A CDU

NMT Medical (Boston) has received FDA permission to enroll half as many patients in its CLOSURE I patent foramen ovale (PFO)/stroke and transient ischemic attack (TIA) trial as originally required.

NMT, a maker of closure devices for PFOs, holes in the heart that fail to close after birth, reported that it has received conditional approval from the FDA to its revised study hypothesis and statistical plan in the CLOSURE I trial.

As part of the revised plan, the company said it will enroll about 800 patients, compared to the original CLOSURE I statistical plan, approved by the FDA five years ago, which required an enrollment of 1,600 patients. The company reported that it has enrolled about 650 patients in the study thus far.

PFOs occur naturally during pre-natal life, but they may persist into adulthood in as many as three in 10 cases. This hole between the left and right atria can allow unfiltered blood back into circulation. Companies focused on this problem argue that the condition raises the risks of stroke and may be implicated in migraine.

CLOSURE I is designed to evaluate the effectiveness of NMT's Starflex technology in preventing recurrent stroke and/or TIA due to a presumed, paradoxical embolism through a PFO.

Rick Davis, CFO for NMT Medical, told Medical Device Daily that FDA acceptance of the company's revised plan is "good news from a clinical perspective" because "we will now be a lot closer to getting an answer as to the clinical benefit that PFO patients who have had a stroke get with our technology."

Of course being able to reduce patient enrollment is also good news from a financial perspective, Davis added.

"With the reduction from 1600 patients to 800 patients, in addition to the clinical benefits that we think will be there, we will spend less money to get there which has obvious benefits," Davis said.

On March 2, NMT participated in a public and private FDA advisory panel meeting to discuss the status of the ongoing PFO/stroke trials being sponsored by NMT and other companies. At the close of the meeting, according to NMT, both the FDA and advisory panel concurred that only randomized, controlled trials would provide the necessary data to be considered for pre-market approval (PMA) for devices intended for transcatheter PFO closure in the stroke and TIA indication.

During a private session, NMT also provided the FDA and advisory panel with a revised study hypothesis and statistical plan to complete the CLOSURE I study as a randomized controlled trial.

"The FDA's acceptance of our revised plan to complete enrollment in the CLOSURE I study represents an important milestone for NMT and the medical community," said John Ahern, president/CEO of NMT, in a statement. "The revision is based on the recommendations made at the recently held meeting.

"As a result of this decision, we believe that we are now much closer to completing enrollment in CLOSURE I and thereby understanding the PFO/stroke and TIA connection and the possibility that treatment with a closure device may reduce the frequency of recurrent events. The stroke and TIA indications, which have a potential market of 250,000 U.S. patients annually, have always been a major focus for the company."

Ahern sasid that NMT is "committed to being the first company to complete a randomized controlled trial and to submit a PMA for these indications."

Earlier this year Millennium Research Group (Waltham, Massachusetts) issued a report on Transcatheter Embolization and Occlusion markets in the U.S, saying that "the hottest market" is the PFO closure device market, part of the heart defect closure segment of the report. "With a patient population close to 1.8 million, the potential of the PFO market is huge and will likely entice entry by medical device companies looking for future growth," according to Millennium.

Historically, the PFO market has been small because both companies in the market — NMT Medical and AGA Medical (Golden Valley, Minnesota) —only had Humanitarian Device Exemptions (HDE). In August 2006, however, the FDA asked NMT and AGA to voluntarily remove their HDEs, opening the way to treat many more patients and expected to speed clinical trial enrollment and result in a pre-market approval for PFO closure.

AGA's PFO closure device, the Amplatazer, is in a Phase III trial that began last October, and in that study, the firm proposes a link between PFOs and migraine headaches (MDD, March 6, 2007).

Anthony Furlan, MD, associate director of the Cerebrovascular Center at the Neurological Institute of the Cleveland Clinic (Cleveland, Ohio), principal investigator of CLOSURE I, said, "It is very important to obtain an answer to the stroke/PFO connection based upon a randomized controlled clinical trial. The executive committee and investigators are excited about the recent FDA acceptance of a revised statistical plan and the prospects for completing this important study. The answers from CLOSURE I will help determine the best treatment for patients presenting with cryptogenic stroke and TIA that also have a right to left shunt through a PFO."

