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CIRCULATORY SYSTEM DEVICES PANEL Wednesday, April 21, 2004. Cordis Corporation Precise 5.5F and 6.0F OTW and RX nitinol Stent System Angioguard XP OTW and RX Emboli Capture Guidewire System PMA P030047 Lead FDA Reviewer Lisa Kennell. Introduction. Regulatory history of the Cordis system
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CIRCULATORY SYSTEMDEVICES PANELWednesday, April 21, 2004 Cordis Corporation Precise 5.5F and 6.0F OTW and RX nitinol Stent System Angioguard XP OTW and RX Emboli Capture Guidewire System PMA P030047 Lead FDA Reviewer Lisa Kennell
Introduction • Regulatory history of the Cordis system • Non-clinical study summary • Statistical Summary • Clinical Summary • Panel Questions
FDA Review Team Team Leader Lisa Kennell Clinical Reviewers Ronald Weintraub, M.D. Wolf Sapirstein, M.D. Paul Chandeysson, M.D. Statistics Heng Li Engineering Deanna Busick Vivianne Holt Terry Woods Animal data/remainder Lisa Kennell
Device Description/Sizes • PRECISE 5.5F OTW • 135 cm long • 0.018” guidewire • Sizes 5, 6, 7, and 8 mm x 20, 30, or 40 mm straight and tapered 8-6 x 30 mm • PRECISE 6.0F OTW • 135 cm long • 0.018” guidewire • Sizes 9 and 10mm x 20, 30, and 40 cm straight and 9-7 and 10-7 x 30 cm tapered
Device Description/Sizes continued • PRECISE RX 5.5 and 6.0F • 135 cm long • 0.014” guidewire • Same sizes as OTW but no tapered configurations • RX not under consideration today
Device Description/Sizes continued • ANGIOGUARD XP OTW • 300 or 180 cm long • 0.014” guidewire • Filter diameters 4, 5, 6, 7, and 8 mm • For vessel diameters 3 - </= 7.5 • ANGIOGARD XP RX • 180 cm long • 0.014” guidewire • Filter diameters 4, 5, 6, 7, and 8 mm • RX not under consideration today
Recent Developments Cordis submitted unsolicited amendment to PMA 4/5/04 • problem with air entrained in the RX version when used “off label” in carotid and other non-approved indications • Has resulted in adverse events from air embolism • Event rate estimated at 0.14% for all procedures (carotid and others)
Recent Developments continued • Performed simulated bench testing to determine root cause, but this testing not optimal • Corrective actions • stipulate use of larger guiding catheters/introducer sheaths to potential for air entrapment • Modify IFU prep procedure • Did not perform animal testing to verify if corrective action corrected problem
Precise/AngioGuard Indication The proposed indication for use for the system is: “The Cordis PRECISE Nitinol Stent System used in conjunction with the ANGIOGUARD XP Emboli Capture Guidewire is indicated for use in the treatment of carotid artery disease in high-risk patients. High-risk is defined as patients with neurological symptoms (one or more TIA’ s or one or more completed strokes) AND>/= 50% atherosclerotic stenosis of the common or internal carotid artery by ultrasound or angiogram; OR Patients without neurological symptoms AND >/= 80% atherosclerotic stenosis of the common or internal carotid artery by ultrasound or angiogram. Symptomatic or asymptomatic patients must also have one or more condition(s) that place them at high-risk for carotid endarterectomy.”
Regulatory History • IDE submitted in 1998 • Many design changes to devices • Most significant wereaddition of Angioguard, lowering profile and rapid exchange configuration
Regulatory History Continued • Sponsor terminated randomized study early. Sponsor states reasons for early termination being: • too many competing studies, • physicians reluctant to randomize, • Surgeons unwilling to refer patients
Regulatory History Continued • Competing studies involved Cordis’s own devices • Competing studies were single-investigator sponsored studies authorized by Cordis, but not followed by Cordis • Cordis supplied each investigator copy of feasibility (non-randomized) protocol, CRFs, consent, and letter of authorization to facilitate opening their own IDE
Regulatory History Continued • Most single investigator-sponsors followed Cordis protocol, with little deviation, however Cordis not certain of exact protocol amendments • Investigator-sponsored studies each approved for 50-100 subjects
Regulatory History Continued • No contractual relationship between Cordis and investigator-sponsors for sharing data HOWEVER • PMA regulation stipulates that sponsor must report all data that they are aware of or should be aware of, so Cordis made effort to supplement PMA with this data
Regulatory History Continued • Cordis did not fund, sponsor or monitor these studies • 34 sites contributed data in PMA, 2 did not participate • Single investigator sites following to 12 months, but only 30 day data in PMA
Non-Clinical Study Summary • Sponsor conducted simulated use, fatigue and device specification and integrity tests on the bench and in animals for both the stent and the embolic protection device, with each iteration of the devices. • RX iteration has only pre-clinical bench and animal testing; FDA agreed to allow clinical use without clinical data since “working end” not changed • Still working with sponsor on RX validation; only OTW under consideration today
Non-Clinical Study Summary - continued • Engineering reviews complete and satisfactory • Biocompatibility review complete and satisfactory • Sterilization review ongoing but do not anticipate issues
Other non-Clinical Issues • FDA issued warning letter on April 1, 2004 • Cited non conformance with the Current Good Manufacturing Practice (CGMP) requirements • “FDA is concerned with the breadth and scope of the …violations” • “symptomatic of serious underlying problems in [Cordis’ s] manufacturing and quality systems” • FDA sought Corporate Corrective and Preventive Action plan which ties all facilities
Statistical Summary Heng Li, FDA Statistician
Statistical Issues • SAPPHIRE Randomized Trial • SAPPHIRE Stent Registry • Propensity Score Analysis • Conclusions
Randomized Trial:Study Protocol Adherence • The randomized clinical study was originally designed as a group sequential clinical trial using the sequential triangular test. • Interim analyses were scheduled every 100 patients. • The expected sample size was 600 to 900, with a maximum sample size of 2400.
