ACTIVECONTROLTRIALS-Amstat主动控制试验News

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1、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. D’AGOSTINO, SR.,,BOSTON UNIVERSITY,,HARVARD CLINICAL RESEARCH INSTITUTE,,OBJECTIVES,,REVIEW ISSUES: PAST, P

2、RESENT 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-In

3、feriority,,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

4、 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〞 AB

5、OUT 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.

6、 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

7、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we get?,,For Aspirin vs. PlaceboAntiplatelet Trialists’ Collaboration Meta-Analysis,Meta-analysis of all published and unpublished unconfounded randomized trials available March 1990,,Trials identified by literature search, trial registry and inquiry of investigators and pharmaceut

8、ical 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 I

9、ntervals,Overall Patient Population,Endpoint,,,All Strokes, MIs,,,or Vascular Deaths p < 0.000001,,,All Strokes, MIs,,or Death from p < 0.000001,,Any Cause,,,Vascular p < 0.0016,,Deaths,,,All Cause p < 0.0045,,Deaths,,0.4 0.6 0.8 1.0

10、 1.2 1.4 1.6,,First Drug Better Second Drug Better,,,CAPRIE: Clopidogrel Vs. Aspirin,,Meta-Analysis: Aspirin Vs. Placebo,,Estimated: Clopidogrel Vs. Placebo,,Meta-analysis studies contain very old studies (only up to 1990), many prior to all of the elaborate m

11、edical interventions (procedures) now routinely provided,,,Many of the studies did not have MI, IS or vascular death as their outcomes (the meta-analysis went back to original investigators who in turn, had to generate data).,Ever try to get data on something you did not collect?,,,None of the studi

12、es used for Clopidogrel with aspirin comparison had PAD as an entry criteria (PAD represented 1/3 of Clopidogrel Study),,,EFFECT SIZE: Relative Risk Reduction by Qualifying Condition (ASA vs Clopidogrel),,IS n = 6431,,MI n = 6302,,PAD n = 6452,,,Total n =19185,,,30 20 10

13、 0 10 20,,Clopidogrel Better Aspirin Better,,Problems With Historical Controls,Biases,,Time Biases,,Change in recognition or diagnosis of disease,,Changing disease process,,Change in usual therapy,,(Myocardial Infarctions MI, Dx, Tx),,Selection Biases,,Patients/Health care systems,,Are

14、 we really seeing the same patients in historical studies as those in active control trial?,,,Problems With Meta-AnalysesSo What Is Sponsor to DO?,If we plan to use placebo controlled trials, what should we require of the historical placebo trials?,,Same Disease/Conditions?,,Same Population,,Same D

15、ose and Administration Levels of Active Control C?,,Same Outcomes?,,Combine “All〞 or “Some (good)〞 Placebo Controlled Studies,,Still Other Problems With Meta-Analyses,,What if previous studies had multiple arms? How to put correctly into meta-analysis?,,,What if none of the individual studies achi

16、eved significance?,,,What are we to believe from meta-analyses?,,Do we believe the p-levels of the meta-analysis? (I do not think we should.),,,,APPROACH 2NON-INFERIORITY STUDIESACTIVE CONTROL STUDIES,,NON-INFERIORITY TEST,,H,0,: T-C >= M vs. H,1,: T-C < M,,,(Say data are event rates),,T is new tr

17、eatment,,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 Contr

18、ol 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

19、 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,

20、 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 Infan

21、ts,,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 differ

22、ent from historical,,Historical Data says C=0.5 and P=0.6,,Want T<=0.55,,P-C=0.10, M=0.5(0.10) = 0.05,,(T-C)/C = 0.05/0.50 = 10%,,Data is C=0.30 and T=0.33, T-C=0.03,,(T-C)/C = 0.03/0.30 = 10%,,IS STUDY A SUCCESS? USE RATIOS?,,,ANSWER TO CONSISTENCY,,There was consistency,,,Differences related to bi

23、rth weight,,,Non-Inferiority and Inferiority at the same time,Sponsor falls apart,,0,M,,Non-Inferiority and Superiority,,Sponsor jumps for joy (Sequential test),,0,M,,Switching trial design (Cardiac Stent Trials),,(1) New drug coated stents, we can do non-inferiority study with margin set (15%),,(2

24、) We can do superiority study with non-coated stent as control,,With first option we have to worry about evaluating Ms, Effect size and CREEP,,With superiority trial “clean〞 results,,,Respiratory Distress,,Compare new surfaxin to another “not so great〞 one, but still used in practice,,,Switching fro

25、m Superiority to non-Inferiority,HOW CAN WE SWITCH FROM A SUPERIORITY TEST TO NON-INFERIORITY ?,,,This is a question thrown at me constantly,,,Assessing Efficacy Non-Inferiority and Safety Superiority,,Carotid artery Magnetic Resonance Imaging agent,,Imaging Agents,,Agent N (New) Agent C (Comparator

26、),,Non-inferiority〞 Outcome,,Endpoint: agent’s ability to classify correctly patients with > 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 (Cont’d),,There is a specific adverse eve

27、nt 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 STU

28、DY,,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 <=

29、 0 vs. H,11,: T-C > 0,,H,02,: RR=T/C <= 1 vs. H,12,: 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,,H,0,: RR=T/C >= M vs. H,1,: RR=T/C < M,,Safety Studies,,OLD,,,,NEW,,,1,M,,SAFETY STUDY TO NON-INFERIORITY STUD

30、Y(QT LONGATION),,Safety issue: drug may cause QT problem,,Ho: A/B = 1.0 vs H1: R = A/B > 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 < 1.5 was not original objective,,If we do not reject Ho is that en

31、ough?,,Form of Interest and Sample Size,,Ho: p1-p2 >= 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〞 difference

32、s of treatments,,In non-inferiority should we use PP?,,,Intent-to-Treat vs. Per-Protocol (Cont’d),,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

33、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

34、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,,,