Fundamentals of Clinical Trials [5 ed.] 9783319185392, 2015942127

Table of contents :
1 Introduction to Clinical Trials
Fundamental Point
What Is a Clinical Trial?​
Clinical Trial Phases
Phase I Studies
Phase II Studies
Phase III/​IV Trials
Why Are Clinical Trials Needed?​
Problems in the Timing of a Trial
Study Protocol
Appendices
References

2 Ethical Issues
Fundamental Point
Planning and Design
Ethics Training
Does the Question Require a Clinical Trial?​
Randomization
Control Group
Protection from Conflicts of Interest
Informed Consent
Conduct
Trials in Low- and Middle-Income Countries
Recruitment
Safety and Efficacy Monitoring
Early Termination for Other Than Scientific or Safety Reasons
Privacy and Confidentiality
Data Falsification
Reporting
Publication Bias, Suppression, and Delays
Conflicts of Interest and Publication
References

3 What Is the Question?​
Fundamental Point
Selection of the Questions
Primary Question
Secondary Questions Regarding Benefit
Questions Regarding Harm
Ancillary Questions
Kinds of Trials
Trials with Extensive Data Collection vs.​ Large, Simple
Superiority vs.​ Noninferiority Trials
Comparative Effectiveness Trials
Intervention
Response Variables
Kinds of Response Variables
Specifying the Question
Biomarkers and Surrogate Response Variables
Changing the Question
General Comments
References

4 Study Population
Fundamental Point
Definition of Study Population
Considerations in Defining the Study Population
Potential for Benefit
High Likelihood of Showing Benefit
Avoiding Adverse Effects
Competing Risk
Avoiding Poor Adherers
Pharmacogenetics​
Generalization
Recruitment
References

5 Basic Study Design
Fundamental Point
Overview
Randomized Control Trials
Nonrandomized Concurrent Control Studies
Historical Controls and Databases
Strengths of Historical Control Studies
Limitations of Historical Control Studies
Role of Historical Controls
Cross-Over Designs
Withdrawal Studies
Factorial Design
Group Allocation Designs
Hybrid Designs
Large, Simple and Pragmatic Clinical Trials
Studies of Equivalency and Noninferiority
Adaptive Designs
References

6 The Randomization Process
Fundamental Point
Fixed Allocation Randomization
Simple Randomization
Blocked Randomization
Stratified Randomization
Adaptive Randomization Procedures
Baseline Adaptive Randomization Procedures
Minimization
Response Adaptive Randomization
Mechanics of Randomization
Recommendations
Appendix:​ Adaptive Randomization Algorithm
References

7 Blinding
Fundamental Point
Who Is Blinded?​
Types of Blinding
Unblinded
Single-Blind
Double-Blind
Triple-Blind
Protecting the Double-Blind Design
Matching of Drugs
Coding of Drugs
Official Unblinding
Inadvertent Unblinding
Assessment and Reporting of Blinding
Debriefing of Participants
References

8 Sample Size
Fundamental Point
Statistical Concepts
Dichotomous Response Variables
Two Independent Samples
Paired Dichotomous Response
Adjusting Sample Size to Compensate for Nonadherence
Sample Size Calculations for Continuous Response Variables
Two Independent Samples
Paired Data
Sample Size for Repeated Measures
Sample Size Calculations for “Time to Failure”
Sample Size for Testing “Equivalency” or Noninferiority of Interventions
Sample Size for Cluster Randomization
Multiple Response Variables
Estimating Sample Size Parameters
References

9 Baseline Assessment
Fundamental Point
Uses of Baseline Data
Description of Trial Participants
Baseline Comparability
Controlling for Imbalances in the Analysis
Subgrouping
What Constitutes a True Baseline Measurement?​
Screening for Participants
Regression Toward the Mean
Interim Events
Uncertainty About Qualifying Diagnosis
Contamination of the Intervention
Changes of Baseline Measurement
References

10 Recruitment of Study Participants
Fundamental Point
Considerations Before Participant Enrollment
Selection of Study Sample
Common Recruitment Problems
Planning
Recruitment Sources
Conduct
Monitoring
Approaches to Lagging Recruitment
References

11 Data Collection and Quality Control
Fundamental Point
Problems in Data Collection
Major Types
Minimizing Poor Quality Data
Design of Protocol and Manual
Development of Forms and Data Entry Tools
Training and Certification
Pretesting
Techniques to Reduce Variability Including Central Adjudication of Events
Data Entry
Electronic Source Data
Quality Monitoring
Monitoring of Data
Monitoring of Procedures
Monitoring of Drug Handling
Audits
References