Randomized Trial:Study Protocol Adherence • The randomized study was not conducted according to the original group sequential protocol • An alternative protocol seems to have never been developed • FDA was not informed of any change in protocol prior to PMA submission
Randomized Trial:Statistical Inference • Statistical inferences (e.g., declaring non-inferiority) for designed studies should be made according to the study design. • Since the initial protocol was neither followed nor replaced by an alternative one, a nominal protocol needs to be referred to when statistical inference is conducted.
Randomized Trial:Statistical Inference • The nominal protocol used by the sponsor for this PMA submission is a fixed sample size design with the planned sample size equal to the sample size at which the trial was discontinued. • This is probably the most favorable choice for declaring non-inferiority.
Stent Registry:Pre-specified analysis • OPC=16.94% • Observed 360 day MAE rate: 15.76% • 95% CI = (12.36%, 19.68%) • OPC not met
Stent Registry:comparison with randomized CEA • The sponsor carried out a comparison of the stent registry versus the CEA arm of the randomized studies • Since by definition the patient characteristics of the two groups are different, a simple comparison is not appropriate • The sponsor used the propensity score method to compare the two groups
Propensity Score Method • A class of statistical procedures that can help evaluate difference in treatment effect when the treatment groups are not necessarily comparable (e.g., treatments are not randomly assigned). • The propensity score methodology reduces bias by balancing (on average) a set of chosen covariates
Propensity Score Method • Propensity score method has the advantage of typically being able to simultaneously balance a large number of covariates.
Stent Registry:Comparison with randomized CEA • It is not clear whether the analysis that the sponsor performed has taken full advantage of the potential to balance all the clinically relevant covariates • Key covariates such as baseline demographics and angiographic data were not considered
Conclusions • Randomized trial • Original group sequential protocol not followed • A second protocol not developed • No evidence of crossing non-inferiority boundary at termination of study
Conclusions continued • Randomized trial • Original group sequential protocol not followed • A second protocol not developed • No evidence of crossing non-inferiority boundary at termination of study • Registry • Fails to meet original OPC • Propensity score analysis not adequate
Clinical Review Dr. Ronald Weintraub, FDA Consultant
Overview • Randomized SAPPHIRE trial • Stent Registry cohort • Subgroup results • Effectiveness results • Historical surgical trials
Inclusion Criteria • Symptomatic patients (ipsilateral TIA or completed stroke) with >/= 50% stenosis OR • Asymptomatic patients with >/= 80% stenosis AND • A co-morbid condition indicating higher risk for CAE
Inclusion Criteria ContinuedCo-Morbid Risks • Significant Cardiac disease • Severe pulmonary disease • Contralateral carotid occlusion • Contralateral laryngeal palsy • Post radiation treatment • Previous CEA/stent • Other anatomic risk factors
Exclusion Criteria • Stroke-in-progress, or stroke within 48 hours • Intracranial mass • stent in target vessel • Intraluminal thrombus visible • Total occlusion of target vessel site • Known PVD, supra-aortic or ICA tortuosity precluding interventional approach
Exclusion Criteria Continued • Intracranial aneurysm >9mm • Lesion requires >2 stents • Stent in contralateral vessel <30 days • Subclavian ostial lesion (added later) • Percutaneous interventions planned <30 days after index procedure (initially one year) • Staged procedure for bilateral disease <30 past index procedure
Protocol overview Sponsor contracted out some aspects, or had independent oversight: • Clinical Events Committed to adjudicate adverse events • Core lab for angiographic analyses • Core lab for ultrasound analyses • Core lab for analysis of filter baskets • Data analysis contracted to Harvard Clinical Research Institute
Study Endpoints • Primary Endpoints • Composite major adverse events (death, any stroke, and/or MI at 30-days) • Composite MAE as above, plus death and/or ipsilateral stroke 31 days to 12 months
Study Endpoints Continued • Secondary Endpoints • Successful stent deployment • Successful filter deployment and retrieval • <30% residual stenosis by angiography post-dilatation • Access site complications • Surgical site complications • Patency (>50% restenosis by US at 48 hours, 6, 12, 24, and 36 months
Study Endpoints Continued • Independent neurological assessments at 24 hours, 30 days, 6, 12, 24, 36 months • 30-day and 6 month evaluation for stroke • MAE composite at 6, 12, 24, and 36 months (death and ipsilateral stroke) • Safety assessment of Angioguard XP • Presence of trapped material in filter • Laboratory analysis of trapped material
Enrollment Distribution Most patients were enrolled at 5 sites: Cleveland Clinic 93 subjects (27.8%) Prairie Cardiovascular 43 subjects (12.9%) St. Luke’s Medical Center (WI) 30 subjects (9.0%) St. Luke’s Medical Towers (AZ) 29 subjects (8.7%) Midwest Card. Res. Found. 19 subjects (5.7%) Total enrolled in these sites 214/334 (64%)
