1. Overview of Adaptive Design
Zoran Antonijevic
Regulatory SIAC
16 Oct, 2013

2. Presentation Contents
FDA Guidance
Exploratory Stage
More efficient drug development
Confirmatory Stage (A&WC Trials)
Different Types
FDA approvals based on adaptive designs in Phase 3
DMC for Adaptive Clinical Trials

3. 2010 FDA Guidance

4. Well Understood Adaptive Designs
A. Adaptation of Study Eligibility Criteria Based on Analyses of Pretreatment (Baseline) Data
B. Adaptations to Maintain Study Power Based on Blinded Interim Analyses of Aggregate Data
C. Adaptations Based on Interim Results of an Outcome Unrelated to Efficacy
D. Adaptations Using Group Sequential Methods and Unblinded Analyses for Early Study Termination Because of Either Lack of Benefit or Demonstrated Efficacy
E. Adaptations in the Data Analysis Plan Not Dependent on Within Study, Between-Group Outcome Differences

5. Less Well Understood (LWU) Adaptive Designs
Exploratory
A. Adaptations for Dose Selection Studies
B. Adaptive Randomization Based on Relative Treatment Group Responses
Confirmatory (but it could be done at Exploratory Stage as well)
C. Adaptation of Sample Size Based on Interim-Effect Size Estimates
D. Adaptation of Patient Population Based on Treatment-Effect Estimates
E. Adaptation for Endpoint Selection Based on Interim Estimate of Treatment Effect

6. Exploratory Stage

7. Adaptation for Dose Selection
Value of Design
Easily under-appreciated, trial designs have a major impact on the value of a pharmaceutical product
Adaptive Phase 2 Designs
FDA AD Guidance recommends use of AD in Phase 2
AD is the most efficient approach for this stage of development
Development Program Optimization
Phase 2 most critical for optimal drug development
Development Scenario Simulation
Comparing relative efficiency of various development options. Accomplished only with simulations

8. Traditional Phase 2 Program .
A Single Dose-Adaptive Design can replace Traditional PoC trial and Ph2 Trials
Traditional Phase 2 Program
Phase 3
PoC (1b/2a)
(High Dose
vs. Placebo)
Dose-
Finding
Definitive
Dose-Response
(if needed)
Phase 2 with Dose-Adaptive PoC Trial
Phase 3
PoC + Dose-Finding
Definitive
Dose-Response
(if needed)

9. Phase 3: Seamless Phase 2/3 Adaptive Design
Single Dose-Adaptive Design can replace Typical PoC and Ph2a and Ph2b Trials
Traditional Phase 2 Program
Phase 3
PoC (Ib/IIa)
(High Dose
vs. Placebo)
Dose-
Finding
Definitive
Dose-Response
(if needed)
Phase 2 with Dose-Adaptive PoC Trial
Phase 3: Seamless Phase 2/3 Adaptive Design
PoC + Dose-Finding

10. Confirmatory Stage

11. Novel (LWU) Adaptive Designs at Confirmatory Stage
Unblinded Sample Size Re-Assessment (Adaptation of Sample Size)
Two stage design with dose selection (Seamless Phase 2b/3 design)
Adaptive Enrichment Design
(Adaptation of Patient Population)

12. Selected Approvals Based on Adaptive Designs
PROCYSBI™ ; Approved in 2013
Raptor Pharmaceuticals
Nephrophatic Cystinosis
Unblinded Sample Size Re-assessment
Fulyzaq™; Approved in 2012
Napo/Salix
HIV-associated diarrhea
Two-Stage (non-stop) Phase 2/3 Design

13. Unblinded SSR
Two stage slow horiz reveal

14. Two Stage Design With Dose Selection

15. Predictive Enrichment
Identification of patients more likely to respond to a given treatment
Adaptive Enrichment Design validates predictive marker and confirms efficacy within a single trial.

16. Phase 2 to 3 Biomarker Development Paths
Whole Population
Biomarker Subpopulation _ +
Biomarker Subpopulation _ = + + ?
Phase III in Full population. Drug works, no differentiation between subpopulations.
Phase III in Enriched population only.
Drug works in biomarker subpopulation only.
Phase III with an Adaptive Enrichment Design.
Phase 2 data inconclusive.
Phase III in Enriched population only.
Drug works in biomarker subpopulation only.
Stop development.
Drug does not work.

17. Adaptive Enrichment Design
Enroll subjects from full population
Interim Analysis at … PFS events
Favorable Zone: CPFull> X%
Inconclusive: Z % ≤ CPFull ≤ X%
Futility:
CPFull≤ Z%
Enrichment Zone:
CPSub-CPFull> Y%
Unfavorable Zone:
CPSub-CPFull≤ Y%
Continue as Planned: enrollment with full population
Restrict enrollment to biomarker sub. Increase Nsub
Continue as Planned: enrollment with full population

18. DMC for Adaptive Clinical Trials

19. Pro-activity of the DMC
The FDA Adaptive Design Guidance: “Because the DMC is unblinded to interim study results it can help implement the adaptation decision according to the prospective adaptation algorithm, but it should not be in a position to otherwise change the study design except for serious safety-related concerns that are the usual responsibility of a DMC”

20. Novel (LWU) Adaptive Designs
Basics; Unblinded Sample Size Re-assessment
Complex Adaptive Designs at Confirmatory Stage
Two-Stage with Dose-Selection
Adaptation of Patient Population
Adaptive Designs in Exploratory Studies
Dose Selection Studies

21. Unblinded Sample Size Reassessment
Similarities with GSD:
- Both address the same objective/concern which is uncertainty regarding the treatment effect
- The adaptation algorithm can be pre-specified in a relatively straightforward manner
Differences:
GSD; concerns re overflow
SSR; design carefully not to reveal treatment effect

22. Complex Adaptive Designs at Confirmatory Stage
Decisions involve parameters beyond just ethical considerations.
Include decisions that traditionally have been sponsor responsibilities.
May have major commercial implications, for example dose selection or sub-population selection.
Complex algorithms
DMC may desire to consult with the steering committee that includes a sponsor representative not involved in trial management.

23. Adaptive Designs in Exploratory Studies
Not intended to demonstrate confirmatory evidence; less rigor in restricting knowledge of interim results
Lesser regulatory implications, though avoiding operational bias should be recommended in any trial
May require frequent updates based on interim data
Adaptations are often driven by a pre-specified algorithm automated through an integrated response system
Therefore, it may be preferable that recommendations are endorsed by an Internal Review Committee

24. References
US Food and Drug Administration. Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February, 2010.
Zoran Antonijevic, Jose Pinheiro, Parvin Fardipour, Roger J. Lewis. Impact of Dose Selection Strategies Used in Phase II on the Probability of Success in Phase III. Statistics in Biopharmaceutical Research :4,
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: A practical guide with examples. Stat Med 2011; 30:3267–84.
Zoran Antonijevic, Paul Gallo, Christy Chuang-Stein, Vlad Dragalin, John Loewy, Sandeep Menon, Eva Miller, Caroline Morgan, Matilde Sanchez. Views on Emerging Issues Pertaining to Data Monitoring Committees for Adaptive Trials. Therapeutic Innovation & Regulatory Science July 2013 47: 

25. Back-Ups

26. Case Study Scenarios Results (7) different statistical approaches
(2) Phase 2 strategies
(3) Phase 3 strategies
For a total of 42 scenarios. Same assumptions for safety and efficacy used for all scenarios
Cost and development time calculated using real data from existing databases
Results
The expected NPV for different scenarios ranged from $0.5B to $1.2B
Adaptive Designs far outperformed traditional approaches

27. Expected NPV
Method