FDA finalizes multiple endpoints guidance

Regulatory NewsRegulatory News | 20 October 2022 |  By 

The US Food and Drug Administration’s (FDA) on Thursday finalized guidance to sponsors on managing multiple endpoints in clinical trials to minimize the likelihood of making false conclusions of a drug’s effects.
“Most clinical trials performed in drug development contain multiple endpoints to assess the effects of the drug and to document the ability of the drug to favorably affect one or more disease characteristics. As the number of endpoints analyzed in a single trial increase, 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,” the agency said.
The final version makes several changes, including the addition of language discussing the differences and the relationship between primary, secondary and exploratory endpoints. In addition, FDA said editorial changes were made to “improve clarity by reducing redundancies in the text.”
Commenters on the January 2017 draft had sought additional revisions to the guidance. (RELATED: Multiple Endpoints in Clinical Trials: Biopharma Companies Seek More From FDA Draft Guidance, Regulatory Focus 16 March 2017)
Final guidance offers clarity on different endpoints
At the request of industry, the final guidance provides more detail on the differences between secondary and exploratory endpoints, as well as greater clarity on interpreting the endpoints in the primary and secondary endpoint families.
It states that “when an effect on the primary endpoint is shown, the secondary endpoints can be formally tested. A secondary endpoint could be a clinical effect related to the primary endpoint that extends the understanding of that effect (e.g., an effect on survival when a cardiovascular drug has shown an effect on the primary endpoint of heart failure-related hospitalizations) or provide evidence of a clinical benefit distinct from the effect shown by the primary endpoint (e.g., a disability endpoint in a multiple sclerosis treatment trial in which relapse rate is the primary endpoint).”
It further adds that “exploratory endpoints do not need multiplicity adjustment because they are generally not used to support conclusions.”
Novartis and Boehringer Ingelheim had requested such clarity on the distinctions between secondary and exploratory endpoints.
At the request of Novo Nordisk, the final guidance incorporates a reference to the International Council for Harmonization’s (ICH) E9(R1) guideline on estimands and how these fit into primary and secondary endpoint families. The ICH guideline was issued in January 2022. (RELATED: ICH guide provides clarity on estimands, sensitivity analyses, Regulatory Focus 31 January 2022)
The final guidance states that “the issues of multiplicity and methods that apply to multiple endpoints also generally apply to other sources of multiplicity, including other estimand attributes (e.g., multiple doses, time points, or study population subgroups); however, these other sources of multiplicity will not be specifically addressed in this guidance.”
Estimands are defined as a “precise description of the treatment effect reflecting the clinical questions posed by a given trial objective [and] summarizes at a population level what the outcomes would be in these same patents under different treatment conditions being compared.”
Also, the appendix has been expanded to include a section on statistical methods, which was previously included in the body of the draft guidance. This change was made at the request of Merck.
FDA final guidance


© 2023 Regulatory Affairs Professionals Society.

Discover more of what matters to you