Biopharmaceutical heavyweights – from Novartis to GlaxoSmithKline to Regeneron – are seeking additional clarification from the US Food and Drug Administration (FDA) on draft guidance on multiple endpoints in clinical trials, according to comments posted to the docket on Thursday.

Background

On 12 January, FDA issued a 54-page draft guidance to provide sponsors and review staff with the agency’s thinking on the problems posed by multiple endpoints in the analysis and interpretation of study results and how these problems can be managed in clinical trials for drugs and biologics.

“As the number of endpoints analyzed in a single trial increases, the likelihood of making false conclusions about a drug’s effects with respect to one or more of those endpoints becomes a concern if there is not appropriate adjustment for multiplicity,” FDA says. “The purpose of this guidance is to describe various strategies for grouping and ordering endpoints for analysis and applying some well-recognized statistical methods for managing multiplicity within a study in order to control the chance of making erroneous conclusions about a drug’s effects.”

The guidance also addresses the three families of endpoints – primary, secondary and exploratory – and cases when companies go back and try to find a positive result from a failed study.

Industry Comments

On Thursday, comments from industry group BIO, and biopharma companies Novartis, Takeda, Celgene, Teva Pharmaceuticals, Novo Nordisk, Merck, Alexion, AstraZeneca, GlaxoSmithKline and Vertex Pharmaceuticals all offered their takes on the draft.

BIO notes that the draft fails to address several points that it believes are worthy of attention, including multiplicity adjustments at the interim analysis and on safety endpoints when assessing safety signals, as well as a further “elucidation of the calculation methods to be used with the truncated Holm and truncated Hochberg procedures (e.g., for the truncated Hochberg example, the α passed to the next level); and basic principles, such as closed test or partition principles, which many of the multiple comparison methods in the guidance are based upon.

“While we understand that the guidance cannot cover every statistical method that could be relevant for multiple endpoints, we do believe it would be helpful if the guidance provided some information about the criteria used to decide which methods to include,” BIO adds.

Novartis, meanwhile, says the draft guidance’s distinction between secondary and exploratory endpoints “remains unclear” and the company suggests that FDA elaborate more on this distinction by considering, for example, clinical importance and regulatory actions like additional labeling claims or descriptive statements in a package insert.
Considering the importance of safety data analyses, Regeneron calls on FDA to draft separate guidance on multiplicity issues with safety evaluations of controlled trials.

And GlaxoSmithKline asks if FDA could provide “further discussion about the issue of multiplicity in studies not intended to demonstrate effectiveness and support drug approval and some of the methods that are more applicable for these studies (i.e. multivariate inferential methods, Bayesian methods, etc.).”

Alexion also calls for FDA to add a section to the guidance on rare diseases and small population trials.

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