CD&D

Medtronic (Minneapolis) last month recalled some of its disposable heart surgery products because of concerns about a coating of contaminated heparin. Included in the recall were disposable products with the Carmeda BioActive surface that are used during cardiopulmonary bypass (CPB) for heart surgeries. The company termed it a "voluntary and precautionary recall."

Medtronic said some of its Carmeda-coated devices were made with heparin contaminated with over-sulfated chondroitin sulfate (OSCS), a coating used on blood oxygenators, reservoirs, pumps, cannulae, and tubing packs.

Daniel Beach, a Medtronic spokesman, told Cardiovascular Devices & Drugs that the recall was relatively small. "We estimate in the U.S. there are fewer than 400 of these products on the shelves," Beach said, adding that the devices run between $200 and $500 each.

Medtronic said the recall is in response to FDA's April 8 recommendation that heparin supplies should be checked with newly-developed tests and that affected products should be evaluated for possible field corrective action.

Medtronic said it has not received reports of any OSCS-related adverse events related to the use of Carmeda CPB products. It is unclear, however, if exposure to Carmeda-coated medical devices, made with "comparatively small amounts" of heparin, could cause adverse events similar to those observed with injectable heparin formulations, the company noted.

The patient risk associated with OSCS in heparin-coated devices is not known, the company said, but the recall follows reports of death and serious illness in patients who have been given injectable heparin products containing high levels of OSCS. According to FDA, at least 81 people in the U.S. given heparin have died since January 2007, the result of allergic reactions.

FDA said it didn't inspect a plant in China that made the main ingredient in Baxter International's (Deerfield, Illinois) blood-thinner heparin, which was contaminated. The agency said it confused records on that facility and another with a similar name. Baxter and its supplier say the contaminant must have been added earlier in the supply chain, before the products reached their facilities.

In addition to the recall, Medtronic issued a warning that some of its Trillum-coated products were also made with heparin containing OSCS. Trillum is another biosurface used on CPB products. The amount of heparin on it is "significantly lower" than that contained on Carmeda-coated products, the company said.

Medtronic said it wants to remove contaminated products from the market but that, based on current data, the benefit of using the affected products outweighs any potential risk to patients. According to the company the maximum possible patient exposure to heparin from Trillum is "extremely low," so customers can continue to use the affected Trillum products until a replacement is available.

After initially recalling nine lots of heparin sodium injection multi-dose vials on Jan. 17, Baxter proceeded to recall all remaining lots and doses of its heparin sodium injection multi-dose, single-dose vials and HEP-LOCK heparin flush products.

Due to the widespread use of the blood thinner and the impact a product shortage would have on operating rooms, dialysis centers and other critical care areas, FDA and Baxter said that removing additional lots and doses of the product from the market earlier would have created more risk to patients requiring heparin therapy than the increased potential for illness or death.

Nearly all reported adverse reactions have occurred in three areas of use: renal dialysis, invasive cardiovascular procedures and apheresis procedures. Patients who have experienced adverse reactions have reported everything from stomach pain or discomfort to dizziness and fainting.

Citing deaths and allergic reactions linked to contaminated versions of heparin from China, lawmakers last month said FDA must conduct more inspections of companies sending drugs to the U.S. to ensure they are safe.

Conditional approval won by Heartware for its trial of its LVAS

HeartWare (Sydney, Australia/Framingham, Massachusetts) earlier this month reported conditional approval from the FDA of an Investigational Device Exemption (IDE) for its left ventricular assist device (LVAS), enabling the company to commence its U.S. clinical trial for the LVAS as a bridge to cardiac transplant in patients suffering from end-stage heart failure.

HeartWare said that the Bridge-to-Transplant trial protocol incorporates a number of novel elements, including:

— the primary endpoint of survival at 180 days, defined to include patients who have received a heart transplant, patients who remain alive and supported by the device at 180 days, and "recovery" patients who have survived for a minimum of 60 days following the explant of their device;

— definition as a "pivotal trial" and therefore not including a feasibility or pilot phase; inclusion of a contemporaneous control group. Patient outcomes will be compared to those of a matched cohort of patients recorded in the InterAgency Registry for Mechanical Assisted Circulatory Support (INTERMACS), a U.S. national registry of patients implanted with an FDA-approved circulatory support device;

— enrollment of up to 150 patients across a maximum of 28 centers. The company can open up to 10 centers immediately. Once 10 patients have been enrolled and supported with the HeartWare LVAS for a mean period of 90 days, the company will submit a clinical safety report to the FDA for review. Enrollment will continue unabated at the initial 10 centers during this review period. Subject to FDA approval of the clinical safety report, enrolment can then be expanded to all 28 centers.

