Role of the Project Statistician in a Phase II/III Seamless Trial

Overall Role

In a Phase II/III seamless trial, the Project Statistician serves as the architect and guardian of the statistical integrity of the study, ensuring that exploratory and confirmatory objectives are integrated within a single, regulatorily acceptable framework.

---

Key Responsibilities

1. Trial Design and Strategy Leadership

The Project Statistician:

• Designs the overall seamless framework, including Stage 1 (exploratory) and Stage 2 (confirmatory) components
• Defines dose/arm selection rules and decision criteria
• Ensures alignment between clinical objectives and statistical methodology

---

2. Interim Analysis and Adaptation Planning

The Project Statistician is responsible for:

• Specifying interim analyses, including timing, data cuts, and decision rules
• Defining adaptation procedures (e.g., dose selection, population enrichment)
• Preventing operational bias and information leakage

All adaptations must be fully pre-specified in the protocol and SAP.

---

3. Control of Type I Error and Statistical Validity

The Project Statistician:

• Develops and justifies methods to control the overall family-wise type I error
• Selects appropriate approaches such as:
• Combination tests
• Alpha-spending functions
• Closed testing procedures
• Evaluates operating characteristics through simulation studies

---

4. Data Pooling and Estimand Consistency

The Project Statistician:

• Defines which Stage 1 data may contribute to confirmatory analyses
• Addresses selection bias arising from arm or dose selection
• Ensures consistency of estimands, endpoints, and intercurrent event handling across stages

---

5. Regulatory Interaction and Risk Management

The Project Statistician:

• Leads statistical discussions with regulatory agencies (e.g., FDA Type C or End-of-Phase 2 meetings)
• Clearly articulates assumptions, risks, and mitigation strategies
• Interprets regulatory feedback and translates it into actionable protocol or SAP updates

---

Role Across the Trial Lifecycle

Before Trial Initiation

• Authors or co-authors statistical sections of the protocol and SAP
• Conducts simulations to evaluate design performance
• Aligns internal stakeholders on acceptable decision boundaries

---

During Trial Conduct

• Oversees interim analyses and ensures compliance with pre-specified rules
• Supports Data Monitoring Committees (DMCs) as appropriate
• Advises on adaptations without compromising trial integrity

---

After Trial Completion

• Leads confirmatory statistical analyses
• Ensures proper inclusion or exclusion of Stage 1 data
• Supports regulatory submissions with clear statistical justification

---

Common Pitfalls the Project Statistician Helps Prevent

• Uncontrolled inflation of type I error
• Post hoc modification of adaptation rules
• Inconsistent endpoints or estimands between stages
• Misinterpretation of exploratory results as confirmatory evidence

---

---

One-Sentence Summary

In a Phase II/III seamless trial, the Project Statistician ensures that speed and efficiency do not come at the expense of statistical rigor or regulatory acceptability.