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Monitoring Randomized Trials

Monitoring Randomized Trials. MOST basic ethical principles in research are to: minimize risk to participants maximize scientific evidence Interim monitoring = looking at the data before the trial is finished Basic goals of interim monitoring: protect participants

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Monitoring Randomized Trials

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  1. Monitoring Randomized Trials • MOST basic ethical principles in research are to: • minimize risk to participants • maximize scientific evidence • Interim monitoring = looking at the data before the trial is finished • Basic goals of interim monitoring: • protect participants • maximize scientific evidence

  2. Topics for Today • Which trials require monitoring? • Why alter/stop a clinical trial early? • Who should decide? • What should be monitored? • How often should you monitor? • What statistical methods to use? • How can a trial be altered? • Fascinating examples...

  3. Which Trials to Monitor • Trials in which there is a possibility • of unexpected harm from the intervention • of unexpected benefit from the intervention • that the question will not be answered • Increasingly viewed by the NIH as an independent advisory board • Generally, all trials should be monitored, but not feasible in small, short trials

  4. Why Stop a Trial Early? • Harm clearly demonstrated • Benefit clearly demonstrated • Not possible to demonstrate benefit • trial design flawed • low enrollment, high noncompliance, poor data, high drop-out • no difference between groups • Research question answered by another study

  5. Who Should Decide? • Sponsor • Investigators • Independent monitoring board, without conflict of interest • experts -? investigators • ethicists - ? representative of Sponsor • statisticians -? representative of NIH - ? lay persons

  6. What Should You Monitor? • Issues early in the trial • trial design • recruitment • adherence • loss to follow-up • data quality and timeliness • information from other studies

  7. What Should You Monitor? • Issues later in the trial • primary and secondary outcomes • clear benefit • clear harm • no conditional power • adverse events • side effects • subgroups

  8. How Often to Monitor? • Initial meeting several months before start-up • review protocol, classification of outcomes and adverse events, adjudication, etc • review and accept DSMB guidelines, statistical methods and meeting schedule • Subsequent meetings • often enough to achieve goals • not so often that there is no new data • depends on the duration of the trial and perceived risk of the intervention

  9. Confidentiality • DSMB usually does not share interim results with sponsors, investigators, ppts • Open session • DSMB, sponsor, investigators, NIH, FDA • recruitment, retention, data quality • overall findings • Closed session • DSMB members, + statistician • between group findings • discussion regarding modifications

  10. Statistical Methods for Interim Monitoring • Perform tests of significance and • stop the trial if any p<.05 • Simple, but wrong total testsoverall alpha 1 .05 2 .08 5 .14 10 .20 20 .35

  11. Interim Analyses in the CDP +2 +1 0 -1 -2 Z Value 10 20 30 40 50 60 70 80 90 100 Month of Follow-up

  12. Statistical Methods • Perform tests of significance and adjust the test-wise alpha • Bonferroni • Classical sequential methods • Group sequential methods • Pocock • Haybittle and Peto • O’Brien and Flemming • Lan and DeMets

  13. Group Sequential Methods • O’Brien - small i for early tests Flemming gradually increasing i N=5 interim tests;  = .05 initial 1=.00001; f=.041 • Lan-  spending function DeMets defined by N previous “looks” proportion of data/time between

  14. O’Brien-Fleming Alpha Spending Function LookZ-valueP-value 1 4.56 .00001 2 3.23 .0001 3 2.63 .009 4 2.28 .023 5 2.04 .041

  15. Symmetric Stopping Boundaries 6 4.56 3.23 2.63 4 2.28 2 2.04 Z Stop for Harm 0 Stop for Benefit 1st Look 2nd Look 3rd Look 4th Look 5th Look -2 -2.04 -2.28 -4 -2.63 -3.23 -4.56 -6

  16. Conditional Power Compute p(reject Ho given data so far) Deterministic Curtailed Sampling • assume all future outcomes in treated • assume all future outcomes in placebo Stochastic Curtailed Sampling • assume Ho true • assume Ha true

  17. How Can a Trial Be Altered? • Early alterations • change entry criteria • Increase/decrease sample size • change outcome • adjust dose • Goals of these changes • make the trial successful (definitive result) • change original protocol as little as possible • Timely, high quality data crucial

