GAITHERSBURG, Maryland — NMT Medical (Boston) and AGA Medical (Plymouth, Minnesota), two firms in the business of making closure devices for patent foramen ovales (PFOs), or holes in the heart, have long sought to persuade FDA to allow them to market their products without undergoing randomized, controlled clinical trials (RCTs).

The agency once again put the question to its circulatory systems advisory committee on Friday, but this third attempt to nudge the panel into giving FDA a green light to allow non-RCT trials for this indication failed — largely because a link between PFOs and stroke is not definitive.

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, raising the risk for strokes.

Donna Buckley, a reviewer at the Center for Devices and Radiological Health, noted that the agency has not yet approved a device to repair a PFO, although the two companies were previously granted the humanitarian device exemption (HDE) protocol. The HDE is used only when the annual rate of diagnosis is less than 4,000 per year, and FDA informed the companies last autumn that the total diagnoses exceeded this number.

Both NMT and AGA then withdrew their exemptions before the agency formally pulled the HDEs.

Buckley indicated that “single-arm studies are ongoing . . . to allow continued patient access” to the therapies.

AGA’s current PFO closure device, the Amplatazer, is currently in a Phase III trial that commenced last October, and in that study, the firm proposes a link between PFOs and migraine headaches. NMT is enrolling patients in a trial for its Starflex closure device under the hypothesis that PFO closure can prevent stroke.

The circulatory systems advisory panel addressed this question in 1997, when the panel concluded that RCTs were necessary for this application and that assessment should include freedom from recurrent stroke.

In a September 2002 meeting, the panel came to the same conclusion about RCTs, but amended the recommended endpoints to stroke and death at two years.

NMT and AGA are not the first to complain about the difficulty of enrolling a Web-educated public in a clinical study control arm.

In a Feb. 22 meeting of the orthopedic and rehabilitative devices advisory committee, the Corin Group (Cirincester, UK) expressed the same frustration regarding its trial for the Cormet 2000 hip resurfacing system.

That panel recommended that FDA give the Cormet the nod, with panelists acknowledging this difficult “reality” of modern clinical trial conduct.

Of the ongoing efforts to roll out Phase III trials with controls, Buckley remarked that “enrollment in those studies has been very slow,” in part because patients want to close the PFO.

Buckley said that another factor is that the use of warfarin is “incompatible with the active lifestyle of younger patients.” Other factors include physician bias, which may be the predilection of interventionists to intervene, and the use of other devices on an off-label basis.

The devices most commonly used for PFO include those to treat atrial and ventricular septal defects.

During the public hearing, Steven Kittner, MD, speaking on behalf of the American Academy of Neurology (St. Paul, Minnesota), disclosed that he is a site principal investigator for one of the trials, and he opposed the petition.

He argued that off-label use to treat PFO “is really the big gorilla in the room,” and that while FDA has no way to control off-label use, the Centers for Medicare & Medicaid Services’ reimbursement mechanism “would be a way to move these trials forward,” presumably a reference to the coverage with evidence development mechanism now in use at CMS.

Larry Latson, MD, director of the pediatric and congenital cardiac catheterization lab at the Cleveland Clinic (Cleveland, Ohio), explained that “after strokes, patients are terribly frightened” and “basic personality traits dictate that they don’t want to give up control.”

The typical patient does not want invasive procedure unless the doctor can guarantee the outcome and only if there is no alternative, but most patients also prefer to avoid a lifetime drug regime. Attitudes toward medications “often do change over time with poor experiences,” and patients see closing the hole as a desirable alternative “if the procedure is not too bad,” according to Latson.

The fact that the PFO closure procedure can be done as an outpatient procedure lowers the resistance.

The panel discussed the possibility of the sponsors pooling their controls, but the counter-arguments included the contorted mathematical adjustments needed to make sense of the data, due to the different approaches to closing the PFO, and the inherent differences in efficacy and safety endpoints.

Panelist Richard Ringel, MD, an associate professor of cardiology at Johns Hopkins University (Baltimore), said that off-label device use is necessary because in the world of pediatric cardiology, “we use devices that have never been in a randomized controlled trial and never will be.”

He was the sole member of the panel to advocate the non-RCT approach for this indication, but after the panel deliberated the questionable link between PFO and stroke, he joined the others in a unanimous vote to recommend that FDA maintain its requirement for RCTs.

