate endpoint.

This finding piqued my curiosity, and I went on a mission to see how many surrogate validation studies the FDA had conducted. I found only four such studies. And the results did not inspire confidence.

Surrogate Validation Studies to Date

The first explored whether pathologic complete response (pCR) could be used as a surrogate for overall survival in patients with early breast cancer. This 2014 analysis found that although pCR was a prognostic marker in individual patients, it was a very poor surrogate endpoint for overall survival. Reassuringly, the FDA has followed these results and has not approved drugs on the basis of pCR in breast cancer.

A 2017 analysis looked at milestone survival as a surrogate endpoint in metastatic non–small cell lung cancer (NSCLC) and found a moderate correlation between overall survival milestones at 12 and 9 months and overall survival hazard ratio, but not 9-month progression-free survival or 6-month overall response rate milestones. These markers have also not been used for cancer drug approvals yet.

However, the FDA did not follow its own evidence on the two remaining studies.

A 2015 study found an association between overall response rate and progression-free survival in patients with advanced NSCLC receiving targeted and standard therapies, but no association between response rate or progression-free survival and overall survival. Still, since that analysis, the FDA has approved a dozen targeted drugs in NSCLC using response rate and progression-free survival as surrogate endpoints.

And a 2018 study, which examined immunotherapy trials across solid tumors, concluded that trial- and individual-level associations between overall response rate or progression-free survival and overall survival were weak. Even so, the FDA has approved several immunotherapy drugs on the basis of overall response rate and progression-free survival. Notably, all immunotherapy drugs that were withdrawn had received accelerated approval  on the basis of these surrogates.

No Clear Threshold for FDA Approval

What surprises me is that although the FDA acknowledges the importance of surrogate marker validation research, it has published only four studies. And none has shown strong surrogacy for the endpoints in question.

So, how can the FDA justify granting regular approvals based on these surrogates? And what is the evidence threshold the FDA is using for its cancer drug approvals?

We need more transparency, at the least. But more important, we need the FDA to examine and follow the evidence.

Bishal Gyawali, MD, PhD, is an associate professor in the Departments of Oncology and Public Health Sciences and a scientist in the Division of Cancer Care and Epidemiology at Queen's University in Kingston, Ontario, Canada, and is also affiliated faculty at the Program on Regulation, Therapeutics, and Law in the Department of Medicine at Brigham and Women's Hospital in Boston. His clinical and research interests revolve around cancer policy, global oncology, evidence-based oncology, financial toxicities of cancer treatment, clinical trial methods, and supportive care. He tweets at @oncology_bg.

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