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Ethics and Interim Monitoring

Ethics and Interim Monitoring. Ethical concerns in general Ethical concerns in trials Monitoring the conduct and findings of trials in progress. Ethical Concerns in all Research. RQ should be important and answerable Benefit should outweigh risk Participants should give consent

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Ethics and Interim Monitoring

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  1. Ethics and Interim Monitoring • Ethical concerns in general • Ethical concerns in trials • Monitoring the conduct and findings of trials in progress

  2. Ethical Concerns in all Research • RQ should be important and answerable • Benefit should outweigh risk • Participants should give consent • Privacy should be protected • Research report should be fair and honest

  3. Ethical Perspectives • Idealism • human beings are special • can never be a means only • Utilitarianism • greatest good for the greatest number

  4. Roles • Physician - Investigator • Patient - Participant • Treatment - Research

  5. Nazi Experiments THE NUREMBERG PHYSICIANS’ TRIAL • “Participants” were placed in freezing water and time to death was measured • “Participants” drank sea water and adverse effects were measured

  6. The Nuremberg Code • Voluntary participation • legal capacity to give consent • free of force, fraud, deceit, duress • free to withdraw at any time • Fruitful results for society • unprocurable by other means • conducted by qualified persons • Avoid unnecessary risk to subjects • risk not greater than importance of RQ

  7. Post WWII Trials • US Atomic Energy Commission tests of the adverse effects of radiation exposure • Clinical trials in federal and state prisoners

  8. Tuskegee Syphillis Study (1932-72) • Prospective cohort funded by USPHS • 600 poor, illiterate, black men • 399 with syphilis; 201 without syphilis • followed for 40 years for tertiary syphilis • Never informed of condition • Never treated

  9. Ethical Principles • Beneficence • Respect for autonomy • Truth-telling • Justice • Promise-keeping • Privacy

  10. World Medical AssociationDeclaration of Helsinki (1964) • Voluntary participation with consent in writing • Design described in written protocol • Review by an independent committee • Responsible scientific publication • Protection of vulnerable populations

  11. Institutional Review Boards • NIH required ethical review of internal studies in1953 and funded studies in 1966 • led to establishment of local IRBs • Oversight by NIH Office of Human Research Protections based on Federal regulations • risks to subjects minimized and reasonable • informed consent in writing • provisions for privacy • safeguards for vulnerable populations • selection of subjects equitable

  12. Federal and Local Regulations • UCSF - Committee on Human Research • NIH - Office for Human Research Protection • http://ohrp.osophs.dhhs.gov/polasur.html • Code of Federal Regulations Title 45, Part 46 • http://ohrp.osophs.dhhs.gov/ humansubjects/guidance/45cfr46.htm.

  13. What’s Special about RCTs? • Randomization - equipoise • Intervention - relativelysafe • Placebo - acceptable clinical option • Measurements - safe and tolerable • Interim monitoring - careful and timely

  14. Equipoise • Question important and not answered • Evidence of benefit, not conclusive • trial of new drug treatment for advanced breast cancer • trial of treatment for common cold

  15. Intervention and Control • Maximize benefit, minimize harm • intervention • control (placebo acceptable?) • Qualified staff and protections for known potential harms • manage known adverse effects • pay costs of known adverse effects • Identify associated harm

  16. Measurements Safe and Tolerable • Trial of estrogen for fracture prevention • substitute TVUS for endometrial biopsy • Trial of accuracy of spiral CT for PE • all get spiral CT and pulmonary angiogram • Trial of effect of estrogen treatment on coronary atherosclerosis (ERA) • randomized to estrogen or placebo • coronary atherosclerosis on angiograms

  17. Fecal Occult Blood TestingKronborg, et al., 1996 • Randomized trial • 60,000 persons in Denmark • FOBT biannually or usual care • Outcome = colon cancer • No informed consent

  18. Informed Consent • Purpose of trial • Why asked to participate • Visits, procedures, time and costs • Discomforts or risks • Benefits to subject and society • Alternatives • Confidentiality • Contact for questions, problems

  19. Active Compression-Decompression for CPR, Schwab et al., 1994 • Randomized trial • 860 persons with cardiac arrest • ACD CPR or standard CPR • Outcome = discharged alive • No informed consent • Trial halted by FDA

  20. Alternatives to Informed Consent • Waiver of consent • life threatening situation • consent not possible • Permission from parent or guardian • Deferred consent • Prospective consent

  21. Cumulative Meta-analysis Effect of beta-blockers on mortality after MI

  22. Antibiotics for AbortionSawaya, et al, 1996 • Cumulative meta-analysis 12 RCTs • after 5 trials (1985), summary RR 0.5, p<.05 • 7 additional trials performed • findings of 5 trials non-significant • trials continued up to 1993

  23. Zalospirone for DepressionRickels, et al, 1996 • Randomized trial • 287 people with major depression • Placebo or 3 doses of drug • Outcome - change in severity of depression • High dose effective; two lower doses not

  24. Prevention of AIDS in Africa • Standard care for HIV+ pregnant women in US • zidovudine orally before delivery • IV during labor, then orally for newborns • RR .33 for infection in newborn • Pregnant HIV+ African women • randomized to oral AZT or placebo • most funded by US agencies

  25. Cardiac Arrhythmia SuppressionEcht, et al., 1991 • Randomized trial • 1498 patients post-MI with PVCs • Encainide, flecainide, or placebo • Outcome = death • Trial stopped after 1 year due to increased deaths in treated group; p = .004

  26. Issues in Interim 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? • Fascinating examples...

  27. Why Stop a Trial Early? • Benefit or harm clearly demonstrated • expected or unexpected • Not possible to demonstrate benefit • no difference between groups • low enrollment, high noncompliance, poor data • Research question answered

  28. Who Should Decide? • Investigators • Sponsor • Independent monitoring board • experts -investigators • ethicists - ? representative of sponsor • statisticians -? lay persons

  29. What Should You Monitor? • Primary and secondary outcomes • Potential adverse effects • Important subgroups • Recruitment and compliance • Data quality

  30. How Can a Trial Be Altered? • Terminate the study • Modify the study • stop one arm of the intervention • terminate high risk subgroups • add safety measures • Extend the study in time • Enlarge the sample size

  31. How Often to Monitor? • Often enough to achieve goals • Not so often that there is no new data • Typically every 6-12 months

  32. Statistical Methods • 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

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

  34. Group Sequential Methods • O’Brien - small i for early tests Flemming gradually increasing i N=5 interim tests;  = .05 initial i=.00001; f=.046 • Lan-  spending function DeMets defined by N previous “looks” proportion of data/time between

  35. Stopping Boundaries 6 5 4.5 4.2 4 3.5 2 2 Z Stop for Harm 0 Stop for Benefit 1st Look 2nd Look 3rd Look 4th Look 5th Look -2 -2 -3.5 -4 -4.2 -4.5 -5 -6

  36. 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

  37. 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 credibility

  38. 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

  39. 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

  40. 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

  41. Physicians’ Aspirin Study • Subjects - 22,071 physicians • Interventions - aspirin 325 mg QOD beta-carotene 50 mg QOD • Follow-up - 5 of planned 8 years • Outcomes - main = CVD death secondary = MI, stroke

  42. Physicians’ Aspirin Study OutcomeAspirinPlacebop value CVD death 44 44 .99 MI 104 189 .00001 Stroke 80 70 .41

  43. 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

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

  45. 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

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

  47. 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

  48. 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

  49. 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

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