Today, the FDA finalized its guidance for industry "Multiple Endpoints in Clinical Trials". The draft version of this guidance was issued in 2017. The guidance is intended to help sponsors better understand FDA's current thinking about the issues related to the multiple endpoints and multiplicity issues for multiple endpoints, and different approaches in handling multiplicity issues. The guidance also discussed composite endpoints and multi-component endpoints.
Typically, an adequate and well-controlled study will include only one primary efficacy endpoint and then multiple secondary efficacy endpoints, and additional exploratory endpoints. Exploratory endpoints are those endpoints for research purposes or for new hypotheses generation and not for the purpose of the product label. Primary and secondary efficacy endpoints can potentially be included on the product label. However, the testing hierarchy and sound approach for multiplicity adjustment must be pre-specified. The Fixed-Sequence Method in the appendix of this guidance seems to be commonly used. With Fixed-Sequence Method, the secondary efficacy endpoints will be tested only if the primary efficacy endpoint is statistically significant. The secondary efficacy endpoints are ranked or ordered based on the importance of the endpoints and the likelihood of getting statistically significant results. The next secondary efficacy endpoint will be tested only if the previous secondary endpoint is statistically significant. The testing hierarchy will stop once the hypothesis test for one of the secondary endpoints is not statistically significant.
If the sponsor wants to include secondary endpoints in the product label, multiplicity adjustment for secondary endpoints must be included in the statistical analysis plan.
In the section discussing the co-primary endpoints, "When Demonstration of Treatment Effects on Two or More Distinct Endpoints Is Recommended to Establish Clinical Benefit (Co-Primary Endpoints)", the examples of clinical trials with co-primary endpoints included in the draft version of this guidance were removed from the final guidance. For example, the draft guidance mentioned the following example and the final guidance did not:
Presumably, this is due to the revised FDA guidance "Early Alzheimer's Disease: Developing Drugs for Treatment" and the availability of the integrated scale - Clinical Dementia Rating Sum of Boxes (CDR-SB) Score:
"An integrated scale that adequately and meaningfully assesses both daily function and cognitive effects in early AD patients is acceptable as a single primary efficacy outcome measure. "
"Common Statistical Methods for Addressing Multiple Endpoint-Related Multiplicity Problems" was included in the body of the guidance in the draft guidance and is now moved to the Appendix: Statistical Methods. The list of methods remains the same and includes the Bonferroni method; the Holm procedure; the Hochberg procedure; prospective alpha allocation scheme; the fixed-sequence method; resampling-based, multiple-testing procedures; gatekeeping testing strategies; and graphical approaches based on sequentially rejective tests.
As a regulatory agency, FDA is conservative and tries to avoid false conclusions. Without adequate adjustment for multiplicity, the alpha level (type I error rate) can be inflated, and statistically, significant differences may be wrongly declared for an ineffective drug. In the summary of this guidance, FDA concludes:
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