1. Equivalence Trials: Understanding the Statistical and Clinical Issues Christopher Cannon, M.D. C. Michael Gibson, M.S., M.D. Brigham and Women’s HospitalBeth Israel Deaconess Med Center

2. Superiority Trials l When a drug in a new class is developed, it is usually tested vs. placebo, in addition to the other standard therapies, to determine if it improves outcomes. Examples: New Classes: Placebo-controlled trials 4S – statin GISSI-1, ISIS-2 – streptokinase GISSI-1, ISIS-2 – streptokinase ASSET – t-PA ASSET – t-PA EPIC, PURSUIT, PRISM-PLUS – IIb/IIIa inhibitors EPIC, PURSUIT, PRISM-PLUS – IIb/IIIa inhibitors

3. Superiority trials (2) l If a new drug in an existing class is developed, there are 3 ways to test it: l Superiority testing vs. placebo in a different patient population, or related indication Example: CARE, LIPID – pravastation (Pts with lower LDL levels than in 4S trial) EPILOG, EPISTENT, ESPRIT - IIb/IIIa inhibitors in low risk patients, and/or stented patients EPILOG, EPISTENT, ESPRIT - IIb/IIIa inhibitors in low risk patients, and/or stented patients

4. Superiority trials (3) l If a new drug in an existing class is developed, and it has properties that make it potentially superior to an existing drug (or device) in that class: l Superiority testing of new drug (device) vs. older drug l Examples: GUSTO – I: t-PA vs. streptokinase ESSENCE, TIMI 11B: enoxaparin vs. unfractionated heparin ESSENCE, TIMI 11B: enoxaparin vs. unfractionated heparin STRESS, BENESTENT: stents vs. balloon angioplasty STRESS, BENESTENT: stents vs. balloon angioplasty

5. Equivalence Trials – Why? If on the other hand, a new drug (or device) is felt likely to be similar to the old drug, and the hypothesis is that they are similar, the third way to compare 2 drugs is an “equivalence” or “non-inferiority” trial l This would be the case if one expects similar overall outcomes for major outcomes (death, MI etc), with perhaps some advantages on other aspects (pharmacokinetics – once/day vs. twice/day dosing, fewer side effects) l If that class of drugs is established as a standard of care, one cannot remove it from clinical care, to test the new drug against placebo.

6. Hypothetical Trial Drug A vs. Drug B for stenting 500 patients randomized 250 per group. 30 day rate of stent thrombosis 4 (1.6%) for Group A 4 (1.6%) for Group B Are the drugs equivalent?

7. Hypothetical trial - Answer NO – too small sample size. How do you tell? Confidence intervals 4/250 = 1.6%, 95% CI (0.44% – 4.0%)

8. Absolute Difference 04.5 Confidence Intervals to Compare Two Treatments Drug A Drug B -4.5 1.5 Large trial 40/2500 40/2500 (1.6%)(1.6%) Small trial 4/250 4/250 (1.6%)(1.6%) 3-1.5-3

9. Design of Non-Inferiority Trials Region of non-inferiority must be defined in advance  If the upper bound 95% Confidence Interval of the difference between two treatments lies entirely below the pre-specified boundary then these treatments may be considered clinically equivalent Region of non-inferiority must be defined in advance  If the upper bound 95% Confidence Interval of the difference between two treatments lies entirely below the pre-specified boundary then these treatments may be considered clinically equivalent

10. Superiority vs. Equivalence Trial Design Superiority: l Hypothesis is Treatment A is better than Treatment B l Statistical testing: Prove that Tx A is not equal to Tx B (disprove Null hypothesis) Non-Inferiority (Clinical Equivalence): l Hypothesis is Tx A is at least as good as Tx B l Statistical testing: Prove that Tx A is not worse than Tx B Equivalence: l Statistical testing: Prove that Tx B is not worse (and not better) than Tx A

11. Relative Risk 1.01.5 Designing a Non-inferiority Trial Standard Therapy Aggressive Therapy 0.5 1.20 Non-inferiority “clinical equivalence” 420/2000 400/2000 (21%)(20%) Superiority 800/4000 640/4000 (20%)(16%) Equivalence 4000/20000 4000/20000 (20%)(20%) 0.8

