FDA and Industry Happenings

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Used with permission from the Academy of Transcatheter Cardiovascular Therapeutics

FDA and Industry Happenings

(J Interven Cardiol 2006;19:107–111)

Agency Approves IDE for MitralRegurgitation Trial

Cardiac Dimensions, Inc. has been granted IDE ap-proval by the FDA to begin its COMPETENT pilotstudy of the company’s Carillon Mitral Contour Sys-tem for the treatment of mitral insufficiency in patientssuffering from heart failure. The Carillon system repre-sents the first percutaneous coronary sinus-based treat-ment approach to be evaluated in the United Statesunder an IDE-approved study. The COMPETENT trialis planned to be an eight-center, U.S.-based study con-ducted in parallel with the AMADEUS trial, a safetystudy at seven European centers. The Carillon systememploys an implantable device with a delivery system.The implant consists of a shaping ribbon between distaland proximal anchors. The device, which is deliveredpercutaneously via jugular access, is designed to bepositioned, adjusted, and anchored in the coronary si-nus/great cardiac vein to reshape the annulus aroundthe mitral valve and reduce mitral regurgitation.

Advisory Panel Gives Thumbs Down toArtificial Heart

In the wake of a 7-6 vote for a resolution stating thatAbiomed’s data supporting its AbioCor total artificialheart do not meet the regulatory burden of proof for ahumanitarian device exemption (HDE), the companywill give FDA additional anticoagulation and quality-of-life data from a 14-patient trial supporting the firm’sHDE application. The company decided to file moredata because the clinical data it has already submitted

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failed to convince FDA’s Circulatory System DevicesPanel that the probable benefits of AbioCor outweighthe risk of injury or illness (in this case stroke), givencurrent alternatives. AbioCor’s proposed indication ap-plies to end-stage heart disease patients under 75 yearswho are ineligible for transplant and cannot be treatedwith a left-ventricular assist device. FDA’s materialsto the panel noted a high proportion of neurologicaladverse events in AbioCor patients.

DES Rivals Work Together to Obtain GreaterCarotid Payments

In response to the Centers for Medicare and Medi-caid Services (CMS) FY 2006 proposed rule that wouldrecognize more complex cases in the hospital inpa-tient system, Cordis and Boston Scientific are shar-ing recent clinical trial data with CMS in the hopesof generating greater payments for carotid stent caseswith complications and comorbidities. The firms arebuilding on the CMS proposal that would create fourdiagnosis-related groups (DRGs) for coronary stents.The new DRGs—547, 548, 549, and 550—would alignwith the presence or absence of a secondary diagnosisfor complications and comorbidities such as congestiveheart failure, cerebrovascular disease, or renal failure.In adopting a similar tactic in pursuing higher payingDRGs for carotid stents, Boston Scientific and Cordisare including recent clinical trial data in comments onthe proposed rule that show underpayment of carotidstenting procedures after analysis of MedPAR data.

Endeavor DES Gains CE Mark

Medtronic, Inc. has received CE Mark approval forits Endeavor drug-eluting coronary stent with the rapidexchange delivery system in European Union member

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FDA AND INDUSTRY HAPPENINGS

countries. The Endeavor system combines the Driverbare-metal stent with a sirolimus analogue, ABT-578,and a biocompatible polymer known as PC Technol-ogy. Medtronic licenses ABT-578 and its phospho-rylcholine polymer coating technology from AbbottLaboratories.

Thrombolytic/PCI Study Halted Early

The ASSENT 4 PCI study, a randomized, open-label phase IIIb/IV clinical study of the single-bolusthrombolytic TNKase (tenecteplase) in combinationwith a planned percutaneous coronary intervention(PCI) versus PCI alone in patients with large acutemyocardial infarctions has been stopped early due tosafety concerns, according to Boehringer Ingelheimand Genentech. Specifically, differences were noted inthe 30-day mortality rate between the TNKase plusPCI arm and the PCI alone arm. Patient enrollmentin the trial was suspended in April 2005 followingthe recommendation of the Data Safety MonitoringBoard during a planned interim analysis. While themortality rate in the TNKase plus PCI arm was con-sistent with that observed in prior large-scale throm-bolytic trials (ASSENT-2 and 3 trials), the mortalityrates in the PCI alone arm were lower than expected.The difference in mortality was not attributable to ma-jor bleeding or intracranial hemorrhage. Additional re-sults from this study were presented during a hotlinesession on September 6, 2005, at the annual meetingof the European Society of Cardiology in Stockholm,Sweden.

