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

1. Can One Evaluate An Outcomes Claim Based On An Active Controlled Study? Pfizer Response Cardiovascular and Renal Drugs Advisory CommitteeRockville, MarylandJune 15, 2005

2. Sponsor Representatives And Introduction Introduction and Objective Lance 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 ALLHAT results demonstrated that amlodipine-based therapy was not superior to chlorthalidone based therapy Post-hoc analysis was done to demonstrate that amlodipine (A) was “not inferior” to chlorthalidone (C) treatment in ALLHAT A vs C

7. Outline Of Approach To Determining The Benefit Of Amlodipine ALLHAT results demonstrated that amlodipine-based therapy was not superior to chlorthalidone based therapy Post-hoc analysis was done to demonstrate that amlodipine (A) was “not inferior” to chlorthalidone (C) treatment in ALLHAT A vs C Need first to establish the efficacy and consistency of the standard treatment (chlorthalidone) vs placebo in reducing CV events C vs placebo Effect of C is consistent and reproducible

8. Outline Of Approach To Determining The Benefit Of Amlodipine ALLHAT results demonstrated that amlodipine-based therapy was not superior to chlorthalidone based therapy Post-hoc analysis was done to demonstrate that amlodipine (A) was “not inferior” to chlorthalidone (C) treatment in ALLHAT A vs C Need first to establish the efficacy and consistency of the standard treatment (chlorthalidone) vs placebo in reducing CV events C vs placebo Effect of C is consistent and reproducible Non-inferiority A relative to C Estimate the benefit A relative to placebo Then show that the new treatment (amlodipine) preserves a substantial portion of this effect Estimate the effects of amlodipine relative to placebo

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

10. Meta-AnalysisStudy Characteristics 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 Trial SHEP-Pilot SHEP MRC-O EWPHE Combined 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) The relative risks were combined across trials by the Mantel–Haenszel method. P=.66 homogeneity of RR

12. Chlorthalidone Benefit On Fatal/Non-Fatal MI Preserved By Amlodipine

13. Chlorthalidone Benefit On Fatal/Non-Fatal MI Preserved By Amlodipine

14. Estimating The Benefit Of Amlodipine Relative To Placebo Meta-analysis ALLHAT chlorthalidone x amlodipine = amlodipine placebo chlorthalidone placebo

15. Estimated Relative Risk Of CHD Death/Non-Fatal MI Of Amlodipine To Placebo And 95% Confidence Limit

16. Estimated Relative Risk Of Stroke Of Amlodipine To Placebo

17. Estimated Relative Risk Of Hospitalized/ Fatal CHF For Amlodipine vs 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.