— patients enrolled in the HeartWare trial eligible for discharge from hospital immediately following implant.

"Receipt of this conditional approval of an IDE represents one of the most significant milestones since HeartWare's inception," said Doug Godshall, president/CEO of HeartWare. "We believe that the HeartWare LVAS is poised to make a significant impact on the U.S. mechanical circulatory support market. This is reinforced by the high level of interest we are receiving from U.S. physicians, many of whom already anticipate the potential clinical advantages associated with our device's small size, pericardial placement and advanced peripheral systems.

"[W]e are now within a month or two of generating our first revenue. As previously indicated, we expect to be able to charge for our system during the course of our U.S. clinical trial. We expect to supplement this revenue through commercial sales in Europe once we receive CE mark later this year."

HeartWare said it will commence training for its initial U.S. clinical sites this month and, in parallel, will seek investigational review board approval for these sites while working towards satisfying the few conditions to our IDE.

HeartWare makes miniaturized implantable heart pumps designed to treat patients suffering from advanced heart failure.

The company describes its LVAS as a full-output pump designed to be implanted in the chest, avoiding the abdominal surgery generally required to implant competing devices. The pump is currently the subject of an international clinical trial involving five investigational centers in Europe and Australia.

HeartWare also has reported that it is moving to an "expanded, upgraded" manufacturing facility in Miami Lakes, Florida. The 59,000- square-foot facility will enable a scaling up in manufacturing output and is expected to meet all of the company's operational needs indefinitely, it said.

Medtronic, Physio-Control in injunction accord on AEDs

Physio-Control (Redmond, Washington), its parent company, Medtronic (Minneapolis), and their two top executives have signed a consent decree of permanent injunction with the FDA related to automated external defibrillators (AEDs) manufactured by Physio-Control.

The consent decree prohibits the manufacture, distribution and export of specified AEDs at or from Physio-Control's facility in Redmond until the devices and facilities have been shown to be in compliance with the FDA's current Good Manufacturing Practice (cGMP) requirements, as set forth in the Quality System regulation for devices.

The news will most likely put the kibosh on the previously disclosed planned spin-off of Physio-Control, which Medtronic had reported at the end of 2006.

The FDA said inspections conducted in October 2006 and January of this year revealed cGMP deficiencies, including failure to establish and maintain adequate procedures for validating the device design and failure to establish and maintain adequate procedures for implementing corrective and preventive actions.

While the agency noted that these deficiencies do not necessarily mean that the defibrillators currently on the market will harm patients, it is requiring corrections to ensure "the continued availability of safe, effective, and reliable products."

Previous FDA inspections in 2000, 2003 and 2005 showed similar violations, the agency said. FDA issued warning letters after the 2000 and 2005 inspections, citing the cGMP violations.

The AEDs subject to the decree include Lifepak 12, Lifepak 20, Lifepak 500, Lifepak 1000, Lifepak CR Plus, Lifepak Express, and their components and accessories, including the Lifenet Systems

The companies agreed to take necessary measures to ensure that AEDs manufactured and designed at the Redmond facility comply with cGMP requirements and FDA regulations for reporting device corrections and removals. The company sasid that manufacturing and distribution may resume once the FDA is satisfied that the facility is in compliance with the law. It said that to ensure compliance, an outside expert will conduct yearly audit inspections for five years, submitting findings to the agency.

The decree also provides that the companies are subject to liquidated damages in the amount of $15,000 per day if they fail to comply with any of the provisions of the decree, and an additional sum of $15,000 for each violation of the consent decree, the Federal Food, Drug, and Cosmetic Act, or FDA regulations.

Cardiva adds $15.5 million, targets expansion of U.S. sales force

Cardiva Medical (Mountain View, California) reported closing a $15.5 million private equity financing led by PTV Sciences, plus existing investors Galen Partners, Sycamore Ventures, Amkey Ventures, Lexli Investment, and Eminent Venture Capital.

Cardiva said it intends to use the proceeds of the financing for general corporate purposes, including the expansion of its U.S. sales force.

Glenn Foy, president of Cardiva, told Cardiovascular Devices & Drugs that the company expects the Series D financing to carry it through to profitability. Cardiva develops devices designed to close the vascular access site.

Its first product, the Boomerang Wire System, was approved in Europe and in the U.S. in 2004. Cardiva's second-generation product, the Boomerang Catalyst System, was FDA-approved in March 2007 and launched in July.

The enhanced Boomerang Catalyst, trade-named as Boomerang Catalyst II System, received FDA clearance in September 2007 and launched in January.