Firm Acquires Exclusive EptifibatideInjection Marketing Rights in the United

States

Under a restructuring of the copromotion agree-ment between Schering-Plough Corporation andMillennium Pharmaceuticals, Inc. for eptifibatide(Integrilin), Kenilworth, NJ-based Schering-Ploughwill acquire exclusive U.S. development and commer-cialization rights to the GP IIb/IIIa inhibitor. Under theterms of the agreement, Schering-Plough will pay anupfront sum of $35.5 million, in addition to royaltiesover the U.S. lifespan of eptifibatide to Cambridge,MA-based Millennium. In 2006 and 2007, minimumroyalty payments for each year are set at $85 million,with some extraordinary conditions that could reduce

these minimums. In addition, Schering-Plough willpay Millennium approximately $45–$50 million forthe purchase of existing eptifibatide inventories. Theagreement is subject to federal antitrust review and isexpected to become effective September 1, 2005.

Stent Balloon Case Settled

The Department of Justice will drop civil chargesagainst Boston Scientific for product adulteration andmisbranding in exchange for a BSC payment of$74 million in damages. The complaint revolves aroundBoston Scientific’s continued distribution of the Nir-On Ranger with Sox coronary stent delivery systems in1998 after the company learned that the stent-deployingballoons could leak or burst at pressures below thosespecified on the labeling. BSC continued to distributethe stents even after running internal tests, consultingoutside counsel, and convening a field action commit-tee to address reports of balloon failure. Following con-sultation with FDA, the company began a Class II recallin October 1998. In settling, Boston Scientific claimsno liability. The company no longer sells products onthe Nir platform.

Company Awarded First DES CE Mark

Occam International BV, a subsidiary of BiosensorsInternational Group, Ltd., has received CE Mark ap-proval for the company’s first DES, Axxion. Biosen-sors’ Axxion DES is a polymer-free system thatincorporates its Calix stent delivery system and thecommercially available drug paclitaxel. The drug is di-rectly coated on the stent over a layer of glycocalix, asubstrate designed to improve biocompatibility of themetal stent surface after the drug is released. This tech-nology is licensed exclusively by Netherlands-basedOccam from a privately held company in Germany.

BSC Wins Latest Patent Battle

In the ongoing U.S. patent disputes betweenCordis/Johnson & Johnson and Boston Scientific, aDelaware court has ruled in favor of Boston Scientific,saying that the process of applying the polymer coat-ing on Cordis’ Cypher DES infringes on BSC’s Dingpatent. Three other bare-metal stents made by Cordis—Velocity, Sonic, and Genesis—were found to infringe

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on a separate BSC patent known as the Jang patent.Cordis is asking U.S. District Court Judge Sue Robin-son to overturn the ruling. Should that not occur, Cordishas stated it will appeal to the U.S. Court of Appealsin Washington, DC.

Agency Clears New Carotid Stent Plus DistalProtection System

Abbott Laboratories received approval from theFood and Drug Administration (FDA) for the Xactcarotid stent and the Emboshield embolic protectionsystem to treat patients at risk of stroke who are not fa-vorable candidates for surgery. This marks the secondentry into the U.S. carotid stent market, the first beingGuidant’s Acculink and RX Acculink carotid stent sys-tem. The Xact stent is self-expanding and has a closed-cell design, while the Emboshield is a fully retractablefilter featuring a proprietary technology (Barewire) de-veloped to enable better control of stent placement oncethe filter is in place and fully apposed to the vessel wall.Abbott received approval based on its submission of theSECuRITY registry study data in 2004. SECuRITYwas a prospective, multicenter registry study involv-ing 305 patients. One-year data showed that the Xactstent in combination with the Emboshield system wascomparable to carotid surgery for treatment of carotiddisease in patients deemed too high risk for carotidendarterectomy.

