TABLE 1.

FDA 2018 Draft guidance recommendations on clinical outcome assessments (COAs) by clinical stage of Alzheimer’s disease.⁴

Stage	Description	Diagnostic label	Recommendations on COAs as described in FDA 2018 draft guidance
1	Patients with characteristic pathophysiologic changes of AD but no evidence of clinical impact.	Preclinical AD	- A clinically meaningful benefit in cognition cannot be measured in these patients because there is no clinical impairment to assess (assuming that the duration of a trial is not sufficient to observe and assess the development of clinical impairment during the conduct of the trial). - An effect on the characteristic pathophysiologic changes of AD, as demonstrated by an effect on various biomarkers, analyzed asa primary efficacy measure, may, in principle, serve as the basis for an accelerated approval - As with the use of neuropsychological tests, a pattern of treatment effects seen across multiple individual biomarker measures would increase the persuasiveness of the putative effect.
2	Patients with characteristic pathophysiologic changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment.	Preclinical AD	- A possible approach is to conduct a study of sufficient duration to allow the evaluation of the measures discussed below for Stage 3 patients - Alternatively, FDA will consider strongly justified arguments that a persuasive effect on sensitive measures of neuropsychological performance may provide adequate support for a marketing approval. - 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
3	Patients with characteristic pathophysiologic changes of AD, subtle or more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment.	Prodromal AD/MCI due to AD	- Ideally, the outcome measure used in this stage of disease will provide an assessment of meaningful cognitive function. - An integrated scale that adequately and meaningfully assesses both daily function and cognitive effects is acceptable as a single primary efficacy outcome measure. - The independent assessment of daily function and cognitive effects is also an acceptable approach. In this setting, effect on a sensitive measure of neuropsychological performance of uncertain independent clinical meaning (e.g., a word-list recall test) should not allow for an overall finding of efficacy in the absence of meaningful functional benefit.

Abbreviations: AD, Alzheimer’s disease; COAs, clinical outcome assessments; FDA, Food and Drug Administration.