Advances in the Design and Regulation of Adaptive Clinical Trials

Date: November 22, 2010
Pages: 129
Price:
US$ 3,835.00
Publisher: Business Insights
Report type: Strategic Report
Delivery: E-mail Delivery (PDF)
ID: AAD661D68F3EN
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Advances in the Design and Regulation of Adaptive Clinical Trials
As the pharma industry comes under increasing pressure to replenish revenues which are under threat from generic competition, there is an increased focus on technologies and trial designs which aim to maximize success and reduce development time. This report reviews the use of adaptive designs across all phases of development. Dose-ranging and seamless trials are explored through case studies of important adaptive trials. Regulation by the FDA and EMA is covered in detail. The report also reviews logistical and technological aspects of adaptive designs as well as presenting an outlook for their use in drug development.

Scope of this research
  • Learn how the largest companies are applying adaptive methods to improve drug development.
  • Identify situations in which adaptive trials could benefit drug development in your company.
  • Analyze the importance of adaptive trials in the context of a drug’s development program and a company’s portfolio of compounds.
  • Assess how the FDA’s draft guidelines on adaptive trials are influencing companies to use adaptive trials in their drug development programs.
  • Evaluate the providers of key skills and technologies for adaptive trials.
Research and analysis highlights

The large majority of adaptive trials currently being undertaken in the pharma industry are Phase 2 – ‘Learning’ – trials that aim to establish the most effective dose and the dose response curve. Exploratory trials may also aim to combine proof of concept with dose finding, stop early for futility or investigate biomarkers and patient subsets.

Ground-breaking research using adaptive designs with biomarkers is currently shaping the future of research in the field of oncology. The highly collaborative I SPY2 study may deliver changes to the field on a number of levels such as demonstrating the feasibility of cooperation at this level and the efficiency of the adaptive design.

Companies are learning how to implement adaptive studies in the confirmatory stages of drug development and regulators are developing their views on what is acceptable. Interaction with regulators to gain acceptance for a particular design and implementation plan, and proper documentation of decisions and actions, are a key success factors.

Key reasons to purchase this research
  • What is the current regulatory position on the use of adaptive trials in the exploratory and confirmatory stages of drug development?
  • Where and how have adaptive trials been used by the industry already? Which companies are pioneering their use?
  • How can adaptive trials improve drug development?
  • What are the costs associated with adaptive trials? Can they save money?
  • How can adaptive trials be used in clinical trials with biomarkers?
About the authors
Disclaimer
Executive summary
Introduction
Adaptive trials in the ‘learn’ development phase
Adaptive trials in the ‘confirm’ development phase
Simulation in the design of adaptive trials
Logistics and technology requirements for adaptive trials
Regulation of adaptive trials
Outlook for adaptive trials

CHAPTER 1 INTRODUCTION

Summary
Introduction
Defining adaptive clinical trials
Why adapt?
Redesigning drug development
Potential advantages of adaptive trials
Companies working together
Report outline

CHAPTER 2 ADAPTIVE TRIALS IN THE ‘LEARN’ DEVELOPMENT PHASE

Summary
Introduction
Finding the right dose
The Adaptive Dose-Ranging Studies Working Group
Case studies
Pfizer’s ASTIN study
Dose-ranging study in neuropathic pain (Pfizer)
Dose-finding study of anti-migraine compound (Merck & Co)
Adaptive dose finding study (Wyeth)
A Bayesian dose-finding trial in patients with diabetes (Wyeth)
A Bayesian adaptive randomization seamless Phase IIa/b study (Abbott Labs)
Adaptive Phase I oncology trials: the continual re-assessment method
Biomarkers and adaptation in the ‘learn’ phase
Adaptive trials with predictive biomarkers
Adaptive signature designs
Adaptive randomization designs
Case study: Biomarker-Integrated Approaches of Targeted Therapy of Lung Cancer Elimination (BATTLE) Trial
Case study: I-SPY2
Conclusions

CHAPTER 3 ADAPTIVE TRIALS IN THE ‘CONFIRM’ DEVELOPMENT PHASE

Summary
Introduction
‘Seamless’ confirmatory trials
Case studies
Eli Lilly case study
Novartis case study 1
Novartis case study 2
AstraZeneca case study
Napo Pharmaceuticals case study
Cempra Pharmaceuticals case study
Pros and cons of seamless designs
Regulatory view
White space
When are seamless designs appropriate?
Sample size re-estimation in confirmatory trials
Conclusions

