The Agile Approach to Adaptive Research: Optimizing Efficiency in Clinical Development
The pharmaceutical industry today faces a deepening crisis: inefficiency in its core business, the development of new drugs. The Agile Approach to Adaptive Research offers a solution. It outlines how adaptive research, using already-available tools and techniques, can enable the industry to streamline clinical trials and reach decision points faster and more efficiently.
With a wealth of real-world cases and examples, author Michael Rosenberg gives readers a practical overview of drug development, the problems inherent in current practices, and the advantages of adaptive research technology and methods. He explains the concepts, principles, and specific techniques of adaptive research, and demonstrates why it is an essential evolutionary step toward improving drug research and development.
Chapters explore such subjects as:
The adaptive concept
Design and operational adaptations
Agile clinical development
Safety and dose finding
Statistics in adaptive research, including frequentist and Bayesian approaches
Data management technologies
The future of clinical development
By combining centuries-old intellectual foundations, recent technological advances, and modern management techniques, adaptive research preserves the integrity and validity of clinical research but dramatically improves efficiency.
1 Opportunity for Efficiency.
The Adaptive Solution.
An Industrial Success Story.
Signs of Trouble Ahead.
The Struggle to Replace Lost Revenues.
Clinical Research is the Key.
Behind the High Costs of Clinical Development.
High Costs and Increasing Prices.
Growing Pressures Mandate Greater Efficiency.
The High Risk of Current Development Practices.
Economic Consequences of Faster Clinical Development.
Thriving in a New Era.
2 Defining and Extending the Adaptive Approach.
The Adaptive Concept.
Knowledge, Time and Decision-Making.
The Value of Early Knowledge.
The Spectrum of Design and Operational Adaptations.
Maximizing the Adaptive Approach: Agile Clinical Development.
Measure Performance in Real-time.
Metrics in Action.
Right Information to the Right Eyes at the Right Time.
Make Timely Decisions.
Organize Work in Lean Processes.
Rework in Clinical Studies.
Backflow of Patient Data.
Match Technology with Tasks.
Objections to Adaptive Methods.
Integrity and Validity.
The Regulatory Environment.
The Complexity of Clinical Research.
3 Design Adaptations Part One: Finding the Right Dose.
Types of Design Adaptations.
Order of Discussion.
Determining Maximum Safe Dose.
Continual Reassessment Method.
Other Bayesian Dose-Finding Methods.
Determining Optimal Dose (Pruning).
Improvements over Conventional Approaches to Dose Finding.
Dose Selection in Practice.
Optimizing Dose Selection.
Minimizing Costs versus Maximizing Information.
4 Design Adaptations Part Two: Additional Design Changes.
The Trouble with Planning Estimates.
The High Cost of "Underbuilt" Studies.
The Benefits of Reestimation and Rightsizing.
Reestimation and Trial Stages.
Rules to Restrict Reestimation.
Adjusting Sample Size for Nuisance Parameters.
Seamless Designs: Combining Multiple Phases.
When to Consider Seamless Studies.
Seamless Phase I/Phase II Trials.
Seamless Phase II/Phase III Trials.
Planning Issues in Seamless Trials.
Phase I-II-III Designs.
Other Forms of Adaptive Randomization.
Other Types of Design Adaptations.
Adaptive Hypotheses and Subpopulations.
5 Operational Adaptations.
Design and Operational Adaptations.
The Nature and Significance of Operational Adaptations.
Implementing Operational Adaptations.
Enrollment and Other Site Issues.
Site Closeout and Database Lock.
Supporting Functions for Efficient Operations.
The Bottom Line.
6 Agile Clinical Development.
Benefits of Agile Development.
A Development Example.
Safety Testing (Phase I).
Putting the Plan into Action.
Transition to Dose-Finding Study.
Dose Finding (Phase II).
Putting the Plan into Action.
Transition to Confirmatory Studies.
Confirmatory Testing (Phase III).
Putting the Plan into Action.
Transition to Regulatory Filings.
Summing Up: The Power of Agile Development.
7 Planning Adaptive Programs.
Determining Design Adaptations and their Requirements.
Determining Operational Requirements to Support Design Adaptations.
Ensuring the Ability to Meet Operational Requirements.
The Importance of Programmatic Thinking.
Advisory and Oversight Groups.
Optimizing the Planning Process.
Planning Tools and Techniques.
Uncertainties in Clinical Research.
Simulation Step by Step.
The Limitations of Simulation.
Sources of Simulation Software.
8 Statistics and Decision Making in Adaptive Research.
The Frequentist Approach.
What Frequentist Results Say about the Results of a Clinical Study.
Using Frequentist Results to Make Decisions Based on Individual Trials.
Other Issues with Frequentist Methods.
The Bayesian Approach.
How Bayesian Statistics Works.
Bayesian Statistics in the Real World.
Bayesian Methods in Clinical Research.
Comparing Bayesian and Frequentist Methods.
The Pharma Context.
Learning and Confirming.
Ethical and Operational Issues.
Frequentists, Bayesians, and Pragmatists.
9 The Agile Platform.
Essential Types of Data.
Management Cycles in Clinical Studies.
The Common Platform for Design and Operational Adaptations.
The First Generation.
The Second Generation.
The Third Generation.
Data Cleaning and Validation Technology.
Data Analysis Tools.
10 The Future of Clinical Development.
Is Restructuring an Alternative to Improving Clinical Development?
Greater Efficiency: Changes that Everyone Can Applaud.
Biotechs and Emerging Low-Cost Competitors.
Globalization, Offshoring, and Outsourcing.
Managing More Complex Trials.
Individualized Medicine Demands Greater Efficiency.
A More Important Role for Postmarketing Studies.
The Reward for Greater Efficiency.
Financial Implications of the Agile Approach.
Financial Implications of the Agile Approach for the Drug Industry.
A Brighter Future for Clinical Development.
First Steps toward Agile Development.
An Eight-Point Program for Embracing the Adaptive Approach.
"It is ideal for senior executives who want a strategic view of adaptive methods, managers looking for practical opportunities to significantly improve the efficiency of their operations, and statisticians interested in learning the broader ramifications of their arcane expertise." (Journal of Clinical Research Best Practices, April 2010)
"Rosenberg captures the current excitement surrounding adaptive clinical research, and provides a very readable introduction to the methodologies involved in implementing such research." (Journal for Clinical Studies, March 2010)