Guidant ICD-related lawsuit actions surge

Despite the purported benefits of Boston Scientific’s (Natick, Massachusetts) $27.2 billion acquisition of Guidant (Indianapolis) last year, the company continues to see lawsuits piling up over problems with Guidant’s heart rhythm devices.

According to a recent regulatory filing with the SEC, the company reported that lawsuits against it have grown at a rate of nearly three new cases per day. It acknowledged more than 1,100 individual and 75 class-action lawsuits over recalls and safety warnings issued in 2005 and 2006 involving Guidant’s implantable defibrillators and pacemakers.

The total is up from 842 cases when Boston Scientific filed a quarterly update with the SEC on Nov. 9. The increase amounts to 333 cases over 112 days.

Although the lawsuits are still pending in various courts, Boston Scientific said it had set aside $485 million “for legal matters that are probable and estimable” as of Dec. 31, primarily related to products made by Guidant. That’s up from $35 million at the end of 2005, and $384 million at the end of last September. The company said that most of the cases against Guidant are pending in federal court, with 83 in state courts. Federal cases have been consolidated in U.S. District Court in Minnesota, where a trial is set to begin July 16. Most plaintiffs in that case allege no physical injury, but are suing for anxiety and to reclaim the costs of medical monitoring.

Additionally, Boston Scientific said that Guidant has been informed of more than 4,500 claims of individuals that “may or may not mature into filed suits.”

Jan Wald, an industry analyst with A.G. Edwards & Sons (New York), wrote in a research report that it was “awfully hard to know” how the recent flurry of litigation will affect how much Boston Scientific may ultimately have to pay in damages.

But Wald said he found the recent rate of new lawsuits surprising, since most of the problems involving Guidant’s heart devices became public in 2005.

“It seems to me it might have been trickling down to less than three a day by now,” Wald said.

Boston Scientific spokesman Paul Donovan declined to comment to the Associated Press concerning the legal update the company provided in its annual filing concerning the company’s operations.

The filing by Boston Scientific says the company is “substantially self-insured with respect to general, product liability and securities claims.”

Since June 2005, Guidant has issued safety warnings or recalled more than 88,000 defibrillators and has recalled or issued warnings on about 200,000 pacemakers. Electrical problems with the products have been linked to at least seven deaths.

Guidant has been criticized for failing to notify doctors, patients and regulators of the extent of its product problems, and Boston Scientific has vowed to do a better job.

Industry analysts have estimated the Guidant-related legal liabilities inherited when Boston Scientific closed the acquisition last April could reach as high as $2 billion. Since then, Boston Scientific’s stock has lost about 29% of its value.

The company said it remains focused on accelerating the recovery of the Cardiac Rhythm Management (CRM) business it acquired from Guidant, including the market share that was damaged by the recalls. However, it noted that if the CRM market does not recover according to the company’s expectations, or is unable to regain market share and net sale on a timely basis, “our business, financial condition and results of operations could be materially adversely affected.”

The company did note a 10% sequential increase in net sales from its CRM business in 4Q06, including a 13% increase for U.S. ICD sales, which the company said it believes is a sign that the company’s market share has increased and that the CRM market is stabilizing and will return to growth.

Cook pays Cardica $1.25M for closure device progress

Cardica (Redwood City, California) yesterday reported receiving $1.25 million from Cook Medical (Bloomington, Indiana) for development and “high-volume” production tooling for the Cook Vascular Access Closure Device, an automated system for closing access openings in femoral arteries after interventional vascular procedures.

The device, also known as the X-Port device, is being developed by Cardica in partnership with Cook.

Brian Bates, senior VP of business development for Cook, said, “We are pleased with Cardica’s development of the Cook Vascular Access Closure Device, and believe that with its unique features and streamlined design, this product has the potential to address the large and growing market need for next-generation vascular closure devices. We have initiated human feasibility studies with the goal of securing CE mark.”

In December 2005, Cardica and Cook entered into an agreement to develop the X-Port device, with Cardica responsible for design and pre-clinical development, and Cook responsible for clinical development and regulatory approval. With regulatory approval, Cook will have exclusive commercialization rights to market the X-Port.

