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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,ISSUES THAT PLAGUE NON-INFERIORITY TRIALSPAST AND FUTURE,RALPH B. DAGOSTINO, SR.,BOSTON UNIVERSITY,HARVARD CLINICAL RESEARCH INSTITUTE,OBJECTIVES,REVIEW ISSUES: PAST, PRESENT AND FUTURE IN NON-INFERIORITY (NI) STUDIES,PRESENT/ DISCUSS EXAMPLES,MAKE SOME COMMENTS FOR IMPROVEMENTS,PRESENT A PERSONAL VIEW,OUTLINE,Early Objectives and Issues,Approaches to Non-inferiority Trials,Examples (Here are some Problems),Non-Inferiority AND/OR Superiority,All is Non-Inferiority,Intent-to-Treat vs. Per Protocol,New Major Issues,EARLY OBJECTIVES AND ISSUES: EQUIVALENCY,American Dental Association (ADA 1980s),CREST equivalent to COLGATE?,Ho: A-B= 10% or A-B= 10%,What does the 10% mean?,DFMS or DFMT for 2 years, 3 years?,Study done on differences and ratio used as descriptive measure of “effect,5.0 vs 5.4 becomes (5.4-5.0)/5.0 = .4/5.= 8%,EARLY OBJECTIVES,M = 10% CAME FROM NOWHERE, BUT WE KNEW WHAT IT WAS, That is, 10%,TREATMENT DIFFERENCES CONCERNED DIFFERENCES (RATIOS) BETWEEN ACTIVE TREATMENTS,WE WERE LOST BUT WE BELIEVED WE HAD A “SENSE ABOUT IT,APPROACHES TO NI TESTS,MUST DO BETTER THAN PLACEBO,But you cannot use a Placebo (P),Putative Placebo Approach,Test Treatment (T),vs,Positive Control (C) directly with given Margin M (Assay Sensitivity approach),APPROACH 1 (Putative Placebo),Stellar Example from the Past,CAPRIE Study. Hasselblad and Kong (2001) present this as their major example for using meta-analyses for dealing with estimating assay sensitivity (T vs. P),Want T vs. C, C vs. P, T vs. P,21,CAPRIE STUDY (cont),Can we obtain effect of Clopidogrel vs. Aspirin,Yes, if we can locate Asprin vs. Placebo,Do we believe what we get?,For Aspirin vs. PlaceboAntiplatelet Trialists Collaboration Meta-Analysis,Meta-analysis of all published and unpublished unconfounded randomized trials available March 1990,Trials identified by literature search, trial registry and inquiry of investigators and pharmaceutical manufacturers,Clear definitions of endpoints,Well defined statistical methodology,APPROACH,T vs. C(from Caprie trial),C vs. P(from Meta-analysis),Obtain T vs. P (from multiplication),(T/C) (C/P) = (T/P),Clopidogrel Vs. Synthetic Placebo Control Odds Ratios and 95% Confidence Intervals,Overall Patient Population,Endpoint,All Strokes, MIs,or Vascular Deathsp 0.000001,All Strokes, MIs,or Death from p 0.000001,Any Cause,Vascular p 0.0016,Deaths,All Cause p = M vs. H,1,: T-C M,(Say data are event rates),T is new treatment,C is positive control,M IS NON-INFERIORITY MARGIN,NON-INFERIORITY STUDIES,APPROACH 2,SELECT A VALUE OF M THAT MAKES SENSE,WANT ASSURANCE THAT ASSAY SENSITIVITY IS PRESENT (Placebo is working),WANT CONSISTENCY WITH PAST,NON-INFERIORITY STUDIES Statistical Approach,Need Active Control C vs. Placebo P data from Historical data (C vs. P),Need to test effectiveness of T vs. C,Need estimate of fraction of C-P preserved by T (e.g., (T-P)/(C-P) = M) M=0.5 (,C-P,),METHODS EXIST THAT ALLOW TEST TO BUILD IN NEW AND HISTORICAL DATA,(STATISTICS IN MEDICINE, 2002),WHAT IS NEEDED FOR 2,CONFIDENCE INTERVAL IS OFTEN USED. WANT