Medical Device Daily Washington Editor
GAITHERSBURG, Maryland — The circulatory systems advisory committee met Wednesday to discuss an application for a humanitarian device exemption (HDE) for the Melody pulmonary valve, a prosthetic replacement of bovine origin made by Medtronic (Minneapolis). The final vote was hardly a squeaker, with the application wining a unanimous vote for approvability, but a series of concerns peppered the panel's discussions, including the issue of stent fragmentation.
Another issue is that the expected life of the device is only two years, but the prospect that the use of the valve could stave off at least one invasive procedure to fix the malfunctioning valve was enough to sway the panel.
Tom Armitage, Medtronic's VP for clinical and regulatory affairs, reminded the panel that the device is designed to address right ventricular outflow tract in patients with regurgitation when the condition is indicated for "invasive or surgical intervention," or in patients with stenosis of the outflow tract, including of the pulmonary valve, when the condition contraindicates balloon dilation or stenting. The population that Medtronic sees as the humanitarian use group numbers roughly 1,000 in the U.S., Armitage said.
Armitage noted that the valve is composed of a bovine jugular vein valve affixed to a stent 28 mm long and is available in three diameters, 18 mm, 20 mm and 22 mm. He said the firm decided in 2003 to affix the bovine tissue to the stent at each stent crossing point. "There are worldwide almost a thousand patients implanted" at more than 75 centers since the device first made its way into human use in 2000, he said.
John Cheatham, MD, director of cardiac catheterization at Nationwide Children's Hospital (Cleveland), reminded the panel that "there are transcatheter options available" in the form of stents and angioplasty to fix stenosis, but "you induce pulmonary regurgitation." The use of a patient's native vasculature to address the problem leaves something to be desired, too, partly because this requires opening the sternum, and regurgitation recurs in half these patients after a year. Another factor in favor of the Melody is that when the first implant begins to wear, a second of smaller diameter can be placed inside the original, thus further staving off open-heart surgery.
One of the major issues facing the sponsor and the panel was a rate of stent fracture of 20% at six months in the U.S. trial, but there was no consensus that these breaks triggered embolization in the lung, assuming a fragment escaped the device.
FDA's lead reviewer for this application, Carolyn Vaughn, said Medtronic submitted an application for an HDE in August 2008 and that FDA decreed a lock on data of Dec. 12 last year. She noted that Medtronic conducted an initial bench test of 16 stents to 400 million cycles, equivalent to 10 years of wear and that the company reported no cracks or failures after examination via scanning electron microscopy (SEM) other than those seen in two of the stents, which the company attributed to procedural manipulation. Medtronic is said to run the remaining 14 through another 200 million cycles, a test which was reported to FDA as having generated a weld fracture in only one stent.
"FDA disagreed with this finding, citing visible cracks in several welds" under SEM, Vaughn said, adding that FDA asked the company to perform more testing, which "showed a higher stent fracture rate which was more consistent" with rates seen in study conducted in the UK.
Later in the day, Armitage acknowledged that some of the newer stents seem to have fewer problems with fracturing, but argued, "I don't believe it's a fair comparison to look at those devices" because of differences in the force the Melody is subjected to, which he characterized as stretching and shortening forces that "are significantly greater" than encountered in stents placed into other anatomical features of the heart.
FDA acknowledged that the single-arm trial of 99 enrolled patients, nine of whom dropped out due to various exclusionary conditions, met the safety and "probable benefit" endpoints, and that there were no marked differences across the five participating surgical centers. One of the confounding elements in the trial is that exercise capacity in the treated subjects did not seem improved over patients receiving a replacement valve via conventional surgery.
Several panelists opined that they saw little clinical significance in stent fractures, given that the fragments tend to remain embedded and that the fragments that migrated to the lungs were clinically silent. Others said a longer follow-up might demonstrate clinical relevance, but that there was nothing to suggest fractures would become so in a widespread fashion.
Panelist and former panel chairman Bill Maisel, MD, director of the Medical Device Safety Institute (Boston), said, "I think we've looked at a relatively small population, but it's possible there would be rare but catastrophic" fractures over time. He also said that he sees fractures as "clinically relevant, but not a safety deal breaker," but added that doctors should be advised as to the significance of migrated fractures. "One bad thing is that they overreact" to such developments and operate when an operation may be unnecessary, he said.
Panel chairman Jeffrey Borer, MD, of Weill Cornell Medical College (New York) summarized the panel's view that "stent fractures do not present a show-stopper, but we don't know how frequently to look for them."
Joe McGrath, director of public relations for Medtronic's cardiovascular division, told Medical Device Daily that the firm would hold production to the 1,000 anticipated units needed to fulfill humanitarian use in the U.S.
One of the panelists challenged Medtronic and other device makers to come up with a stent that resists fracture, but McGrath said that the materials used in the Melody "are more than sufficient to ensure the structural integrity of the stent and the valve during transcatheter placement of this device. We don't see materials science as limiting in any way the application" of the device, he said.
Another consideration for the panel was physician training, always an issue for novel implantable devices, and McGrath said Medtronic expects "that this procedure will be performed primarily by pediatric interventional cardiology" surgeons "along with a much smaller number of adult interventionists who specialize in congenital defects." All the same, he said, "a robust peer-to-peer physician training and education program is critically important to maximize clinical success" for the device and patients.