Bruce et al. recently published a paper (PLOS Medicine, 2019) that provides a trend on the use of surrogate biomarkers to evaluate clinical benefits. The study primarily reviewed European Public Assessment Reports (EPARs) to identify the use of surrogate biomarkers for the primary endpoint. The Following are the excerpts and the result summary from the study:
Journal: PLOS Medicine
Abstract
BACKGROUND:
In situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorization (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorization recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorization remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and post-authorization measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorized through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.
METHODS AND FINDINGS:
We used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorized through CMA or AA pathways during January 1, 2011, to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomized controlled trials supporting the surrogate-clinical outcome relationship were rated as 'validated'. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorized based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being 'reasonably likely' (n = 30; 61%) or of having 'biological plausibility' (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorizations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalizable to products authorized through the standard assessment pathway.
CONCLUSIONS:
The pivotal trial evidence supporting marketing authorizations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorizations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, post-authorization measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorization holders.
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