Warning Letter Cites Defective TaxusShipments

In Boston Scientific’s third warning letter since May,FDA faults the firm for shipping defective Taxus drug-eluting stents and not adequately addressing the qualitysystem problem once it was discovered. The warningletter stems from a March 28 to May 20 inspection ofthe company’s Quincy, Massachusetts, facility. In addi-tion to the stents, the warning letter implicates similardistribution errors for Vaxcel low profile infusion portsand Symmetry balloon dilatation catheters. The Vax-cel ports were the subject of previous warning letters,all of which refer to problems with Boston Scientific’sability to prevent acceptance or shipment of out-of-specification products. The most recent letter notes aJanuary 2005 incident in which the company sent hos-pitals eight Taxus Express2 stent systems that had beenremoved by a worker from a quality assurance quaran-

tine area. The products were part of a batch that failedkinetic drug-release testing. According to an agencyspokesman, companies that fail to fix quality systemproblems found by FDA investigators risk more seri-ous enforcement action from the agency.

Company’s First Stented Tissue Valve Cleared

St. Jude Medical’s Biocore stented tissue heart valvewas cleared for U.S. marketing by the FDA. TheBiocor family of stented porcine tissue valves—including aortic and mitral valves and the Biocor Suprasupra-annular valve—are St. Jude’s first products in theroughly $350 million U.S. stented tissue heart valvemarket. St. Jude currently markets the Regent andMasters Series mechanical replacement valves and thestentless Toronto SPV. The Biocor PMA was approvedbased on the 17-year follow-up data collected outsidethe United States, where the devices have been ap-proved since the mid-1980s. Tissue valves only lastabout 10–15 years but do not require anticoagulantsand are preferred over mechanical valves for older pa-tients. Over the past decade, tissue valve technology hasimproved to make the devices more durable and there-fore have taken market share from mechanical valves.St. Jude estimates that about 90% of valve and valverepair procedures using tissue valves involve stentedtissue valves.

Intracranial Stent Granted HumanitarianExemption

Boston Scientific’s Wingspan intracranial stent wasgranted an HDE for improving cerebral artery lumendiameter in patients with accumulated plaque in in-tracranial arteries after unsuccessful medical therapy.The Wingspan system includes the self-expanding niti-nol Wingspan stent and the Gateway balloon catheter.HDE approval limits the device to 4,000 patients peryear, and only requires evidence that the device is safeand probably benefits patients. The company’s HDEapplication was based on a 45-patient safety study thatenrolled patients who suffered a stroke caused by ac-cumulated plaque in an intracranial artery and then an-other stroke despite receiving drug therapy. Boston Sci-entific will market the device to a select group of centersexperienced in endovascular treatment of patients withaccumulated plaque in intracranial arteries.

While the approval allows the company to marketWingspan in the United States, Medicare currently will



not reimburse for it. The CMS rejected Boston Scien-tific’s application to create a new technology add-onpayment for Wingspan because the device was not yetFDA-approved when the FY 2006 Medicare inpatientpayment rule was made. CMS has a national noncov-erage policy for percutaneous transluminal angioplastyto treat lesions of intracranial vessels.

PAD Balloon Catheter Cleared

AngioScore, Inc.’s AngioSculpt Scoring BalloonCatheter was 510(k) cleared by the FDA for treatinginfrapopliteal peripheral arterial disease (PAD). An-gioSculpt is one of a new class of specialty medicaldevices aimed at treating PAD. The balloon catheter isAlameda, CA-based AngioScore’s first product.

Balloon Dilatation Device for ResistantBlockages Cleared

The FDA has cleared Boston Scientific’s FlextomeCutting Balloon Dilatation Device for the treatmentof coronary artery blockages that are often resistant toconventional balloon angioplasty. The Flextome deviceconsists of a new balloon with 3–4 microsurgical blades(atherotomes) mounted lengthwise on its outer surface.Upon inflation, the atherotomes score the plaque bysevering the elastic and fibrotic components of the ves-sel with tiny incisions. This process allows expansionof the target lesion with less pressure on the vessel walland may reduce trauma compared with standard bal-loon angioplasty. Boston Scientific plans to launch theproduct in the United States immediately. The Flex-tome device received CE Mark approval in Europe inJanuary 2005.