CHAPTER 4 SIMULATION IN THE DESIGN OF ADAPTIVE TRIALS

Summary
Introduction
Clinical trial simulations
Including pharmacometric data
Providers of clinical trial simulation software
Berry Consultants
Cytel Inc
Documenting simulations
Statisticians in drug development
Conclusions

CHAPTER 5 LOGISTICS AND TECHNOLOGY REQUIREMENTS FOR ADAPTIVE TRIALS

Summary
Introduction
Suppliers of clinical technologies
Consolidation within the industry
Endpoint selection and real-time data collection
Technologies for data collection and their integration
Case study: Timaeus (Cmed Technology Ltd)
Electronic data capture (EDC)
Standards in EDC
Special considerations for safety parameters
Interactive voice recognition and interactive web response
Electronic patient reported outcomes (ePRO)
Cleaning data
Testing data flow
Clinical supply management
Key challenges in supply chain management
IXRS
Simulation
Case study – clinical trial supply scenario simulation
Case study – Wyeth dose finding trial
Documenting design decisions
Conclusions

CHAPTER 6 REGULATION OF ADAPTIVE TRIALS

Summary
Introduction
The EMA position on adaptive designs
FDA draft guidance on adaptive designs
Bayesian statistics
Regulatory documents
Interacting with the FDA
Industry response to the draft guidelines
Causes for regulatory concern
Type 1 error rate control
Maintaining confidentiality
Conclusions

CHAPTER 7 OUTLOOK FOR ADAPTIVE TRIALS

Summary
Introduction
Impact of adaptive clinical trials on costs and success in drug development
Cost savings associated with stopping early
Modeling costs and the probability of success
Portfolio planning for clinical trials with biomarkers
Organizational changes for adaptive trials
Outlook for adaptive trials
Conclusions
Appendix
Primary research methodology
Acknowledgments
Glossary
Bibliography

TABLE OF FIGURES

Figure 1: Summary of strategic motivations for using adaptive trials
Figure 2: Examples of strategic motivations for adapting clinical trials
Figure 3: The ‘learn and confirm’ model of drug development
Figure 4: Types of dose finding adaptive trial design tested by the PhRMA Adaptive Dose-Ranging Studies Working Group in 2009
Figure 5: Structure of the ASTIN study
Figure 6: Data from the ASTIN study
Figure 7: Design of an adaptive dose finding study with telcagepant (Merck & Co)
Figure 8: The adaptive signature design
Figure 9: Design of the BATTLE study to identify molecular signatures targeted by drugs for non-small cell lung cancer
Figure 10: Overview of the I-SPY2 trial design
Figure 11: Design of operationally and inferentially seamless trials
Figure 12: Key elements of Eli Lilly’s seamless Phase II/III study in patients with type 2 diabetes
Figure 13: Design Eli Lilly’s seamless Phase IIb/III study in patients with type 2 diabetes
Figure 14: Key elements of Novartis’ seamless Phase IIb/III study in COPD
Figure 15: Novartis’ completed seamless adaptive Phase IIb/III study design
Figure 16: Seamless adaptive Phase IIb/III trial designs; Novartis case study
Figure 17: HORIZON III Phase II/III clinical study
Figure 18: When to use seamless adaptive Phase IIb/III designs
Figure 19: The clinical trial design simulation process
Figure 20: Information utilized in model-based drug development
Figure 21: Choosing an adaptive design: infrastructure and process requirements
Figure 22: Providers of clinical technologies to support adaptive trials
Figure 23: Automated implementation for adaptive designs
Figure 24: Acceptance of different adaptive designs
Figure 25: Relationship between the size of Phase IIb and the probability of success in Phase III
Figure 26: Relationship between the size of Phase IIb and the product’s expected net present value

TABLE OF TABLES

Table 1: Definitions of adaptive clinical trials
Table 2: Advantages and disadvantages of using adaptive clinical trial designs
Table 3: Bayesian designs can investigate more doses
Table 4: Comparison of features of different designs for a dose finding study
Table 5: Adaptive dose finding study comparisons: probabilities of success and potential cost savings
Table 6: Definitions of four key types of biomarker
Table 7: Advantages and disadvantages of seamless adaptive designs
Table 8: Consequences of incorrect planning for treatment difference and/or standard deviation
Table 9: Leading companies offering statistical expertise for adaptive trials
Table 10: Cost savings associated with stopping early for futility
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Pharma Clinical Trial Services: World Market 2013-2023 US$ 2,400.00 Jan, 2013 · 189 pages

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