Early Alzheimer’s Disease: Developing Drugs for Treatment

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

21115964dft.docx
03/05/24
Early Alzheimer’s
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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

Early Alzheimer’s
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

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Early Alzheimer’s Disease: Developing Drugs for Treatment	1
Guidance for Industry1
2
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person	7
and is not binding on FDA or the public. You can use an alternative approach if it satisfies the	8
requirements of the applicable statutes and regulations. To discuss an alternative approach,	9
contact the FDA staff responsible for this guidance as listed on the title page.	10
11
12
13
I. 	INTRODUCTION	14
15
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the	16
treatment of the stages of sporadic Alzheimer’s disease (AD) that occur before the onset of overt	17
dementia (i.e., Stages 1 through 3; discussed in section III). These stages are collectively	18
referred to as “early AD” in this guidance; however, it is recognized that AD occurs on a	19
continuum and patients in the last stage of early AD (i.e., late Stage 3) and patients with AD in	20
the earliest stages of overt dementia (i.e., early Stage 4) may not differ significantly in clinical	21
presentation. This guidance is intended to serve as a focus for continued discussions among	22
representatives of the Office of Neuroscience in the Center for Drug Evaluation and Research or	23
the Office of Therapeutic Products in the Center for Biologics Evaluation and Research, as	24
appropriate, pharmaceutical sponsors, the scientific community, and the public about the	25
development of drugs for the treatment of early AD.2	
26
27
This guidance revises the draft guidance for industry Early Alzheimer’s Disease: Developing	28
Drugs for Treatment (February 2018). This revision, when finalized, will represent FDA’s	29
current thinking regarding the selection of subjects with early AD for enrollment in clinical trials	30
and the selection of endpoints for clinical trials in this population.3	
31
32
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	33
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	34
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	35
the word should in Agency guidances means that something is suggested or recommended, but	36
not required.	37
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.

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38
39
II. 	BACKGROUND	40
41
Historically, clinical criteria that defined later stages of AD, after the onset of overt dementia,	42
were used for enrollment in clinical trials. Accordingly, subjects included in these trials	43
exhibited both the cognitive changes typical of clinically evident AD and the degree of	44
functional impairment associated with overt dementia. Drugs that were approved for dementia	45
during that time were evaluated in that context.	46
47
As the scientific understanding of AD has evolved, efforts have been made to incorporate in	48
clinical trials the use of biomarkers reflecting underlying AD pathophysiological changes and the	49
enrollment of subjects with AD at earlier stages of the disease, in which there may be minimal or	50
no detectable abnormality on clinical assessments. These efforts are particularly important	51
because there may be an opportunity to intervene very early in the disease process of AD, given	52
the slowly progressive course of AD and the development of characteristic pathophysiological	53
changes that greatly precede the development of clinically evident findings. Delaying or,	54
preferably, halting or reversing the pathophysiological process that will lead to the initial clinical	55
deficits of AD is the ultimate goal of presymptomatic or very early symptomatic intervention,	56
and treatment directed at this goal must begin before there are overt clinical symptoms. This	57
opportunity carries with it the need to understand ways to assess treatment benefit in these earlier	58
stages of disease.	59
60
This document provides an overview on the Agency’s current thinking on diagnostic criteria and	61
clinical staging of AD to inform enrollment in clinical trials and the selection of appropriate	62
endpoints for the stage(s) of disease proposed to be enrolled in a clinical trial. The design of	63
clinical trials that are specifically focused on the treatment of patients with AD who have	64
developed overt dementia (i.e., Stages 4 through 6; discussed in section III), or any of the	65
autosomal dominant forms of AD, is not discussed, although some of the principles in this	66
guidance may be pertinent. This guidance does not discuss treatment of dementias other than	67
AD.	68
69
70
III. 	DIAGNOSTIC CRITERIA FOR EARLY AD	71
72
Eligibility for enrollment in trials intended to support an application for approval for treatment of	73
early AD should be based on current consensus diagnostic criteria intended to establish the true	74
biological presence of AD rather than criteria based on syndromic or other definitions; this	75
approach is intended to avoid enrollment of a substantial number of subjects who would not	76
actually have AD.	77
78
FDA supports the use of biologically based diagnostic criteria that are grounded in a	79
contemporary understanding of the pathophysiology and evolution of AD. The characteristic	80
pathophysiological changes of AD precede, often by many years or even decades, the	81
development of clinically evident findings and progress as a continuous disease process that can	82
be categorized into stages. Those stages are defined below, initially only by those	83

