Study Finds Extent of Unvalidated Surrogate Endpoint Use in Expedited Approvals ‘Concerning’

Regulatory NewsRegulatory News | 11 September 2019 |  By 

Research published this week in PLOS Medicine raises concerns about the use of surrogate endpoints to support the marketing authorizations of products assessed via the European Medicines Agency’s (EMA) conditional marketing authorisation (CMA) and accelerated assessment (AA) pathways.

The use of the CMA and AA pathways, which is restricted to situations of “unmet medical need” and/or “in the interests of public health,” are often based on incomplete benefit-risk assessment data and may have post-authorization conditions or restrictions to ensure the products live up to early data.

The study evaluated 33 pivotal trials for CMA and 58 trials for products using the AA pathway between January 2011 and December 2018, with the researchers finding that most of the marketing authorizations were based on pivotal trials that reported unvalidated surrogate endpoints.

“While it was unsurprising that none of the products granted CMA were authorised on the basis of clinical outcomes, it was astonishing that just 20% of the products granted AA were supported by pivotal trials reporting clinical outcomes,” the UK-based researchers write.

They also explain how the “extensive use” of unvalidated surrogate endpoints in these pathways “is concerning because the likelihood that treatment will provide the intended clinical benefit is unknown. In the current study, it was not clear from the publicly available information about the products whether surrogate endpoints were validated or nonvalidated. Neither was it clear whether postauthorisation measures—when they were required—would confirm clinical benefits.”

They also made the case that marketing authorization holders using these two pathways should ultimately be required to demonstrate that they fulfill these goals in confirming clinical benefits.

“If surrogate endpoints have supported the authorisation, then postauthorisation measures to be completed in a reasonable time frame are needed, including for rare disease treatments, to confirm that the clinical outcomes are achieved. When such measures fail to confirm clinical benefit, then—as in the case of olaratumab—the regulator should consider withdrawal of the marketing authorization,” they add.



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