1. Phase II/III Design: Case Study
Case study: Seamless Phase II/III Design for Registration Program
Jeff Maca, Ph.D.
Senior Associate Director
Novartis Pharmaceuticals

2. Outline – Adaptive Seamless Case Study
Motivation/definitions
Adaptive seamless designs considerations
Case study example
Simulation details
Conclusions
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3. Motivation
Adaptive Designs: Using accumulating data to decide on how to modify aspects of the trial design, during the conduct of the trial and without violating the integrity of the trial
An adaptive trial can plan at the design stage to correct for incorrect assumptions
Adaptive trials can merge what might be considered two separate trials into one trial
Improve efficiency in clinical development
Careful planning is necessity
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4. Adaptive Seamless designs
Primary objective – combine “dose selection” and “confirmation” into one trial
Although dose is most common phase IIb objective, other choices could be made, e.g. population
After dose selection, change usually to new enrollments (patients could be re-randomized, and analyzed separately)
Patients on terminated treatment groups can be followed
All data from the chosen group and comparator is used in the final analysis. Appropriate statistical methods must be used
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5. Adaptive Seamless designs
Statistical methodology for Adaptive Seamless Designs must account for potential biases and statistical issues
Selection bias (multiplicity)
Multiple looks at the data (interim analysis)
Combination of data from independent stages
Closed testing procedure (data from stages are separated) and Bonferroni type adjustment (data is pooled across stages) are two possible methods
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6. Adaptive Seamless designs
With the added flexibility of seamless designs, comes added complexity.
Careful consideration should be given to the feasibility for a seamless design for the project.
Not all projects can use seamless development
Even if two programs can use seamless development, one might be better suited than the other
Many characteristics add or subtract to the feasibility
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7. Adaptive Seamless designs
Enrollment vs. Endpoint
The length of time needed to make a decision relative to the time of enrollment must be small
Otherwise enrollment must be paused
Endpoint must be well known and accepted
If the goal of Phase II is to determine the endpoint for registration, seamless development would be difficult
If surrogate marker will be used for dose selection, it must be accepted, validated and well understood
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8. Adaptive Seamless designs
Clinical Development Time
There will usually be two pivotal trials for registration
Entire program must be completed in shorter timelines, not just the adaptive trial
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9. Adaptive Seamless designs
Logistical considerations
Helpful if final product is available for adaptive trial (otherwise bioequivalence study is needed)
Decision process, and personnel must be carefully planned and pre-specified
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10. Phase II/III Adaptive Design – Case Study
Case Study Introduction
Indication is a chronic disease
Adaptive seamless design (ASD) to select final dose to support registration of new formulation
Study will provide pivotal confirmation of efficacy, safety and tolerability of selected dose
Two adaptive studies are running concurrently, one in mono-therapy, one in add-on therapy
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11. Phase II/III Adaptive Design – Case Study
Case Study Introduction
Bias towards selecting the lower dose, unless
Low dose would not have high likelihood of success
High dose had considerably better efficacy
Selection probabilities and overall power derived via extensive simulation study
Studies are planned to have interim analysis occurring at the same time
Dose selection simultaneous for both studies
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12. Phase II/III adaptive design : Study 1
Independent
Dose
Selection
STAGE 1 (phase IIb)
STAGE 2 (phase III)
High Dose
Selected Dose
Low Dose
Placebo
Active control
Screening
Dose Ranging
24 weeks
Interim
Analysis
Efficacy and Safety
52 weeks
Final
Analysis
Ongoing treatment
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13. Phase II/III adaptive design : Study 2
Independent
Dose
Selection
STAGE 1 (phase IIb)
STAGE 2 (phase III)
High Dose
Selected Dose
Low Dose
Placebo
Selected Dose
Active control
Active control
Screening
Dose Ranging
24 weeks
Interim
Analysis
Efficacy and Safety
52 weeks
Final
Analysis
Ongoing treatment
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14. Phase II/III Adaptive Design – Case Study
Studies are divided into three periods
Period 1 (Dose selection)
Intermediate period (during dose selection)
Period 2 (long term safety and efficacy)
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15. Phase II/III Adaptive Design – Case Study
Period 1
Patients randomized equally to high dose, low dose and control (s)
All patients complete 24 weeks of treatment which is the time to primary endpoint
Roughly 100 and 150 patients in the two studies will be randomized
Data from both studies will be used in selection
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16. Phase II/III Adaptive Design – Case Study
Intermediate Period
Patients randomized to non-placebo treatments will stay on treatment until dose selection is complete
Patients on placebo will be switched to active treatment (if completed 24 weeks)
Recruitment continues through this period
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17. Phase II/III Adaptive Design – Case Study
Period 2
Patients randomized to non selected dose(s) are switched to selected dose
Placebo patients are switched to active treatment
Patient randomized to selected dose or active control
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18. Phase II/III adaptive design: Case study
Primary endpoint
Continuous variable – measured after 24 weeks
Dose selected on a 12 week measurement (early readout)
Comparison with placebo for superiority
Secondary endpoints
Comparison of safety and efficacy over 24 weeks
Long term safety measured over 52 weeks
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19. Phase II/III adaptive design: Case study
Objective of interim analysis
To investigate two doses of new treatment versus placebo and active controls with respect to primary endpoint after 12 weeks of treatment (early read-out)
Independent external DMC will select dose to continue into period 2
DMC would see analysis from both studies, and make same selection of dose for both studies
Interim analyses must be timed to occur at the same time (harder to do in practice than on paper)
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20. Phase II/III adaptive design: Simulations
Sample sizes for stage 1 and 2 based on extensive simulation work
Stage 1 sample size chosen to ensure the “optimal” dose was chosen with high probability
Various dose responses were investigated
Stage 2 sample size sufficient to satisfy primary and secondary objectives of the study
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21. Phase II/III adaptive design: Simulations
Decision rule has tendency towards picking lower dose
In general, the low dose is selected unless high dose has “much” higher efficacy outcome, or low dose does not have “much” chance to succeed.
Different thresholds were investigated to make this determination of “much”
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22. Phase II/III adaptive design: Simulations
Output from simulation
Selection probabilities for each of the two treatment doses
Power conditional on the dose selected
Overall power that the selected doses would be confirmed
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23. Phase II/III adaptive design: Simulations
Statistical methodology
A multiplicity correction will be used for the final analysis to account for the two treatments
Dunnett step-down methodology will be used
Data not split by period with separate p-values (inverse normal/closed testing methodology), although would have similar power
Procedure will control family-wise type I error rate for the primary endpoint
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24. Phase II/III adaptive design: Case study
DMC guidelines
Numerical values given (not inferential)
Thresholds are pre-defined (results from simulations ), for implementation by DMC
Trials will not be stopped for efficacy at interim analysis
Trials currently ongoing, with dose selection analysis upcoming shortly
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25. Conclusions
Adaptive seamless designs have an ability to improve the development process by reducing timelines for approval
Extra planning is necessary to implement an adaptive seamless design protocol
Simulations can be used to determine decision rules, and operating characteristics of such a design
This case study successfully used simulations to plan and execute two simultaneous adaptive seamless designs which incorporate dose selection
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