Early Alzheimers 
Disease:  Developing 
Drugs for Treatment  
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Office of Communications, 
Division of Drug Information at 855-543-3784 or 301-796-3400 or (CBER) Office of 
Communication, Outreach, and Development at 800-835-4709 or 240-402-8010.  
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
March 2024 
Clinical/Medical 
Revision 2 
21115964dft.docx 
03/05/24   
Early Alzheimers 
Disease:  Developing 
Drugs for Treatment  
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD  20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
and/or 
 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
February 2024 
Clinical/Medical 
Revision 2 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DIAGNOSTIC CRITERIA FOR EARLY AD ............................................................... 2 
IV.  OUTCOME MEASURES ................................................................................................ 4 
A.  Clinical Endpoints .......................................................................................................................... 4 
B.  Time-to-Event Analysis ................................................................................................................. 6 
C.  Surrogate Endpoints ...................................................................................................................... 6 
D.  Considerations for Specific Stages of Early AD .......................................................................... 6 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Early Alzheimers Disease:  Developing Drugs for Treatment  
2  Guidance for Industry1 
3   
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person 
8  and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the 
9  requirements of the applicable statutes and regulations.  To discuss an alternative approach, 
10  contact the FDA staff responsible for this guidance as listed on the title page. 
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
17  treatment of the stages of sporadic Alzheimers disease (AD) that occur before the onset of overt 
18  dementia (i.e., Stages 1 through 3; discussed in section III).  These stages are collectively 
19  referred to as early AD in this guidance; however, it is recognized that AD occurs on a 
20  continuum and patients in the last stage of early AD (i.e., late Stage 3) and patients with AD in 
21  the earliest stages of overt dementia (i.e., early Stage 4) may not differ significantly in clinical 
22  presentation.  This guidance is intended to serve as a focus for continued discussions among 
23  representatives of the Office of Neuroscience in the Center for Drug Evaluation and Research or 
24  the Office of Therapeutic Products in the Center for Biologics Evaluation and Research, as 
25  appropriate, pharmaceutical sponsors, the scientific community, and the public about the 
26  development of drugs for the treatment of early AD.2   
27   
28  This guidance revises the draft guidance for industry Early Alzheimers Disease:  Developing 
29  Drugs for Treatment (February 2018).  This revision, when finalized, will represent FDAs 
30  current thinking regarding the selection of subjects with early AD for enrollment in clinical trials 
31  and the selection of endpoints for clinical trials in this population.3 
32   
33  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
34  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
35  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
36  the word should in Agency guidances means that something is suggested or recommended, but 
37  not required.  
 
1 This guidance has been prepared by the Office of Neuroscience in the Center for Drug Evaluation and Research in 
cooperation with the Center for Biologics Evaluation and Research at the Food and Drug Administration (FDA). 
 
2 In addition to consulting guidances, sponsors are encouraged to contact the Office of Neuroscience or the Office of 
Therapeutic Products to discuss specific issues that arise during the development of drugs to treat early AD. 
 
3 For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38   
39   
40  II.  BACKGROUND 
41   
42  Historically, clinical criteria that defined later stages of AD, after the onset of overt dementia, 
43  were used for enrollment in clinical trials.  Accordingly, subjects included in these trials 
44  exhibited both the cognitive changes typical of clinically evident AD and the degree of 
45  functional impairment associated with overt dementia.  Drugs that were approved for dementia 
46  during that time were evaluated in that context.   
47   
48  As the scientific understanding of AD has evolved, efforts have been made to incorporate in 
49  clinical trials the use of biomarkers reflecting underlying AD pathophysiological changes and the 
50  enrollment of subjects with AD at earlier stages of the disease, in which there may be minimal or 
51  no detectable abnormality on clinical assessments.  These efforts are particularly important 
52  because there may be an opportunity to intervene very early in the disease process of AD, given 
53  the slowly progressive course of AD and the development of characteristic pathophysiological 
54  changes that greatly precede the development of clinically evident findings.  Delaying or, 
55  preferably, halting or reversing the pathophysiological process that will lead to the initial clinical 
56  deficits of AD is the ultimate goal of presymptomatic or very early symptomatic intervention, 
57  and treatment directed at this goal must begin before there are overt clinical symptoms.  This 
58  opportunity carries with it the need to understand ways to assess treatment benefit in these earlier 
59  stages of disease. 