Furlan said that to date, more than 650 patients have been randomized into the trial.

"We are not aware of any other randomized stroke and TIA studies as far along or with as much accumulated clinical information," Furlan said. "Based on the revised statistical plan, we currently expect to complete enrollment by year-end. Follow-up with the patients will continue to be over a two-year period."

Davis told CDU that NMT began patient enrollment for the CLOSURE I trial nearly five years ago. He said the company took a conservative approach when it began the trial but "it was also the first trial of its kind."

Davis said the revised statistical plan for the trial is based on new information that has surfaced in the last few years as well as the length of time it has taken for enrollment to get to where it is today.

Medtronic combines vascular and cardiac surgery businesses

Medtronic (Minneapolis) reported the formation of Medtronic CardioVascular, a new, global business combining its existing Vascular and Cardiac Surgery businesses. The company said the new CardioVascular business will bring together people, technology and worldwide operations focused on delivering products, treatments and therapies for coronary artery, vascular and structural heart disease. It will have combined revenues of about $1.9 billion in FY07 and will consist of four major divisions:

* Coronary and Peripheral — minimally invasive catheter and stent-based technologies for the treatment of atherosclerosis;

* Endovascular Innovations — stent grafts for the treatment of aortic abdominal and thoracic aneurysms;

* Structural Heart Disease — products for the treatment of heart valve disease and atrial fibrillation;

* and Revascularization and Surgical Therapies —open heart and coronary bypass grafting surgical products.

The four divisions will remain in their current locations but will leverage common business processes and specific functional infrastructure while expanding scientific knowledge and engineering capabilities to advance cardiovascular care.

According to Medtronic spokesperson Rob Clark, the company decided to merge the divisions because of the ever increasing trend towards performing minimally invasive procedures in the vascular space coupled with the more recent push towards performing MIS procedures by cardiac surgeons.

"You just see that trend of physicians moving more and more towards those types of procedures," Clark told Cardiovascular Device Update. "From our vantage point, it made a lot of sense to bring these two units together." Clark also said that the company also gains some other efficiencies internally by merging these divisions. "You can eliminate some duplication in some areas and then take some of those efficiencies and reinvest them in clinical trials and other future technologies."

He said the new combination would not result in any "substantive" employee layoffs or facility closings. This unit merger, he added is "not really a cost-savings move," it's more about "focusing existing resources."

Scott Ward, currently senior VP and president of the company's Vascular business, will serve as the new head of the CardioVascular business unit. Ward joined Medtronic in 1981 and has been president of the Vascular business since May 2004. Prior to his current position, Ward served as president of the company's Neurological and Diabetes businesses.

"The new CardioVascular business will assemble an exceptional collection of people, technology and global operations that will be focused on collaborating with physicians to improve the quality of care for people with cardiovascular disease," said Ward. "Medtronic will continue to be a powerful innovative force supporting the convergence of cardiovascular specialties focused on applying both surgical and minimally invasive approaches to patient care."

After the merger, Scott said the company will, for now, have six primary business units: CardioVascular; Cardiac Rhythm and Disease Management; Spinal; Neurological; Diabetes; and Physio-Control.

The company said back in December that it planned to spin-off its Physio-Control (Redmond, Washington) unit, which makes automated external defibrillators to focus on opportunities that it said "align better with its strategic aims."

FDA clears plant restrictions at Boston Scientific's St. Paul facility

Boston Scientific (Natick, Massachusetts), a company that has been beset by a variety of problems lately, last month received a large piece of good news for a unit that has caused much of its problems. The company reported that the FDA lifted restrictions from a warning letter following the agency's re-inspection of one of its plants in St. Paul, Minnesota, that makes cardiac rhythm management devices. That warning letter resulted in the company being unable to win agency approvals for products produced by that facility over the past 16 months.

While the lifting of the warning letter allows the company to get FDA approval on devices made at the plant and receive approvals for certificates needed to market devices made at the plant overseas, the company still has a corporate-wide warning letter looming over its head. That warning letter prevents it from receiving FDA approvals for other new products.

The company-wide warning letter — only the third of its kind ever issued to a medical device company — was disclosed in January 2006.

