Innovative Phase 2 Designs: Understanding Platform and Basket Trials

Introduction

Traditional Phase 2 trials typically evaluate one treatment in one patient population using a fixed design. However, the evolution of precision medicine, rare disease drug development, and oncology research has led to the rise of adaptive, multi-arm trial designs such as platform trials and basket trials. These innovative designs increase trial efficiency, allow simultaneous testing of multiple interventions, and enable real-time decision-making. In this tutorial, we explore how platform and basket trials are applied in Phase 2, their advantages, challenges, and regulatory perspectives.

What Are Platform and Basket Trials?

1. Basket Trials

A basket trial tests a single therapeutic intervention across multiple disease types or subtypes that share a common molecular or genetic characteristic.

• Example: Testing one drug in multiple cancers with the same genetic mutation (e.g., BRAF V600E)
• Each “basket” represents a separate disease site or histology

2. Platform Trials

A platform trial is a perpetual, multi-arm trial that allows for ongoing testing of multiple therapies within a disease, adding or dropping arms based on interim results.

• Can include shared controls and adaptive randomization
• Designed to continue as a research “platform” over time

Why Use Platform and Basket Designs in Phase 2?

• Efficiency: Evaluates multiple hypotheses with fewer patients and shorter timelines
• Precision: Matches therapies with biomarker-defined subgroups
• Flexibility: New arms can be added without launching a new trial
• Ethical use of controls: Shared control arms reduce placebo burden

Design Elements of Basket Trials

• Single treatment across genetically defined subgroups (regardless of organ/site)
• May include a central primary endpoint (e.g., objective response rate)
• Each basket is statistically powered independently

Design Elements of Platform Trials

• Common infrastructure (protocol, control arm, data platform)
• Pre-planned interim analyses using adaptive Bayesian or frequentist models
• Arms may be stopped early for futility, efficacy, or safety
• New therapies or regimens can be introduced during the trial

Examples of Phase 2 Basket and Platform Trials

Basket Trial Example

NCI-MATCH (US): Evaluates targeted therapies in patients with different cancer types sharing the same mutation.

Platform Trial Example

I-SPY 2 Trial: A neoadjuvant breast cancer platform trial testing multiple investigational agents using adaptive randomization and shared control.

Statistical Considerations

• Each basket should control its own Type I error rate
• Platform trials may use alpha sharing or hierarchical testing
• Response-adaptive randomization increases probability of assignment to promising arms
• Bayesian modeling is commonly used for interim decision-making

Operational Requirements

• Strong central coordination and data management infrastructure
• Integrated electronic data capture and real-time analytics
• Protocol amendments and additions must be pre-planned and regulatorily aligned

Regulatory Considerations

FDA (U.S.)

• Supports master protocols in oncology and infectious diseases
• Requires clear rules for adaptation and statistical inference
• Guidance: “Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics”

EMA (Europe)

• Allows basket/platform trials with adequate control of multiplicity
• Scientific Advice recommended early for adaptive designs

PMDA (Japan)

• Supports platform trials under collaboration with global sponsors
• Recommends robust justification and trial simulations

CDSCO (India)

• Still emerging; accepts basket trials on case-by-case basis
• Requires thorough review by Subject Expert Committees (SECs)

Advantages of Platform and Basket Designs

• Accelerated evaluation of treatments for rare or biomarker-defined populations
• More efficient use of resources
• Dynamic and future-proof trial infrastructure

Challenges to Consider

• Complex regulatory submissions and approvals for adaptations
• Higher operational and statistical complexity
• Logistical burden of managing multiple drugs and arms
• Need for advanced trial simulation and data monitoring tools

Conclusion

Basket and platform trials represent a modern and efficient evolution of Phase 2 study design. Their flexibility, adaptability, and efficiency make them ideal for exploring therapies in precision medicine and complex disease landscapes. However, their implementation requires careful planning, advanced statistical strategies, and early alignment with regulators. When executed well, these innovative designs can accelerate drug development and deliver targeted therapies to patients faster.