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Can One Evaluate An Outcomes Claim Based On An Active Controlled Study?

Pfizer Response

Cardiovascular and Renal Drugs Advisory CommitteeRockville, Maryland

June 15, 2005

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Conclusion

This non-inferiority analysis provides an illustrative example of how one can use an active controlled trial to support an

outcomes claim.