Innovative Clinical Trial Design and Management: Trends, success stories and impact upon R&D budgets

Table of Contents

Executive Summary

• Introduction
• Adaptive clinical trials
• Adaptive dose-finding studies
• Seamless adaptive trials
• Adaptive trials in drug-diagnostic co-development
• Simulation, logistics and technology in adaptive trials
• Regulating adaptive trials
• Outlook for adaptive trials in the pharma industry

Chapter 1 Introduction

• Summary
• State of the industry
• Rising development costs
• Longer development times
• Increasing complexity
• Higher attrition
• Increasing innovation
• Innovation in drug discovery and development
• Adaptive clinical trials - an introduction
• Report outline

Chapter 2 Adaptive clinical trials

• Summary
• Introduction
• Adaptive designs
• Flexibility in adaptive trials
• Statistics for adaptive designs
• Group Sequential Designs
• Stopping early for benefit - controversy
• Case study: RALES - a Searle Phase 3 Group Sequential Design
• Case study: CAPTURE - a Centocor study in refractory unstable angina
• Case study: Proof-of-concept study in neuropathic pain - GlaxoSmithKline
• Case study: PURSUIT - a Millennium Pharmaceuticals study in unstable angina
• Sample size re-estimation
• Case study: a group sequential study for sample size re-estimation
• Case study: GlaxoSmithKline pivotal study for Advair Diskus
• Response adaptive randomization
• Case study: Troxacitabine in acute myeloid leukemia
• Case study: Eli Lilly out-patient study in depression
• Case study: Three dosing schedules of decitabine in myelodysplastic syndrome
• Case studies: A study of sorafenib in different types of cancer
• Bayesian methods in First in Man studies
• Conclusions

Chapter 3 Adaptive dose-finding studies

• Summary
• Introduction
• Case study: ASTIN
• Case study: Phase 2 Pfizer dose-ranging study in neuropathic pain
• Case study: Phase 2 Merck dose-finding study of anti-migraine compound
• Case study: Phase 3 Napo Pharmaceuticals study in HIV patients with diarrhea
• The PhRMA Adaptive Dose-Ranging Studies Working Group
• Conclusions

Chapter 4 Seamless adaptive trials

• Summary
• Introduction
• Pros, cons and controversy
• Speeding up clinical development
• Efficiency gains in seamless trials
• When are seamless designs appropriate?
• Regulatory view of seamless Phase 2b/3 studies
• Case study: Phase 1/2 trials in oncology
• Case study: Phase 2b/3 Novartis study in a chronic disease indication
• Case study: HORIZON III an AstraZeneca study in oncology
• Conclusions

Chapter 5 Adaptive trials in drug-diagnostic co-development projects

• Summary
• Introduction
• Biomarkers and classifiers
• Co-development of drugs and companion diagnostics
• Pivotal Phase 3 trial designs using predictive biomarkers
• Enrichment designs
• Patient stratification
• Sample size calculation for enrichment and stratification designs
• Adaptive signature designs
• Biomarker adaptive threshold determination
• Case study: identifying a classifier of response to Velcade
• Conclusions

Chapter 6 Simulation, logistics and technology in adaptive trials

• Summary
• Introduction
• Preplanning and simulation
• Case study: A study design and simulation using Cytel' s East® simulation package
• Logistical issues
• Real-time data collection
  • Electronic data capture (EDC)
  • Electronic patient reported outcomes (ePRO)
  • Interactive voice recognition and interactive web response
  • Companies involved in real-time data collection
• Maintaining data confidentiality
• Minimizing operational bias and assuring consistency between study stages
• Clinical supply management
• Case study: simulating drug supply
• Summary - logistical considerations for adaptive trials
• Conclusions

Chapter 7 Regulating adaptive trials

• Summary
• Introduction
• FDA guidance on adaptive designs
• EMEA guidance on adaptive designs
• PhRMA working groups
• Conclusions

Chapter 8 Outlook for adaptive trials in the pharma industry

• Summary
• Introduction
• Adaptive trials and success rates in clinical drug development
• Costs in adaptive clinical trials
• Time means money
• Costs in a dose-finding clinical trial
• Cost savings in a seamless Phase 2b/3 trial
• Cost savings in a random adaptive allocation trial
• Costs in a sample size re-estimation study
• Costs of clinical trials in pharmacogenomics
• Pharma' s uptake of adaptive designs
• Outlook for adaptive trials

