1. Finding a Balance of Synergy and Flexibility in Master Protocols
Melanie Quintana, Kristine Broglio, Scott Berry
JSM 2019

2. Traditional “Standard” Trial Design
Disease
Treatment
Type A ?
One Treatment
One Disease/Population

3. Basket Trial Design Disease Treatment Type A ? Type B Type C … Type K
One Treatment
Multiple Diseases/Populations

4. Platform Trial Design Multiple Treatments One Disease
Tx 1
Tx 2 …
Tx N
Type A ?
Multiple Treatments
One Disease
Statistical/Inferential synergy
Perpetual/Standing Trial
Efficiently Evaluate emerging treatments

5. Platform Efficiencies
Shared infrastructure means quicker time to start a new therapy
Statistical efficiency in terms of sample size from a shared/common control arm
Fewer participants on control
Ability to screen more agents faster and quickly reject ineffective therapies

6. Structure: Protocol Vs Appendix
The master protocol specifies global rules
A treatment is added to the master protocol via an regimen specific appendix (RSA)
The appendix specifies local rules particular to the treatment being studied
Appendices can accommodate the necessary flexibility to the sponsor and the agent under investigation
Compromise between what is global and what is local
Global rules to develop and protect the two biggest platform commodities – shared infrastructure and shared control

7. Examples of Platform Trials

8. ALS: Phase II (or III) Trial in Amyotrophic Lateral Sclerosis

9. ALS: Phase II (or III) Trial in Amyotrophic Lateral Sclerosis
Global Interims Every 3 months. Arm is active in an interim if there are at least 40 patients in that arm with 3 months of data
*Time Estimates based on Accrual of 40 ppm 6 12 18
Reg A
N=120
Reg B
Reg C
Reg D
Adaptations at Interims:
Early Success flag or stop
Futility: Due to lack of efficacy

10. ALS Example: When will we find first effective therapy?
Traditional Drug Development
Sequence of fixed trials
All N=180 with 90 treated and 90 placebo
All 6-month Follow-up
Lag of 3 months between trials
Adaptive Platform Trial
Perpetually enrolling max. of 3 regimens
Frequent interims for early success or futility
Max N=120 with 90 treated and 30 controls
Max 6-month Follow-up
Share controls across regimens
8 Treatments Tested
8 Treatments Tested
8.5 Years
3.4 Years
1400 Participants
700 on Placebo
880 Participants
220 on Placebo
*Assumes 10% of therapies tested are effective with a 30% slowing in rate of progression. Both Designs have 80% power to detect a truly effective therapy. Accrual rate is 40 ppm.

11. ALS: Phase II (or III) Trial in Amyotrophic Lateral Sclerosis
Master Protocol
Trial Eligibility
Visit schedule & data collection
Randomization: 3:1 Active:PBO
Follow-up Time: 6 Months
Primary Endpoint: ASLFRS-R
Recommended
Sample Size: 120 per reg
Primary Analysis: Bayesian mixed effects repeated measures model
Success Criteria: Prob. Slow Progression > Thresh. (OF)
Futility Criteria: Prob. Slow Progression by at least 10% < .05
Regimen Flexibility
Additional restrictions on Inclusion/exclusion: Due only to safety / MOA
Additional endpoints to be collected
Study Stage / Goals
Success threshold / Type I error
Primary analysis
Bigger / smaller SS
More aggressive futility

12. Need for Careful Consideration: RSA-specific inclusion / exclusion
RSA’s may need additional more restrictive inclusion / exclusion
Safety
Mechanism of action
Every appendix having its own population of interest has the potential to negatively impact the shared placebo arm as well as enrollment to other appendices

13. Subgroups: Example
Appendix A
Appendix B
Appendix C

14. Subgroups: Example
Appendix A
Appendix B
Appendix C

15. Subgroups: Example
Appendix A
Appendix B
Appendix C

16. Subgroups: Example
Appendix A
Appendix B
Appendix C

17. Subgroups: Example
Appendix A
Appendix B
Appendix C

18. Subgroups: Example
Appendix A
Appendix B
Appendix C

19. Subgroups: Example
Appendix A
Appendix B
Appendix C

20. Subgroups: Example
*More about complexities with shared control tomorrow!
Appendix A
Appendix B
Appendix C

21. Platform Trial Design Key Challenge
Find Balance of Synergy vs. Flexibility
What is specified in the Master Protocol vs. Appendix
Too much in the Master Protocol – hard to reach consensus
Too much left to the Appendix – lose efficiencies
Early and frequent communication with key stakeholders and FDA!
Collaborate to develop and get buy-in on recommended design
Set expectations for areas of flexibility / differences in RSAs