FDA Pulls Back the Veil on Surrogate Endpoints


A surrogate endpoint is a clinical measurement—associated with a specific treatment—that indicates whether the treatment may provide a statistically significant clinical benefit.1 A possible example of a surrogate endpoint is tumor shrinkage after administration of an anti-cancer drug candidate. The shrunken tumor would reasonably be expected to predict a clinical benefit, like increased survival. But shrinking the tumor, by itself, does not necessarily mean the drug candidate should become an approved drug. For example, the mortality rate of patients taking the drug candidate, versus placebo, may not be significantly different even with significant tumor shrinkage.

The regulatory importance of a surrogate endpoint is that, if the data is compelling enough, the drug candidate can be approved2 by the U.S. Food and Drug Administration (FDA)—in part based upon the surrogate endpoint data. Upon FDA approval based on the surrogate endpoint, the drug sponsor can then market the drug while conducting post-approval clinical trials3 to determine if the drug actually provides a statistically significant clinical benefit (e.g., increases patient survival).4

FDA's Surrogate Endpoint List

Recently, the FDA published a list of surrogate endpoints—one table for adults and one table for pediatrics—that have been used to support approval. The list, which is intended to be updated every six months, was published pursuant to Section 2011 of the 21st Century Cures Act (the act), which mandates that the FDA publish a list of surrogate endpoints that were the basis of approval or licensure (as applicable) of a drug or biological product under both accelerated and traditional approval provisions.

The act seeks to further the goal of expediting the process by which new drugs are approved, and a formal list can help inform critical discussions with the FDA regarding the acceptability of a surrogate endpoint.

The FDA's list features surrogate endpoints for a number of adult and pediatric diseases and conditions, including: acromegaly, asthma, various forms of cancer, chronic kidney disease, cystic fibrosis, Duchenne muscular dystrophy, gout, heart failure, all three forms of hepatitis, hypercholesterolemia hypertension, opioid dependence, osteoporosis, pulmonary tuberculosis, and types 1 and 2 diabetes mellitus, among others.

In addition, the FDA's list includes surrogate endpoints for both accelerated and traditional approvals. Examples of surrogate endpoints include: durable progression-free survival (cancer), disease-free survival (cancer), event-free survival (cancer), forced expiratory volume in 1 second (FEV1) (COPD and asthma), serum creatinine (chronic kidney disease), and skeletal muscle dystrophin (Duchenne muscular dystrophy).

The complete list of current surrogate endpoints can be found here.


Pharmaceutical companies that are considering relying on surrogate endpoints for FDA approval would do well to consult FDA's surrogate endpoint list.

1 Federal Food, Drug, and Cosmetic Act (FDCA), section 507(e)(9): "The term 'surrogate endpoint' means a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is not itself a direct measurement of clinical benefit, and . . . is reasonably likely to predict clinical benefit and could be used to support the accelerated approval of a drug or biological product . . ."
2 E.g., via accelerated approval—which provides faster approval of drugs for serious conditions that fill an unmet medical need.
3 E.g., phase 4 clinical trials.
4 If a conditionally approved drug fails to demonstrate a statistically significant clinical benefit, the FDA can withdraw the drug's conditional approval.

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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