Title: ISSUES THAT PLAGUE NON-INFERIORITY TRIALS PAST AND FUTURE
1ISSUES THAT PLAGUE NON-INFERIORITY TRIALSPAST
AND FUTURE
- RALPH B. DAGOSTINO, SR.
- BOSTON UNIVERSITY
- HARVARD CLINICAL RESEARCH INSTITUTE
2OBJECTIVES
- REVIEW ISSUES PAST, PRESENT AND FUTURE IN
NON-INFERIORITY (NI) STUDIES - PRESENT/ DISCUSS EXAMPLES
- MAKE SOME COMMENTS FOR IMPROVEMENTS
- PRESENT A PERSONAL VIEW
3OUTLINE
- 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
4EARLY 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
5EARLY 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
6APPROACHES 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)
7APPROACH 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
821
9CAPRIE STUDY (cont)
- Can we obtain effect of Clopidogrel vs. Aspirin
- Yes, if we can locate Asprin vs. Placebo
- Do we believe what we get?
10For 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- Meta-analysis of all published and unpublished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
11APPROACH
- T vs. C (from Caprie trial)
- C vs. P (from Meta-analysis)
- Obtain T vs. P (from multiplication)
- (T/C) (C/P) (T/P)
12 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 -
13- 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)
14EFFECT 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
15Problems 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?
16Problems 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
17Still 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.) -
18APPROACH 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
19NON-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
20NON-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)
21WHAT 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
22SOME REALITIES
23Anti-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?
24ANOTHER EXAMPLERespiratory Distress
- Respiratory Distress Syndrome in Premature
Infants - Treatments
- New Drug
- Comparator
- Outcome
- Survival at 28 Day
25Respiratory 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?
26CONSISTENCY 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?
27ANSWER TO CONSISTENCY
- There was consistency
- Differences related to birth weight
28Non-Inferiority and Inferiority at the same time
0
M
29Non-Inferiority and Superiority
- Sponsor jumps for joy (Sequential test)
0
M
30Switching 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
31Respiratory Distress
- Compare new surfaxin to another not so great
one, but still used in practice
32Switching from Superiority to non-Inferiority
- HOW CAN WE SWITCH FROM A SUPERIORITY TEST TO
NON-INFERIORITY ? - This is a question thrown at me constantly
33Assessing 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
34Assessing 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?
35Non US STUDIES
- Forced off shore (ethical and other reasons)
36The BLOB EFFECT
- Everything is suddenly Non-Inferiority
37ALLHAT STUDY
- COMPARISON OF ANTI-HYPERTENSIVE MEDICATIONS
(MULTIPLE ARMS) - NOT A NON-INFERIORITY STUDY
38Safety Studies
- Safety studies have become carefully designed and
executed studies - Should they be non-inferiority studies?
39SAFETY 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
40Safety Studies
1
M
41SAFETY 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?
42Form 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)
43Intent-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?
44Intent-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.
45- 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?
46NEW MAJOR ISSUES
- Missing Data
- Noncompliance
- Interim Analysis
- OUR USUAL LOGIC INCREASES CHANCE OF ACCEPTANCE OF
non-inferiority
47MORE NEW ISSUES
- Multiple endpoints
- Multiple groups
- Repeated Measures
48WHERE ARE WE?
- NON-INFERIORITY TRIALS HAVE MADE A BIG IMPACT
- They have brought many new problems and
challenges with them