Cancer drug approvals with new surrogate endpoints are common and concerning

Is the U.S. Food and Drug Administration (FDA) approving new cancer drugs based on the right evidence? Oncologists, researchers, and patient advocates have been concerned that the FDA is accelerating cancer drug approval, without sufficient proof that the treatments actually improve overall survival or quality of life for cancer patients.

The increasing use of surrogate endpoints is a significant driver of these approvals. Surrogate endpoints (also known as “surrogate markers”) are metrics that are not generally meaningful on their own, but correlate with clinical benefits that matter to patients. Examples of surrogate markers include tumor size or progression-free survival in the case of cancer drugs. Another example: In a recent trial of hydroxychloroquine for Covid-19, researchers measured “viral load,” a supposed surrogate marker for survival.

If the FDA is not approving drugs based on the right evidence, they could be sacrificing effectiveness for speed.

In the FDA’s “accelerated approval” program, rather than prove a cancer drug has a beneficial clinical outcome, such as improved survival or better quality of life, the drugmaker just has to prove that the drug improved a surrogate endpoint, making it much quicker to develop these drugs and bring them to market. But if the FDA is not approving drugs based on the right surrogate markers, they could be sacrificing drug effectiveness for speed.

It would make sense if the FDA only approved drugs based on surrogate endpoints if 1) The endpoint is strongly correlated with overall survival or quality of life, or 2) The endpoint has been previously used in treating the condition. However, according to a recent study in JAMA Internal Medicine, the FDA has frequently approved cancer drugs based on a surrogate endpoint that had never before been used for that type of cancer.

Oncology researchers at Oregon Health and Science University Emerson Chen, Alyson Haslam, and Vinay Prasad examined 194 cancer drug approvals based on surrogate endpoints that occurred from 1992-2019. They found that about one-third of these approvals were based on a surrogate endpoint that had not been previously used for that specific cancer.

Among the 64 new surrogate marker-based approvals, only 4 had a relatively strong correlation with meaningful outcomes.

If the FDA approved these drugs based on a new surrogate marker, it must be because those marker were proven to correlate with clinical outcomes…right? Not exactly. Among the 64 new surrogate marker-based approvals, Chen et al. found that only 4 had a relatively strong correlation with meaningful outcomes. This means that over the past few decades, a full quarter of cancer drug approvals based on surrogate endpoints were not based on validated surrogates or previous regulatory standard.

The authors conclude that “the FDA is steadily accepting more surrogate measures over time, which are not justified by scientific validity or adherence to regulatory precedent.” This pattern is especially concerning, because the FDA rarely holds drugmakers accountable for conducting postmarketing studies to validate the effectiveness of drugs approved based on surrogate markers. The method by which new cancer drugs are approved seems to only benefit drugmakers, allowing them to get drugs to the market faster with little evidence of benefit. Meanwhile, patients are taking on the increased risks of financial cost and potential side effects without having the confidence that these new drugs will improve the outcomes that matter most to them.


Judith Garber is the Health Policy and Communications Fellow at the Lown Institute. She holds a masters degree in public policy from the Heller School of Social Policy and Management.

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