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pathophysiological changes and then by the development of subtle clinical abnormalities,	84
detectable using sensitive neuropsychological measures. These initial clinical findings are	85
followed by the development of more apparent cognitive abnormalities, accompanied by initially	86
mild and then more severe or more extensive functional impairment. Based on knowledge	87
gained from previous clinical trials and the evolving understanding of the pathophysiology of	88
AD, there is an increased focus on evaluating drug treatments for AD in the earliest stages of the	89
disease. Diagnostic criteria that reliably define a population with early AD, including the earliest	90
stages characterized only by pathophysiological changes, are suited to the evaluation of drugs	91
intended to delay or prevent the emergence of overt symptoms.	92
93
Important findings applicable to the categorization of AD along its continuum of progression	94
include the presence of pathophysiological changes as measured by biomarkers, the presence or	95
absence of detectable abnormalities on sensitive neuropsychological measures, and cognitive	96
symptoms reported by patients or observers with the presence or absence of functional	97
impairment manifested as meaningful impact on daily activities. Although FDA recognizes that	98
variations in the selection and application of clinical characteristics and biomarkers may lead to	99
the enrollment of subjects in clinical trials who are at slightly different stages of a progressive	100
disease process, the following categories are conceptually useful for the design and evaluation of	101
clinical trials in different stages of AD:	102
103
• 	Stage 1: Patients with characteristic pathophysiological changes of AD but no	104
evidence of clinical impact. These patients are truly asymptomatic with no subjective	105
complaint, functional impairment, or detectable abnormalities on sensitive	106
neuropsychological measures. The characteristic pathophysiological changes are	107
typically demonstrated by assessment of various biomarker measures.	108
109
• 	Stage 2: Patients with characteristic pathophysiological changes of AD and subtle	110
detectable abnormalities on sensitive neuropsychological measures or subjective	111
complaints of mild cognitive symptoms but no functional impairment. This may be	112
considered a transitional stage in which slight cognitive symptoms first appear. The	113
emergence of subtle functional impairment signals a transition to Stage 3.	114
115
• 	Stage 3: Patients with characteristic pathophysiological changes of AD, generally	116
more apparent detectable abnormalities on sensitive neuropsychological measures,	117
and mild but detectable functional impairment. The functional impairment in this	118
stage is not severe enough to warrant a diagnosis of overt dementia. This stage roughly	119
corresponds with the syndrome of “mild cognitive impairment”; however, it is noted that	120
the term “mild cognitive impairment” may also encompass patients in late Stage 2 or	121
early Stage 4.	122
123
• 	Stages 4, 5, and 6: Patients with overt dementia, progressing through mild,	124
moderate, and severe stages. This diagnosis is made as functional impairment worsens	125
from that seen in Stage 3. A discussion of these three disease stages is not the focus of	126
this guidance.	127
128

