1. The 3rd Stat4Onc Annual Symposium
Session “Master Protocols and Seamless Trials” Discussion
Yihua Zhao, Boehringer Ingelheim Pharmaceuticals, Inc.

2. Master Protocols in Practice: Tumor Agnostic Approvals
Larotrectini b
&
NTRK fusion positive solid tumors
Master Protocols in Practice: Tumor Agnostic Approvals
Dr. Nora Ku

3. Master Protocols
A master protocol is defined as a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure (FDA draft guidance “Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics”, September 2018)
Single investigational drug or investigational drug combination across multiple cancer populations – basket trial
Investigational drugs or investigational drug combination(s) in single cancer type: umbrella trials
Multiple investigational drugs and/or drug combination regimens across multiple tumor types: platform trial
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019

4. Basket Trial No control Not randomized
Woodcock & LaVange “Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both”, NEJM 2017; 377:
No control
Not randomized
Usually multiple disease subtypes share similar molecular characteristics
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019

5. Adaptive Multi-Arm Multi-Stage Design (aMAMS)
FWER
vs.
PWER
Adaptive Multi-Arm Multi-Stage Design (aMAMS)
Dr. Lingyun Liu

6. Umbrella Trial Can have one common control Randomized
Usually different investigational drugs target different molecular characteristics of the same disease type
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019

7. In Common
Can be adaptive, i.e. interim analysis to stop, expand or add a cohort
Basket trial: expand, drop or add a disease cohort
Umbrella trial: expand, drop or add an investigational drug arm
Usually involve biomarker
Basket trial: biomarkers that are common in different disease types
Umbrella: different biomarkers to indicate different molecular characteristics targeted by different investigational drugs
Precision medicine
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019

8. Challenges in Master Protocol Study Design and Analysis (1/2)
Pooling of data in Go/NoGo decision making – basket trial
Bayesian Optimal Phase 2 (BOP2) design (Zhou, Lee and Yuan, 2017)
Borrowing treatment information across indications
Bayesian hierarchical model
Homogeneity vs. heterogeneity
Calibrated Bayesian hierarchical model (CBHM) (Chu & Yuan, 2018, “A Bayesian Basket Trial Design Using a Calibrated Bayesian Hierarchical Model”, Clinical Trials, 15: )
Bayesian latent subgroup trial (BLAST) design (Chu & Yuan, 2018, “Bayesian Latent Subgroup Design for Basket Trials Accounting for Patient Heterogeneity”, JRSS Series C, 67: )
Control of type I error rate for multiple comparisons and interim analyses – umbrella trial / aMAMS
FWER vs. PWER
Still open question
Need simulations to evaluate
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019

9. Challenges in Master Protocol Study Design and Analysis (2/2)
Randomization
Imbalanced
Response adaptive randomization (RAR), e.g. I-SPY 2, ADAPT
Control
Share one common control
Temporal trend in control arm
Use of historical data/external control, e.g. Bayesian Augmented Control (BAC)
Adaptation
Stop, expand, or add treatment arms/disease cohorts
Bayesian
simulation
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019

10. Success Stories of Master Protocols (1/3)
Dr. Gideon Blumenthal “Master View”, DIA Master Protocol Workshop, Nov. 9, 2018
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019

11. Where we are and where we are going (2/3)
Dr. Gideon Blumenthal “Master View”, DIA Master Protocol Workshop, Nov. 9, 2018
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019

12. Where we are and where we are going (3/3)
Dr. Gideon Blumenthal “Master View”, DIA Master Protocol Workshop, Nov. 9, 2018
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019

13. Conclusions and Next Steps
Master protocols have gained more and more popularity and research interest recently because of the flexibility in the trial designs and efficiency in trial conduct
There are interesting/unresolved statistical issues that need to be tackled
pooling of data
control
type I error rate control
adaptation
randomization & blinding
Collaboration among multiple functions are needed to further understand the resolve these challenges
3rd Stat4Onc, "Master Protocols and Seamless Trials"
April 27, 2019