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Interim Monitoring in Randomized Trials

Interim Monitoring in Randomized Trials. Why alter/stop a clinical trial early? Who should decide? What should be monitored? How often should you monitor? What statistical methods to use? Fascinating examples. A Little History.

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Interim Monitoring in Randomized Trials

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  1. Interim Monitoring inRandomized Trials • Why alter/stop a clinical trial early? • Who should decide? • What should be monitored? • How often should you monitor? • What statistical methods to use? • Fascinating examples...

  2. A Little History • NIH task force on administration of multicenter trials (Greenberg Report, 1966) • Trial Chair • Steering or Executive Committees • Statistical or Coordinating Center • Policy Advisory Board • Data Safety and Monitoring Board, or • Data Monitoring Committee

  3. 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

  4. Which Trials Should be Monitored? • Most phase II and III trials, unless • no possibility of harm? • duration too short to be practical?

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

  6. What Should You Monitor? • Issues early in the trial • trial design • recruitment • compliance • 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 or harm • no conditional power • adverse events • side effects • subgroups

  8. How Can a Trial Be Altered? • Early alterations • change entry criteria - others? • increase sample size • change definition of 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

  9. 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

  10. How Often to Monitor? • Often enough to achieve goals • Not so often that there is no new data • Typically every 6-12 months or when an additional 20% of the expected outcomes have occurred

  11. Confidentiality • DSMB usually does not share interim results with sponsor, 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

  12. Example • RCT: transdermal E2 for prevention of atherosclerosis in healthy middle-aged women • DSMB meetings • 3 months prior to enrollment to review protocol, establish guidelines • 6 months to review recruitment, etc. • Annually for between groups comparisons

  13. 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

  14. 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

  15. 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

  16. 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

  17. Alpha Spending LookZ-valueP-value 1 4.56 .00001 2 3.23 .0001 3 2.63 .009 4 2.28 .023 5 2.04 .041

  18. 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

  19. Curtailed Sampling 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

  20. Interim Monitoring • NOT simply a statistical issue • Must weigh: • 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

  21. 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

  22. Beta-blocker Heart Attack Trial • 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

  23. 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

  24. 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 2.5 of planned 5 years • Outcomes - death, MI, cancer, VTE

  25. Coronary Drug Project 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

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

  27. Physicians’ Aspirin Study • Subjects - 22,071 physicians • Interventions - aspirin 325 mg QOD beta-carotene 50 mg QOD • Follow-up - 5 of planned 7 years • Outcomes - main = CVD death secondary = MI, stroke

  28. Physicians’ Aspirin Study OutcomeAspirinPlaceboRR p value CVD death 81 83 1.0 .87 MI 139 239 0.6 .00001 Stroke 119 98 1.2 .15 ischemic 91 82 1.1 .50 hemorrh 23 12 2.1 .06

  29. Coronary Arrhythmia Suppression Trial • 1727 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

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

  31. Canadian Atrial Fibrillation Study • 383 of planned 660 subjects with AF • randomized to warfarin or placebo • follow-up 1.2 of planned 3.5 years • results of two other large trials available

  32. Findings of Other Trials STROKE RATE WarfarinPlacebo AFASK Trial 2.0% 5.5% SPAF Trial 1.6% 8.3%

  33. 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

  34. 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

  35. WHI - Overall Risk and Benefit Harm% Change in Risk • CHD +29% • Stroke +41% • Breast cancer +26% • Pulm. embolus +2.1X Benefit • Hip fracture -34% • Colorectal cancer -37%

  36. Letrozole for Breast Cancer • In early stage ER+ breast cancer • 5 years of tamoxifen reduces risk of recurrence • longer treatment LESS effective • tamoxifen may have partial estrogen agonist activity • Treatment with letrozole after tamoxifen might reduce recurrence

  37. Letrozole after Tamoxifen Trial • Subjects - 5187 postmenopausal women treated with 4.5-6 years of adjuvant tamoxifen for breast cancer • Intervention - letrozole 2.5 mg QD • Follow-up - 2.5 of planned 5 years • Outcomes - disease free survival overall survival quality of life safety Goss, NEJM, 2003

  38. DSMB Guidelines • Enroll 4800 women, follow for 5 years • Expect 515 events (recurrent cancer) • Review safety twice yearly • Interim analysis twice, after • 171 (1/3 expected total) events • 342 (2/3 expected total) events • Lan and DeMets a-spending function with O’Brien-Flemming boundaries

  39. First Interim Analysis • 5187 women enrolled (planned 4800) • Mean of 2.4 years of follow-up • 207 (40% of expected events) LetrozolePlacebo RH P-value N events 75 132 .57 .00008 4-year DFS 93% 87% .001 Deaths 31 42 4-year S 96% 94% .76

  40. First Interim Analysis LetrozolePlaceboP-value Flushes 47% 40% <.001 Arthritis 6% 3% <.001 Arthralgia 21% 17% <.001 Osteoporosis 5.8% 4.5% 0.07 Fracture 3.6% 2.9% 0.24 CVD events 4.1% 3.6% 0.40

  41. Issues • How long does benefit last? • Does benefit strengthen over time? • Does treatment reduce mortality? • Do findings support 5 years of treatment with letrozole? • Were side effects underestimated? • How will other trials be altered?

  42. Summary • 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

  43. Conclusions • Stopping a trial for harm often not adequately planned • harm goes on too long • stopping boundaries unreasonable • Stopping a trial for benefit always raises issues • loss of additional data on long-term benefit and side effects

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