Talon38 Saturday, 12/01/18 02:32:52 PM Re: nidan7500 post# 173439 Post # of 243613 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! --------- 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.