Cardica said that, to date, it has received about $2.75 million in development milestones and payments for high volume production tooling under the collaboration, and it could receive $500,000 upon completing final product development milestones. It will receive royalties on any worldwide sales.

“Our partnership with Cook highlights the broad applicability and diverse market opportunities for our proprietary microclip technology, and we look forward to exploring additional uses for this innovative device,” said Bernard Hausen, MD, PhD, Cardica president/CEO.

Cardica manufactures automated anastomosis systems for coronary artery bypass graft surgery to replace hand-sewn sutures connecting blood vessels.

Cardica’s C-Port Distal Anastomosis Systems are marketed in Europe and the U.S. The PAS-Port Proximal Anastomosis System is marketed in Europe and Japan and is being evaluated in a pivotal trial in the U.S. and Europe.

Cook bills itself as the world’s largest privately held manufacturer of medical devices.

St. Jude in neurostimulation trial for treatment of chronic angina

Neurostimulation technology is being used to treat a host of conditions, including epilepsy, Parkinson’s disease, stroke, depression and chronic pain of the arms, legs and trunk. Now, St. Jude Medical (St. Paul, Minnesota) is attempting to bring this technology to the U.S. for the treatment of chronic chest pain caused by angina.

St. Jude last month reported the first patient implant in a pilot study that will provide preliminary evaluation of the ability to stimulate the nerves near the spinal cord to control chronic angina chest pain.

A 53-year-old Massachusetts woman was the first person to receive this investigational device, called the Genesis neurostimulation system. She is one of the 1.3 million Americans — estimated by the American Heart Association (Dallas) — who suffer from chronic angina, with 75,000 new cases of treatment-resistant angina each year.

The Genesis system was developed by St. Jude Medical’s neuromodulation division, Advanced Neuromodulation Systems (ANS; Plano, Texas), which last month had two tripolar leads FDA-cleared for use on its Renew neurostimulation system for the treatment of neuropathic low back pain.

“The procedure went smoothly,” said Thomas Simopoulos, MD, interventional pain specialist with the Arnold Pain Management Center at Beth Israel Deaconess Medical Center, who performed the implant. “I am hopeful that spinal cord stimulation will offer a minimally invasive treatment option for patients with chronic, intractable angina.”

According to Rohan Hoare, VP, strategy and emerging therapies for ANS, spinal cord stimulation (SCS) for the treatment of angina has been used extensively in Europe “for a number of years,” and used in the U.S. for some time, but primarily in off-label applications.

He told Cardiovascular Device Update that in Europe doctors have been treating angina with neurostimulation technology “on the order of 15 to 20 years.” He noted that data from the Electrical Stimulation Bypass Surgery (ESBY) trial — which was published in Circulation in 1998 — suggested that SCS may be a therapeutic alternative for patients with an increased risk of surgical complications and no prognostic benefit from surgery.

The 104-patient study (SCS, 53; CABG, 51) showed that CABG and SCS appeared to be equivalent methods in terms of symptom relief in this group of patients.

While Hoare said that the Genesis is primarily intended to alleviate the pain associated with an anginal attack, he noted that there is some evidence from the European literature that it may have some prophylactic benefit as well. “So that you not only alleviate the pain of an attack but you actually reduce the frequency of the attack, so you get a benefit two ways,” Hoare said.

The Genesis functions much like the Renew system used for back pain, with one distinctive difference; the Genesis uses an internal battery instead of relying on an external power source as the Renew does.

Hoare said that the Renew is very useful in situations where a larger power supply is needed for a treatment, however, the angina indication does not require as large an energy source, thus allowing the power supply to be completely internalized.

To be eligible for enrollment in the newly launched pilot study of the Genesis system — the study not being given the standard clever acrynomed name, Hoare told MDD — patients must be at least 18 years old and have been diagnosed with inoperable coronary artery disease.

While Hoare declined to provide further details about the trial, he noted that “angina is a long-term condition and basically I think that you need to sort of view this as a long-term therapy to help a patient with this condition.”

Cetero reports ‘enhanced focus’ on cardiac drug trial work

Contract research organization Cetero Research (Cary, North Carolina) reported what it called “enhanced focus” on conducting cardiac safety assessments through its CorWatch system, a suite of services designed for cardiac safety trials in any phase of development.

Cetero says CorWatch combines “significant clinical pharmacology expertise, strategic relationships with key core ECG laboratories, data management, study design consultation and program development.”