Annette Ruzicka, director of media relations for Boston Sci's CRM unit, said it was her understanding that since the CRM warning was issued to the Guidant facility prior to its acquisition by Boston Scientific, that unit is now free to go about business as usual.

"It's an outstanding warning letter to Guidant, now Boston Scientific CRM, so what it does is free up CRM products," Ruzicka told CDU. She added that she believes the CRM unit has "definitely turned a corner and the warning letter being resolved is a major proof point" of that.

The FDA found the company's St. Paul plant is now up to code during a November-December 2006 inspection. The same plant failed an inspection in late 2005, resulting in the agency issuing the company a warning letter that December.

Boston Scientific acquired the plant from Guidant (Indianapolis) in early 2006 when it bought the company for $27.2 billion. The plant makes pacemakers and implantable cardioverter defibrillators.

In its disclosure on the FDA's CRM facility inspection in September 2005, Guidant had said that that the agency noted "several observations of non-compliance, including an observation with commentary on two specific trends in its Insignia and Nexus families of pacemakers." In December 2005, the company said it had provided the agency with "a thorough written response to the observations," including steps taken to address them.

"We are very pleased with the FDA's conclusion," said Jim Tobin, president/CEO Boston Scientific in a company statement. "This achievement is the result of a lot of hard work by employees across our CRM organization. The improvements made to our CRM quality system demonstrate our ongoing commitment to deliver the highest quality products to physicians and the patients they serve."

Company spokesman Paul Donovan said Boston Scientific is still making "steady progress" in resolving its company-wide warning letter.

Bear Stearns med-tech analyst Rick Wise wrote in a research note that he view the resolution of the CRM warning letter as a positive for Boston Scientific since it removes that regulatory overhang and should allow the company to once again gain CRM approvals.

Wise said he sees this event as a positive for all the players in the U.S. ICD market, including Medtronic (Minneapolis) and St. Jude (St. Paul, Minnesota), despite bringing another competitor back to the fold. Anything "that reduces ICD-related controversies is a positive," he said. Additionally, he said that with all three companies "putting their shoulder to the wheel" and building patient referrals, the possibility of an ICD market rebound would seem a more tangible and realistic possibility.

He noted that the most recent new product update regarding new ICD product releases (Cognis, Teligen, and Vitality NXT ICDs, with wireless data connectivity) appears still on track for late 2007/early 2008.

A day after Boston Scientific reported lifting of the warning letter restrictions, it announced a product approval in its rhythm management line. It said that the FDA approved the Acuity Steerable left ventricular lead for use with cardiac resynchronization therapy defibrillators and cardiac resynchronization therapy pacemakers, both of which treat heart failure. This product features a deflectable tip for precise placement of the lead — even in difficult-to-access branch vessels on the left side of the heart.

CardioNet, Cardiac Telecom form arrhythmia detection consortium

CardioNet (San Diego), a provider of wireless mobile cardiac outpatient monitoring solutions, in partnership with Cardiac Telecom (Greensburg, Pennsylvania), a developer of cardiac outpatient telemetry monitoring, reported formation of the Arrhythmia Detection and Alarm Consortium (ADAAC). The consortium will address issues related to products cleared by the FDA such as arrhythmia detection and alarm systems, and will initially work with the American Medical Association (AMA; Chicago), American College of Cardiology (ACC; Bethesda, Maryland), the Heart Rhythm Society (HRS; Washington) and other industry groups to obtain CPT coding for its technology.

Previously, the Remote Cardiac Services Provider Group (RCSPG) served to broadly represent the interests of all remote cardiac services manufacturers and providers.

"RCSPG, as a united group of 'service providers,' has been successful in defending reimbursement and fighting cuts initiated by Medicare for Holter, event, and pacemaker monitoring services," said James Sweeney, CEO and chairman of CardioNet. "As the RCSPG is now being asked to expand its scope of activity to such things as writing code descriptions for the ACC/HRS and the AMA and to assist in developing CPT codes, there is a more pressing need for a consortium to represent the best interest of arrhythmia detection and alarm systems specifically."