M=1.11 (SAY) OUTSIDE UPPER LIMIT OF CONFIDENCE INTERVAL (M is relative risk),FDA ODAC 8/04 (,non-small cell lung cancer),1.0,1.11= M,SOME REALITIES,Sounds nice,What happens,Anti-infective Product No placebo data,Historical data is not Placebo, but C,VRE (vancomycin resistant enterococcal),High dose Low dose,MITT 60.0 % (N=65) vs. 46.2 % (N=52),Bacteremic,55.6 (N=18) vs. 25.0 (N=16),What is M? One trial OK? Any superiority?,ANOTHER EXAMPLERespiratory Distress,Respiratory Distress Syndrome in Premature Infants,Treatments,New Drug,Comparator,Outcome,Survival at 28 Day,Respiratory Distress (cont),Survanta versus Sham (two studies one positive, other negative) All Cause mortality,Study 1: 8% vs. 23% Study2: 17% vs. 14%,What is M? .23-.08? .180-.125?,CONSISTENCY Example Control rate different from historical,Historical Data says C=0.5 and P=0.6,Want T 25% stenosis (sensitivity),Sensitivity of Comparator is .80 or 80%,Non-inferiority margin M set to 0.10,Assessing Efficacy Non-Inferiority and Safety Superiority (Contd),There is a specific adverse event that is hypothesized to occur less often with New than with Comparator,Do we want to make the specific adverse event rate an,additional,primary endpoint? WHY NOT?,Non US STUDIES,Forced off shore (ethical and other reasons),The BLOB EFFECT,Everything is suddenly Non-Inferiority,ALLHAT STUDY,COMPARISON OF ANTI-HYPERTENSIVE MEDICATIONS (MULTIPLE ARMS),NOT A NON-INFERIORITY STUDY,Safety Studies,Safety studies have become carefully designed and executed studies,Should they be non-inferiority studies?,SAFETY STUDIES (PHASE 4),HISTORICAL APPROACH: NEW RATE OLD,H,01,: T-C 0,H,02,: RR=T/C 1,STUDY POWERED TO REJECT T/C 1.5 (SAY),SHIFT IS TO MAKING THESE NON-INFERIORITY STUDIES,H,0,: T-C = M vs. H,1,: T-C = M vs. H,1,: RR=T/C 1.0,Study powered for R 1.0,When interest in risk fades can we suddenly say this should be a non-inferiority study?,Ho:R = 1.5 vs. H1:R = M,Ho: p1-p2=Rp2,Ho: p1/p2 = R,Best Choice does depend on p2 (control rates),Intent-to-Treat vs. Per-Protocol,In superiority trials, the primary analysis is often on intent-to-treat (ITT) population,Per Protocol (PP) “bigger differences of treatments,In non-inferiority should we use PP?,Intent-to-Treat vs. Per-Protocol (Contd),PP as primary not always accepted,“the ITT analysis is as important as the PP analysis,“need to reconcile differences between ITT and PP analysis,Perform “sensitivity analyses. Results should be similar in both populations (ROBUSTNESS).,The Committee on Proprietary Medicinal Products draft Points to Consider: “similar conclusions from both the ITT and PP are required in a noninferiority trial.,We ask sponsor to do both (ITT and PP) and expect to achiev the sam significant result on both.,What is the true alpha associated with this?,NEW MAJOR ISSUES,Missing Data,Noncompliance,Interim Analysis,OUR USUAL LOGIC INCREASES CHANCE OF ACCEPTANCE OF non-inferiority,MORE NEW ISSUES,Multiple endpoints,Multiple groups,Repeated Measures,WHERE ARE WE?,NON-INFERIORITY TRIALS HAVE MADE A BIG IMPACT,They have brought many new problems and challenges with them,
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