12. Relative Risk 1.31.41.51.61.71.21.11.00.90.8 Therapy A Better Therapy B Better COMPASS 95% CI no worse than 1.5 TARGET 95% CI no worse than 1.47 ASSENT-2 1.14 REPLACE 2 1.18 PROVE-IT 1.17* Criteria for Clinical Equivalence in ACS Trials Non-inferiority: upper 95% CI of the RR between 2 agents can be no worse than pre-specified range *relative risk of 1.17 at 2 years = 1.198 hazard ratio

13. INJECT: r-PA vs. Streptokinase INJECT: designed to determine the effect of reteplase on survival was at least equivalent (within 1% of fatality rate) to that of a standard streptokinase regimen. Patients (n = 6010) randomised. 35-Day Mortality: 9.02% in the reteplase 9.53% in the streptokinase group, a non-significant difference (95% CI -1.98% to 0.96%). Because the upper limit of the 90% CI (one-sided 95% CI) for this difference is 0.71%, this result shows that reteplase is at least as effective as streptokinase.. Lancet. 1995;346:329-336.

14. COBALT: double bolus vs. accelerated t-PA COBALT definition for double-bolus t-PA to be considered equivalent to an accelerated t-PA: the upper limit of the one-sided 95 percent confidence interval of the difference in 30-day mortality could not exceed an absolute difference of 0.4 percent; This difference corresponds to the lower 95 percent confidence limit of the absolute difference in 30-day mortality between an accelerated infusion of alteplase and streptokinase in the GUSTO I trial. The COBALT investigators asserted that if equivalence based on this criterion could be demonstrated, one might infer that double-bolus alteplase is superior to streptokinase. N Engl J Med 1997;337:1124-1130

15. COBALT: Results COBALT randomized 7169 patients. 30-day mortality rates: l 7.98 percent in the double-bolus t-PA l 7.53 percent in the accelerated t-PA, an unfavorable absolute difference of 0.44 percent. l Because the one-sided 95 percent confidence limit for the difference in mortality rates exceeded the prespecified limit, the authors concluded that double- bolus alteplase had not been shown to be equivalent to an accelerated infusion of alteplase. N Engl J Med 1997;337:1124-1130

16. COBALT: Results 0.40 0.4 0.4 D-B (%) Accel. (%) Absol Diff (95% CI) DB Better Accel Better 30 Day Mortality 7.98 7.53 -0.44 Absolute Event difference N Engl J Med 1997;337:1124-1130

17. TNK-tPA: Phase III study: ASSENT-2 ASSENT-2 Protocol Design ST-Segment Elevation MI < 6 h ASA Heparin (aPTT 50-75s) 1:1 (double-blind) TNK-tPA single bolus weight-adjusted Accel tPA <100 mg/90 min Primary endpoint All Cause Mortality (30 days) n=16,500 pts

18. Primary Endpoint Null and Alternative Hypotheses Primary Endpoint: 30 Day Mortality (All Causes) Null and Alternative Hypotheses H 0 : m TNK-tPA - m tPA > 1% H 1 : m TNK-tPA - m tPA  1% vs H 0 : m TNK-tPA / m tPA > 1.14 H 1 : m TNK-tPA / m tPA  1.14 vs or Absolute Difference Relative Risk

19. Null Hypotheses: Absolute vs Relative Mortality Difference If 30 Day Mortality t-PA = 10% upper 90% boundary for equivalence = 11% (10% + 1%) If 30 Day Mortality t-PA = 5% upper 90% boundary for equivalence = 5.7% (5% + 14% of 5%)

20. Sample Size Assumptions: –30-Day Mortality After rt-PA = 7.2% –Equal Mortality After TNK-tPA ïSample size of 16,500 randomized and treated patients provides 80% power to reject null hypothesis at a one- sided significance level of 5%

21. Kaplan-Meier Curve for 30 Day Mortality rt-PATNK-tPA Days to Death

22. 30-Day Mortality: Absolute Difference 1. Primary Analysis (Adjusted Rate) 2. Secondary Analysis (Unadjusted Rate) 3. Logistic Regression TNK-tPA % 6.17 6.16 6.10 rt-PA % 6.15 6.18 6.15 Absolute Difference (90% CI) 0.02 (-0.56,0.60) -0.02 (-0.62,0.59) -0.05 (-0.62,0.52) P-value for equivalence 0.006 0.003 TNK-tPA better rt-PA better 10

23. 30-Day Mortality: Relative Risk 1. Primary Analysis (Adjusted Rate) 2. Secondary Analysis (Unadjusted Rate) 3. Logistic Regression TNK-tPA % 6.17 6.16 6.10 rt-PA % 6.15 6.18 6.15 Relative Risk (90% CI) 1.00 (0.91,1.10) 1.00 (0.90,1.10) 0.99 (0.90,1.09) P-value for equivalence 0.027 0.026 0.015 TNK-tPA better rt-PA better 0.881.141

24. 1 1.147 n-PA (%) t-PA (%) RelativeRisk (95% CI) n-PA Better t-PA Better P Value for Equivalence Death 6.75 6.6 1.02 1.143 0.047 InTIME-2: n-PA and t-PA Equivalent for 30-Day Mortality InTIME-II Investigators. Eur Heart J 2000;21:2005-13.

