Klaus Romero Alzforum webinar may2015
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Transcript of Klaus Romero Alzforum webinar may2015
Clinical Trial Simulation Tool for Alzheimer’s Disease
Klaus Romero MD MS FCP
Director of Clinical Pharmacology
Critical Path Institute
Why do drug development programs fail?
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0
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Preclinical Phase I Phase II Phase III Registration
% F
ailu
res
Development stage
Reason by phase
Clinical safety
Efficacy
Formulation
Market potential
PK/Bioavailability
Strategic
Resources
Toxicology
COGS
Unknown
Other
Clinical Trial Simulations
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Evaluate different design options
Design selection
Drug-Disease-Trial
Models
Simulated results
Trial optimization through simulations
𝜃𝑖𝑝𝑘 = E 𝐴𝐷𝐴𝑆𝑖𝑝𝑘
70 patient𝑝
𝑇𝑝𝑘~Weibull 𝛼, ℎ𝑝𝑘
Trial Execution
•X dose
•N
•Frequency of observations
•Inclusion/exclusion criteria
Statistical Analysis
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Data integration for model development
ADNI:• 224 patients• Natural history• Inter-patient variability
Competitive Information:
• Pre-clinical
• Class effects
• Individual effects
CAMD:
• 3179 patients
• Inter-study variability
• Inter-patient variability
• Dropouts
• Placebo effect
Literature:
• Inter-patient variability
• Dropouts
• Drug effectsModel
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• Longitudinal cognitive instrument:
- ADAS-Cog: 11items, 0-70points
• Basal cognitive instrument:
- MMSE: 8items, 30-0points
• Demographics:
- Baseline age and gender
• Genetics:
- APOE4 allele
Relevant variables
6Rogers JA, et al. Alzheimer's disease modeling and simulation. J Pharmacokinet Pharmacodyn. 2012 Oct;39(5):479-98.
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Disease progression:75year-old men, by APOE4 and baseline severity
Balancing power, sample size and duration,given varying effect magnitudes
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Crossover Parallel
91Week Crossover
Versus
78 Week Parallel
By effect magnitude
Regulatory conclusions
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This model adequately captures relevant information regarding disease progression, drug effects and clinical trial aspects (placebo effect and dropouts)
Clinical Trial Simulations based on this tool allows the objective, prospective and realistic evaluation of the operating characteristics of different trial designs.
FDA fit-for-purpose decision on CAMD CTS tool. 2013EMA qualification opinion on CAMD CTS tool. 2013
Thank You
www.c-path.org