1 can one evaluate an outcomes claim based on an active controlled study? pfizer response...
TRANSCRIPT
1
Can One Evaluate An Outcomes Claim Based On An Active Controlled Study?
Pfizer Response
Cardiovascular and Renal Drugs Advisory CommitteeRockville, Maryland
June 15, 2005
2
Sponsor Representatives And Introduction
Introduction and ObjectiveLance Berman, MDMedical DirectorUS Team LeaderPfizer Inc
Methodology and Analysis Overview Michael Gaffney, PhDSenior DirectorStatistical Research and Consulting Pfizer Inc
3
Introduction
Placebo-controlled CV outcome studies in hypertensive patients are no longer ethical
ALLHAT can be considered a well-conducted, large, randomized, double-blind, active-controlled study that provides CV outcomes for amlodipine besylate*
Using a non-inferiority analysis of the ALLHAT data, Pfizer submitted an sNDA for inclusion of the results in the amlodipine label
Invited by FDA to present this methodology as an illustrative example of how an active controlled study that showed no superiority between treatment arms might be used to support an outcomes claim.
* From here on, all mention of amlodipine besylate will be referred to as amlodipine
4
Brief Summary of ALLHAT
ALLHAT, an NHLBI study
Designed to determine if newer antihypertensive agents (amlodipine, lisinopril and doxazosin) were superior to first-line treatment with a diuretic (chlorthalidone)
Began in 1994
First major trial to assess the long-term CV effects of amlodipine in a large hypertensive population
5
Brief Summary of ALLHAT
ALLHAT enrolled an ethnically diverse patient population across North America: N=42,418, age > 55 years Mild-to-moderate hypertension + at least 1 other CHD risk factor.
Median follow-up was 4.9 years
Subjects randomized to treatment initiated with amlodipine, lisinopril, doxazosin or chlorthalidone with add-on therapy to achieve BP<140/90 mm Hg
Primary endpoint (CHD death and nonfatal MI): Amlodipine-based treatment vs chlorthalidone-based treatment
RR=0.98; 95% CI, 0.90-1.07 ALLHAT showed that long-term amlodipine-based
treatment was not superior to chlorthalidone-based treatment with respect to cardiovascular outcomes
6
Outline Of Approach To Determining The Benefit Of Amlodipine
A vs C Post-hoc analysis was done to demonstrate that amlodipine
(A) was “not inferior” to chlorthalidone (C) treatment in
ALLHAT
ALLHAT results demonstrated that amlodipine-based therapy was not superior to chlorthalidone based therapy
7
Outline Of Approach To Determining The Benefit Of Amlodipine
A vs C
C vs placebo
Effect of C is consistent and reproducible
Post-hoc analysis was done to demonstrate that amlodipine
(A) was “not inferior” to chlorthalidone (C) treatment in
ALLHAT Need first to establish the efficacy and
consistency of the standard treatment (chlorthalidone) vs placebo in reducing
CV events
ALLHAT results demonstrated that amlodipine-based therapy was not superior to chlorthalidone based therapy
8
Outline Of Approach To Determining The Benefit Of Amlodipine
A vs C
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
Post-hoc analysis was done to demonstrate that amlodipine
(A) was “not inferior” to chlorthalidone (C) treatment in
ALLHAT
Then show that the new treatment (amlodipine) preserves a substantial
portion of this effect
Estimate the effects of amlodipine relative to placebo
Need first to establish the efficacy and
consistency of the standard treatment (chlorthalidone) vs placebo in reducing
CV events
ALLHAT results demonstrated that amlodipine-based therapy was not superior to chlorthalidone based therapy
9
Establishing The Benefit And Consistency Of Chlorthalidone Treatment
SHEP study
Placebo-controlled trial in a population with isolated-systolic hypertension. Chlorthalidone-based treatment was shown to reduce the risks of fatal coronary events, non-fatal MI and stroke
Meta-analysis
Identify all randomized placebo-controlled hypertension studies that used low-dose diuretics to evaluate CV risk reduction
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
10
Meta-AnalysisStudy Characteristics
Treatment Comparison
N PopulationPrimary
EndpointFollow-
up
SHEP-Pilot
Chlorthalidone 25 mg/day vs
placebo551
≥60 years,ISH
Events collected
2.8years