25. 110 +1 n-PA (%) t-PA (%) Absolute Difference (95% CI) n-PA Better t-PA Better P Value for Equivalence Death 6.77 6.60.17 ( .068, 1.0) 0.047 InTIME-2: n-PA and t-PA Equivalent for 30- Day Mortality Giugliano RP, et al. Circulation. 1999;100:I-651.

26. 11 0 +1 r-PA (%) t-PA (%) Absolute Difference (95% CI) r-PA Better t-PA Better P Value for Equivalence Death 7.47 7.24   0.23  (  1.11, 0.66) P=NS GUSTO-III: r-PA and t-PA Not Equivalent for 30-Day Mortality Adapted from GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123.

27. 0 +1 Mortality (%) Absolute Difference (95% CI) T-PA BetterBetter P Value for Equivalence InTIME-2 6.776.60   0.17 (  1.0, 0.68) 0.047 ASSENT-2 6.166.18 0.02 (  0.59, 0.62) 0.006 GUSTO-III 7.477.24  0.23 (  1.11, 0.66) NS Comparison Among Equivalency Analyses for 30-Day Mortality ASSENT-2 Investigators. Lancet. 1999;354:716-722; Adapted from GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123. Adapted from Giugliano RP, et al. Circulation. 1999;100:I-651. n-PA TNK-tPA r-PA Other t-PA t-PA t-PA

28. Net Clinical Benefit Death or Non-Fatal Stroke at 30 Days (%) Death or Non-Fatal ICH (%) Death or Non-Fatal Disabling Stroke (%) Death or Non-Fatal Disabling ICH (%) TNK-tPA (n=8,462) 7.10 5.95 6.21 5.85 rt-PA (n=8,488) 7.04 5.87 6.05 5.78 Relative Risk (95% CI) 1.01 (0.91,1.13) 1.01 (0.90,1.14) 1.03 (0.91,1.15) 1.01 (0.90,1.14) P-value 0.881 0.845 0.701 0.870

29. ASSENT 2: Conclusions The Primary Objective of ASSENT-2 Has Been Achieved: Demonstration That Single Bolus TNK-tPA is Equivalent to Accelerated rt-PA in Reducing 30-Day Mortality. l Stringent Criteria for Equivalence l Mortality Rates Virtually Identical

30. Study Design A Phase (open-label) Z Phase * (double-blind) Admission UAP/NSTE-MI Unfractionatedheparin Tirofiban (48 to 108 hours) Enoxaparin Randomized Diet and placebo 4 months 1 month Simvastatin 40 mg Stabilized ** Simvastatin 80 mg Simvastatin 20 mg STE-MI Optimal treatment

31. 0.881 1.144 Enox (%) Hep (%) HazardRatio (95% CI) Enox Better Hep Better D/MI/RI 8.4 9.4 0.88 1.05 Blazing M. presented ACC 2003. Primary Endpoint at 7 days Death, MI and Refractory Ischemia

32. Primary Endpoint * * 30 day Death, MI, Urgent TVR Upper bound of 95% confidence interval = 1.52 Non-inferiority boundary RR = 1.26 1.47 1.00 Abciximabbetter Tirofibanbetter Relative Risk Tirofiban Abciximab 7.5% 6.0%

33. Double-blind, randomized trial in 4,162 patients with Acute Coronary Syndrome <10 days and Total Cholesterol < 240 mg/dL ASA + Standard Medical Therapy Pravastatin 40 mg qhs Atorvastatin 80 mg qhs Gatifloxacin * Placebo Duration: Mean 2 year follow-up (925 events) Primary Endpoint: Death, MI, Stroke, UA requiring hosp., or revascularization (> 30 days after randomization) Primary Endpoint: Death, MI, Stroke, UA requiring hosp., or revascularization (> 30 days after randomization) PROVE IT (TIMI 22): Study Design * Gatifloxacin 400mg qd X 10 days/month Cannon et al. Am J Card 2002;89:860–861.