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For study design, it is important to define the study population using these conceptual categories,	129
even in the presence of a single continuous disease process, to allow and inform appropriate	130
outcome measure selection. In descriptions of studies, sponsors should identify both the stage of	131
AD defined for study eligibility and enrollment and the stage of AD anticipated for the majority	132
of the enrolled study population at the time of primary outcome assessment.	133
134
As discussed above, it is expected that biomarker evidence of disease will establish the reliable	135
diagnosis of subjects in trials of early AD. As copathology is common in AD, sponsors may	136
consider including assessments of other copathologies in their clinical trials to inform exclusion	137
criteria or for preplanned analyses of safety and efficacy in subgroups of the enrolled population.	138
If biomarker evidence will be needed to adequately define the anticipated indicated population	139
and an FDA-approved or cleared diagnostic test is not available, sponsors should engage early in	140
development with the appropriate review division at FDA to discuss the potential need for the	141
codevelopment of a companion diagnostic device.	142
143
144
IV. 	OUTCOME MEASURES	145
146
Both clinical outcome assessments and biomarkers4 should be included in clinical trials enrolling	147
subjects with AD Stages 1-3; however, the approval pathway may differ based on the selection	148
of the primary endpoint and its ability to measure a clinically meaningful change. Direct	149
measures of clinical benefit or validated surrogate endpoints may support a traditional approval.5	
150
Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical	151
benefit but that are considered reasonably likely to predict clinical benefit may support an	152
accelerated approval6 (see section IV. C.). Under the accelerated approval pathway,	153
postapproval trials have been required to verify and describe clinical benefit.	154
155
A. 	Clinical Endpoints	156
157
Historically, studies to support approval for drugs in the overt dementia stages of AD (Stages 4	158
through 6) have used an approach which required the assessment of both cognitive and	159
functional (or global) measures as co-primary endpoints. The co-primary endpoint approach was	160
used, in part, because the cognitive assessments used in the studies were not considered	161
inherently clinically meaningful. Conventional approaches to assessing the cognitive deficits of	162
AD use highly sensitive formalized measures of neuropsychological performance directed at	163
particular domains that are capable of discriminating small changes in cognitive measures that	164
may be of uncertain clinical meaningfulness when assessed alone. This approach was typically	165
used in the setting of a therapy intended to treat disease symptoms in later stages of AD (i.e.,	166
Stages 4 through 6) and was intended to ensure that a change on a cognitive assessment was	167
accompanied by an observed functional benefit, and alternately, that any observed functional	168
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)).

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benefit could be attributed to a benefit on cognition and was not attributable to changes in other	169
conditions. This remains a generally acceptable approach for stages of AD with detectable	170
cognitive and functional impairments (Stages 3 and higher). Using this approach, the typical	171
duration of a clinical trial in the symptomatic stages of AD has been 2 years or less; however,	172
FDA recognizes that it may take longer to establish a clinically meaningful treatment effect in	173
early AD due to the minimal or absent cognitive and functional deficits seen in those stages of	174
the disease. Additionally, many of the assessment tools typically used to measure functional	175
impairment in patients with later dementia stages of AD (Stages 4 through 6) would not be	176
sensitive to detect subtle functional changes in early AD. Therefore, FDA may consider other	177
approaches, including endpoints based on cognitive assessments or surrogate endpoints, which	178
may allow for shorter trial durations as a basis for approval in the earliest stages of AD (i.e.,	179
Stages 1, 2, and early 3).	180
181
Cognition, in its entirety, encompassing all its constituent processes and domains, is essential for	182
daily functioning. As previously noted, it can be challenging to interpret the clinical	183
meaningfulness of small changes detected on sensitive neuropsychological tests; however, more	184
marked cognitive changes may represent a change that is clearly clinically meaningful. It	185
follows, in concept, that cognitive changes of a particular magnitude, or breadth of effects across	186
multiple domains, or change in trajectory over time, may represent clinically meaningful change,	187
independent of measures of functional change.	188
189
In the setting of therapy that targets underlying disease pathophysiology, changes in the long-	190
term course of core cognitive measures of AD relative to placebo may potentially provide	191
evidence of clinically meaningful effect with respect to the clinical progression of the disease. It	192
would generally be expected that such effects on cognitive measures would be supported by	193
similarly persuasive effects on the characteristic pathophysiological changes of AD.	194
195
In patients in the earliest clinical stages of AD (refer to section IV. D., Considerations for	196
Specific Stages of Early AD), FDA will consider strong justifications that a persuasive effect,	197
considering both magnitude of effect and statistical robustness of the findings, on cognition alone	198
as assessed by sensitive neuropsychological tests may provide adequate support for a marketing	199
approval. Given the array of available neuropsychological tests, a pattern of putatively	200
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. Whether effects on cognitive outcome	203
measures would be capable of providing evidence of effectiveness in the absence of a	204
meaningful change in function to support either traditional or accelerated approval would require	205
detailed discussion with the Agency. However, in a trial with relatively short-term assessments,	206
such as a trial for a therapy intended to treat symptoms of AD, an effect on sensitive measures of	207
neuropsychological performance of uncertain independent clinical meaning (e.g., a word-list	208
recall test) would generally not allow for an overall finding of efficacy in the absence of	209
meaningful functional benefit.	210
211
212

