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:

 

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

 

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

 

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

 

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 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

 

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

Number used

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

 

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 P910001/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

 

Non-clinical

 

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

 

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

 

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.