The Learning Portal will be under maintenance Monday, 6 December between 6 AM and 5 PM EST. Portal functionality will be unavailable during this window.
We apologize for any inconvenience caused during this time.

Regulatory Focus™ > News Articles > 2019 > 11 > Researchers Call on FDA to Rethink Guidance Allowing Use of Surrogate Outcomes

Researchers Call on FDA to Rethink Guidance Allowing Use of Surrogate Outcomes

Posted 13 November 2019 | By Zachary Brennan 

Researchers Call on FDA to Rethink Guidance Allowing Use of Surrogate Outcomes

The US Food and Drug Administration (FDA) needs to reconsider its use of surrogate outcomes in some guidance documents on developing treatments for infectious diseases, researchers from Harvard and George Washington University School of Medicine wrote in a review published Tuesday in JAMA Internal Medicine.

The review evaluated 22 FDA guidance documents, which included recommendations for pivotal clinical trials in 27 disease indications. For six indications (22%), only direct clinical outcomes were specified as primary endpoints, while for the other 21 indications, guidance documents recommended surrogate outcomes as sole primary endpoints or as part of composite primary endpoints.

“None of the recommendations for the use of surrogate measures matched the regulatory and scientific conditions favoring indirect outcomes in place of clinical outcomes,” they wrote.

While the researchers noted that surrogate outcomes can be appropriate as primary endpoints in anti-infective clinical trials (e.g. “the biomarker of HIV viral load has been shown to be a valid surrogate outcome in a chronic life-threatening disease predicting risk of clinical progression or death”), the researchers stressed that surrogates should only be used as primary endpoints in the correct setting (e.g., chronic, life-threatening disease) and when there is strong evidence that the effects on the surrogate are informative for clinical outcomes.

Of the 22 guidance documents reviewed, the researchers noted that five documents recommended surrogates and were classified as both chronic and serious or life-threatening conditions, including ones for chronic hepatitis C, H pylori, HIV infection or prevention and pulmonary tuberculosis.

“However, the guidances for these 5 indications still allowed noninferiority hypotheses, and did not require the new agent to have improved efficacy compared with available therapy or mention evaluation of nonefficacy benefits such as decreased adverse effects to justify the use of noninferiority hypotheses,” they wrote.

As far as improving FDA’s guidance documents moving forward, the researchers sought to discourage the use of surrogate endpoints in acute and non-life-threatening diseases “when symptoms, patient function, and survival can be directly measured and are common outcomes in a short period.”

They also recommended that FDA reexamine the use of surrogate measures in trials of infectious disease products designed with noninferiority hypotheses. And they called on FDA to use citations when recommending surrogates as their analysis found that only seven of the 21 guidance documents suggesting surrogates provided specific citations to evidence supporting the validity of the surrogate.

“Our analysis suggests that FDA guidance documents relating to infectious diseases may be recommending the use of surrogate outcomes in ways that are inconsistent with expert norms. There is therefore a need to reconsider and update these guidance documents to ensure that they recommend appropriate use of more direct measures of how patients feel, function, and survive in clinical trials of new anti-infective drugs,” they wrote.

JAMA Internal Medicine


© 2021 Regulatory Affairs Professionals Society.

Regulatory Focus newsletters

All the biggest regulatory news and happenings.