Anavex Life Sciences Corp (AVXL)

[hnbadger1]

Interesting details on the new FDA AD guidance-

IV. OUTCOME MEASURES
Both clinical outcome assessments and biomarkers* should be included in clinical trials enrolling subjects with AD Stages 1-3; however, the approval pathway may differ based on the selection of the primary endpoint and its ability to measure a clinically meaningful change. Direct measures of clinical benefit or validated surrogate endpoints may support a traditional approval.' Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical benefit but that are considered reasonably likely to predict clinical benefit may support an accelerated approval® (see section IV. C.). Under the accelerated approval pathway, postapproval trials have been required to verify and describe clinical benefit.
A.
Clinical Endpoints
Historically, studies to support approval for drugs in the overt dementia stages of AD (Stages 4 through 6) have used an approach which required the assessment of both cognitive and functional (or global) measures as co-primary endpoints. The co-primary endpoint approach was used, in part, because the cognitive assessments used in the studies were not considered inherently clinically meaningful. Conventional approaches to assessing the cognitive deficits of AD use highly sensitive formalized measures of neuropsychological performance directed at particular domains that are capable of discriminating small changes in cognitive measures that may be of uncertain clinical meaningfulness when assessed alone. This approach was typically used in the setting of a therapy intended to treat disease symptoms in later stages of AD (i.e., Stages 4 through 6) and was intended to ensure that a change on a cognitive assessment was accompanied by an observed functional benefit, and alternately, that any observed functional
4 For definitions of clinical outcome assessments and biomarkers, refer to the BEST (Biomarker, 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Draft — Not for Implementation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.
Contains Nonbinding Recommendations
Draft — Not for Implementation
B.
Time-to-Event Analysis
The use of a time-to-event analysis approach (e.g., time to the occurrence of a clinically
development.
C.
Surrogate Endpoints
Clinical trials showing an effect on a surrogate endpoint that is determined to be "reasonably likely to predict clinical benefit" can be the basis for accelerated approval,' including for drugs intended for the treatment of AD. For example, in certain circumstances, FDA has considered a reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a surrogate endpoint that is "reasonably likely to predict clinical benefit." That endpoint, in clinical trials that enrolled participants with Stage 3 and 4 AD, has thus been used as a basis for accelerated approval for monoclonal antibodies directed against aggregated forms of amyloid beta, with postapproval trials required to verify and describe clinical benefit.
The acceptability of a surrogate endpoint for use in a particular therapeutic development program for early AD may depend on the stage of disease, population enrolled in trials, therapeutic mechanism of action, and availability of current treatments. A surrogate endpoint that is determined to be appropriate for use in a particular therapeutic clinical development program should not be assumed to be appropriate for use with a different product or trial population.
Sponsors considering the use of a biomarker as the primary measure of effect should discuss their plans with FDA early in development. In general, even if accelerated approval is considered as the initial approval pathway, clinical outcome assessments should be included in clinical trials for early AD to assess early clinical changes that may potentially provide support for any changes observed on biomarkers. Evolution of the scientific understanding of AD may also influence these considerations.
FDA strongly supports and encourages continued research in understanding the role of biomarkers in AD and stresses the potential importance of biomarkers in the successful development of effective treatments appropriate for use in the earliest stages of AD.
Precompetitive structured sharing across the AD scientific community of rigorously collected standardized data is a crucial component of this research.