Adaptive Clinical Trials: Innovations in Trial Design, Management, and Analysis
By Hermann A.M. Mucke, PhD
CHAPTER 1
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
CHAPTER 2
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
CHAPTER 3
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
Chapter 4
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
Chapter 5
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
Chapter 6
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 and Comments
Chapter 7
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
Chapter 8
INTERVIEWS
References
Glossary of Selected Terms
Company Index with Web Addresses