Cetero is a provider of QTc data, QTc being the measurement of an electrical cycle in the heart that is dependent on heart rate. The company says it has conducted more than 20 trials and recruited more than 2,000 participants in the last two years, “more than any other CRO in the world.” It reports having the largest bed capacity of any CRO and the most experience conducting QTc trials.

Alan Copa, president of PRACS Institute (Fargo, North Dakota), a founding company of Cetero, said, “QTc assessments are critical to drug development programs. . . . The key is to be able to conduct a trial in one place, with the least number of groups.”

The required identification of any QT/QTc interval prolongation and proarrhythmic potential for new non-antiarrhythmic drugs is based on the FDA’s ICH E14 industry guidance. Cetero says that “a thorough, well-designed and effectively executed QTc trial with statistical significance lies at the heart of submitting an NDA.”

“Cetero is focusing on cardiac safety assessments based on how crucial they are to our clients. We have formed strategic partnerships with core ECG laboratories and equipped our facilities with state-of-the-art equipment and experienced staff,” said John Capicchioni, VP of business development.

CryoCor must go before FDA panel for atrial flutter indication

Continuing a long effort to win U.S. approval for its cryoablation system in the treatment of atrial flutter (AFL), CryoCor (San Diego) reported that the FDA will now convene an advisory panel meeting to review the company's premarket approval application (PMA).

The agency's decision is the latest turn in a series of developments stretching back to early last year, and slows the progress for the company, considering that the agency told it in February that an advisory panel was likely not needed to consider the PMA application.

The company said it expects the panel meeting to be held in June or July, with a ruling from the agency expected in August.

The company has developed a cryoablation system designed to treat cardiac arrhythmias through the use of cryoenergy, or extreme cold, to destroy targeted cardiac tissue.

It received a "not approvable" letter from the FDA in February 2006 for its PMA for AFL, because, according to the agency, the data presented did not meet "chronic efficacy" criteria, the criteria the company used in its trial supporting the application.

Upon receiving the "not approvable" letter, CEO Greg Ayers said that the primary reason for the agency's decision was based on the "subjective" method required for interpreting chronic efficacy. "The process requires complex interpretation of clinical data and can result in different interpretations as to the results," Ayers said.

"We provided analysis of our chronic data, based on what we feel were appropriate classifications of the patients and measures of effectiveness of our ablation procedure, based on clinical experience with similar patients treated with our systems outside the U.S. and with our clinical interpretation of the patients in this trial and their post-procedure clinical course."

The device is approved in Europe for the treatment of atrial fibrillation and AFL.

The company clearly needs a positive recommendation from the panel if it is going to continue on with any real traction. At the end of March it disclosed that its annual report contained a "going concern" qualification from its auditors.

Additional capital would be needed to fund operations in 2008, the company said in a statement.

Helen Barold, MD, chief medical officer of CryoCor said in a statement, "The FDA has stated that, as cryoablation is a new medical technology for the treatment of atrial flutter, it intends to convene an advisory panel to advise on our chronic effectiveness results. We look forward to presenting all of our data to the advisory panel." He added that the company "strongly believe[s] that our clinical data demonstrate a reasonable assurance of safety and effectiveness, and believe our device has an important role in the clinical arena for physician's use in treating patients."

CryoCor reported that the chronic effectiveness of its cryoablation system, based upon a strict expert core lab analysis completed by an independent electrophysiologist, was statistically computed to be above 80%. An additional analysis performed utilizing a clinical assessment that the company believes is comparable to the analysis from published literature demonstrates a chronic effectiveness above 90%. CryoCor believes the use of an expert core lab to determine the chronic effectiveness is a more rigorous evaluation than has been completed in other clinical trials for the treatment of AFL.

Gregory Feld, MD, the principal investigator for CryoCor's AFL pivotal trial said in a statement that he is excited to participate in the presentation of clinical data on behalf of CryoCor at the upcoming advisory panel meeting. "I believe it is important to make this new medical technology available as an alternative to existing treatments, as there are specific atrial flutter patients that would benefit from cryoablation therapy."

CryoCor is also conducting a pivotal trial in the U.S. to evaluate the safety and efficacy of the cryoablation system for the treatment of atrial fibrillation.