Cardiac Telecom and CardioNet said they have been serving patients with this technology since 1998 and 2002, respectively and that they are the only companies allowed to bill Medicare under the HGSA M-60D policy. Recognizing their position as the only firms competent to comment on coverage, coding and reimbursement issues affecting their technology, the two companies joined together to form ADAAC.

"RCSPG is not expert in arrhythmia detection and alarm systems," said Lee Ehrlichman, CEO and chairman of Cardiac Telecom. "Just as the RCSPG is in the best position to represent Holter and event monitors, so is ADAAC in the best position to accurately represent our technology."

ADAAC will be open to all qualified manufacturers of arrhythmia detection and alarm system devices.

CardioNet, a provider of ambulatory, wireless, real-time arrhythmia monitoring, says it has provided services to more than 70,000 patients nationwide. The company has invested more than $84 million and seven years developing its medical devices and 24-hour monitoring service center.

Cardiac Telecom says it is the first single-source provider in the U.S. for cardiac monitoring services covering the patient acuity chain from 24/48 hour Holter to 30-day event monitoring through its outpatient telemetry service Telemetry@Home.

Acusphere sees Imagify as superior to gold-standard nuclear stress test

If Acusphere (Watertown, Massachusetts) succeeds in its quest to secure FDA approval for its Imagify contrast agent, it says that testing for coronary artery disease (CAD) could be much simpler and less expensive, as opposed to today's gold standard of nuclear stress perfusion testing.

In a conference call lAcusphere CEO Sherri Oberg released detail the results of its RAMP-2 test, its second Phase III clinical trial of Imagify (perflubutane polymer microspheres) injectable suspension. The company said that the data results exceeded the criteria for superiority to nuclear testing in two of primary endpoints, accuracy and sensitivity, in RAMP-2.

But since a third endpoint was not met — superiority in predicting the absence of heart disease — investors were not so upbeat about the trial results. The company's share price dropped nearly 30%, falling to $1.14 to $2.85 in the day's trading.

Acusphere, however, bannered the results as supporting ultimate FDA approval. "We are thrilled with these results, because the goal of the Phase III program was to demonstrate non-inferiority to nuclear stress, and we believe we've accomplished that goal," Oberg told call listeners.

Acusphere describes Imagify as the first ultrasound contrast agent designed to assess myocardial perfusion, blood flow in the heart muscle and considered a sensitive marker for coronary artery disease (CAD).

Currently, according to Acusphere, perfusion information is not available using cardiac ultrasound but must be obtained using a nuclear stress test.

Oberg said that ultrasound is "much less expensive, at half the cost; it is much faster, taking only 30 minutes; and it does not involve" nuclear material. Nuclear testing, she said, costs about $800 and takes about five hours to complete. It also involves the injection of a radioactive contrast agent, which she described as a "hazardous waste that has to be handled and disposed of by licensed professionals . . . "

"These RAMP-2 results suggest that the perfusion information that Imagify adds can enable ultrasound to detect disease just as well as nuclear, but with many other advantages," Oberg said.

Acusphere believes the "potential market" for Imagify includes 10 million CAD evaluations "representing an annual opportunity of more than $2 billion," Oberg said.

In RAMP-2, all three of the ultrasound-blinded readers had superior sensitivity and non-inferior accuracy to nuclear stress, the most frequently used imaging procedure.

The endpoint not achieved in RAMP-2 was specificity, though the company had previously reported superior specificity for Imagify in its first trial, RAMP-1, those results reported last June. High accuracy and sensitivity were the top priorities in RAMP-2.

Richard Walovitch, PhD, senior VP of clinical research at Acusphere, who oversaw the design and management of the Phase III program, said during the conference call that the company is in a "position to move forward towards filing a strong NDA for Imagify." He also said the "efficacy analysis plan" for both Ramp-1 and Ramp-2 was very similar.

"In these trials, the first question we asked was, 'Is Imagify enhanced ultrasound as accurate as nuclear imaging?' Accuracy is a term that defines how many of the patients were correctly diagnosed," he said. "In our trial, accuracy is the principle primary endpoint, and if accuracy is not met, there is no reason to ask questions regarding sensitivity and specificity."

