Approvals Based on Surrogate Markers: Research Raises Questions

Regulatory NewsRegulatory News | 21 March 2018 |  By 

New research published in BMC Medicine on Wednesday highlights the potential problems in estimating the magnitude of a treatment’s effect for approvals based on surrogate markers of a disease.

The study, written by researchers from Yale University, the University of Exeter Medical School and the Department of Surgery at Boston’s Beth Israel Deaconess Medical Center, sought to compare the treatment effects in pivotal trials supporting US Food and Drug Administration (FDA) approval of novel drugs based on surrogate markers with effects observed among postapproval trials for the same indication.

The authors noted that many postmarketing trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection.

Joshua Wallach, the first author of the article and a research associate at Yale, explained to Focus: "I believe that one of most surprising findings was that we were often unable to locate trials conducted after drug approval that evaluated the same drug for the same uses (indications) with either the same surrogate markers as trials used to support FDA approval or appropriate patient-relevant endpoints. After drugs are approved based on surrogate markers as primary outcomes, additional trials should be conducted to confirm long term safety and efficacy."

The article also noted that an FDA advisory committee may be necessary to examine why the same surrogate markers for the same drugs "do not always replicate exactly in postapproval studies.

“Requirements for postapproval trials should also be enhanced to strengthen the lifecyle evaluation. In particular, investigators should conduct postapproval studies that have adequate sample sizes, study durations, and design characteristics, including endpoints, to allow comparison to pivotal trials.”

The research follows another study from last May, co-authored by two of the co-authors on this latest study, which urged FDA to take a cautious approach in increasing its reliance on surrogate markers. 

More information on the use of surrogate endpoints is expected from FDA, as the 21st Century Cures Act requires the agency to make publicly available on its website (on at least a biannual basis) all surrogate endpoints which were the basis of approval or licensure of a drug or biologic.

Results and Conclusion

Between 2005 and 2012, the researchers found that FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches.

“For nine (75%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials,” the study found. “On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials.”

And for 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials, they found, though on average, there was no difference in treatment effects between pivotal and postapproval trials.

In explaining the results, the authors said the findings “highlight the potential problem in the estimation of the magnitude of treatment effects of drugs that are approved based on surrogate markers of disease. Furthermore, we found that many postapproval drug trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection.”

But the researchers also said they did not understand why there were differences between continuous and non-continuous surrogate markers.

“New proposals for increased reliance on smaller and shorter trials with surrogate markers carry the risk of demonstrating larger, and potentially exaggerated, treatment effects, which may ultimately lack reproducibility or generalizability” the authors wrote in the conclusion. “Policymakers, doctors, and patients should interpret treatment effects based on surrogate markers of disease as primary endpoints with caution, and in the absence of clinical outcomes, regulators and payers should focus on those surrogate markers that have been validated.”

Wallach added to Focus: "We hope that our work leads to a larger discussion about why surrogate markers for the same drugs do not always replicate exactly in trials conducted after drugs are approved and how often such failures to replicate should occur. Furthermore, there may be opportunities for the FDA and drug sponsors to strengthen postmarket clinical evidence generation, in particular for drugs approved on the basis of surrogate markers."



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