Cook Zenith® AAA Endovascular Graft and the H&L-B One-Shot  Introduction System P April 10, 2003 FDA Circulatory System Devices Panel Meeting Gaithersburg, MD

FDA Review Summary Dorothy B. Abel and A. Doyle Gantt DCD/PVDB

FDA Review Team LeadA. Doyle Gantt and Dorothy Abel ClinicalPaul Chandeysson, M.D. StatisticalGary Kamer In Vivo: Animal Studies John Karanian, Ph.D. In Vitro: Graft Mechanical Testing Terry Woods, Ph.D. In Vitro: Graft Corrosion Testing Stan Brown, D.Eng. In Vitro: Delivery System Kachi Enyinna

FDA Review Team, cont. Biocompatibility, Packaging and Sterilization Lisa Kennell Bioresearch Monitoring Rachel Solomon Manufacturing/QSR John Glass/Kent Berthold Patient Labeling Walter Scott, Ph.D.

Zenith Components

Unique Aspects of this PMA This device utilizes supra-renal fixation, whereas other approved endovascular grafts are implanted infra-renal. There are various configurations as well as multiple sizes in the product line (94 components). The device is indicated for isolated iliac aneurysms (i.e., in addition to abdominal aortic aneurysms, with and without iliac involvement). There have been device integrity issues identified in pre-clinical and clinical evaluations.

US Clinical Study IDE G – 15 centers – 52 patients in Phase I (roll-in patients) – 200 standard-risk patients in Phase II – 100 high-risk patients in Phase II – 80 patients who met the general inclusion criteria for the low risk arm of the study but whose arterial anatomy was not suited for endovascular treatment were treated surgically as a concurrent control

Additional Clinical Studies Australasian study – 291 patients at 16 clinical centers in Australia and New Zealand 24-month follow-up for the US pivotal study US continued access study – 193 standard-risk patients – 143 high-risk patients – 15 additional female, standard-risk patients – 14 patients treated under the compassionate use and emergency use provisions

Additional Clinical Studies, cont. Worldwide marketing experience – Western Australia Registry 170 patients who were treated during the Australasian study with longer-term follow-up, providing some follow- up data out to 6 years – Eurostar Registry 828 patients treated at 45 clinical centers in Europe – ASERNIP-S (Australian Safety and Efficacy Register of New Interventional Procedures – Surgical) Registry 515 patients in a registry conducted by the Australian government

Clinical Review Synopsis All clarification and additional information requested during the review of the clinical data have been provided and the review process continues. The company will continue to follow patients out to 5 years. Data are not available for treatment of isolated iliac aneurysms, however, this indication could still be considered.

Clinical Review Synopsis, cont. No studies have been designed to compare the effect of supra-renal versus infra-renal fixation on renal function. The data that are available do not demonstrate a concern. There is a large amount of clinical data available for this device. The clinical and statistical reviews of this PMA have been provided to the panel and Dr. Chandeysson and Mr. Kamer will present additional information.

Pre-clinical Review Summary 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 regarding the pre- clinical in vitro studies for a device modification has been received and the review process is ongoing.

Device Integrity In order to fully characterize the potential for problems with device integrity over time and any associated clinical implications, the sponsor was asked to clearly describe and analyze all available data related to device integrity. This included bench testing, animal data, clinical data and explant analyses to evaluate corrosion, stent fracture, barb separation, suture breaks and graft material wear.

Device Integrity, cont. The sponsor’s presentations have appropriately described the information available to assess device integrity. The descriptions and analyses regarding device integrity have been provided to the panel.

Device Integrity Summary There have been no clinical sequelae associated with corrosion, stent fracture, and single-barb and double-barb separations; there is a potential for solder loss due to corrosion, however, the loss in solder is not anticipated to be greater than 50% over 10 years and there is a redundancy in design intended to provide additional protection from migration as a result of barb slippage due to solder loss;

Device Integrity Summary, cont. stents are not expected to fracture under normal conditions, when the device is used in accordance with the IFU; barb separations are an anticipated event for this device, however, the barb design is considered by the sponsor to be adequate under normal clinical conditions and there is a redundancy in design intended to provide additional protection from migration as a result of barb separation;

Device Integrity Summary, cont. suture breaks resulting in suprarenal stent detachment have been reported in 5 cases world-wide and the device has been modified in an attempt to address this issue; graft material wear has not been observed to be a clinical problem; appropriate patient selection may reduce the risk of device integrity problems; and

Device Integrity Summary, cont. periodic imaging follow-up is necessary for identification of device integrity issues and any potentially associated complications to allow for timely intervention to avoid serious clinical sequelae.

Design Changes Flexibility in the bifurcated region had been increased to reduce the likelihood of stent fracture; the number, positioning and method of attachment to the stent of the barbs on the suprarenal stent have been modified to reduce the likelihood of migration; stents are now attached to the outside of the graft instead of the inside to reduce graft wear and to make a smooth inner lumen; and

Design Changes, cont. the number of sutures holding the components of the device together have been increased to minimize the potential for separation of the suprarenal stent.

Device Integrity Review Synopsis There is extensive clinical information available for the Zenith Endovascular Graft. The reports of device integrity observations are complete. Although some devices will have integrity problems after implantation, adequate information has been provided to define the risk and to allow for a determination regarding safety and effectiveness.

Conclusions All FDA requests for additional information have been satisfied. The issues identified by the review team as warranting discussion are outlined in the questions for the panel.