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B. 	Time-to-Event Analysis	213
214
The use of a time-to-event analysis approach (e.g., time to the occurrence of a clinically	215
meaningful event during the progressive course of AD, such as the occurrence of some degree of	216
meaningful impairment of cognition or daily function, perhaps represented by certain disease	217
stage transitions) would generally be an acceptable primary efficacy measure in clinical trials in	218
early AD. Sponsors considering such an approach should discuss their plans with FDA early in	219
development.	220
221
C. 	Surrogate Endpoints	222
223
Clinical trials showing an effect on a surrogate endpoint that is determined to be “reasonably	224
likely to predict clinical benefit” can be the basis for accelerated approval,7 including for drugs	225
intended for the treatment of AD. For example, in certain circumstances, FDA has considered a	226
reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a	227
surrogate endpoint that is “reasonably likely to predict clinical benefit.” That endpoint, in	228
clinical trials that enrolled participants with Stage 3 and 4 AD, has thus been used as a basis for	229
accelerated approval for monoclonal antibodies directed against aggregated forms of amyloid	230
beta, with postapproval trials required to verify and describe clinical benefit.	231
232
The acceptability of a surrogate endpoint for use in a particular therapeutic development program	233
for early AD may depend on the stage of disease, population enrolled in trials, therapeutic	234
mechanism of action, and availability of current treatments. A surrogate endpoint that is	235
determined to be appropriate for use in a particular therapeutic clinical development program	236
should not be assumed to be appropriate for use with a different product or trial population.	237
Sponsors considering the use of a biomarker as the primary measure of effect should discuss	238
their plans with FDA early in development. In general, even if accelerated approval is	239
considered as the initial approval pathway, clinical outcome assessments should be included in	240
clinical trials for early AD to assess early clinical changes that may potentially provide support	241
for any changes observed on biomarkers. Evolution of the scientific understanding of AD may	242
also influence these considerations.	243
244
FDA strongly supports and encourages continued research in understanding the role of	245
biomarkers in AD and stresses the potential importance of biomarkers in the successful	246
development of effective treatments appropriate for use in the earliest stages of AD.	247
Precompetitive structured sharing across the AD scientific community of rigorously collected	248
standardized data is a crucial component of this research.	249
250
D. 	Considerations for Specific Stages of Early AD	251
252
Stage 1	253
254
Because it is highly desirable to intervene as early as possible in AD, it follows that patients with	255
characteristic pathophysiological changes of AD but no subjective complaint, functional	256
impairment, or detectable abnormalities on sensitive neuropsychological measures (Stage 1 AD	257
7 Section 506(c)(1)(A) of the FD&C Act (21 U.S.C. 356(c)(1)(A)).

