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2. Spectranetics Corporation CVX-300 Excimer Laser System for Critical Limb Ischemia (CLI) FDA Circulatory System Devices Panel Meeting P910001/S022 October 2, 2003

3. Introduction and Preclinical Evaluation John P. Holden, Ph.D. Division of Cardiovascular Devices

4. 3 Overview of Presentation  FDA Review Team  History of Clinical trial & PMA application  Non-clinical Evaluation comments  Clinical Evaluation comments  Statistical Evaluation comments  Clinical/Statistical Summary

5. 4 PMA Supplement Review Team John P. Holden, PhD, Lead Reviewer Wolf Sapirstein, MD, Clinical Review Barbara Krasnicka, PhD, Statistical Review Murty Ponnapalli, PhD, Statistical Review Richard P. Felten, Laser Engineering Review Lisa Kennell, Sterilization/Biocompatibility Review Laurie Bernato, Bioresearch Monitoring Review

6. 5 Proposed Indications for Use The currently proposed indications for use are: "For facilitating limb salvage in patients with critical limb ischemia (associated with Rutherford Categories 4, 5 and 6) who have angiographically evident culprit stenoses and/or occlusions in the SFA, popliteal and/or infrapopliteal arteries, who are poor surgical candidates and who are acceptable candidates for revascularization."

7. 6 Device Description  CVX-300 Excimer Laser System  15 models of Spectranetics Excimer Laser Atherectomy (ELA) catheters –Over-the-Wire (Extreme, Extreme II) –Rapid Exchange (Vitesse) –Eccentric (Vitesse E) Catheter sizes: 0.9 - 2.5 mm Catheters conduct 308 nm pulsed laser light, from the CVX 300 source to the lesion or thrombus

8. 7 Brief History of LACI clinical trial & PMA application LACI (Laser Angioplasty for Critical limb Ischemia) December 1998 Approval to begin feasibility study (LACI 1) –25 patients

9. 8 LACI History (cont’d) January 2001 Approval to begin pivotal trial (LACI 2) –Single arm registry, 167 patients (30 for training) –Historical control: from control group in ICAI Study Group. Prostanoids for Chronic Critical Leg Ischemia: A randomized, controlled, open-label trial with Prostaglandin E1. Ann Intern Med 1999; 130:412-421. –Primary effectiveness endpoint: Freedom from amputation, at or above the ankle, at 6 months –Primary safety endpoint: Death within 6 months following procedure

10. 9 History (cont’d) FDA conditional approval letter for pivotal trial: –Risk-benefit analysis will be needed for PMA, and should include an analysis of all device- and procedure- related adverse events. –Suggest that risk-benefit analysis also quantify the purported benefits of the device (e.g., reducing stent use and/or the creation of surgical options). –It will be necessary to show that stenting does not confound the analysis of the study endpoints.

11. 10 History (cont’d) February 2002 Three models of “Extreme II” Excimer Laser Catheters (2.0 - 2.5mm) added to LACI 2 Lasing parameters changed from cycle of 5 sec on / 10 sec off to 10 sec on / 5 sec off

12. 11 Laser catheter usage in LACI 2 trial Model #Model description# used 110-0010.9 mm Extreme 16 110-0020.9 mm Extreme 1 110-0030.9 mm Vitesse 5 114-0011.4 mm Extreme 1 114-0091.4 mm Vitesse COS 24 117-0071.7 mm Vitesse C 1 117-0161.7 mm Vitesse COS 22 120-0012.0 mm Extreme 10 120-0082.0 mm Vitesse E 10 120-0092.0 mm Vitesse COS 17 220-0062.0 mm Extreme II 4 222-0052.2 mm Extreme 54 223-0012.3 mm Extreme II 1 225-0042.5 mm Extreme 34 225-0102.5 mm Extreme II 3 Total: 203

13. 12 History (cont’d) January 2003 PMA Supplement P910001/S022 submitted with clinical data from LACI 2 Highly interactive review process, including face- to-face meeting with sponsor to discuss FDA questions related to risk analysis, safety and effectiveness results, clinical protocol, and device software and instructions for use October 2003 Review by Circulatory System Devices Advisory Panel

14. 13 Catheter Preclinical Testing (Peripheral Catheters) - Tissue ablation and tip integrity testing - Artery model testing - Collateral tissue testing - Software Validation - Biocompatibility of catheter materials - Qualification of EtO sterilization procedures No additional questions from FDA

15. FDA Clinical Summary Wolf Sapirstein, M.D. Division of Cardiovascular Devices

16. 15 Study Design  Difficult patient population  Primary amputation justified in some cases  These issues to some degree dictated the LACI study design –However, difficulties in interpreting outcomes  LACI study well-conducted

17. 16 Patient Population  Patients with CLI identified by Rutherford clinical categories (comparable to Fontaine classes used in ICAI control)  Problems with historical control –Single study –Lack of access to ICAI original data Per patient (ICAI) vs. per lesion (LACI) analyses  Sponsor: unethical to randomize –However, alternative treatments are available

18. 17 TASC Working Group document Management of Peripheral Arterial Disease TransAtlantic Inter-Society Consensus (TASC) Working Group -Recommendations for studying the treatment of Critical Limb Ischemia J. Vascular Surgery, Vol 31, No 1, 2000

19. 18 LACI Inclusion Criteria  Planned criteria: –Poor surgical candidates ≥ ASA Class 4 Absence of SAV for conduit Extent of pathology  Actual enrollment: –Only 46% met ASA criteria –Only 32% did not have SAV –Lesions: 41% SFA, 27% popliteal/tibio-peroneal Mean of 2.7 lesions/limb Mean length: 6 ± 7 cm –Lesions amenable to PTA?