The private company reported closing a $13.99 million Series C financing in May 2006, about a year after receiving $8.3 million in its Series B round of financing.

Cardiva said that Rick Anderson, a managing director with PTV Sciences, would join its board of directors. Prior to PTV Sciences, Anderson served as company group chairman for Johnson & Johnson (New Brunswick, New Jersey), and worldwide franchise chairman at Cordis (Miami Lakes, Florida). According to Cardiva, Anderson was a "key architect" behind the launch of the Cypher sirolimus-eluting coronary stent.

"When we started this process and started to get serious in the beginning part of February identifying an investor for Series D, we were looking for an investor that had a tremendous amount of commercialization experience," Foy said.

In a company statement, Anderson said that Cardiva "represents an outstanding opportunity to improve patient care by allowing patients to be discharged from the hospital faster without the complications usually associated with vascular closure devices, especially in interventional cardiology."

Heartsbreath test finally gets a look from CMS for coverage

The Centers for Medicare & Medicaid Services is finally taking a look at coverage for the Heartsbreath test from Menssana Research (Fort Lee, New Jersey), a diagnostic that measures the amount of methylated alkanes in a patient's breath to determine the probability of rejecting a transplanted heart.

Michael Phillips, MD, president of Mensanna, filed the latest request in late 2006, stating in a letter to the agency's director of coverage analysis that his first meeting with CMS personnel on the question was in 2004, when he was informed that "CMS was not considering NCDs with HDE [humanitarian device exemption] approval from FDA."

After two years of working with local Medicare carriers, "I have now come back full circle to CMS," he said, asking that the agency "review this application expeditiously."

CMS accepted the request April 10 and expects to propose a decision memo by Oct. 10.

Among the local carriers Mensanna struck out with was Anthem Blue Cross/Blue Shield of Wisconsin (Waukesha), which gave the application a "no" vote last May, citing inadequate data for scientific conclusions regarding the test's clinical utility.

CMS said that the Heartsbreath test "may predict the probability of grade 3 rejection in heart transplant recipients who received their transplants in the preceding year."

If adopted, it would replace endomyocardial biopsy, but "the use of the device is [currently] limited to patients who have had endomyocardial biopsy within the previous month." Public comments will be accepted through May 10.

Navy awarded $3.4 million to develop TBI indication of Hemopure

The U.S. Naval Medical Research Center (NMRC; Silver Sporing, Maryland) has received about $3.4 million from the Department of Defense to develop Hemopure, a blood substitute product made by Biopure (Cambridge, Massachusetts), as a potential treatment of combat casualties with brain injury and concomitant hemorrhagic shock.

Biopure is collaborating with NMRC to develop HBOC-201 as a platform for what it says would be the first multifunction blood substitute for trauma patients. The NMRC is expected to conduct the preclinical work towards a multi-functional product for traumatic brain injury.

The project is part of the Post Traumatic Stress Disorder/Traumatic Brain Injury Research Program of the Office of the Congressionally Directed Medical Research Programs, the company said.

The funding is in addition to the $22.5 million previously allocated by Congress for the military for research of HBOC-201, Biopure said. The company said it anticipates the work relating to the multi-function blood substitute development will begin as soon as "certain agreements" are completed.

It also said it continues to support the NMRC's efforts toward lifting the clinical hold on the NMRC's investigational new drug application to conduct the pending, proposed clinical trial in trauma patients, Restore Effective Survival in Shock (RESUS).

Hemopure is approved for sale in South Africa for the treatment of surgical patients who are acutely anemic. The company is developing Hemopure for other indications and is supporting the U.S. Navy's government-funded efforts to develop a potential out-of-hospital trauma indication.

Vermillion forms group for development of PAD test

Vermillion (Fremont, California) reported that has formed a clinical steering committee to advise the company on clinical development and commercialization for its peripheral artery disease (PAD) blood test. The steering committee will provide strategic scientific guidance regarding the development of a clinical trial to support registration of the PAD test with the FDA, Vermillion said.

In collaboration with researchers at Stanford University (Stanford, California), Vermillion is working to develop a blood test to help determine an individual's risk of developing PAD, a serious disease estimated to affect up to 12 million Americans and can lead to myocardial infarction, stroke and death.

Eric Fung, MD, PhD, chief scientific officer for Vermillion and a member of the steering committee, said that committee membership will offer "strong scientific expertise and unparalleled leadership in vascular medicine and we are privileged to have them serve on our clinical steering committee. We believe the formation of this committee will help Vermillion remain at the forefront in the development and commercialization of a blood test for PAD."

Vermillion is a diagnostic test developer.