Endeavor PMA on the Way

Medtronic planned on submitting the first module ofthe company’s PMA for the Endeavor ABT-578-elutingstent to FDA in October 2005 and will complete thefinal module sometime in 2006. The PMA will be sup-ported by the ENDEAVOR I study (100 patients), EN-DEAVOR II (1,200 patients), and ENDEAVOR III (436patients), which is a noninferiority comparison with theCypher (Cordis/Johnson & Johnson) sirolimus-elutingstent. Results from ENDEAVOR III were presented atTCT 2005 in Washington, DC, in October. The submis-sion may also include safety data from the 1,500-patient

ENDEAVOR IV trial, depending on FDA’s reactionto the safety data from ENDEAVOR III, the companysaid. ENDEAVOR IV will randomize patients to ei-ther the Endeavor stent or the Taxus (Boston Scientific)paclitaxel-eluting stent.

SPIRIT III Trial Expands

Guidant has received permission from the FDA toexpand the SPIRIT III trial of the company’s XienceV everolimus-eluting stent to the full cohort of 1,292patients at up to 80 sites. The trial compares the XienceV cobalt chromium stent with Boston Scientific’s Taxusstent.

Company Starts TMR, MyocardialChanneling Studies at Agency Request

Cardiogenesis is developing a minimally invasivetransmyocardial revascularization (TMR) procedurefor use on its Pearl 5.0 robotic laser delivery sys-tem, which is currently under review at the FDA. Atthe agency’s request, the company is sponsoring a 30-patient study that the firm hopes will corroborate resultsreported with the TMR system at Healthpark MedicalCenter in Fort Myers, FL. Cardiogenesis is also tryingto gain approval for its percutaneous myocardial chan-neling (PMC) technology, which has been stalled in thePMA process since 2000. Again at FDA’s suggestion,the company is conducting a 550-patient, double-blind,randomized clinical trial, which could take 2–3 yearsto complete. In July 2001, FDA’s Circulatory SystemsDevice Panel voted 7-2 against Cardiogenesis’ PMAapplication for the firm’s PMC system, spurring con-tinued, ongoing discussions with the agency.

Around the Industry

Next-Generation Stent Approved in Europe.Boston Scientific has received CE Mark approval for itsnext-generation Taxus Liberte paclitaxel-eluting stentsystem. The Liberte stent features the Veriflex stentdesign, incorporating flexible cell geometry with thinstruts and uniform strut distribution. Taxus Libertealso makes use of the enhanced TrakTip catheter tip,mounted on the Maverick2 delivery catheter, to providebetter lesion crossability. Boston Scientific receivedFDA approval for the bare-metal Liberte stent system inthe United States in January 2005. In May, the company

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announced the 30-day safety data from the ATLAS piv-otal study, designed to support U.S. FDA approval ofthe Taxus Liberte system.

European Commission Clears J&J/GuidantMerger, J&J Divests

The European Commission (EC) has clearedJohnson & Johnson’s (J&J’s) proposed acquisition ofGuidant Corporation. In conjunction with the EC’sclearance, J&J has agreed to divest its Cordis steerableguidewires business and the Guidant Endovascular So-lutions business in Europe to preserve competition inthe medical device markets where Guidant and J&J are

active. Remedies addressing overlap in the endoscopicvessel harvesting product lines are also being pursued.The proposed transaction is also being reviewed byother regulatory authorities, including the U.S. Fed-eral Trade Commission. In other merger news, J&Jhas been advised by the Canadian Competition Bureauthat has decided not to take any action at this time onthe company’s proposed acquisition of Guidant in rela-tion to markets affected by the acquisition. The Com-petition Bureau conducted an extensive review underthe provisions of the Canadian Competition Act. How-ever, in response to the Competition Bureau’s specificconcerns relating to the Canadian market for steerableguidewires, J&J will be offering for sale its Cordis coro-nary steerable guidewires business in Canada.


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FDA and Industry Happenings