20. 19 Equivalence Hypothesis Hypothesis: Equivalence to historical non-intervention control –Sponsor: Conservative comparison because LACI patients will be more comorbid and at greater risk for poor outcome

21. 20 Equivalence Hypothesis –However: ASA class does not correlate to risk/benefit of a regional intervention Only patient age predicted mortality and need for amputation (the same in LACI and ICAI studies) Difficult to determine if one group was more sick than the other, given the differences in risk factors

22. 21 LACI Procedure  Delivery via guide wire required  Guide wire crossed lesions 83% of cases w/o laser ablation  Step-wise laser use in 13 cases  Procedural success (reduction of stenosis to ≤ 50% residual stenosis) achieved in 91% of cases, and required balloon PTA in 100% of cases and stents in 70 (45%) patients

23. LACI Study Outcomes VariableLACIICAI Patients enrolled145789 Censored/withdrawn--[116] Patients for analysis145673 Lost to follow-up11 (7.6%)7 (1.0%) Patients not lost to f/u134666 Deaths15 (11.2%)96 (14.4%) Alive w/ amputation at 6m9 (7.6%)76 (13.3%) Limb salvage at 6 months110 (75.9%)494 (73.4%) Persisting CLI43 (29.7%)211 (31.4%) Serious AEs58 (40.0%)239 (35.5%) Re-interventions24 (17.9%)34 (5.1%)

24. 23 Post-hoc Literature Comparisons  Problems: –Study / patient heterogeneity –Disease process –Study design and follow-up  Amputation –TASC Critical Issue 45 – need for more data  Medication –No alternative –LACI study  Arterial Bypass –Gold standard –Alternative conduits  PTA –Advances in Technique/Devices

25. 24 Clinical Review Conclusions 1.LACI achieved equivalent patient survival with limb salvage to that in an historical non-interventional control. 2.The benefit claimed for ELA in CLI is attenuated by the re-interventions required and by persistence of CLI. 3.The value added to PTA for management of CLI is uncertain.

26. Statistical Summary Barbara Krasnicka, Ph.D. Division of Biostatistics

27. 26 Study Design  Objective of the study To determine safety and effectiveness of excimer laser ablation of vascular obstruction  Safety and Effectiveness outcomes Safety endpoint: any death occurrence in 6 months Effectiveness endpoint: the percentage of alive patients without major amputations at 6 months

28. 27 Study Design  Nonrandomized study Prospective treatment group called LACI ‘Historical’ control group with data based on a single published paper (ICAI Study Group. Prostanoids for Chronic Critical Leg Ischemia: a randomized, controlled, open-label trial with Prostaglandin E1. Ann Intern Med 1999; 130: 412- 421)

29. 28 Study Design  Treatment group – LACI –Study carried out at 14 sites in the US and Germany −145 patients, 155 treated limbs −11 (8%) patients dropped out  Control group –Study carried out at 20 sites in Italy −673 patients for analysis −7 (1%) patients dropped out

30. 29 Study Design  The sponsor’s objective was to show that the results in the treatment group were at least as good as for the control group – an equivalence design.  FDA agreed to accept the equivalence design based on the assumption that the control patients would be less sick than the LACI registry patients.

31. 30 Primary Effectiveness Endpoint Percentage of alive patients without amputation at 6 months The effectiveness endpoint was met. LACIControl 75.9% (110/145) 73.4% (494/673) 95% CI (-5.3%, 10.2%)

32. 31 Limitations to the Analysis of the Primary Endpoint  Nonrandomized study Visible differences 1.LACI and control patients were not comparable, e.g., due to differences in rest pain, previous minor amputations, and previous major amputations 2.Country/hospital factors

33. 32 Limitations to the Analysis of the Primary Endpoint Historical control (raw data at the patient level are not available) Visible differences cannot be accounted for Formal sensitivity analysis for hidden biases cannot be carried out Missing information Country/hospital factors

34. 33 Limitations to the Analysis of the Primary Endpoint LACI  Treatment: –Laser –PTA –Sometimes stenting in SFA Control group  Treatment: –Standard medications against limb ischemia (Some pts had a bypass surgery and/or other procedure at enrollment, but continued with CLI.)

35. 34 One of the Secondary Endpoints: Survival Time in 6 months Kaplan-Meier estimates of the survival functions for LACI and control groups

36. 35 One of the Secondary Endpoints: Survival Time  Visual impression based on the Kaplan-Meier estimates of the survival functions suggests that LACI patients could survive longer However:  Wilcoxon test: Value of the Chi-square statistic is 1.86 and the corresponding P-value is 0.1728

37. 36 Limitations to the Analysis of Survival Time (secondary endpoint) Range of LACI patients’ ages was 41 to 91. Heterogeneity can seriously affect comparison of the treatments Non-stratified comparison of survival times Covariates and their interactions with the treatment could influence the treatment effects LACI and control patient groups are different (at patient and country/hospital level) The laser treatment was used with adjunctive PTA

38. Clinical & Statistical Summation Wolf Sapirstein, M.D.

39. 38 Summary 1.The study met the primary endpoints of equivalence in 6-month limb salvage and death rates. 2.The assumption that the patients in the LACI registry would be more comorbid and at greater risk for poor outcome, compared to the control group, is not evident from the data.

40. 39 Summary 3.Due to the non-randomized study design, all analyses should be interpreted with caution. The association between the laser treatment and patient outcomes could be influenced by other covariates. It is difficult to determine to what extent the laser treatment influenced the effectiveness outcomes. 4.The higher re-intervention rate in the LACI registry raises questions about the risk- benefit profile of the laser device.