The use of surrogate markers was observed for breakthrough-designated indications that were approved through both traditional pathways and accelerated pathways.
Essential trials supporting the approvals of FDA breakthrough therapy-designated drugs often used surrogate markers as primary end points—even when not approved through the accelerated approval pathway—and often lacked post-marketing studies to confirm a drug’s clinical benefit, according to the results of a study published in the Journal of the American medical Association.1
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These findings could lead to uncertainties and confusion for both clinicians and patients surrounding the use of breakthrough therapy-designated drugs and suggest that the requiring of post-marketing studies—regardless of approval pathway—could heighten certainty that key stakeholders have in the expected clinical benefit.1
Contrastingly with clinical outcomes, which measures drug efficacy based on how patients feel, function, or survive, surrogate markers—such as laboratory measurements or imaging findings—serve as a proxy instead of directly measuring clinical outcomes, and are considered predictive of a drug’s clinical benefits.1
The FDA allows for the use of surrogate markers as primary end points in trials supporting approval for drugs that address serious diseases. However, they can also be used in pivotal trials for drugs approved outside of accelerated approval; previous studies have raised questions around the association between surrogate markers and the clinical outcomes they predict.1
These previously conducted studies cover multiple indications. For example, Wallach et al. examined the associations between surrogate markers and clinical outcomes for non-oncologic chronic disease treatments in a meta-analysis. They found that many of these surrogate markers “lacked high-strength evidence of associations with clinical outcomes.”2
Furthermore, a study conducted by Prasad et al. specifically analyzed this phenomenon in oncology through a systematic review of trial-level meta-analyses. In their analysis, they included 36 articles in which 65 specific correlations between a surrogate end point and survival were identified.3
Most of these surrogate end points had low correlations with survival, with the investigators deeming the evidence supporting the use of surrogate end points in oncology as “limited.” Accordingly, the investigators of the current study sought to evaluate the primary end points used in clinical trials for all FDA breakthrough therapy-designated approvals and determining whether the FDA requested further studies to confirm clinical efficacy for these drugs.1,3
1. Surrogate markers have been used as primary efficacy end points in dozens of pivotal trials for FDA breakthrough designation therapy indications.
2. Observations were made for indications using both the traditional approval pathway and the accelerated approval pathway.
3. Especially for traditionally-approved drugs, many instances of the FDA not requiring post-marketing confirmation studies were seen.
Of the 157 FDA-approved indications with a breakthrough therapy designation, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All 52 accelerated approval drugs utilized surrogate markers as primary end points, and the FDA required post-marketing studies to confirm drug efficacy.1
The status of these 52 required studies follows: 6 (12%) were released; 26 (50%) were fulfilled; 1 (2%) was submitted; 5 (10%) were delayed; 7 (13%) were ongoing, and 7 (13%) were pending. For the 26 that fulfilled requirements, the median duration from approval to fulfillment was 27.6 months.1
Shifting attention to indications with traditional approval, 44 (42%) were approved based on pivotal trials that used at least 1 clinical outcome as a primary end point, while 61 (58%) were approved based on trials that only used surrogate markers. Of the studies that used surrogate markers, only 4 (7%) had FDA-required post-marketing studies to confirm efficacy.1
Overall, two-thirds of FDA breakthrough therapy-designated approvals between 2013 and 2023 were based on trials that used surrogate markers as efficacy end points. The investigators discussed the underlying uncertainty these results suggest for patients and clinicians alike.1
Wallach et al. and Prasad et al. each have previously pointed out the concerns around the little correlation between surrogate markers and clinical outcomes, and the FDA has acknowledged these concerns. As the investigators of the current study write, certain treatments that have demonstrated a clinical benefit for a certain indication could be ineffective or harmful for others due to potential effects from surrogate markers.1-3
“Requiring post-marketing requirements for breakthrough therapy–designated indications approved based on surrogate markers, regardless of approval pathway, would ensure that clinical benefits are confirmed,” the study authors concluded.1
