**MEMORANDUM**

3 September 2003

**To:** File **P910001/S022/A001,A002,A003,A004**

**From:** John P. Holden, Ph.D.

FDA/CDRH/ODE/DCD/PVDB

**Device:** **CVX-300 Excimer Laser System**

**Sponsor:** Spectranetics Corporation

96 Talamine Ct

Colorado Springs, CO 80907-5186

**Contacts:** Neil Burris (Clinical Data Analyst) Phone: 719-633-8333

Christopher Reiser, Ph.D. (VP Technology & Clin Research) 719-442-2471

This report includes an FDA summary of the clinical, statistical, and
preclinical testing review memorandums regarding P910001/S022. This PMA
Supplement from Spectranetics seeks marketing approval for the CVX-300
Excimer Laser System and 15 models of laser catheters for the treatment
of critical limb ischemia (CLI). Ten of the catheter models have been
previously approved for use in coronary arteries; five are new catheter
models specific to this use in peripheral arteries to treat CLI.

**[Indications for Use:]{.underline}**

The currently proposed indications for use are as follows: \"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.\"

**[Review team]{.underline}**

The FDA review team for this file is as follows:

Lead John Holden, Ph.D.

Lead Clinical Wolf Sapirstein, M.D.

Statistical Barbara Krasnicka, Ph.D.

Murty Ponnapalli, Ph.D.

Laser device: Richard Felten

Biocompatibility, Packaging and Sterilization Lisa Kennell

Bioresearch Monitoring D. Laurie Bernato

The Office of Compliance determined that there is no need for an
inspection for compliance with the Quality System (QS)/GMP regulations
to cover PMA supplement P910001/S22. There are no technological changes
not previously covered during previous inspections. Also, there is no
patient labeling for this device.

**[Device description]{.underline}**

Spectranetics\' Excimer Laser Angioplasty (ELA) catheters consist of a
bundle of optical glass fibers arranged around a guidewire lumen. Three
types of ELA catheters have been evaluated in the LACI trial: Extreme
Over-the-Wire (OTW), Vitesse Rapid Exchange (Rx), and Vitesse Eccentric
(Vitesse-E) models. All models consist of a proximal end that which
couples exclusively with the Spectranetics CVX-300 Excimer Laser. The
CVX-300 Laser System is controlled by software that instructs the laser
to deliver the correct energy for each catheter model. In OTW models, a
bifurcation at the juncture of the proximal and distal catheter portions
permits insertion of an appropriately sized quidewire (between 0.014"
and 0.035" diameter) through the lumen of the catheter. In Rx models,
the guidewire lumen begins 9 cm from the distal tip, to facilitate
speedier removal of the laser catheter. Vitesse-E models are equipped
with a torque handle to control rotation of the distal catheter tip
through a 360°arc around the eccentrically positioned guidewire lumen.
The ELA catheters conduct 308 nm, pulsed laser light, from the CVX 300
source to the atherosclerotic lesion or thrombus within an artery. The
ultraviolet pulses ablate and debulk the lesion as the catheter tip is
slowly advanced through the blockage.

**[Clinical study history and design]{.underline}**

The company refers to its IDE study as the LACI (Laser Angioplasty for
Critical limb Ischemia) trial. The IDE was conditionally approved as a
feasibility study on December 22, 1998. The initial feasibility study
(LACI l) was completed using the device for treatment of ischemic
gangrene in 25 limbs of 23 patients.

An expansion of the study to a total of 192 patients (including the 25
approved for the feasibility study) and 20 sites (both US & OUS) was
conditionally approved on January 26, 2001. Of the 167 patients allotted
for phase 2, 30 were reserved for training (though not all of these were
used). FDA\'s conditional approval letter for the pivotal trial included
several comments and recommendations: A risk-benefit analysis would be
needed for the PMA, and should include an analysis of all device- and
procedure-related adverse events; the risk-benefit analysis should also
quantify the purported benefits of the device (e.g., reducing stent use
and/or the creation of surgical options); and it would be necessary to
show that stenting (which was to be discouraged) does not confound the
analysis of the study endpoints.

