ISSUES THAT PLAGUE NON-INFERIORITY TRIALS PAST AND FUTURE

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ISSUES THAT PLAGUE NON-INFERIORITY TRIALSPAST
AND FUTURE

• RALPH B. DAGOSTINO, SR.
• BOSTON UNIVERSITY
• HARVARD CLINICAL RESEARCH INSTITUTE

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OBJECTIVES

1. REVIEW ISSUES PAST, PRESENT AND FUTURE IN
   NON-INFERIORITY (NI) STUDIES
2. PRESENT/ DISCUSS EXAMPLES
3. MAKE SOME COMMENTS FOR IMPROVEMENTS
4. PRESENT A PERSONAL VIEW

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OUTLINE

1. Early Objectives and Issues
2. Approaches to Non-inferiority Trials
3. Examples (Here are some Problems)
4. Non-Inferiority AND/OR Superiority
5. All is Non-Inferiority
6. Intent-to-Treat vs. Per Protocol
7. New Major Issues

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EARLY OBJECTIVES AND ISSUES EQUIVALENCY

• American Dental Association (ADA 1980s)
• CREST equivalent to COLGATE?
• Ho A-Bgt 10 or A-Blt 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• Meta-analysis of all published and unpublished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 Intervals
Overall Patient Population
CAPRIE Clopidogrel Vs. Aspirin
Meta-Analysis Aspirin Vs. Placebo
Estimated Clopidogrel Vs. Placebo

• Endpoint
• All Strokes, MIs,
• or Vascular Deaths p lt 0.000001
• All Strokes, MIs
• or Death from p lt 0.000001
• Any Cause
• Vascular p lt 0.0016
• Deaths
• All Cause p lt 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

• 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-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 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 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 2NON-INFERIORITY STUDIESACTIVE CONTROL
STUDIES

• NON-INFERIORITY TEST
• H0 T-C gt M vs. H1 T-C lt 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

• 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 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) M0.5 (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

• CONFIDENCE INTERVAL IS OFTEN USED. WANT M1.11
  (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

• Sounds nice
• What happens

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Anti-infective Product No placebo data

• Historical data is not Placebo, but C
• VRE (vancomycin resistant enterococcal)
• High dose Low dose
• MITT 60.0 (N65) vs. 46.2 (N52)
• Bacteremic
• 55.6 (N18) vs. 25.0
  (N16)
• What is M? One trial OK? Any superiority?

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ANOTHER EXAMPLERespiratory Distress

• Respiratory Distress Syndrome in Premature
  Infants
• Treatments
• New Drug
• Comparator
• Outcome
• Survival at 28 Day

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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?

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CONSISTENCY Example Control rate different from
historical

• Historical Data says C0.5 and P0.6
• Want Tlt0.55
• P-C0.10, M0.5(0.10) 0.05
• (T-C)/C 0.05/0.50 10
• Data is C0.30 and T0.33, T-C0.03
• (T-C)/C 0.03/0.30 10
• IS STUDY A SUCCESS? USE RATIOS?

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ANSWER TO CONSISTENCY

• There was consistency
• Differences related to birth weight

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Non-Inferiority and Inferiority at the same time

• Sponsor falls apart

0
M
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Non-Inferiority and Superiority

• Sponsor jumps for joy (Sequential test)

0
M
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Switching trial design (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

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

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Switching from Superiority to non-Inferiority

• 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

• Carotid artery Magnetic Resonance Imaging agent
• Imaging Agents
• Agent N (New) Agent C (Comparator)
• Non-inferiority Outcome
• Endpoint agents ability to classify correctly
  patients with gt 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 (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?

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Non US STUDIES

• Forced off shore (ethical and other reasons)

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The BLOB EFFECT

• Everything is suddenly Non-Inferiority

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ALLHAT STUDY

• COMPARISON OF ANTI-HYPERTENSIVE MEDICATIONS
  (MULTIPLE ARMS)
• NOT A NON-INFERIORITY STUDY

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Safety Studies

• Safety studies have become carefully designed and
  executed studies
• Should they be non-inferiority studies?

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SAFETY STUDIES (PHASE 4)

• HISTORICAL APPROACH NEW RATE gt OLD
• H01 T-C lt 0 vs. H11 T-C gt 0
• H02 RRT/C lt 1 vs. H12 RRT/C gt 1
• STUDY POWERED TO REJECT T/C gt1.5 (SAY)
• SHIFT IS TO MAKING THESE NON-INFERIORITY STUDIES
• H0 T-C gt M vs. H1 T-C lt M
• H0 RRT/C gt M vs. H1 RRT/C lt M

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Safety Studies

• OLD
• NEW

1
M
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SAFETY STUDY TO NON-INFERIORITY STUDY(QT
LONGATION)

• Safety issue drug may cause QT problem
• Ho A/B 1.0 vs H1 R A/B gt 1.0
• Study powered for R gt 1.0
• When interest in risk fades can we suddenly say
  this should be a non-inferiority study?
• HoR gt 1.5 vs. H1R lt 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

• Ho p1-p2 gt M
• Ho p1-p2gtRp2
• Ho p1/p2 gt R
• Best Choice does depend on p2 (control rates)

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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?

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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.

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• 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?

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NEW MAJOR ISSUES

• Missing Data
• Noncompliance
• Interim Analysis
• OUR USUAL LOGIC INCREASES CHANCE OF ACCEPTANCE OF
  non-inferiority

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MORE NEW ISSUES

• Multiple endpoints
• Multiple groups
• Repeated Measures

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WHERE ARE WE?

• NON-INFERIORITY TRIALS HAVE MADE A BIG IMPACT
• They have brought many new problems and
  challenges with them