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

2. Future DES Issues Sept 16 2005 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. Future DES Issues Sept 16 2005 3 Zone for TLR stented segment proximal edge distal edge 5 mm Zone for Target Lesion Revascularization (TLR)

4. Future DES Issues Sept 16 2005 4 Background: breakthrough technologies 5% BMS PTCA DES Need for revascularization Driver of restenosis recoil neointima formation implantation technique mechanical stabilization of acute result local delivery of anti-proliferative agents 40% 20% fool-proof delivery system ?

5. Future DES Issues Sept 16 2005 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. Future DES Issues Sept 16 2005 6 Which needs have not been addressed so far ? Cardiac death Myocardial infarction Need for revascularization

7. Future DES Issues Sept 16 2005 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 Reduction7% vs. 6%6% vs. 5%5% vs. 4% N/group*970084007000 *80% power with 2 sided alpha of 5%

8. Future DES Issues Sept 16 2005 8 Silber (Sept 6, 2005, ESC)

9. Future DES Issues Sept 16 2005 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. Future DES Issues Sept 16 2005 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) 9-M* Event Rate (%) TAXUS II (N=529) TAXUS IV (N=1314) TAXUS VI (N=446) TAXUS V (N=1156) Pooled (N=3445) DESBMSDESBMSDESBMSDESBMSDESBMS TLR4.614.13.813.26.818.98.315.25.814.8 Non-TLR1.92.0 2.13.70.94.74.13.12.7 TVR 6.5 16.05.714.79.619.411.816.88.416.2 *284 days for TAXUS II, IV and V; 300 days for TAXUS VI.

11. Future DES Issues Sept 16 2005 11 QCA Surrogate Endpoints for Clinical Endpoint choice of QCA surrogate endpoints: 1)minimum lumen diameter 2)percent diameter stenosis 3)binary restenosis (%DS 50%) 4)late loss Currently it is up to the sponsor to justify the choice of QCA.

12. Correlation of QCA parameters and TLR H. Wang, JSM 2005 QCA Measures as Predictors of TLR All Patients in pooled TAXUS studies ROC c-statistic TLR % (n/N) MLD (mm) In-stent0.90412.6 (330/2624) In-segment0.94612.7 (333/2627) %DS In-stent0.89912.5 (329/2623) In-segment0.95412.7 (333/2627) Late Loss (mm) In-stent0.87112.6 (330/2620) In-segment0.89912.7 (333/2623)

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

14. Future DES Issues Sept 16 2005 14 Regulatory approach Pharmaceutical environment DES device environment high risk patient population low risk patient population proof-of-principle expansion workhorse (low risk) high risk patient population proof-of-principle expansion

15. TAXUS ARRIVE – Usage Patterns Which needs have not been addressed so far? 50 Sites 319 Physicians 2585 Patients 3070 Vessels 3769 Lesions 4204 Stents TAXUS IV-like Long Lesions (>26 mm) AMI Ostial Lesions Bifurcations Expanded Use Observed in 58% of patients treated ISR SVG Small vessels (<2.5 mm) LM Total Occlusions

16. Future DES Issues Sept 16 2005 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