400 likes | 909 Views
Introduction and Preclinical Evaluation. John P. Holden, Ph.D.Division of Cardiovascular Devices. 3. Overview of Presentation. FDA Review TeamHistory of Clinical trial
E N D
1. 0
2. Spectranetics CorporationCVX-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
110-001 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
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
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 LACI achieved equivalent patient survival with limb salvage to that in an historical non-interventional control.
The benefit claimed for ELA in CLI is attenuated by the re-interventions required and by persistence of CLI.
The value added to PTA for management of CLI is uncertain.
26. 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.
32. 31 Limitations to the Analysis of the Primary Endpoint
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
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
39. 38 Summary 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 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.