34. 200 LDL-C(mg/dL) Placebo LDL-C levels Statin LDL-C levels 4S LIPID CARE Secondary Prevention Trials 31%24%24% HPS 26% PROSPER * 24% Relative Risk Reduction (CHD Death/NFMI): Overview of Degree of LDL-C Lowering, Achieved LDL-C Levels, and Reduction in Clinical Events from Randomized Trials * Only secondary prevention patients included LDL-C  35% 75 100 125 150 175 LDL-C  28% LDL-C  25% LDL-C  35% LDL-C  34%

35. 175 LDL-C(mg/dL) LDL-C >135 (>3.5 mmol) HPS LDL-C Subgroup Analysis 39% Relative Risk Reduction (Major vascular events): HPS: Effects of Fixed Dose Statin by LDL-C Subgroups Placebo LDL-C levels Simvastatin LDL-C levels 50 75 100 125 150 LDL-C 116-135 (3-3.5 mmol) 37% LDL-C < 116 (<3 mmol) 35% LDL-C  35% LDL-C  35% LDL-C  37%

36. 175 150 125 100 75 LDL-C(mg/dL) Baseline LDL-C levels On Statin LDL-C levels Standard Dose Statin Therapy (Pravastatin 40mg) ??? Event Reduction: Is Aggressive LDL-C Lowering More Effective in Reducing Clinical Events?  25-35%  50% Aggressive Statin Therapy (Atorvastatin 80mg)

37. PROVE IT: PRavastatin Or atorVastatin Evaluation and Infection Therapy (TIMI 22) Primary Objectives: l To determine if there is clinical equivalence between pravastatin and atorvastatin in reducing major cardiovascular events in patients with ACS AND AND l To determine if the antimicrobial agent gatifloxacin is superior to placebo in reducing major cardiovascular events in patients with ACS Cannon et al. Am J Card 2002;89:860–1.

38. Primary Statin Non-inferiority Comparison: PROVE-IT is designed to determine whether the 2 year CV event rate of pravastatin is ‘clinically equivalent’ to atorvastatin – –‘Clinical equivalence’ declared if the upper 95% CI of relative risk of event rates at 2 years is < 1.17 – –Using Cox proportional Hazard model, hazard ratio (over the entire period of follow-up) of 1.197 leads to a relative risk of 1.17 for events at 2 years. – –Assuming 22% event rate in atorvastatin arm, the greatest absolute difference between pravastatin and atorvastatin that would meet the pre-spcified definition would be 1.2% (eg. atorva 22% vs. prava 23.2%). Cannon et al. Am J Card 2002;89:860-861; Crit Path Cardio 2003;2:150-7.

39. Relative Risk Pravastatin BetterAtorvastatin Better Upper 95% confidence limit of the relative risk between pravastatin and atorvastatin can be no worse than 1.17 at 2 years (1.198 hazard ratio) to demonstrate equivalence Clinical equivalence (& superior) Clinical equivalence 1.01.17 Possible PROVE-IT Outcomes Uncertain No clinical equivalence (& inferior) Secondary Analysis

40. PatientsDurationEndpointsPower* COMPASS 3089 30 days 19280% ASSENT-2 16949 104480% REPLACE 2 6010 30 days 57492% TARGET 5308 32788% * Power calculations are based on number of endpoints and are function of number of patients and trial duration ** relative risk of 1.17 at 2 years = 1.198 hazard ratio of Cox proportional model PROVE-IT4160 2 years 92587% Upper 95%CI 1.50 1.14 1.18 1.47 1.17** Is PROVE-IT Powered Appropriately to Detect Non-Inferiority?

41. PROVE-IT (TIMI 22): What Will it Tell Us? PROVE-IT designed to evaluate ACS patients and determine the 2 year impact of: l Different degrees of LDL-C lowering l Different statins (pravastatin vs atorvastatin) on safety l Continual pulsed antibiotic therapy in patients following an acute coronary syndrome (ACS) l will directly compare efficacy and safety of two statins l strictly defines clinical equivalence l follows 4162 patients for 2 years l is endpoint driven l is adequately powered (>87%)

42. Equivalence Trials l More common in current era of multiple effective therapies l Used to test hypothesis of equivalence between 2 drugs or devices l Must have pre-defined criteria for “non-inferiority”, based on confidence intervals, to ensure adequate power l Definition of equivalence limit is 1) preserves benefit over placebo, or 2) is clinically based difference

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