1. New FDA Guidance on Early Alzheimer’s Disease
Janice Hitchcock, Ph.D.
Hitchcock Regulatory Consulting, Inc.
Alzheimer’s Association Business Consortium
Ask the Expert Webinar
29 August 2018

2. Disclosures Former employee of Eli Lilly and Company
Independent regulatory consultant on Alzheimer’s disease and other neurodegenerative disorders
Pharmaceutical industry
Academia
Advocacy groups
Note: Advice is my opinion based on experience and is meant to start discussion; whether it applies or not will depend on individual development program

3. Outline Overview of each section Differences from 2013 guidance
Interpretations and recommendations for Alzheimer’s disease drug development strategy

4. Guidance Section I: Introduction
Similar to 2013 guidance, scope limited to sporadic AD prior to dementia
Autosomal dominant AD and AD dementia not included; some principles may apply
Recommendation: Trial designs in excluded populations should still consider this guidance
Unlike 2013 guidance, specifically recognizes overlap between later stages of early AD and early stage of dementia
Allows flexibility for continued use of mixed population of mild cognitive impairment (MCI) + mild AD

5. Guidance Section II: Background
Newly rewritten section; cognition as core symptom
Discusses clinical meaningfulness in historical context of co-primary endpoints in dementia trials
Cognition and global
Cognition and function
Acknowledges that cognition can be clinically meaningful, depending on magnitude and/or breadth of effect
But small effects on sensitive measures may not have apparent clinical meaning
Discusses need for
Intervention at earliest stages of disease
Appropriate outcome measures

6. Guidance Section III: Diagnostic Criteria for Early Alzheimer’s Disease
Newly rewritten section; retains importance of biomarkers to identify pathophysiological changes
States that enrollment should be based on current consensus diagnostic criteria
NIA-AA research diagnostic criteria, International Working Group criteria, NIA-AA research framework (Ab/tau/neurodegeneration [AT(N)] criteria)
Proposes AD stages to categorize clinical trial subjects to determine outcome measures
Consistent with numeric clinical staging proposed in NIA-AA research framework
Albert et al (2011) Alzheimer’s & Dementia 7:270–9; Sperling et al (2011) Alzheimer’s & Dementia 7:280–92; Dubois et al (2010) Lancet Neurology 9:1118–27; Dubois et al (2014) Lancet Neurology 13:614–29; Jack et al (2018) Alzheimer’s & Dementia 14:

7. Diagnostic Criteria for Early Alzheimer’s Disease (cont.)
FDA stage
Description
Presumed corresponding research diagnosis
Stage 1
“Patients with characteristic pathophysiologic changes of AD but no evidence of clinical impact”
Early preclinical AD
Stage 2
“Patients with characteristic pathophysiologic changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment”
Late preclinical AD
Stage 3
“Patients with characteristic pathophysiologic changes of AD, subtle or more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment”
Mild cognitive impairment (MCI) due to AD/prodromal AD
Stage 4, 5, 6
“Patients with overt dementia…Stages 4, 5, and 6, corresponding with mild, moderate, and severe dementia”
Mild, moderate, severe AD dementia
Quotes are from FDA guidance “Early Alzheimer’s Disease: Developing Drugs for Treatment” (2018)

8. Diagnostic Criteria (cont.)
Need to consider stage at beginning and projected stage at end of trial
Recommendation: Use consensus research diagnostic criteria to enroll subjects for trial, but also include reference to corresponding FDA-defined AD stage
at enrollment
projected for majority of subjects at end of trial
Does not preclude use of more than one AD stage in trial population
But FDA may expect use of endpoint for latest stage; impacts powering / probability of technical success
Recommendation: Consider proportion of each stage and discuss proposed primary endpoint with FDA
Mentions possibility of co-development of companion diagnostic
Recommendation: Discuss with FDA early in development; time and resource implications if required

9. Guidance Section IV: Outcome Measures
FDA stage
Outcome measure and regulatory pathway
Stage 3
(~MCI / prodromal AD)
Cognitive-functional composite standard approval, or
Co-primaries standard approval
Stage 2
(~late preclinical AD)
Cognition only accelerated approval, or
Cognition only standard approval possible, depending on effect magnitude and/or breadth
Stage 1
(~early preclinical AD)
Biomarker only accelerated approval theoretically possible, but not yet
Alternative: Longer duration and use Stage 2 measure (cognition)
Newly rewritten section
Stage 3 (MCI/prodromal AD)
Similar to 2013 guidance, accepts composite endpoint (cognitive and functional) or co-primaries
Recommendation: Discuss with FDA if your trial proposes primary endpoint not consistent with guidance; provide scientific justification
Stage 2 (late preclinical AD)
Different from 2013 guidance, opens possibility of standard (full) rather than accelerated approval pathway with cognitive endpoint
Depends on magnitude and/or breadth of cognitive effect
Biomarker effects also expected
Notes that “evolution of the scientific understanding of AD may also influence these considerations”
Recommendation: Include several cognitive and biomarker endpoints

10. Outcome Measures (cont.)
FDA stage
Outcome measure and regulatory pathway
Stage 3
(~MCI / prodromal AD)
Cognitive-functional composite standard approval, or
Co-primaries standard approval
Stage 2
(~late preclinical AD)
Cognition only accelerated approval, or
Cognition only standard approval possible, depending on effect magnitude and/or breadth
Stage 1
(~early preclinical AD)
Biomarker only accelerated approval theoretically possible, but not yet
Alternative: Longer duration and use Stage 2 measure (cognition)
Stage 1 (early preclinical AD): Suggests theoretical possibility (“in principle”) of accelerated approval pathway based on biomarker effect(s)
But not yet supported by current state of science as “reasonably likely to predict clinical benefit” (regulatory standard)
Suggests alternative – sufficient duration for Stage 1 subjects transition to Stage 2; use Stage 2 outcomes
Recommendation: Include biomarkers and cognitive endpoints; consider longer duration with interim analysis
Similar to 2013 guidance, time-to-event analysis is possible endpoint for early AD
No discussion of potential issues from empirical standpoint
Recommendation: Consult with AD thought leaders on pros and cons

11. Guidance Section IV. E: Assessment of Disease Course
Unlike 2013 guidance, does not mention “disease modification”; instead “permanently alter disease course” or “persistent effect on disease course”
Recommendation: Consider disease modification as concept for labeling; if allowed, likely to be different wording – consider market research on alternatives
Similar to 2013 guidance, discusses randomized (delayed) start design; “most convincing” approach to demonstrate persistent effect on disease course
Recommendation: Include delayed start extension if disease modification claim is sought
Different than 2013 guidance, states that biomarkers are not yet well enough understood to demonstrate persistent effect on disease course (disease modification)
Recommendation: Include biomarkers as supportive evidence for drug effect (not disease modification claim)
Similar to 2013 guidance, states that biomarker data can be analyzed without hierarchical structure; this could change depending on advances in AD research

12. Questions?

13. Potential questions
What is the probability that FDA would allow a disease modification claim in labeling? What trial design features and outcome measures should be included to enable such a claim?
How does FDA determine whether an outcome measure is clinically meaningful?
Which diagnostic criteria should be used for inclusion of subjects in a clinical trial?
Which biomarkers are most important to include in a clinical trial?
What are the pros and cons of pursuing an accelerated approval pathway vs. a standard (full) approval pathway in AD?