Issues that plague non inferiority trials past and future
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ISSUES THAT PLAGUE NON-INFERIORITY TRIALS PAST AND FUTURE RALPH B. D’AGOSTINO, 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

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Issues that plague non inferiority trials past and future l.jpg
ISSUES THAT PLAGUE NON-INFERIORITY TRIALSPAST AND FUTURE

RALPH B. D’AGOSTINO, SR.

BOSTON UNIVERSITY

HARVARD CLINICAL RESEARCH INSTITUTE


Objectives l.jpg
OBJECTIVES

  • REVIEW ISSUES: PAST, PRESENT AND FUTURE IN NON-INFERIORITY (NI) STUDIES

  • PRESENT/ DISCUSS EXAMPLES

  • MAKE SOME COMMENTS FOR IMPROVEMENTS

  • PRESENT A PERSONAL VIEW


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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


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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%


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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


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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)


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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



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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?


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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


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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)


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Clopidogrel Vs. Synthetic Placebo Control Odds Ratios and 95% Confidence IntervalsOverall Patient Population

CAPRIE: Clopidogrel Vs. Aspirin

Meta-Analysis: Aspirin Vs. Placebo

Estimated: Clopidogrel Vs. Placebo

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 1.2 1.4 1.6

First Drug Better Second Drug Better


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  • Meta-analysis studies contain very old studies (only up to 1990), many prior to all of the elaborate medical 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 studies used for Clopidogrel with aspirin comparison had PAD as an entry criteria (PAD represented 1/3 of Clopidogrel Study)


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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 0 10 20

Clopidogrel Better Aspirin Better


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Problems With Historical Controls (ASA vs Clopidogrel)

  • 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 we really seeing the same patients in historical studies as those in active control trial?


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Problems With Meta-Analyses (ASA vs Clopidogrel)So 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 Dose and Administration Levels of Active Control C?

  • Same Outcomes?

  • Combine “All” or “Some (good)” Placebo Controlled Studies


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Still Other Problems With (ASA vs Clopidogrel)Meta-Analyses

  • What if previous studies had multiple arms? How to put correctly into meta-analysis?

  • What if none of the individual studies achieved 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.)


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APPROACH 2 (ASA vs Clopidogrel)NON-INFERIORITY STUDIESACTIVE CONTROL STUDIES

NON-INFERIORITY TEST

H0: T-C >= M vs. H1: T-C < M

(Say data are event rates)

T is new treatment

C is positive control

M IS NON-INFERIORITY MARGIN


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NON-INFERIORITY STUDIES (ASA vs Clopidogrel)

APPROACH 2

  • SELECT A VALUE OF M THAT MAKES SENSE

  • WANT ASSURANCE THAT ASSAY SENSITIVITY IS PRESENT (Placebo is working)

  • WANT CONSISTENCY WITH PAST


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NON-INFERIORITY STUDIES (ASA vs Clopidogrel)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)


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WHAT IS NEEDED FOR 2 (ASA vs Clopidogrel)

  • 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


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SOME REALITIES (ASA vs Clopidogrel)

  • Sounds nice

  • What happens


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Anti-infective Product (ASA vs Clopidogrel)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?


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ANOTHER EXAMPLE (ASA vs Clopidogrel)Respiratory Distress

  • Respiratory Distress Syndrome in Premature Infants

    • Treatments

      • New Drug

      • Comparator

    • Outcome

      • Survival at 28 Day


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Respiratory Distress (cont) (ASA vs Clopidogrel)

  • 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?


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CONSISTENCY (ASA vs Clopidogrel)Example Control rate different 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?


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ANSWER TO CONSISTENCY (ASA vs Clopidogrel)

  • There was consistency

  • Differences related to birth weight


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Non-Inferiority and Inferiority at the same time (ASA vs Clopidogrel)

  • Sponsor falls apart

0

M


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Non-Inferiority and Superiority (ASA vs Clopidogrel)

  • Sponsor jumps for joy (Sequential test)

0

M


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Switching trial design (ASA vs Clopidogrel) (Cardiac Stent Trials)

  • (1) New drug coated stents, we can do non-inferiority study with margin set (15%)

  • (2) 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


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Respiratory Distress (ASA vs Clopidogrel)

  • Compare new surfaxin to another “not so great” one, but still used in practice


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Switching from Superiority to non-Inferiority (ASA vs Clopidogrel)

  • HOW CAN WE SWITCH FROM A SUPERIORITY TEST TO NON-INFERIORITY ?

  • This is a question thrown at me constantly


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Assessing Efficacy Non-Inferiority and Safety Superiority (ASA vs Clopidogrel)

  • Carotid artery Magnetic Resonance Imaging agent

  • Imaging Agents

    • Agent N (New) Agent C (Comparator)

  • 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


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Assessing Efficacy Non-Inferiority and Safety Superiority (Cont’d)

  • 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?


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Non US STUDIES (Cont’d)

  • Forced off shore (ethical and other reasons)


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The BLOB EFFECT (Cont’d)

  • Everything is suddenly Non-Inferiority


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ALLHAT STUDY (Cont’d)

  • COMPARISON OF ANTI-HYPERTENSIVE MEDICATIONS (MULTIPLE ARMS)

  • NOT A NON-INFERIORITY STUDY


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Safety Studies (Cont’d)

  • Safety studies have become carefully designed and executed studies

  • Should they be non-inferiority studies?


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SAFETY STUDIES (PHASE 4) (Cont’d)

HISTORICAL APPROACH: NEW RATE > OLD

H01: T-C <= 0 vs. H11: T-C > 0

H02: RR=T/C <= 1 vs. H12: RR=T/C > 1

STUDY POWERED TO REJECT T/C >1.5 (SAY)

SHIFT IS TO MAKING THESE NON-INFERIORITY STUDIES

  • H0: T-C >= M vs. H1: T-C < M

    H0: RR=T/C >= M vs. H1: RR=T/C < M


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Safety Studies (Cont’d)

  • OLD

  • NEW

1

M


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SAFETY STUDY TO NON-INFERIORITY STUDY (Cont’d)(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 enough?


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Form of Interest and Sample Size (Cont’d)

  • Ho: p1-p2 >= M

  • Ho: p1-p2>=Rp2

  • Ho: p1/p2 >= R

  • Best Choice does depend on p2 (control rates)


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Intent-to-Treat vs. Per-Protocol (Cont’d)

  • 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?


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Intent-to-Treat vs. Per-Protocol (Cont’d) (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 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”.


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NEW MAJOR ISSUES the sam significant result on both.

  • Missing Data

  • Noncompliance

  • Interim Analysis

  • OUR USUAL LOGIC INCREASES CHANCE OF ACCEPTANCE OF non-inferiority


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MORE NEW ISSUES the sam significant result on both.

  • Multiple endpoints

  • Multiple groups

  • Repeated Measures


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WHERE ARE WE? the sam significant result on both.

  • NON-INFERIORITY TRIALS HAVE MADE A BIG IMPACT

  • They have brought many new problems and challenges with them


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