60   
61  This document provides an overview on the Agencys current thinking on diagnostic criteria and 
62  clinical staging of AD to inform enrollment in clinical trials and the selection of appropriate 
63  endpoints for the stage(s) of disease proposed to be enrolled in a clinical trial.  The design of 
64  clinical trials that are specifically focused on the treatment of patients with AD who have 
65  developed overt dementia (i.e., Stages 4 through 6; discussed in section III), or any of the 
66  autosomal dominant forms of AD, is not discussed, although some of the principles in this 
67  guidance may be pertinent.  This guidance does not discuss treatment of dementias other than 
68  AD.  
69   
70   
71  III.  DIAGNOSTIC CRITERIA FOR EARLY AD 
72   
73  Eligibility for enrollment in trials intended to support an application for approval for treatment of 
74  early AD should be based on current consensus diagnostic criteria intended to establish the true 
75  biological presence of AD rather than criteria based on syndromic or other definitions; this 
76  approach is intended to avoid enrollment of a substantial number of subjects who would not 
77  actually have AD.  
78   
79  FDA supports the use of biologically based diagnostic criteria that are grounded in a 
80  contemporary understanding of the pathophysiology and evolution of AD.  The characteristic 
81  pathophysiological changes of AD precede, often by many years or even decades, the 
82  development of clinically evident findings and progress as a continuous disease process that can 
83  be categorized into stages.  Those stages are defined below, initially only by those 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
84  pathophysiological changes and then by the development of subtle clinical abnormalities, 
85  detectable using sensitive neuropsychological measures.  These initial clinical findings are 
86  followed by the development of more apparent cognitive abnormalities, accompanied by initially 
87  mild and then more severe or more extensive functional impairment.  Based on knowledge 
88  gained from previous clinical trials and the evolving understanding of the pathophysiology of 
89  AD, there is an increased focus on evaluating drug treatments for AD in the earliest stages of the 
90  disease.  Diagnostic criteria that reliably define a population with early AD, including the earliest 
91  stages characterized only by pathophysiological changes, are suited to the evaluation of drugs 
92  intended to delay or prevent the emergence of overt symptoms.  
93   
94  Important findings applicable to the categorization of AD along its continuum of progression 
95  include the presence of pathophysiological changes as measured by biomarkers, the presence or 
96  absence of detectable abnormalities on sensitive neuropsychological measures, and cognitive 
97  symptoms reported by patients or observers with the presence or absence of functional 
98  impairment manifested as meaningful impact on daily activities.  Although FDA recognizes that 
99  variations in the selection and application of clinical characteristics and biomarkers may lead to 
100  the enrollment of subjects in clinical trials who are at slightly different stages of a progressive 
101  disease process, the following categories are conceptually useful for the design and evaluation of 
102  clinical trials in different stages of AD: 
103   
104    Stage 1:  Patients with characteristic pathophysiological changes of AD but no 
105  evidence of clinical impact.  These patients are truly asymptomatic with no subjective 
106  complaint, functional impairment, or detectable abnormalities on sensitive 
107  neuropsychological measures.  The characteristic pathophysiological changes are 
108  typically demonstrated by assessment of various biomarker measures. 
109   
110    Stage 2:  Patients with characteristic pathophysiological changes of AD and subtle 
111  detectable abnormalities on sensitive neuropsychological measures or subjective 
112  complaints of mild cognitive symptoms but no functional impairment.  This may be 
113  considered a transitional stage in which slight cognitive symptoms first appear.  The 
114  emergence of subtle functional impairment signals a transition to Stage 3. 
115   
116    Stage 3:  Patients with characteristic pathophysiological changes of AD, generally 
117  more apparent detectable abnormalities on sensitive neuropsychological measures, 
118  and mild but detectable functional impairment.  The functional impairment in this 
119  stage is not severe enough to warrant a diagnosis of overt dementia.  This stage roughly 
120  corresponds with the syndrome of mild cognitive impairment; however, it is noted that 
121  the term mild cognitive impairment may also encompass patients in late Stage 2 or 
122  early Stage 4.  
123   
124    Stages 4, 5, and 6:  Patients with overt dementia, progressing through mild, 
125  moderate, and severe stages.  This diagnosis is made as functional impairment worsens 
126  from that seen in Stage 3.  A discussion of these three disease stages is not the focus of 
127  this guidance. 