12 Assessment and Reporting of Harm
Fundamental Point
Assessment of Harm
Strengths
Limitations
Identification of Harm in Clinical Trials
Classification of Adverse Events
Ascertainment
Prespecified Adverse Events
Characteristics of Adverse Events
Length of Follow-up
Analyzing Adverse Events
Standard Reporting
Prespecified Analysis
Post Hoc Analysis
Meta-analysis
Reporting of Harm
Scientific Journal Publication
Regulatory Considerations
Recommendations for Assessing and Reporting Harm
References

13 Assessment of Health Related Quality of Life
Fundamental Point
Types of HRQL Measures
Primary Measures
Additional Measures
Uses of HRQL Measures
Methodological Issues
Design Issues
Study Population
Type of Intervention
Frequency of Assessment (Acute Versus Chronic)
Protocol Considerations
Modifying and Mediating Factors
Selection of HRQL Instruments
Types of Measures
Scoring of HRQL Measures
Determining the Significance of HRQL Measures
Utility Measures/​Preference Scaling and Comparative Effectiveness Research
References

14 Participant Adherence
Fundamental Point
Definitions
Medication Adherence
Considerations Before Participant Enrollment
Design Factors
Participant Factors
Maintaining Good Participant Adherence
Adherence Monitoring
Dealing with Low Adherence
Special Populations
References

15 Survival Analysis
Fundamental Point
Estimation of the Survival Curve
Cutler-Ederer Estimate
Kaplan-Meier Estimate
Comparison of Two Survival Curves
Point-by-Point Comparison
Comparison of Median Survival Times
Total Curve Comparison
Generalizations
Covariate Adjusted Analysis
References

16 Monitoring Committee Structure and Function
Fundamental Point
Monitoring Committee
Repeated Testing for Significance
Decision for Early Termination
Decision to Extend a Trial
Accelerated Approval Paradigm
References

17 Statistical Methods Used in Interim Monitoring
Fundamental Point
Classical Sequential Methods
Group Sequential Methods
Flexible Group Sequential Procedures:​ Alpha Spending Functions
Applications of Group Sequential Boundaries
Asymmetric Boundaries
Curtailed Sampling and Conditional Power Procedures
Other Approaches
Trend Adaptive Designs and Sample Size Adjustments
References

18 Issues in Data Analysis
Fundamental Point
Which Participants Should Be Analyzed?​
Ineligibility
Nonadherence
Missing or Poor Quality Data
Competing Events
Composite Outcomes
Covariate Adjustment
Surrogates as a Covariate
Baseline Variables as Covariates
Subgroup Analyses
Not Counting Some Events
Comparison of Multiple Variables
Use of Cutpoints
Noninferiority Trial Analysis
Analysis Following Trend Adaptive Designs
Meta-analysis of Multiple Studies
Rationale and Issues
Statistical Methods
Analysis for Harmful Effects
References

19 Closeout
Fundamental Point
Termination Procedures
Planning
Scheduling of Closeout Visits
Final Response Ascertainment
Transfer of Post-trial Care
Data and Other Study Material
Cleanup and Verification
Storage
Dissemination of Results
Post Study Follow-up
References

20 Reporting and Interpreting of Results
Fundamental Point
Guidelines for Reporting
Authorship
Duplicate Publication
Disclosure of Conflict of Interest
Presentation of Data
Interpretation
Publication Bias
Did the Trial Work as Planned?​
Baseline Comparability
Blinding
Adherence and Concomitant Treatment
What Are the Limitations?​
What Kinds of Analyses?​
How Do the Findings Compare with Those from Other Studies?​
What Are the Clinical Implications of the Findings?​
Data Sharing
References

21 Multicenter Trials
Fundamental Point
Reasons for Multicenter Trials
Conduct of Multicenter Trials
Globalization of Trials
Large, Simple Trials
References
22 Regulatory Issues
Fundamental Point
Background
Overview
History
Regulatory Requirements
Trial Phases
Pretrial Requirements
Conduct
Interventions:​ Drugs
Interventions:​ Devices
Interventions:​ Biologics
Post-trial Requirements
Documents for FDA submission
Advisory Committee Meeting
Post-approval Issues and Postmarketing Investigations
Key Links
International Conference on Harmonisation
U.​S.​ Food and Drug Administration
European Medicines Agency
Health Canada
Pharmaceuticals and Medical Devices Agency, Japan
Bioethics Resources
References

Erratum
Index

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