Thx for this hnbadger1: It is gratifying to see that even the FDA will learn and adapt over time. CNS science will (must) prevail . IMO AVXL presents the best path for this process.
EndpointS, and Other Tools) Resource, available at https://www.ncbi.nlm.nih.gov/books/NBK338448. for serine distin sues and halogies May all, please see the guidance for industry Expedited Programs "Section 506(c)(I)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 356(c)(1)(A)). Contains Nonbinding Recommendations Draft — Not for Implementation benefit could be attributed to a benefit on cognition and was not attributable to changes in other conditions. This remains a generally acceptable approach for stages of AD with detectable cognitive and functional impairments (Stages 3 and higher). Using this approach, the typical duration of a clinical trial in the symptomatic stages of AD has been 2 years or less; however, FDA recognizes that it may take longer to establish a clinically meaningful treatment effect in early AD due to the minimal or absent cognitive and functional deficits seen in those stages of the disease. Additionally, many of the assessment tools typically used to measure functional impairment in patients with later dementia stages of AD (Stages 4 through 6) would not be sensitive to detect subtle functional changes in early AD. Therefore, FDA may consider other approaches, including endpoints based on cognitive assessments or surrogate endpoints, which may allow for shorter trial durations as a basis for approval in the earliest stages of AD (i.e., Stages 1, 2, and early 3). Cognition, in its entirety, encompassing all its constituent processes and domains, is essential for daily functioning. As previously noted, it can be challenging to interpret the clinical meaningfulness of small changes detected on sensitive neuropsychological tests; however, more marked cognitive changes may represent a change that is clearly clinically meaningful. It follows, in concept, that cognitive changes of a particular magnitude, or breadth of effects across multiple domains, or change in trajectory over time, may represent clinically meaningful change, independent of measures of functional change. In the setting of therapy that targets underlying disease pathophysiology, changes in the long-term course of core cognitive measures of AD relative to placebo may potentially provide evidence of clinically meaningful effect with respect to the clinical progression of the disease. It would generally be expected that such effects on cognitive measures would be supported by similarly persuasive effects on the characteristic pathophysiological changes of AD. In patients in the earliest clinical stages of AD (refer to section IV. D., Considerations for Specific Stages of Early AD), FDA will consider strong justifications that a persuasive effect, considering both magnitude of effect and statistical robustness of the findings, on cognition alone as assessed by sensitive neuropsychological tests may provide adequate support for a marketing approval. Given the array of available neuropsychological tests, a pattern of putatively beneficial effects demonstrated across multiple individual tests would increase the persuasiveness of the finding; conversely, a finding on a single test unsupported by consistent findings on other tests would be less persuasive. Whether effects on cognitive outcome measures would be capable of providing evidence of effectiveness in the absence of a meaningful change in function to support either traditional or accelerated approval would require detailed discussion with the Agency. However, in a trial with relatively short-term assessments, such as a trial for a therapy intended to treat symptoms of AD, an effect on sensitive measures of neuropsychological performance of uncertain independent clinical meaning (e.g., a word-list recall test) would generally not allow for an overall finding of efficacy in the absence of meaningful functional benefit.