128   
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
129  For study design, it is important to define the study population using these conceptual categories, 
130  even in the presence of a single continuous disease process, to allow and inform appropriate 
131  outcome measure selection.  In descriptions of studies, sponsors should identify both the stage of 
132  AD defined for study eligibility and enrollment and the stage of AD anticipated for the majority 
133  of the enrolled study population at the time of primary outcome assessment.  
134   
135  As discussed above, it is expected that biomarker evidence of disease will establish the reliable 
136  diagnosis of subjects in trials of early AD.  As copathology is common in AD, sponsors may 
137  consider including assessments of other copathologies in their clinical trials to inform exclusion 
138  criteria or for preplanned analyses of safety and efficacy in subgroups of the enrolled population.  
139  If biomarker evidence will be needed to adequately define the anticipated indicated population 
140  and an FDA-approved or cleared diagnostic test is not available, sponsors should engage early in 
141  development with the appropriate review division at FDA to discuss the potential need for the 
142  codevelopment of a companion diagnostic device. 
143   
144   
145  IV.  OUTCOME MEASURES 
146   
147  Both clinical outcome assessments and biomarkers4 should be included in clinical trials enrolling 
148  subjects with AD Stages 1-3; however, the approval pathway may differ based on the selection 
149  of the primary endpoint and its ability to measure a clinically meaningful change.  Direct 
150  measures of clinical benefit or validated surrogate endpoints may support a traditional approval.5  
151  Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical 
152  benefit but that are considered reasonably likely to predict clinical benefit may support an 
153  accelerated approval6 (see section IV. C.).  Under the accelerated approval pathway, 
154  postapproval trials have been required to verify and describe clinical benefit.  
155   
156  A.  Clinical Endpoints 
157   
158  Historically, studies to support approval for drugs in the overt dementia stages of AD (Stages 4 
159  through 6) have used an approach which required the assessment of both cognitive and 
160  functional (or global) measures as co-primary endpoints.  The co-primary endpoint approach was 
161  used, in part, because the cognitive assessments used in the studies were not considered 
162  inherently clinically meaningful.  Conventional approaches to assessing the cognitive deficits of 
163  AD use highly sensitive formalized measures of neuropsychological performance directed at 
164  particular domains that are capable of discriminating small changes in cognitive measures that 
165  may be of uncertain clinical meaningfulness when assessed alone.  This approach was typically 
166  used in the setting of a therapy intended to treat disease symptoms in later stages of AD (i.e., 
167  Stages 4 through 6) and was intended to ensure that a change on a cognitive assessment was 
168  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. 
 
5 For further discussion of surrogate endpoints generally, please see the guidance for industry Expedited Programs 
for Serious Conditions  Drugs and Biologics (May 2014). 
  
6 Section 506(c)(1)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 356(c)(1)(A)). 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
169  benefit could be attributed to a benefit on cognition and was not attributable to changes in other 
170  conditions.  This remains a generally acceptable approach for stages of AD with detectable 
171  cognitive and functional impairments (Stages 3 and higher).  Using this approach, the typical 
172  duration of a clinical trial in the symptomatic stages of AD has been 2 years or less; however, 
173  FDA recognizes that it may take longer to establish a clinically meaningful treatment effect in 
174  early AD due to the minimal or absent cognitive and functional deficits seen in those stages of 
175  the disease.  Additionally, many of the assessment tools typically used to measure functional 
176  impairment in patients with later dementia stages of AD (Stages 4 through 6) would not be 
177  sensitive to detect subtle functional changes in early AD.  Therefore, FDA may consider other 
178  approaches, including endpoints based on cognitive assessments or surrogate endpoints, which 
179  may allow for shorter trial durations as a basis for approval in the earliest stages of AD (i.e., 
180  Stages 1, 2, and early 3).  
181   
182  Cognition, in its entirety, encompassing all its constituent processes and domains, is essential for 
183  daily functioning.  As previously noted, it can be challenging to interpret the clinical 
184  meaningfulness of small changes detected on sensitive neuropsychological tests; however, more 
185  marked cognitive changes may represent a change that is clearly clinically meaningful.  It 
186  follows, in concept, that cognitive changes of a particular magnitude, or breadth of effects across 
187  multiple domains, or change in trajectory over time, may represent clinically meaningful change, 
188  independent of measures of functional change.  
