Randomized Trials. Why do Randomized Trials? Presenter Disclosure Information Christopher Cannon

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1 Randomized Trials Christopher P. Cannon, MD TIMI Study Group, Cardiovascular Division Brigham and Women s Hospital Boston, MA I would like to thank my colleague Dr. Elliott Antman for developing and sharing some of the slides in this talk Presenter Disclosure Information Christopher Cannon The following relationships exist related to this presentation: Research Grant Support: Accumetrics, AstraZeneca, GSK, Merck, Takeda - Advisory Boards (but funds donated to charity) BMS-Sanofi partnership, Novartis, Alnylam - Honoraria for independent educational symposia Pfizer, AstraZeneca - Clinical Advisor and equity: Automedics Medical Systems Why do Randomized Trials? Identify new treatments Advance medical care Get approval of new drugs/devices Change Guidelines for care Improve outcomes of our patients Presenter: Christopher P. Cannon, M.D. Page 1 1

2 Advantages of Randomized trials In testing a new therapy, randomly assigning patients to one Rx or the other will ensure that all other aspects of treatment are balanced at the start of the trial Avoids confounding Double-blinding treatment (if possible) ensures: Other aspects of treatment don t differ over time during the trial in the 2 groups Unbiased assessment of endpoint events Disadvantages of Randomized trials More complex, costly Often more selective: Have inclusion/exclusion criteria 5 FDA Phases of Trials of New Therapies Phase Features Purpose I II III IV 1st admin of new Rx Early trial in patients Large scale comparison vs Std Rx Monitoring in clinical practice Is further investigation warranted? Dose ranging, AE s, Pathophysiologic insights Definitive Eval. clinical outcomes Registration Pathway Post marketing surveillance Adapted from Meinert C: Clinical Trials. Design, conduct, and analysis. New York, Oxford University Press, Presenter: Christopher P. Cannon, M.D. Page 2 2

3 Guidelines: I IIa IIb III Classes of Recommendation Intervention is useful and effective Evidence conflicts/opinions differ but lean towards efficacy Evidence conflicts/opinions differ but lean against efficacy Intervention is not useful/effective and may be harmful Weight of evidence grades: = Data from many randomized clinical trials = Data from single randomized trial or nonrandomized studies = Expert consensus Randomized Control Trial Enrollment Criteria Randomized Control Treatment A (Control Rx*) Treatment B (Test Rx) Ascertainment of Primary Endpoint *May be placebo or active Rx Statistics Details: Dr. Orav will cover Various Stages of Conducting a Clinical Trial Stage Initial Design Protocol Design Recruitment Followup Close-Out Termination Long Term Followup Activities Scientific question, EP s, Size Operations Manual, Inv Mtgs Subject Acquisition, Monitoring, DSMB Interim Analyses Events (Efficacy, Safety) Prepare Clean + Locked Database Report Results (LBCT, Manuscript, Reg. Agencies, CME talks, Conferences Link Findings With Initial Trial Data Adapted from Meinert C: Clinical Trials. Design, conduct, and analysis. New York, Oxford University Press, Presenter: Christopher P. Cannon, M.D. Page

4 Design Manuscript Important Elements Rationale, Protocol Description Definitions of Endpoints Analysis Plan Efficacy ( intention to treat ) Safety Subgroups Substudies AHJ 104 : 217, Interpreting the Results of a Clinical Trial Are the Results Valid? Primary Guides Randomized? Accounting for pts: complete, ITT Secondary Guides Blinded? ( pts, study personnel) Baseline characteristics similar? Similar treatment except test Rx? What Were The Results? Size of treatment effect Precision of estimate of treatment effect Guyatt et al JAMA 270: 2598, 199 Guyatt et al JAMA 271: 271, 1994 Describing Results Observational study: was associated with a lower/higher risk of (Cannot use an active verb of reduced ) Randomized trial: Rx reduced the risk of by % 12 Presenter: Christopher P. Cannon, M.D. Page 4 4

5 Major TIMI Trials: Publications Impacting FDA, Guidelines and Care TIMI 1: tpa vs. Streptokinase in STEMI TIMI 10: TNK-tPA in STEMI TACTICS-TIMI 18 Inv. vs. Cons Strategy PROVE IT-TIMI 22: Intensive statin Rx ExTRACT-TIMI 25: Enox in STEMI CLARITY-TIMI 28: Clopidogrel in STEMI TRITON-TIMI 8: Prasugrel in PCI for ACS PLATO (TIMI 40): Ticagrelor in ACS Guess what journal they were all published in? 1 Example of one Trial Publication - FDA Guidelines Pathway 14 Protocol Design MI Symptoms < 6 h Eligible to receive lytic ASA Fibrinolytic ( clot dissolving drug ) choice by MD Double-blind ENOX UFH Day 0 1 Efficacy Endpoint: Death or Nonfatal MI 1 Safety Endpoint: Major Hemorrhage 15 Presenter: Christopher P. Cannon, M.D. Page 5 5

6 Primary End Point (ITT) Death or Nonfatal MI 15 Primary End Point (%) ARD = = 2.1 % RR = 0.8 (0.77 to 0.90) RRR = 0.17 (0.2 to 0.10) NNT = 48 UFH 206 events ENOX P< % (122 / 1022) 9.9% (1017 / 10256) Days Antman EA N Engl J Med 2006;54: Publication of Results N Engl J Med 2006;54: Final Study Report Submitted to FDA Revised Pkg Insert for Enoxaparin Presenter: Christopher P. Cannon, M.D. Page 6 6

7 Presenter: Christopher P. Cannon, M.D. Page 7 7