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

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

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

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

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.

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?

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

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

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

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

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

Relative Risk Therapy A Better Therapy B Better COMPASS 95% CI no worse than 1.5 TARGET 95% CI no worse than 1.47 ASSENT REPLACE 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 = hazard ratio

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:

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:

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:

COBALT: Results D-B (%) Accel. (%) Absol Diff (95% CI) DB Better Accel Better 30 Day Mortality Absolute Event difference N Engl J Med 1997;337:

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

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

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%)

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%

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

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

30-Day Mortality: Relative Risk 1. Primary Analysis (Adjusted Rate) 2. Secondary Analysis (Unadjusted Rate) 3. Logistic Regression TNK-tPA % rt-PA % 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 TNK-tPA better rt-PA better

n-PA (%) t-PA (%) RelativeRisk (95% CI) n-PA Better t-PA Better P Value for Equivalence Death InTIME-2: n-PA and t-PA Equivalent for 30-Day Mortality InTIME-II Investigators. Eur Heart J 2000;21:

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

1 r-PA (%) t-PA (%) Absolute Difference (95% CI) r-PA Better t-PA Better P Value for Equivalence Death   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:

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

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) rt-PA (n=8,488) 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

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

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

Enox (%) Hep (%) HazardRatio (95% CI) Enox Better Hep Better D/MI/RI Blazing M. presented ACC Primary Endpoint at 7 days Death, MI and Refractory Ischemia

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

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.

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% LDL-C  28% LDL-C  25% LDL-C  35% LDL-C  34%

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 LDL-C (3-3.5 mmol) 37% LDL-C < 116 (<3 mmol) 35% LDL-C  35% LDL-C  35% LDL-C  37%

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)

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.

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 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: ; Crit Path Cardio 2003;2:150-7.

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 Possible PROVE-IT Outcomes Uncertain No clinical equivalence (& inferior) Secondary Analysis

PatientsDurationEndpointsPower* COMPASS days 19280% ASSENT % REPLACE days 57492% TARGET % * 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 = hazard ratio of Cox proportional model PROVE-IT years 92587% Upper 95%CI ** Is PROVE-IT Powered Appropriately to Detect Non-Inferiority?

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%)

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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