SHEP
Chlorthalidone 12.5-25 mg/d +/-
atenolol or reserpine vs placebo
4736
≥60 years, BP 160-219/<90, no signs of major
CVD
Stroke4.5
years
MRC-OAmiloride 2.5-5 mg/HCTZ 25-50 mg vs atenolol vs placebo
439665-74 years,
BP 160-209/<115
All-cause mortality, stroke,
coronary events
5.8 years
EWPHEHCTZ/triamterene +/-
methyldopa vs placebo
840>60 years,
BP 160-239/90-119
Death and non-fatal CV, renal
events
4.7 years
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
Psaty BM, Smith NL, Siscovick DS, etal. Health outcomes associated with antihypertensive therapies used as first line agents. JAMA 1997; 277 (9):739-45
11
Results Of The Meta-Analysis For CHD Death And Nonfatal MI
The relative risks were combined across trials by the Mantel–Haenszel method. P=.66 homogeneity of RR
0 1 2 3
Relative Risk (95% CI)
0.914 (0.309-2.704)
0.739 (0.578-0.945)
0.618 (0.453-0.842)
0.829 (0.581-1.183)
0.719 (0.608-0.850)
Diuretic Events/N (%)
Placebo Events/N (%)
15/443 (3.4) 4/108 (3.7)
104/2365 (4.4) 141/2371 (6.0)
48/1081 (4.4) 159/2213 (7.2)
48/416 (11.5) 59/424 (13.9)
Trial
SHEP-Pilot
SHEP
MRC-O
EWPHE
Combined
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
12
Chlorthalidone Benefit On Fatal/Non-Fatal MI Preserved By Amlodipine
Chlorthalidone (n=15255)
Amlodipine (n=9048) A/C
One-Sided 97.5 Upper CL
A/C
CHD Death/Non-Fatal MI
1362 (8.93) 798 (8.82) 0.98 1.07
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
13
Chlorthalidone Benefit On Fatal/Non-Fatal MI Preserved By Amlodipine
Benefit of Chlorthalidone to Placebo Estimated by:
Imputed Placebo RR
% of Chl Effect Preserved
Point Estimate 1/0.72 =1.39 1−0.07/0.39= 82%
Upper CL 1/0.85 = 1.18 1−0.07/0.18= 60%
Chlorthalidone (n=15255)
Amlodipine (n=9048) A/C
One-Sided 97.5 Upper CL
A/C
CHD Death/Non-Fatal MI
1362 (8.93) 798 (8.82) 0.98 1.07
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
14
Estimating The Benefit Of Amlodipine Relative To Placebo
Meta-analysis ALLHAT
chlorthalidone x amlodipine =amlodipine
placebo chlorthalidoneplacebo
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
15
Estimated Relative Risk Of CHD Death/Non-Fatal MI Of Amlodipine To Placebo And 95% Confidence Limit
Chlorthalidone/Placebo Amlodipine/Chlorthalidone(Low-Dose Diuretic Studies) (ALLHAT)
RR Ln RR SE RR Ln RR SE
0.72 -0.330 0.085 0.98 -0.020 0.045
Amlodipine/Placebo
Ln RR SE RR 95% CI
-0.350 0.096 0.71 (0.58, 0.85)
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
16
Estimated Relative Risk Of Stroke Of Amlodipine To Placebo
Chlorthalidone/Placebo Amlodipine/Chlorthalidone(Low-Dose Diuretic Studies) (ALLHAT)
RR Ln RR SE RR Ln RR SE
0.66 -0.417 0.088 0.93 -0.073 0.067
Amlodipine/Placebo
Ln RR SE RR 95% CI
-0.490 0.111 0.61 (0.49, 0.76)
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
17
Estimated Relative Risk Of Hospitalized/ Fatal CHF For Amlodipine vs Placebo
Chlorthalidone/Placebo Amlodipine/Chlorthalidone(Low-Dose Diuretic Studies) (ALLHAT)
RR Ln RR SE RR Ln RR SE
0.58 -0.553 0.138 1.35 0.297 0.054
Amlodipine/Placebo
Ln RR SE RR 95% CI
-0.256 0.148 0.77 (0.58, 1.04)
C vs placebo
Effect of C is consistent and reproducible
Non-inferiority
A relative to C
Estimate the benefit
A relative to placebo
18
Points To Consider
Consistency of effect of active control Meta-analysis Extrapolation of chlorthalidone benefit to ALLHAT
population of ALLHAT vs populations of the trials in the meta-analysis
Conduct of the ALLHAT study Other secondary ALLHAT outcomes Statistical considerations
Adjusting for multiplicity Post-hoc nature
19
Summary
ALLHAT was a large active-controlled study that showed no superiority between
the newer agent (amlodipine) and the standard agent (chlorthalidone)
In the meta-analysis, the standard therapy (chlorthalidone) was found to have a consistent and reproducible effect
(0.72 [0.608-0.850])
The new agent (amlodipine) was found to be non-inferior to the
standard therapy (chlorthalidone)
(82% of chlorthalidone effect was preserved)
The new agent (amlodipine) was estimated to reduce the
risk of CHD death and non-fatal MI by 29% relative to placebo
20
Conclusion
This non-inferiority analysis provides an illustrative example of how one can use an active controlled trial to support an
outcomes claim.