189   
190  In the setting of therapy that targets underlying disease pathophysiology, changes in the long-
191  term course of core cognitive measures of AD relative to placebo may potentially provide 
192  evidence of clinically meaningful effect with respect to the clinical progression of the disease.  It 
193  would generally be expected that such effects on cognitive measures would be supported by 
194  similarly persuasive effects on the characteristic pathophysiological changes of AD.  
195   
196  In patients in the earliest clinical stages of AD (refer to section IV. D., Considerations for 
197  Specific Stages of Early AD), FDA will consider strong justifications that a persuasive effect, 
198  considering both magnitude of effect and statistical robustness of the findings, on cognition alone 
199  as assessed by sensitive neuropsychological tests may provide adequate support for a marketing 
200  approval.  Given the array of available neuropsychological tests, a pattern of putatively 
201  beneficial effects demonstrated across multiple individual tests would increase the 
202  persuasiveness of the finding; conversely, a finding on a single test unsupported by consistent 
203  findings on other tests would be less persuasive.  Whether effects on cognitive outcome 
204  measures would be capable of providing evidence of effectiveness in the absence of a 
205  meaningful change in function to support either traditional or accelerated approval would require 
206  detailed discussion with the Agency.  However, in a trial with relatively short-term assessments, 
207  such as a trial for a therapy intended to treat symptoms of AD, an effect on sensitive measures of 
208  neuropsychological performance of uncertain independent clinical meaning (e.g., a word-list 
209  recall test) would generally not allow for an overall finding of efficacy in the absence of 
210  meaningful functional benefit. 
211   
212     
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
213  B.  Time-to-Event Analysis  
214   
215  The use of a time-to-event analysis approach (e.g., time to the occurrence of a clinically 
216  meaningful event during the progressive course of AD, such as the occurrence of some degree of 
217  meaningful impairment of cognition or daily function, perhaps represented by certain disease 
218  stage transitions) would generally be an acceptable primary efficacy measure in clinical trials in 
219  early AD.  Sponsors considering such an approach should discuss their plans with FDA early in 
220  development. 
221   
222  C.  Surrogate Endpoints 
223   
224  Clinical trials showing an effect on a surrogate endpoint that is determined to be reasonably 
225  likely to predict clinical benefit can be the basis for accelerated approval,7 including for drugs 
226  intended for the treatment of AD.  For example, in certain circumstances, FDA has considered a 
227  reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a 
228  surrogate endpoint that is reasonably likely to predict clinical benefit.  That endpoint, in 
229  clinical trials that enrolled participants with Stage 3 and 4 AD, has thus been used as a basis for 
230  accelerated approval for monoclonal antibodies directed against aggregated forms of amyloid 
231  beta, with postapproval trials required to verify and describe clinical benefit.  
232   
233  The acceptability of a surrogate endpoint for use in a particular therapeutic development program 
234  for early AD may depend on the stage of disease, population enrolled in trials, therapeutic 
235  mechanism of action, and availability of current treatments.  A surrogate endpoint that is 
236  determined to be appropriate for use in a particular therapeutic clinical development program 
237  should not be assumed to be appropriate for use with a different product or trial population.  
238  Sponsors considering the use of a biomarker as the primary measure of effect should discuss 
239  their plans with FDA early in development.  In general, even if accelerated approval is 
240  considered as the initial approval pathway, clinical outcome assessments should be included in 
241  clinical trials for early AD to assess early clinical changes that may potentially provide support 
242  for any changes observed on biomarkers.  Evolution of the scientific understanding of AD may 
243  also influence these considerations. 
244   
245  FDA strongly supports and encourages continued research in understanding the role of 
246  biomarkers in AD and stresses the potential importance of biomarkers in the successful 
247  development of effective treatments appropriate for use in the earliest stages of AD.  
248  Precompetitive structured sharing across the AD scientific community of rigorously collected 
249  standardized data is a crucial component of this research. 
