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160 IV. OUTCOME MEASURES 161 162 A. Clinical Endpoints for Early AD Trials in Stage 3 Patients 163 164 Early AD patients approaching the onset of overt dementia (Stage 3 patients) are likely to have 165 relatively mild but noticeable impairments in their daily functioning. Although studies in this 166 stage of disease will generally include sensitive measures of neuropsychological performance of 167 uncertain independent clinical meaningfulness, it is important to demonstrate that a drug 168 favorably affects these functional deficits. Many of the assessment tools typically used to 169 measure functional impairment in patients with overt dementia may not be suitable for use in 170 these early stage patients. Ideally, the outcome measure used in this stage of disease will provide 171 an assessment of meaningful cognitive function. An integrated scale that adequately and 172 meaningfully assesses both daily function and cognitive effects in early AD patients is 173 acceptable as a single primary efficacy outcome measure. Contains Nonbinding Recommendations Draft — Not for Implementation 5 174 175 FDA encourages the development of novel approaches to the integrated evaluation of subtle 176 early AD (predementia) functional deficits/impact that arise from early cognitive impairment 177 (e.g., facility with financial transactions, adequacy of social conversation). The independent 178 assessment of daily function and cognitive effects is also an acceptable approach. In this setting, 179 an effect on a sensitive measure of neuropsychological performance of uncertain independent 180 clinical meaning (e.g., a word-list recall test) should not allow for an overall finding of efficacy 181 in the absence of meaningful functional benefit. For drugs with the potential to lead to 182 measurable functional benefit without a corresponding cognitive benefit, assessment of an 183 independent cognitive endpoint is important. 184 185 B. Clinical Endpoints for Early AD Trials in Stage 2 Patients 186 187 In patients in the earliest clinical stages of AD (Stage 2 patients), where only subtle cognitive 188 deficits detected on sensitive measures of neuropsychological performance are present, and there 189 is no evidence of functional impairment, it may be difficult to establish a clinically meaningful 190 effect on those subtle cognitive deficits during the course of a trial of reasonable duration. 191 Nonetheless, a possible approach is to conduct a study of sufficient duration to allow the 192 evaluation of the measures discussed above for Stage 3 patients. As patients transition to Stage 3 193 during participation in the trial, the principles applicable to outcome assessment for Stage 3 194 would apply. 195 196 Alternatively, and in view of the rapidly and continually expanding body of knowledge 197 concerning AD, FDA will consider strongly justified arguments that a persuasive effect on 198 sensitive measures of neuropsychological performance may provide adequate support for a 199 marketing approval. Given the panoply of available neuropsychological tests, a pattern of 200 putatively beneficial effects demonstrated across multiple individual tests would increase the 201 persuasiveness of the finding; conversely, a finding on a single test unsupported by consistent 202 findings on other tests would be less persuasive. A large magnitude of effect on sensitive 203 measures of neuropsychological performance may also increase their persuasiveness. It would 204 generally be expected that such arguments would be supported by similarly persuasive effects on 205 the characteristic pathophysiologic changes of AD, as discussed below for Stage 1 patients. 206 207 Importantly, such arguments should be predicated on the certainty of diagnosis of enrolled 208 patients, the certainty of their future clinical course, and the certainty of the relationship of the 209 observed effects on sensitive measures of neuropsychological performance and characteristic 210 pathophysiologic changes to the evolution of more severe cognitive deficits and functional 211 impairment. Whether such arguments, if convincing, would support full approval (i.e., the 212 cognitive effects were found to be inherently clinically meaningful, either on face or because 213 they reliably and inevitably are associated with functional benefit later in the course of the 214 disease) or accelerated approval (i.e., the cognitive effects were found to be reasonably likely to 215 predict clinical benefit, with a post-approval requirement for a study to confirm the predicted 216 clinical benefit) would be a matter of detailed consideration. Sponsors considering these issues 217 should discuss their plans with FDA early in development. Evolution of the scientific 218 understanding of AD may also influence these considerations. 219 Contains Nonbinding Recommendations Draft — Not for Implementation 6 220 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. 252 253 D. Time-to-Event Analysis 254 255 The use of a time-to-event survival analysis approach (e.g., time to the occurrence of a clinically 256 meaningful event during the progressive course of AD, such as the occurrence of some degree of 257 meaningful impairment of daily function) would be an acceptable primary efficacy measure in 258 clinical trials in early AD. Sponsors considering such an approach should discuss their plans 259 with FDA early in development. 260 261 E. Assessment of Disease Course 262 263 Although the demonstration of a substantial clinically meaningful treatment effect of any sort is 264 of paramount importance, this may not be feasible in a clinical trial of reasonable duration, 265 especially very early in the course of the disease, and clinical trials in early stage disease will Contains Nonbinding Recommendations Draft — Not for Implementation 7 266 usually be intended to provide evidence that a drug has permanently altered the course of AD 267 through a direct effect on the underlying disease pathophysiology, an effect that persists in the 268 absence of continued exposure to the drug. 269 270 A randomized-start or randomized-withdrawal trial design (with clinical outcome measures) is 271 the most convincing approach to demonstrating a persistent effect on disease course. Generally, 272 a randomized-start design would be most appropriate for use in AD. In this study design, 273 patients are randomized to drug and placebo, and at some point, placebo patients are crossed 274 over to active treatment. If patients in the trial who were initially on placebo and then assigned 275 to active treatment fail to catch up (after a reasonable period of time) to patients who received 276 active treatment for the entire duration of the trial, a persistent treatment effect on disease course 277 would have been shown. 278 279 Assessment of various biomarkers may provide supportive evidence for a drug that has an 280 established clinically meaningful benefit, but the effects on biomarkers in AD are not sufficiently 281 well understood to provide evidence of a persistent effect on disease course. 282 283 Currently, there is no consensus as to particular biomarkers that would be appropriate to support 284 clinical findings in trials in early AD. For this reason, sponsors at present have insufficient 285 information on which to base a hierarchical structuring of a series of biomarkers as secondary 286 outcome measures in their trial designs. Sponsors are therefore encouraged to analyze the results 287 of these biomarkers independently, though in a prespecified fashion, with the understanding that 288 these findings will be interpreted in the context of the state of the scientific evidence at the time 289 of a future marketing application. 288 these findings will be interpreted in the context of the state of the scientific evidence at the time 289 of a future marketing application.
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