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patients) are an important target population for enrollment in clinical trials. It can be challenging	258
in trials of a typical duration (e.g., 2 years or less) to demonstrate a clinically meaningful benefit	259
in these patients because there is no clinical impairment to assess at baseline and patients may	260
have variable latency to the onset of symptoms. It is anticipated that at this stage of disease, an	261
effect on the characteristic pathophysiological changes of AD, as demonstrated by an effect on	262
various biomarkers, may be an appropriate measure. As with the use of neuropsychological	263
tests, a pattern of treatment effects seen across multiple individual biomarker measures would	264
increase the persuasiveness of the putative effect. Whether effects on biomarkers would support	265
accelerated approval would require detailed discussion with the Agency, including a plan for	266
subsequent confirmation of clinical benefit. However, another approach to Stage 1 patients	267
might be to conduct a study of sufficient duration to allow the evaluation of clinical outcomes, as	268
discussed for Stage 2 patients below. As subjects transition to Stage 2 during participation in the	269
trial, the principles applicable to outcome assessment for Stage 2 would apply. A time-to-event	270
analysis approach could also be considered (see section IV. B.).	271
272
Sponsors considering these issues should meet with FDA early in development to discuss the	273
evidence that would be needed to support a marketing application. Evolution of the scientific	274
understanding of AD may also influence these considerations.	275
276
Stage 2	277
278
In patients with Stage 2 AD, who have only subtle cognitive deficits detected on sensitive	279
measures of neuropsychological performance and no evidence of functional impairment, it may	280
be difficult to establish a clinically meaningful benefit on subtle cognitive deficits unless the trial	281
has a long duration. One possible approach would be to conduct a study of sufficient duration to	282
allow the evaluation of the clinical measures that assess cognition and function, as discussed	283
below for Stage 3 patients. A time-to-event analysis approach could also be considered (see	284
section IV. B.).	285
286
Alternatively, as discussed in section IV. A., FDA will consider strong justifications that a	287
persuasive effect on cognition as measured by sensitive neuropsychological tests may provide	288
adequate support for a marketing approval. It would generally be expected that such effects on	289
cognitive measures would be supported by similarly persuasive effects on the characteristic	290
pathophysiological changes of AD. Whether effects on cognitive outcome measures would, in	291
the absence of a meaningful change in function, support either traditional or accelerated approval	292
would require detailed discussion with the Agency.	293
294
As patients transition to Stage 3 during participation in the trial, the principles applicable to	295
outcome assessment for Stage 3 would apply.	296
297
Sponsors considering these issues should meet with FDA early in development to discuss the	298
evidence that would be needed to support a marketing application. Evolution of the scientific	299
understanding of AD may also influence these considerations.	300
301
Stage 3	302
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Patients with Stage 3 AD approaching the onset of overt dementia have relatively mild but	304
noticeable impairments in their daily functioning. As patients have detectable cognitive and	305
functional impairment at this stage of disease, it is important to demonstrate that a therapy	306
favorably affects the observed impairments in both cognition and daily functioning. The	307
independent assessment of daily function and cognitive effects remains an acceptable approach.	308
However, it is important to note that many of the assessment tools typically used to measure	309
functional impairment in patients with later dementia stages of AD (Stages 4 through 6) may not	310
be suitable for use in early AD patients. An integrated scale that adequately and meaningfully	311
assesses independent effects on both daily function and cognition is also acceptable as a single	312
primary efficacy outcome measure in early AD patients. FDA encourages the development of	313
novel approaches to the integrated evaluation of subtle functional impairment that arise from	314
early cognitive impairment (e.g., facility with financial transactions, adequacy of social	315
conversation).	316
317
In early Stage 3 AD (which may be difficult to distinguish from late Stage 2 AD), FDA will	318
consider strong justifications that a persuasive effect on cognition as measured by sensitive	319
neuropsychological tests may provide adequate support for a marketing approval. It would	320
generally be expected that such effects on cognitive measures would be supported by similarly	321
persuasive effects on the characteristic pathophysiological changes of AD, and positive trends on	322
functional outcome assessments. As previously described, a time-to-event analysis approach	323
could also be considered (see section IV. B.). Whether effects on cognitive outcome measures	324
would, in the absence of a meaningful change in function, support either traditional or	325
accelerated approval would require detailed discussion with the Agency.	326
327