Chapter 9 Appendix

• Primary research methodology
• Index
• Glossary
• Glossary

List of Figures

• Figure 1.1: New drug approvals versus R&D costs, 1995-2006
• Figure 1.2: Trend towards longer drug development times, 1997 to 2005
• Figure 1.3: Increasing complexity of clinical trial
• Figure 1.4: Change in attrition rates, 1994 to 2000
• Figure 1.5: Increasing innovation in drug development
• Figure 1.6: Attrition rates and development times by drug novelty status
• Figure 2.1: Summary of motivations for using adaptive trials
• Figure 2.2: Examples of motivations for adapting clinical trials
• Figure 2.3: Advantages and disadvantages of increasing the flexibility of adaptive trial designs
• Figure 2.4: Bayes Theorem explained
• Figure 2.5: How Bayesian statistics work
• Figure 2.6: Data from interim monitoring visits during the RALES study
• Figure 2.7: The random play-the-winner trial design
• Figure 2.8: Response adaptive randomization - case study with troxacitabine
• Figure 3.1: Advantages of adaptive dose-finding studies over traditional methods
• Figure 3.2: Structure of the ASTIN study
• Figure 3.3: Data from the ASTIN study
• Figure 4.1: Structure of an adaptive seamless clinical trial
• Figure 4.2: Key aims of each phase of drug development
• Figure 4.3: Seamless trials in Phases 1, 2 and 3
• Figure 4.4: When to use seamless adaptive Phase 2b/3 designs
• Figure 4.5: Novartis' ongoing seamless adaptive Phase 2b/3 study design
• Figure 5.1: Examples of targeted treatments and their companion diagnostics
• Figure 5.2: Definitions of predictive and prognostic biomarkers
• Figure 5.3: Co-development of a drug and companion diagnostic
• Figure 5.4: Types of study design for use in drug-diagnostic co-development
• Figure 5.5: The enrichment design
• Figure 5.6: Including classifier positive and negative patients: stratification
• Figure 5.7: Marker-based strategy for patient stratification
• Figure 5.8: Adaptive signature designs
• Figure 5.9: Discovery and testing of a predictive classifier for Velcade
• Figure 6.1: Case study: stopping probabilities calculated using Cytel' s East software
• Figure 6.2: Integrative electronic systems in adaptive trial designs
• Figure 6.3: Working Group proposal for sponsor involvement in decision making
• Figure 6.4: Working Group proposal for selection decisions
• Figure 6.5: Choosing an adaptive design: infrastructure and process requirements
• Figure 8.1: Attrition rates and costs in drug development
• Figure 8.2: Adaptive trials may help to restore success rates
• Figure 8.3: Adaptive trials may help to restore success rates
• Figure 8.4: Cost savings in a hypothetical seamless Phase 2b/3 adaptive trial

List of Tables

• Table 1.1: Advantages and disadvantages of using adaptive clinical trial designs
• Table 1.2: How adaptive designs can fight attrition
• Table 2.1: Group sequential study design may save time
• Table 2.2: Consequences of incorrect planning- treatment difference and/or standard deviation
• Table 2.3: Comparison of simple randomization and response-adaptive randomization
• Table 2.4: Results of a response adaptive randomization study in depression
• Table 3.1: Bayesian designs can investigate more doses
• Table 4.1: Advantages and disadvantages of seamless adaptive designs
• Table 5.1: Efficiency of enrichment study designs
• Table 5.2: Comparison of number of patients needed for enrichment designs: gefitinib example
• Table 5.3: Free software available for calculating sample sizes in pharmacogenomic studies
• Table 6.1: Integrity and validity in adaptive clinical trials
• Table 6.2: Companies offering statistical expertise for adaptive trials
• Table 6.3: Providers of software, tools and services for adaptive trials
• Table 6.4: Clinical trial supply simulation software providers
• Table 8.1: Cost savings for various options in COPD trial
• Table 8.2: Retrospective analysis identifies benefits of an adaptive design
• Table 8.3: Effect of HER2 testing on the development of Herceptin
• Table 8.4: Potential additional sales for a drug targeted to 25% of patients tested
• Table 8.5: Phase distribution of case studies, PhRMA Adaptive Designs Working Group
• Table 8.6: Indications in which Bayesian adaptive designs have been used