250   
251  D.  Considerations for Specific Stages of Early AD 
252   
253  Stage 1  
254   
255  Because it is highly desirable to intervene as early as possible in AD, it follows that patients with 
256  characteristic pathophysiological changes of AD but no subjective complaint, functional 
257  impairment, or detectable abnormalities on sensitive neuropsychological measures (Stage 1 AD 
 
7 Section 506(c)(1)(A) of the FD&C Act (21 U.S.C. 356(c)(1)(A)). 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
258  patients) are an important target population for enrollment in clinical trials.  It can be challenging 
259  in trials of a typical duration (e.g., 2 years or less) to demonstrate a clinically meaningful benefit 
260  in these patients because there is no clinical impairment to assess at baseline and patients may 
261  have variable latency to the onset of symptoms.  It is anticipated that at this stage of disease, an 
262  effect on the characteristic pathophysiological changes of AD, as demonstrated by an effect on 
263  various biomarkers, may be an appropriate measure.  As with the use of neuropsychological 
264  tests, a pattern of treatment effects seen across multiple individual biomarker measures would 
265  increase the persuasiveness of the putative effect.  Whether effects on biomarkers would support 
266  accelerated approval would require detailed discussion with the Agency, including a plan for 
267  subsequent confirmation of clinical benefit.  However, another approach to Stage 1 patients 
268  might be to conduct a study of sufficient duration to allow the evaluation of clinical outcomes, as 
269  discussed for Stage 2 patients below.  As subjects transition to Stage 2 during participation in the 
270  trial, the principles applicable to outcome assessment for Stage 2 would apply.  A time-to-event 
271  analysis approach could also be considered (see section IV. B.).  
272   
273  Sponsors considering these issues should meet with FDA early in development to discuss the 
274  evidence that would be needed to support a marketing application.  Evolution of the scientific 
275  understanding of AD may also influence these considerations. 
276   
277  Stage 2  
278   
279  In patients with Stage 2 AD, who have only subtle cognitive deficits detected on sensitive 
280  measures of neuropsychological performance and no evidence of functional impairment, it may 
281  be difficult to establish a clinically meaningful benefit on subtle cognitive deficits unless the trial 
282  has a long duration.  One possible approach would be to conduct a study of sufficient duration to 
283  allow the evaluation of the clinical measures that assess cognition and function, as discussed 
284  below for Stage 3 patients.  A time-to-event analysis approach could also be considered (see 
285  section IV. B.). 
286   
287  Alternatively, as discussed in section IV. A., FDA will consider strong justifications that a 
288  persuasive effect on cognition as measured by sensitive neuropsychological tests may provide 
289  adequate support for a marketing approval.  It would generally be expected that such effects on 
290  cognitive measures would be supported by similarly persuasive effects on the characteristic 
291  pathophysiological changes of AD.  Whether effects on cognitive outcome measures would, in 
292  the absence of a meaningful change in function, support either traditional or accelerated approval 
293  would require detailed discussion with the Agency.  
294   
295  As patients transition to Stage 3 during participation in the trial, the principles applicable to 
296  outcome assessment for Stage 3 would apply. 
297   
298  Sponsors considering these issues should meet with FDA early in development to discuss the 
299  evidence that would be needed to support a marketing application.  Evolution of the scientific 
300  understanding of AD may also influence these considerations. 
301   
302  Stage 3 
303   
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
304  Patients with Stage 3 AD approaching the onset of overt dementia have relatively mild but 
305  noticeable impairments in their daily functioning.  As patients have detectable cognitive and 
306  functional impairment at this stage of disease, it is important to demonstrate that a therapy 
307  favorably affects the observed impairments in both cognition and daily functioning.  The 
308  independent assessment of daily function and cognitive effects remains an acceptable approach.  
309  However, it is important to note that many of the assessment tools typically used to measure 
310  functional impairment in patients with later dementia stages of AD (Stages 4 through 6) may not 
311  be suitable for use in early AD patients.  An integrated scale that adequately and meaningfully 
312  assesses independent effects on both daily function and cognition is also acceptable as a single 
313  primary efficacy outcome measure in early AD patients.  FDA encourages the development of 
314  novel approaches to the integrated evaluation of subtle functional impairment that arise from 
315  early cognitive impairment (e.g., facility with financial transactions, adequacy of social 
316  conversation).  
317   
318  In early Stage 3 AD (which may be difficult to distinguish from late Stage 2 AD), FDA will 
319  consider strong justifications that a persuasive effect on cognition as measured by sensitive 
320  neuropsychological tests may provide adequate support for a marketing approval.  It would 
321  generally be expected that such effects on cognitive measures would be supported by similarly 
322  persuasive effects on the characteristic pathophysiological changes of AD, and positive trends on 
323  functional outcome assessments.  As previously described, a time-to-event analysis approach 
324  could also be considered (see section IV. B.).  Whether effects on cognitive outcome measures 
325  would, in the absence of a meaningful change in function, support either traditional or 
326  accelerated approval would require detailed discussion with the Agency. 
327   
  8