In a statement, Walovitch said that cardiologists place greater importance — for patients with a higher risk of disease — on sensitivity, the ability to detect existing disease. They place greater importance — in patients with a lower risk of disease — on specificity, the ability to rule out disease when it is not present.

RAMP-1 focused on lower-risk patients, and Oberg said in that trial the company "demonstrated superior specificity." RAMP-2 focused on higher risk patients.

"Perfusion, that is, myocardial blood flow assessment, has been a key goal for heart ultrasound for years," said Michael Picard, MD, director, Clinical Echocardiography at Massachusetts General Hospital (Boston) and clinical monitor for the RAMP-2 trial. "Cardiologists use ultrasound for diagnosis and management of many conditions, and the addition of perfusion information would be a breakthrough. This would allow us to identify in a single, convenient, non-invasive test the patients at risk for a heart attack. Currently, this same assessment often requires multiple tests or invasive tests."

In the RAMP-2 clinical trial, the company said Imagify was well tolerated, with the majority of adverse events (AEs) reported being "mild in intensity, transient and resolved without residual effects." The most common AEs reported were headache, increased white blood cell count, flushing, nausea, and chest pain. Each patient in the trial was subjected to pharmacological stress to assess myocardial perfusion.

The company said it is now working with its clinical investigators to prepare a more detailed description of the clinical trial results for submission to a peer reviewed scientific journal in the next few months. In the meantime, it is also working with its clinical investigators to support them in their preparations for various upcoming scientific meetings.

Edwards satisfies warning letter from FDA

Edwards Lifesciences (Irvine, California) yesterday reported that the FDA has notified it that the company's response to the agency's February 2007 warning letter "adequately addresses" the agency's concerns, and that the agency will not defer approval of pending pre-market submissions or export certificates for products manufactured at the company's Irvine facility.

The warning letter was issued to Edwards in February, saying that the company could not receive premarket approvals for devices until it resolved issues raised in the letter, primarily quality systems, quality systems training, documentation and complaint handling at the company's Irvine facility. The warning reportedly stemmed from an inspection completed last August.

Edwards in its quarterly earnings report revised its financial guidance, but a company spokesperson told Cardiovascular Device Update that the change had no relationship to the FDA letter.

The revised 2007 sales guidance is for between $1.070 billion and $1.110 billion, primarily as a result of the recent divestiture of its TMR product line to Novadaq Technologies (Toronto), for somewhat more than $8 million, including what it called "minor adjustments in Critical Care and Heart Valve Therapy sales guidance." Its previous guidance was for 2007 sales between $1.075 to $1.125 billion.

Following receipt of the warning letter, Edwards said it engaged "independent, external resources to assist in implementing best-in-class quality systems." The spokesperson also noted that it had met with the FDA in March to resolve the issues in the warning letter.

Accuray, CyberHeart in pact for non-invasive cardiac ablation

Accuray (Sunnyvale, California), a developer of radiosurgery products, has entered into an agreement with CyberHeart (Menlo Park, California) for to use Accuray's technology to develop a non-invasive method for performing cardiac ablation. Cardiac ablation is used to destroy a small portion of the heart causing abnormal rhythms. Ultimately, the developed technology may have applications in the treatment of atrial fibrillation, a disorder that prevents the heart from beating properly and can cause blood clots and strokes.

CyberHeart is exploring Accuray's CyberKnife robotic radiosurgery system to generate these lesions non-invasively. The system's intelligent robotics, accuracy and tracking capabilities will be used to target affected tissue and create an ablation lesion.

"The heart is not an organ that is typically treated with radiation. However, CyberHeart believes that by using highly accurate radiosurgery technology, we can effectively ablate cardiac tissue and potentially create a lesion that can block abnormal cardiac rhythm," said Patrick Maguire, MD, PhD, president/CEO of CyberHeart. "Accuray's CyberKnife system is the only technology available today that offers the precision needed to ensure only very specific regions of the heart are treated. We expect to begin initial clinical trials in 12 to 18 months and it is our objective to bring the product to market in the next three to four years."

CyberHeart said that in the event that it is able to develop and commercialize such a system, Accuray will be the sole supplier of radiosurgery equipment to CyberHeart, entitled to receive royalties based on CyberHeart system use.