Learning : Short Courses

 
 


Design, Monitoring, Analysis of Clinical Trials

Scott S. Emerson, MD, PhD

October, 2009

Abstract: Increasingly, clinical trials are conducted using group sequential methods in order to address the ethical and efficiency issues that arise when performing experiments with human volunteers. The design, conduct, and analysis of a sequential clinical trial is necessarily more involved than that for a clinical trial in which the data would only be analyzed at the end of the study. However, the basic tenets of careful consideration of the scientific question and clinical setting remains the same. In this short course we present an overview of the issues that must be considered when conducting a group sequential trial.

Course Materials (pdf):


Learning Material:


  1. Short Courses

  2. Research Talks

  3. Case Studies


1. Introduction and Overview: 
Scientific and clinical setting
(Slides I:1-29) (24:28)

2. Phases of Clinical Trials: 
Definition of an “indication”; Phase I, II, III, IV trials; Efficacy vs effectiveness
(Slides I:30-57) (39:37)

3. Primary Endpoints: 
Multiple comparison problem; Criteria for primary clinical endpoint; Composite or co-primary endpoints
(Slides I:58-72) (36:47)

4. Surrogate Endpoints: 
Historical examples; Potential mechanisms of treatment effect on clinical and surrogate endpoints; Validation of surrogate endpoints
(Slides I:73-101) (22:24)

5. Refining Scientific Hypotheses: 
Causation versus association; Allowing for variation in response
(Slides I:102-114) (13:36)

6. Controls: 
Historical controls; Concurrent controls
(Slides I:1115-123) (6:35)

7. Randomization: 
Establishing cause and effect; Ensuring comparability of treatment arms; Analytic models
(Slides I:124-134) (40:13)

8. Blinding: 
Advantages; Logistics; Blinding of DSMB
(Slides I:135-142) (16:33)

9. Summarizing Treatment Effect: 
Statistical primary endpoint; Summary measures; Criteria for selection of summary measure; Use of the mean; Censored data
(Slides I:143-177) (34:02)



http://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Introduction%20and%20Overview/cber20091015-Introduction%20and%20Overview.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Phases%20of%20Clinical%20Trials/cber20091015-Phases%20of%20Clinical%20Trials.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Primary%20Endpoint/cber20091015-Primary%20Endpoint.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Surrogate%20Endpoints/cber20091015-Surrogate%20Endpoints.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Controls/cber20091015-Controls.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Randomization/cber20091015-Randomization.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Blinding/cber20091015-Blinding.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Summarizing%20Treatment%20Effect/cber20091015-Summarizing%20Treatment%20Effect.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Refining%20Scientific%20Hypotheses/cber20091015-Refining%20Scientific%20Hypotheses.htmlshapeimage_3_link_0shapeimage_3_link_1shapeimage_3_link_2shapeimage_3_link_3shapeimage_3_link_4shapeimage_3_link_5shapeimage_3_link_6shapeimage_3_link_7
10. Scientific Burden of Evidence: 
Superiority, noninferiority, approximate equivalence; Clinical trials with active controls
(Slides I:178-202) (15:51)

11. Ethical Issues re Treatment and Eligibility: 
Definition of treatments; Planning for noncompliance; Definition of target population; Inclusion and exclusion criteria
(Slides I:203-230) (22:41)

12. Statistical Criteria for Evidence: 
Frequentist and Bayesian frameworks; Parametric, semiparametric, and distribution-free (nonparametric) probability models
(Slides I:231-254) (15:30)

13. Criteria for Sample Size: 
Reporting results; Precision of results
(Slides I:255-297) (23:45)

14. Scientific Review of Clinical Trial Design: 
Scientific issues; Scientific review of statistical issues
(Slides I:298-300) (4:05)

16. Sample Size Calculations: 
Standard formula; Application to common probability models; Adjustment for baseline; Crossover; Clustering
(Slides II:1-41) (73:45)

