Adaptive Clinical Trials: Innovations in Trial Design, Management, and Analysis

Table of Contents

INTRODUCTION

• 1.1. General Objectives of a Clinical Trial Program
  • Phase I
  • Phase II
  • Phase III
• 1.2. Science, Regulatory Affairs, and Business: Interdependence and Inertia

THE TRADITIONAL CLINICAL TRIAL: AN EXPERIMENT IN MEDICAL STATISTICS

• 2.1. The Classical Phase I Trial
• 2.2. Implicit and Explicit Assumptions for Phase II and III Efficacy Trials
  • Representativeness of the Trial Population
  • Matching Comparison Groups
  • Strength of Treatment Effect and Compliance
  • Choice of Treatment Duration and Outcome Measures
  • The Neyman-Pearson Approach: Fixed Parameters and the Null Hypothesis
• 2.3. Phase III Today: Unmanageably Large, Prohibitively Expensive
• 2.4. Rescue Attempts for Efficacy Trials with Unexpected Negative Outcome
• 2.5. The Ethical Side
  • The Call to Minimize Exposure in Phase I
  • Forced Unblinding, Active Comparators, and Add-on Trials

ADAPTIVE TRIAL DESIGNS

• 3.1. The Need for Alternate Approaches to Clinical Trials
• 3.2. Adaptive Integration of Pre-existing and Trial-Emergent Knowledge
  • Building an Adaptive Design: "Flexible" Does Not Mean "Less Controlled"
  • Adaptive Statistics: Bayes' Theorem
  • Monte Carlo Methods: Not Gambling, but Probability Design
• 3.3. Application to Phase I: Continual Reassessment Methods and Accelerated Titration Schemes
  • The Expanding Spectrum of CRMs
  • Other Methods
• 3.4. Applications to Phase II: Achieving Dose Finding with Adaptive Randomization
  • The PhRMA Working Group on Adaptive Dose-Ranging Studies
  • Case Studies of Phase IIa Dose-Finding Studies Using Adaptive Designs
• 3.5. Adaptive Strategies for Phase III: The Greatest Challenge
  • Challenges of Trial Design
    • Response-Adaptive Randomization
    • Modifying Trial Endpoints and Outcome Measures
  • Challenges of Conduct: Monitoring Adaptive Trials
    • Staff Training Requirements
    • The Pervasive Near-Real-Time Paradigm
    • Problems in Trial Organization and Logistics
  • Challenges of Prognosis, Analysis, and Interpretation
    • The Simulated Trial: Probabilistic Predictions of the Trial Course
    • Synthesizing and Reporting Outcomes of Adaptive Trials
      • Incorporating Direct and Indirect Evidence
      • A New Way of Handling Missing Data
      • Reporting Issues
  • Case Studies in Adaptive Trials and Their Simulation
    • "Post-hoc Prognosis": Modeling Bayesian Stop Decision Based on Real Trial Data
      • Chemoprophylaxis for Bacterial Coinfection
      • Cure Rate Models for Malignant Melanoma
    • Selected Examples of Actual Adaptive Phase III Trials
      • PURSUIT: Eptifibatide in Unstable Angina
      • ASTIN: A Bayesian Adaptive Dose-Response Trial in Acute Stroke
      • ADVENT: Anti-Diarrhea Therapy in HIV Disease
      • COPERNICUS: A Beta Blocker in Advanced Heart Failure

HYBRID AND SEAMLESS DESIGNS

• 4.1. Blurring the Line Between Trial Stages
• 4.2. Phase I/II Hybrid Designs
• 4.3. The Integrated Phase II/III Adaptive Trial
  • PhRMA Adaptive Design Workshop

THE ADAPTIVE APPROACH, INDUSTRY, AND REGULATORY AUTHORITIES

• 5.1. The Industry Position
• 5.2. FDA, EMEA, and ICH Positions
  • US Food and Drug Administration
  • EMEA Guidelines in Preparation
  • ICH: Toward Future Global Harmonization of Global Trial Principles?
• 5.3. Summary

CHI INSIGHT PHARMA REPORTS- ADAPTIVE TRIALS IN CURRENT PRACTICE SURVEY- MAY 2007

• 6.1. Participant Demographics
• 6.2. Analysis of the Number and Type of Trials Conducted
• 6.3. Motivations, Plans for the Future, and Perceived Impediments to Adaptive Trials
• 6.4. Summary Interpretation ansd Comments

ADAPTIVE TRIALS TO 2015: SCENARIOS FOR ACCEPTANCE

• 7.1. A Multilayered Web of Concern
• 7.2. Three Scenarios to 2015
  • Scenario A
  • Scenario B
  • Scenario C
  • Comparison of Scenarios
• 7.3. Other Factors Beyond Anticipation
• 7.4. Summary

INTERVIEWS

References

Glossary of Selected Terms

Company Index with Web Addresses