LECTURE 24 2011

LECTURE 24 2011 - Interim Analyses of Clinical Trials A...

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Interim Analyses of Clinical Trials A Requirement
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Outline Background and how DSMBs function Group sequential methods Examples
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Suggested Readings Ellenberg S, Fleming TR, DeMets DL. Data Monitoring Committees in Clinical Trials. A Practical Perspective Jennison C and Turnbull BW. Group Sequential Methods with Applications to Clinical Trials Chapman & Hall/CRC 2000
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DSMB Decision Making Can Be Complex Internal consistency Benefit/Risk External consistency Current versus future patients Clinical and public health impact Statistical issues – monitoring guidelines
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Overall Probability of Achieving a Result with Given Nominal Significance of 0.05 After N Repeated Tests Under H o 1 .05 2 .083 3 .107 4 .126 5 .142 10 .193 25 .266 No. of Tests (N) Probability Ref: McPherson, NEJM , 1974.
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Value of Nominal Significance Level Necessary to Achieve a True Level of 0.05 After N Repeated Tests 1 .05 2 .0296 3 .0221 4 .0183 5 .0159 10 .0107 No. of Tests (N) Significance Level Which Should be Used Ref: McPherson, NEJM , 1974.
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Simulated Trial (T. Fleming Example) Patients enter trial over a 3-year period 1 year minimum follow-up 60 on A; 60 on B Survival distributions are equal Log-rank test used for analysis 5 situations 1 Log-rank test - at 4 years 2 Log-rank tests - every 2 years 4 Log-rank tests - every year 8 Log-rank tests - every 6 months 16 Log-rank tests - every 3 months 100 simulations of the study
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Results The log-rank p-value was less than 0.05 at the final test (i.e., at 4 years) in 5 of 100 studies either the 2- or 4-year test in 10 of 100 studies at least 1 of 4 yearly tests in 17 of 100 studies at least 1 of 8 semi-annual tests in 21 of 100 studies at least 1 of 16 3-month tests in 25 of 100 studies
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Conclusions 1. If one monitors one’s data closely and considers a p .05 result obtained at any time to be reflective of a true difference in survival distributions, one will obtain a grossly excessive number of false positives. This excessiveness will be further magnified if one follows multiple endpoints if one uses multiple test statistics 2. 25 of 100 studies have a log-rank p-value < 0.05 at at least one of the 16 3-month tests, whereas only 5 of 100 studies do at the last test. Thus, if there are no differences between true survival curves, very many of the closely monitored studies will have “statistically significant” early differences which will disappear later in time.
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Early Work Acceptance sampling Wald (1947) sequential probability ratio test Manufacturing problems, continuous monitoring of the data, no upper bound on sample size
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Useful References Ellenberg SS, Fleming TR, DeMets DL, Data Monitoring Committees in Clinical Trials, Wiley, 2002. DeMets DL, Furberg CD, Friedman LM.
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LECTURE 24 2011 - Interim Analyses of Clinical Trials A...

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