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Spectranetics CorporationCVX-300 Excimer Laser System

for Critical Limb Ischemia (CLI)

FDA Circulatory System Devices Panel Meeting P910001/S022

October 2, 2003

Introduction and Preclinical Evaluation

John P. Holden, Ph.D.Division of Cardiovascular Devices

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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

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PMA Supplement Review Team

John P. Holden, PhD, Lead ReviewerWolf Sapirstein, MD, Clinical ReviewBarbara Krasnicka, PhD, Statistical ReviewMurty Ponnapalli, PhD, Statistical ReviewRichard P. Felten, Laser Engineering ReviewLisa Kennell, Sterilization/Biocompatibility ReviewLaurie Bernato, Bioresearch Monitoring Review

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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."

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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

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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

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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

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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.

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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

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Laser catheter usage in LACI 2 trial

Model # Model description # used110-001 0.9 mm Extreme 16110-002 0.9 mm Extreme 1110-003 0.9 mm Vitesse 5114-001 1.4 mm Extreme 1114-009 1.4 mm Vitesse COS 24117-007 1.7 mm Vitesse C 1117-016 1.7 mm Vitesse COS 22120-001 2.0 mm Extreme 10120-008 2.0 mm Vitesse E 10120-009 2.0 mm Vitesse COS 17220-006 2.0 mm Extreme II 4222-005 2.2 mm Extreme 54223-001 2.3 mm Extreme II 1225-004 2.5 mm Extreme 34225-010 2.5 mm Extreme II 3

Total: 203

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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

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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

FDA Clinical Summary

Wolf Sapirstein, M.D.

Division of Cardiovascular Devices

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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

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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

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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

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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?

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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

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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

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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

LACI Study OutcomesVariable LACI ICAI

Patients enrolled 145 789

Censored/withdrawn -- [116]

Patients for analysis 145 673

Lost to follow-up 11 (7.6%) 7 (1.0%)

Patients not lost to f/u 134 666

Deaths 15 (11.2%) 96 (14.4%)

Alive w/ amputation at 6m 9 (7.6%) 76 (13.3%)

Limb salvage at 6 months 110 (75.9%) 494 (73.4%)

Persisting CLI 43 (29.7%) 211 (31.4%)

Serious AEs 58 (40.0%) 239 (35.5%)

Re-interventions 24 (17.9%) 34 (5.1%)

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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

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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.

Statistical Summary

Barbara Krasnicka, Ph.D.

Division of Biostatistics

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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

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Study Design

Nonrandomized studyProspective 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)

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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

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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.

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Primary Effectiveness Endpoint

Percentage of alive patients without amputation at 6 months

The effectiveness endpoint was met.

LACI Control

75.9% (110/145)

73.4% (494/673)

95% CI (-5.3%, 10.2%)

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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

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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

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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.)

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One of the Secondary Endpoints: Survival Time in 6 months

80%

85%

90%

95%

100%

0 30 60 90 120 150 180

Days since enrollment

Su

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al,

per

cen

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f p

atie

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Registry Group

Control Group

Kaplan-Meier estimates of the survival functions for LACI and control groups

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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

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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 effectsLACI and control patient groups are different (at

patient and country/hospital level)The laser treatment was used with adjunctive PTA

Clinical & Statistical Summation

Wolf Sapirstein, M.D.

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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.

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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.