Nidan....this is a very important FDA Guidance Document on AD and should be in the final phase of publication given the Feb 2018 call for review (90 limit on comments). It is critical for us as we begin our P3 trial on Pre/Early AD. The FDA realizes the difficulty of identifying Stage 1 AD and the ability to demonstrate drug efficacy in this Stage, That is why having conducted our P2 in Stage 2/3 patients and having the thorough Ariana analysis into the important biomarkers and genomic identifiers is absolutely necessary for our success in this Stage 1 AD Trial. I might say that was excellent planning by Anavex, wouldn't you say!
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From the new AD Regulatory Guidance:
"C. Endpoints for Early AD Trials in Stage 1 Patients 221
222 Because it is highly desirable to intervene as early as possible in AD, it follows that patients with
223 characteristic pathophysiologic changes of AD but no subjective complaint, functional
224 impairment, or detectable abnormalities on sensitive neuropsychological measures (Stage 1
225 patients) are an important target for clinical trials. A clinically meaningful benefit cannot be
226 measured in these patients because there is no clinical impairment to assess (assuming that the
227 duration of a trial is not sufficient to observe and assess the development of clinical impairment
228 during the conduct of the trial). In Stage 1 patients, an effect on the characteristic
229 pathophysiologic changes of AD, as demonstrated by an effect on various biomarkers, may be
230 measured. Such an effect, analyzed as a primary efficacy measure, may, in principle, serve as
231 the basis for an accelerated approval (i.e., the biomarker effects would be found to be reasonably
232 likely to predict clinical benefit, with a post-approval requirement for a study to confirm the
233 predicted clinical benefit). As with the use of neuropsychological tests, a pattern of treatment
234 effects seen across multiple individual biomarker measures would increase the persuasiveness of
235 the putative effect.
236
237 Although the issues and approaches discussed above for Stage 2 patients are relevant for Stage 1
238 patients, there is unfortunately at present no sufficiently reliable evidence that any observed
239 treatment effect on such biomarker measures would be reasonably likely to predict clinical
240 benefit (the standard for accelerated approval), despite a great deal of research interest in
241 understanding the role of biomarkers in AD. FDA strongly supports and encourages continued
242 research in this area and stresses its potential importance in the successful development of
243 effective treatments appropriate for use in the earliest stages of AD. Precompetitive structured
244 sharing across the AD scientific community of rigorously collected standardized data is a crucial
245 component of this research. While research pursues the development of evidence sufficient to
246 support the use of biomarker measures as the primary evidence supporting an accelerated
247 approval, or perhaps a full approval if the fundamental understanding of AD evolves sufficiently
248 to establish surrogacy, a possible approach to Stage 1 patients might be to conduct a study of
249 sufficient duration to allow the evaluation of the measures discussed above for Stage 2 patients.
250 As patients transition to Stage 2 during participation in the trial, the principles applicable to
251 outcome assessment for Stage 2 would apply.
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