Top
| Acknowledgements | |
| Forward | |
| Opportunity for Efficiency | |
| The Adaptive Solution | |
| An Industrial Success Story | |
| Signs of Trouble Ahead | |
| Converging Challenges | |
| 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 | |
| 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 | |
| Conclusion | |
| Design Adaptations Part One: Finding the Right Dose | |
| Background | |
| Types of Design Adaptations | |
| Order of Discussion | |
| Dosing Nomenclature | |
| etermining Maximum Safe Dose | |
| Single Arm | |
| Continual Reassessment Method | |
| Other Bayesian Dose-Finding Methods | |
| Determining Optimal Dose (Pruning) | |
| Multiple Arms | |
| Improvements over Conventional Approaches to Dose Finding | |
| Dose Selection in Practice | |
| Optimizing Dose Selection | |
| Minimizing Costs vs. Maximizing Information | |
| Surrogate Endpoints | |
| Conclusion | |
| Design Adaptations Part Two: Additional Design Changes | |
| Sample-Size Reestimation | |
| 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 | |
| Adaptive Randomization | |
| Response-Adaptive Randomization | |
| Other Forms of Adaptive Randomization | |
| Other Types of Design Adaptations | |
| Noninferiority-to-Superiority Design | |
| Adaptive Hypotheses and Subpopulations | |
| Treatment Switching | |
| Conclusions | |
| Operational Adaptations | |
| Design and Operational Adaptations | |
| The Nature and Significance of Operational Adaptations | |
| Implementing Operational Adaptations | |
| Enrollment and Other Site Issues | |
| Data Quality | |
| Monitoring | |
| Site Closeout and Database Lock | |
| Supporting Functions for Efficient Operations | |
| The Bottom Line | |
| Agile Clinical Development | |
| Benefits of Agile Development | |
| A Development Example | |
| Program Planning | |
| Safety Testing (Phase I) | |
| Design | |
| Planning | |
| Operational Considerations | |
| Putting the Plan into Action | |
| Benefits Realized | |
| Transition to Dose-Finding Study | |
| Dose Finding (Phase II) | |
| Design | |
| Planning | |
| Operational Considerations | |
| Putting the Plan into Action | |
| Benefits Realized | |
| Transition to Confirmatory Studies | |
| Confirmatory Testing (Phase III) | |
| Design | |
| Planning | |
| Operational | |
| Putting the Plan into Action | |
| Benefits Realized | |
| Transition to Regulatory Filings | |
| Summing Up: The Power of Agile Development | |
| 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 | |
| Looking Ahead | |
| Advisory and Oversight Groups | |
| Optimizing the Planning Process | |
| Regulatory Discussions | |
| Contingency Planning | |
| Planning Tools and Techniques | |
| Decision Trees | |
| Simulation | |
| Uncertainties in Clinical Research | |
| Simulation Tools | |
| Simulation Step by Step | |
| The Limitations of Simulation | |
| Conclusions | |
| 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 | |
| Prior Distributions | |
| How Bayesian Statistics Works | |
| Bayesian Statistics in the Real World | |
| Bayesian Methods in Clinical Research | |
| Comparing Bayesian and Frequentist Methods.\ | |
| Prior Distributions | |
| The Pharma Context | |
| Learning and Confirming | |
| Ethical and Operational Issues | |
| Regulatory Considerations | |
| Conclusions | |
| Frequentists, Bayesians, and Pragmatists | |
| The Agile Platform | |
| Essential Types of Data | |
| Management Cycles in Clinical Studies | |
| The Common Platform for Design and Operational Adaptations | |
| Data Capture | |
| Data-Capture Technologies | |
| The First Generation | |
| The Second Generation | |
| The Third Generation | |
| Data Cleaning and Validation Technology | |
| Data Analysis Tools | |
| Randomization | |
| Site Management | |
| Supply-Chain Management | |
| Communications | |
| Conclusions | |
| 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 | |
| A Eight-Point Program for Embracing the Adaptive Approach | |
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