Endpoints selection in registration clinical trials and the needs of real-world clinical practice with the example of anti-VEGF therapy in neovascular age-related macular degeneration

Abstract

The issues of endpoints selection for regulatory requirements and real-world clinical practice using the example of anti-VEGF therapy in neovascular age-related macular degeneration (nAMD) are discussed in the article. New technologies (optical coherent tomography) introduction are shown to change clinical practice but not regulatory requirements on the endpoints. In the same time for regulatory purpose clinical trials design is changed from superiority to non-inferiority. The changes in the approach to primary endpoint selection are not anticipated due to regulators conservatism but there is a requirement to the comparison with best treatment alternative (i.e. same class comparator in case of anti-VEGF therapy) due to ethical reasons. To satisfy real-world clinicians need, the secondary endpoints are analyzed, but multiple testing problem appears. Statistical methods developed in recent years allow using specified comparison to be made without inflating Type I error. HAWK and HARRIER clinical trials demonstrated an example how superiority of brolucizumab over aflibercet on anatomical endpoints was reliably found.