  18. How Can a Trial Be Altered? • Later alterations • increase duration of the trial • modify the trial protocol • stop one arm of the intervention • terminate high risk groups • add safety measures • others • terminate the trial early

  19. Interim Monitoring • NOT simply a statistical issue • Must weigh: • Outcome events still in the “pipeline” • Possible baseline differences in groups • Possible bias in assessment of outcome • Impact of missing data • Differential co-intervention or noncompliance • Internal consistency of findings • Impact of early termination on medical practice and public health

  20. Nuts and Bolts • Board chosen early • Data Monitoring Plan • board members • variables and analyses • frequency of monitoring • statistical methods • guidelines for decisions • Timely, accurate and complete data

  21. Coronary Arrhythmia Suppression Trial - Stopped for HARM • 1455 of planned 4400 subjectsafter MI with ventricular ectopy • Flecainide, encainide or moricizine vs. pbo • Mean follow-up 1 year of planned 5 years • Outcomes - mortality from arrhythmia, total mortality

  22. Coronary Arrhythmia Suppression Trial OutcomeF/EPlacebop N randomized 730 725 Arrhythmic death 33 9 .0006 Total death 56 22 .0003

  23. Beta-blocker Heart Attack TrialStopped for BENEFIT • Subjects - 3,837 persons 5-21 days after MI • Intervention - propranolol 180-240mg/day vs placebo • Follow-up - 40 of planned 48 months • Outcome - mortality

  24. Beta-blocker Heart Attack Trial AnalysesMonth Deaths Z Critical Value 1 11 56 1.68 5.88 2 16 77 2.24 5.04 3 21 126 2.37 3.79 4 28 177 2.30 3.19 5 34 247 2.34 2.64 6 40 318 2.82 2.30 7 48

  25. Coronary Drug Project • Subjects - 8,341 men post-MI • Interventions - estrogen 2.5 and 5.0 mg QD dextrothyroxine 6 mg QD clofibrate 1.8 gm QD niacin 3.0 gm QD placebo • Follow-up - 1.5 to 5 years as planned • Outcomes - death, MI, cancer, VTE

  26. Coronary Drug ProjectHigh-dose CEE stopped for HARM CEE 5 mgPlaceboRR ( n=1,119)(n=2,789) CHD event 11.0% 7.5% 1.5 PE or DVT 3.5% 1.5% 2.3* Total mortality 9.7% 8.2% 1.2 JAMA, 1970

  27. Coronary Drug Project • Low-dose CEE (2.5 mg/d) stopped after 2.5 years for similar findings • D-thyroxin found to increase death rate at 3 years in men with abnormal baseline EKG • D-thyroxin stopped in all men with abnormal baseline EKG

  28. Heart and Estrogen/progestin Replacement Study (HERS) • 2673 postmenopausal women with CHD • Randomized to estrogen plus progestin or placebo, planned follow-up 4 years • Main outcome - CHD events • Secondary outcomes - breast cancer, fractures, venous thromboses

  29. HERS DSMB ReportMonitoring for VTEs . . . 6 . . . . . 4 . Stop for Harm Stop for Benefit 2 . Z 0 6 mo 1.5 yr 2.5yr 3.5 yr End -2 -4 -6

  30. HERS DSMB ReportMonitoring for CHD Death 6 . . . 4 . Stop for Harm . Stop for Benefit . 2 . . . . Z 0 6 mo 1.5 yr 2.5yr 3.5 yr End -2 -4 -6

  31. Complex TrialsWomen’s Health Initiative Trials Harm% Change in Risk • CHD +29% • Stroke +41% • Breast cancer +26% • Pulm. embolus +2.1X Global Index Benefit • Hip fracture -34% • Colorectal cancer -37%

  32. Different Rules for Stopping for Benefit and Harm? • “Liberal” rules to stop for harm to protect participants in the trial • More stringent rules for benefit to answer important questions • Does benefit strengthen over time? • Does treatment reduce mortality? • Were side effects underestimated • What is the impact on secondary outcomes • What is the effect in subgroups

  33. Summary - Interim Monitoring • Interim monitoring very important • Should be planned in advance • Should be performed well • Any change in trial protocol should be carefully considered, weighing many issues

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