17. Sequential Sampling: 
Control of type I error; Error spending
(Slides II:42-58) (29:05)

18. Sampling Distribution: 
Effect on distribution of estimate, Z, P
(Slides II:59-71) (7:47)

19. Inferential Methods: 
Adjusted estimates, p values, confidence intervals
(Slides II:72-101) (20:33)

http://rctdesign.org/ShortCourses/enarMarch2010/enar20100321-Statistical%20Hypotheses/enar20100321-Statistical%20Hypotheses.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Ethical%20Issues%20re%20Treatment%20and%20Eligibility/cber20091015-Ethical%20Issues%20re%20Treatment%20and%20Eligibility.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Ethical%20Issues%20re%20Treatment%20and%20Eligibility/cber20091015-Ethical%20Issues%20re%20Treatment%20and%20Eligibility.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Statistical%20Criteria%20for%20Evidence/cber20091015-Statistical%20Criteria%20for%20Evidence.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Criteria%20for%20Sample%20Size/cber20091015-Criteria%20for%20Sample%20Size.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Scientific%20Review%20of%20Clinical%20Trial%20Design/cber20091015-Scientific%20Review%20of%20Clinical%20Trial%20Design.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Scientific%20Review%20of%20Clinical%20Trial%20Design/cber20091015-Scientific%20Review%20of%20Clinical%20Trial%20Design.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Sample%20Size/cber20091016-Sample%20Size.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Sequential%20Sampling/cber20091016-Sequential%20Sampling.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Sampling%20Distribution/cber20091016-Sampling%20Distribution.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Inferential%20Methods/cber20091016-Inferential%20Methods.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Scientific%20Burden%20of%20Evidence/cber20091015-Scientific%20Burden%20of%20Evidence.htmlshapeimage_4_link_0shapeimage_4_link_1shapeimage_4_link_2shapeimage_4_link_3shapeimage_4_link_4shapeimage_4_link_5shapeimage_4_link_6shapeimage_4_link_7shapeimage_4_link_8shapeimage_4_link_9shapeimage_4_link_10
20. Nonbinding Futility Boundaries: 
Implementation; Effect on power, inference
(Slides II:102-108) (11:45)

21. Boundary Scales: 
Correspondence with error spending, Bayesian statistics, conditional power
(Slides II:109-123) (13:01)

21. Dangers of Statistical Scales: 
Potential for unethical stopping rules
(Slides II:124-136) (13:18)

22. Relative Advantages of Scales: 
(Slides II:137-147) (27:08)

23. Stochastic Curtailment: 
Issues with conditional power; predictive power
(Slides II:148-169) (25:36)

24. Evaluation of Designs: 
Criteria for choosing among candidate designs
(Slides II:170-185) (15:50)

25. Adaptive Designs: 
Adaptive re-powering of study
(Slides II:186-203) (15:57)

26. Documentation of Design: 
Parameters to specify in protocol
(Slides II:204-208) (8:03)

27. Sepsis Case Study: 
Fixed sample design of binary endpoint
(Slides CS 1:37-72) (29:39)

28. Hodgkin’s Case Study: 
Fixed sample design of time to event endpoint
(Slides CS 1:73-126) (40:09)


http://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Nonbinding%20Futility%20Boundaries/cber20091016-Nonbinding%20Futility%20Boundaries.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Boundary%20Scales/cber20091016-Boundary%20Scales.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Dangers%20of%20Statistical%20Scales/cber20091016-Dangers%20of%20Statistical%20Scales.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Relative%20Advantages%20of%20Scales/cber20091016-Relative%20Advantages%20of%20Scales.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Stochastic%20Curtailment/cber20091016-Stochastic%20Curtailment.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Evaluation%20of%20Designs/cber20091016-Evaluation%20of%20Designs.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Adaptive%20Designs/cber20091016-Adaptive%20Designs.htmlhttp://rctdesign.org/ShortCourses/enarMarch2010/enar20100321-Randomization/enar20100321-Randomization.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Sepsis%20Case%20Study/cber20091016-Sepsis%20Case%20Study.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091016-Hodgkins%20Case%20Study/cber20091016-Hodgkins%20Case%20Study.htmlhttp://www.rctdesign.org/shortcourses/cberOctober2009/cber20091015-Scientific%20Review%20of%20Clinical%20Trial%20Design/cber20091015-Scientific%20Review%20of%20Clinical%20Trial%20Design.htmlshapeimage_5_link_0shapeimage_5_link_1shapeimage_5_link_2shapeimage_5_link_3shapeimage_5_link_4shapeimage_5_link_5shapeimage_5_link_6shapeimage_5_link_7shapeimage_5_link_8shapeimage_5_link_9