There are several challenges associated with the design and analysis of
the LACI II trial conducted by Spectranetics. This pivotal trial is a
non-randomized study, relying on a published study as an historical
control. The control is the group of 673 control patients on whom
6-month follow-up was reported in: *ICAI Study Group. Prostanoids for
Chronic Critical Leg Ischemia: A randomized, controlled, open-label
trial with Prostaglandin E1. [Ann Intern Med]{.underline} 1999;
130:412-421.* Of the 673 control group patients, 7 patients (1%) were
lost to follow-up, leaving 666 patients as the most appropriate
denominator for some outcome variables (see statistical review memo). In
the LACI II trial, 155 limbs in 145 patients were treated. Eleven LACI
patients (8%) were lost to follow-up during the 6-month follow-up
period, leaving 134 patients as the most appropriate denominator for
some outcome variables (see statistical review memo). Note: The control
study report makes no distinction between *patients* and *limbs*
treated.

[Laser catheter usage in the clinical trial]{.underline}

The following table lists the laser catheter models (and the number)
used in the LACI study. It is noted that four of the models were each
used only once out of 203 uses in the study.

  ----------------- ---------------------------------------- -------------------
  [Model            [Model description]{.underline}          [Number
  \#]{.underline}                                            used]{.underline}

  110-001           0.9 mm Extreme                           16

  110-002           0.9 mm Extreme                           1

  110-003           0.9 mm Vitesse                           5

  114-001           1.4 mm Extreme                           1

  114-009           1.4 mm Vitesse COS                       24

  117-007           1.7 mm Vitesse C                         1

  117-016           1.7 mm Vitesse COS                       22

  120-001           2.0 mm Extreme                           10

  120-008           2.0 mm Vitesse E                         10

  120-009           2.0 mm Vitesse COS                       17

  220-006           2.0 mm Extreme II                        4

  222-005           2.2 mm Extreme                           54

  223-001           2.3 mm Extreme II                        1

  225-004           2.5 mm Extreme                           34

  225-010           2.5 mm Extreme II                        3

                    Total:                                   203
  ----------------- ---------------------------------------- -------------------

**[PMA Chronology]{.underline}**

The following table provides a chronology of formal interactions for
this PMA. Additional informal (e.g., e-mail, telephone) interactions,
including requests for and receipt of clarification and information,
occurred throughout the review process and are not outlined here.

**PMA Chronology for P**910001/S22

  ------------------ ----------------------------------------------------
  **Date**           **Event**

  January 22, 2003   PMA received with clinical data

  January 22, 2003   PMA filing date

  February 14, 2003  Amendment 1: Response to request for draft SSED

  March 26, 2003     Amendment 2: Response to requests for additional
                     information, including Operator\'s Manual, clinical
                     protocol, and results stratified by study center.

  April 9, 2003      Amendment 3: Response to questions concerning
                     risk-benefit analysis, laser parameters, and
                     catheter recognition by system.

  May 6, 2003        Major deficiency letter issued on risk analysis,
                     safety and effectiveness results, clinical protocol,
                     and device software and instructions for use

  May 13, 2003       Meeting with applicant to discuss May 6, 2003
                     letter.

  June 10, 2003      Amendment 5: Reply to major deficiency letter.

  October 2, 2003    Scheduled for review by Circulatory System Devices
                     Panel
  ------------------ ----------------------------------------------------

**[Review summary]{.underline}**

[Non-clinical]{.underline}

The review of the biocompatibility, *in vivo* animal studies,
manufacturing and sterilization information (including packaging and
shelf-life) have been completed and there are no outstanding issues
regarding these parts of the PMA.

Additional information was requested and received regarding the *in
vitro* data provided, with respect to laser parameters, catheter
recognition by system, results of shelf-life testing. The sponsor has
replied to all requests for additional information.

[Clinical]{.underline}

The sponsor was asked to address concerns raised regarding the clinical
information provided in the PMA, most notably related to the following
issues:

-   risk/benefit analysis in light of deaths, serious adverse events
    (including re-interventions), and persistence of CLI in the LACI
    population;

-   a discrepancy in the reported risk of major amputation;

-   consequences and outcomes of cases in which a perforation occurred;

-   reporting of event rates for the historical control group;

-   the number of LACI cases that met the criterion of high risk for
    surgical mortality, evidenced by ASA Physical Class 4 or higher;

-   reporting of results for the secondary Peripheral Vascular Endpoint
    (rate of amputation or persistent critical limb ischemia in patients
    surviving to 6 months);

-   failed guidewire crossing and use of the step-by-step laser
    technique;

-   the use of adjunctive drug therapy in the LACI study population; and

-   the definition for establishment of straight line flow.

All clarification and additional information requested during the review
of the clinical data have been provided. The lead clinical and
statistical reviews of this PMA are attached.

**[Summary]{.underline}**

All FDA requests for additional information have been satisfied. The
questions identified for the panel outline the issues identified as
requiring discussion by the review team.