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

10

20

30

40

50

60

70

80

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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