Complex Innovative Designs (CID) Pilot Program

Organizers: Freda Cooner (Amgen)
Chair: Xiang Li (Janssen)
Vice Chair: Sudhakar Rao (Janssen)

Speakers:
Telba Irony (Janssen)
Peter Zhang (Otsuka)
Saptarshi Chatterjee (Lilly)

Abstracts:

Title: Complex Innovative Designs – The FDA Pilot Meeting Program
Speaker: Telba Irony (Janssen)

FDA is conducting a pilot program for highly innovative statistical trial designs (Complex Innovative Design or CID) for which analytically derived operating characteristics such as type I error rate and power may not be feasible. In this talk we will discuss the CID pilot program.

Title: Enrichment Design with High Placebo Response –
A case study in identifying targeted patients population in
major depressive disorder by enhanced enrichment design

Speaker: Peter Zhang (Otsuka)

Despite advances in clinical trial design, failure rates near 80% in phase 2 and 50% in phase 3 have recently been reported. The challenges to successful drug development are particularly acute in central nervous system trials such as for pain, schizophrenia, mania, and depression because high‐placebo response rates lessen assay sensitivity, diminish estimated treatment effect sizes, and thereby decrease statistical power. This paper addresses the importance of rigorous patient selection in major depressive disorder trials through an enhanced enrichment paradigm. This approach led to a redefinition of an ongoing, blinded phase 3 trial algorithm for patient inclusion (1) to eliminate further randomization of transient placebo responders and (2) to exclude previously randomized transient responders from the primary analysis of the double blind phase of the trial. It is illustrated for a case study for the comparison between brexpiprazole + antidepressant therapy and placebo + antidepressant therapy. Analysis of the primary endpoint showed that efficacy of brexpiprazole versus placebo could not be established statistically if the original algorithm for identification of placebo responders was used, but the enhanced enrichment approach did statistically demonstrate efficacy. Additionally, the enhanced enrichment approach identified a target population with a clinically meaningful treatment effect. Through its successful identification of a target population, the innovative enhanced enrichment approach enabled the demonstration of a positive treatment effect in a very challenging area of depression research.

Title: Statistical Challenges and Opportunities for a Chronic Pain Master Protocol
Speaker: Saptarshi Chatterjee  (Eli Lilly)

In September of 2019, Eli Lilly and Company announced that the FDA had accepted its application to the Complex Innovative Trial Designs (CID) Pilot Meeting Program. The trial accepted into the CID program is a phase 2 master protocol in chronic pain, a condition that can cause limitations in general activities and daily living and can tremendously burden the patient, family, and caregivers. The chronic pain master protocol will efficiently evaluate the safety and efficacy of multiple assets in multiple pain types. During this talk, we will provide an overview of the design, including both the challenges and opportunities of conducting a master protocol. A key feature of the master protocol is to balance the standardization of design elements where possible, while still allowing for the flexibility to meet the needs for each asset that may enter the master protocol. The statistical model used in the design allows for the borrowing of key statistical information between assets and pain types, either through the pooling of data or through more sophisticated approaches such as Bayesian hierarchical modeling. Pros and cons of various data borrowing strategies will be shared and evaluated, with key operating characteristics being compared between strategies.