Challenges from Drug Eluting Stent (DES) Studies - Future DES Study Design

1. Challenges from Drug Eluting Stent (DES) Studies - Future DES Study Design Peter S. Lam, Ph.D. Director, Biostatistics, Medical Sciences

2. Topics • Background (History, Definition of MACE/TVR) • Challenges in future study design/planning … • Clinical Endpoint -> future use of “TLR” • QCA Surrogate Endpoint -> more works need to be done • Post-approval study ARRIVE to show real world stent use (heterogeneity) • Address these off-label uses • Summary

3. Zone for Target Lesion Revascularization (TLR) Zone for TLR 5 mm 5 mm stented segment proximaledge distaledge

4. Background: breakthrough technologies Driver of restenosis recoil 40% mechanical stabilization of acute result Need for revascularization neointima formation 20% local delivery of anti-proliferative agents 5% implantation technique ‘fool-proof’ delivery system ? PTCA BMS DES

5. Safety Endpoint – MACE Definition • Major Adverse Coronary Event is a composite endpoint of • 1. Cardiac death, • 2. MI (Non-Q-Wave and Q-Wave), and • 3. TVR (TLR and non-TLR)

6. Cardiac death Myocardial infarction Need for revascularization Which needs have not been addressed so far ?

7. Superiority over DES? • Current technologies have reduced the incidence of remaining safety and efficacy into the 5%-8% rate • Proof of superiority of attempts to further reduce these events will require at least 14,000 patient studies with long term follow-up Reduction 7% vs. 6% 6% vs. 5% 5% vs. 4% N/group* 9700 8400 7000 *80% power with 2 sided alpha of 5%

8. Silber (Sept 6, 2005, ESC)

9. New DES study design challenges • BMS controlled trial – no long feasible • Active controlled trial – non-inferiority approach • Operator technique – more aggressive to treat more complex lesions, more direct stenting, …

10. Efficacy Clinical Endpoint – TVR should be replaced by TLR • Target Vessel Revascularization is a composite endpoint of TLR and non-TLR, where non-TLR is disease progression in the target vessel (noise) *284 days for TAXUS II, IV and V; 300 days for TAXUS VI.

11. QCA Surrogate Endpoints for Clinical Endpoint • choice of QCA surrogate endpoints: • minimum lumen diameter • percent diameter stenosis • binary restenosis (%DS ≥ 50%) • late loss • Currently it is up to the sponsor to justify the choice of QCA.

12. QCA Measures as Predictors of TLRAll Patients in pooled TAXUS studies H. Wang, JSM 2005

13. ROC AnalysisAll Patients in pooled TAXUS studies In-segment % Diameter Stenosis In-stent Late Loss Sensitivity Sensitivity c-statistic = 0.871 c-statistic = 0.954 1-Specificity 1-Specificity In-stent late loss has the lowest AUC, while in-segment %DS has the highest AUC H. Wang, JSM 2005

14. Regulatory approach Pharmaceutical environment DES device environment high risk patient population workhorse(low risk) proof-of-principle proof-of-principle expansion expansion low risk patient population high risk patient population

15. TAXUS ARRIVE – Usage PatternsWhich needs have not been addressed so far? Long Lesions (>26 mm) AMI Ostial Lesions Bifurcations ISR SVG TAXUS IV-like Small vessels (<2.5 mm) LM Total Occlusions Expanded Use Observed in 58% of patients treated

16. Summary - challenges • Future DES studies most likely to be “non-inferiority trial” – choice of gold standard DES/margin • Change of primary efficacy endpoint from TVR to TLR • QCA surrogate endpoints (advantage, choice) • Studies to address DES use in high risk patients