Table 2.6.
Staging system for AD proposed by the FDA with means of achieving full approval or accelerated approval of drugs developed for early AD (FDA Guidance [10])
| Stage 1 | Stage 2 | Stage 3 | Stage 4, 5, and 6 | |
|---|---|---|---|---|
| Biomarkers reflecting underlying AD pathophysiological changes | Positive | Positive | Positive | Positive |
| Cognition | Truly asymptomatic with no subjective complaint or detectable abnormalities on sensitive neuropsychological measures | Subtle detectable abnormalities on sensitive neuropsychological measures | Subtle or more apparent detectable abnormalities on sensitive neuropsychological measures | Mild, moderate, and severe AD dementia with worsening cognitive impairment |
| Function | No functional impairment | No functional impairment. The emergence of subtle functional impairment signals a transition to Stage 3 | Mild but detectable functional impairment. The functional impairment in this stage is not severe enough to warrant a diagnosis of overt dementia | Mild, moderate, and severe AD dementia with worsening functional impairment |
| Clinical endpoints | A clinically meaningful benefit 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) | 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. A large magnitude of effect on sensitive measures of neuropsychological performance may also increase their persuasiveness | Favorable effect on cognitive and functional deficits. 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 | Co-primary approach to assessment of cognitive and functional (or global) measures |
| Alternate approach to clinical endpoints | Conduct a study of sufficient duration to allow the evaluation of the measures indicated for Stage 2 patients | A possible approach is to conduct a study of sufficient duration to allow the evaluation of the measures discussed for Stage 3 patients | Not specified in the guidance | Not specified in the guidance |
| Biomarker endpoints | An effect on the characteristic pathophysiologic changes of AD. A pattern of treatment effects seen across multiple individual biomarker measures would increase the persuasiveness of the putative effect | Supported by similarly persuasive effects on the characteristic pathophysiologic changes of AD | Not specified in the guidance | Not specified in the guidance |
| Full approval | An effect on the characteristic pathophysiologic changes of AD when the fundamental understanding of AD evolves sufficiently to establish surrogacy (no AD biomarkers currently meet the criteria for surrogacy) | The cognitive effects were found to be inherently clinically meaningful, either on face or because they reliably and inevitably are associated with functional benefit later in the course of the disease | Not specified in the guidance | Not specified in the guidance |
| Accelerated approval | An effect on the characteristic pathophysiologic changes of AD analyzed as a primary efficacy measure, may, serve as the basis for an accelerated approval (i.e., the biomarker effects would be found to be reasonably likely to predict clinical benefit, with a post-approval requirement for a study to confirm the predicted clinical benefit) | The cognitive effects were found to be reasonably likely to predict clinical benefit, with a post-approval requirement for a study to confirm the predicted clinical benefit required | Not specified in the guidance | Not specified in the guidance |