Increased CDRH Post-Approval Vigilance Plays Out In Medtronic X-Stop Trials

Medtronic clinical executive Ruchir Sehra says CDRH's newfound rigor in the postmarket area is evident in its approach to the firm's post-approval study of the X-Stop spinal implant.

"They seem to be encouraging more post-approval follow-up," said Sehra, VP-clinical and research of Medtronic's spinal and biologics business in Sunnyvale, Calif.

Sehra says the agency called for two post-approval follow-up studies on X-Stop, which received PMA approval in November 2005 ("¹The Gray Sheet" Nov. 28, 2005, p. 6). The implant offers a non-fusion option for alleviating the painful symptoms of lumbar spinal stenosis. Inserted between the spinous processes of symptomatic discs, it "distracts" the space around the nerves, preventing pinching.

One of the post-approval studies will provide five-year follow-up data on patients in the original X-Stop pivotal premarket trial. The other is a five-year study in centers that were not part of the original trial.

"There's always, every year, a little more we have to do in our regulatory filings. It's nothing dramatic; they are just asking us to do more follow-up," Sehra said.

"It's clear it's not just with us, it's with other studies and other products, too."

X-Stop was originally owned by St. Francis Medical and later purchased by Kyphon, which itself was acquired by Medtronic in a $3.9 billion deal that closed Nov. 2, 2007 ("²The Gray Sheet" July 30, 2007, p. 3).

FDA Staffer: Post-Approval Studies "Improved"

Danica Marinac-Dabic, chief of the epidemiology branch in CDRH's Office of Surveillance and Biometrics, acknowledges that FDA's device center is devoting more effort to post-approval studies.

"During the last couple of years, CDRH devoted a significant amount of resources toward transformation of the post-approval study program," she told "The Gray Sheet."

"The major changes involve review functions, tracking of the post-approval study commitments, Web posting of the ongoing studies and outreach to all stakeholders."

Marinac-Dabic added that the post-approval studies designed since the program was transferred to CDRH's Office of Surveillance and Biometrics in 2005 "are improved because new scientific knowledge and epidemiologic methods are being incorporated more consistently in the design of these studies."

She also noted: "The center fully recognizes the critical importance of post-approval studies and is actively working with sponsors and the clinical community to maximize their value and utility for patients, clinicians and the public health."

CDRH Requires Two Five-Year Follow-Up Studies

CDRH confirmed Jan. 23 that two post-approval studies were designed and approved for X-Stop. One is a long-term outcomes study, which FDA is calling LTOS and Medtronic is calling "Outlast."

The trial is a multi-center, cohort study to evaluate the long-term safety and effectiveness in patients who underwent X-Stop implantation in the premarket trial. The estimated completion date is 2011, CDRH said.

A second, condition-of-approval study, which Medtronic is calling COAST, will examine device performance under actual conditions of use, and entails recruitment of new physicians, clinical sites and patients.

According to Sehra, the agency wanted to see more experience with the device in centers that were not part of the original study, including a mix of community-based and academic centers, "so it wasn't a purely academic center study."

"I think their inclination - and I don't sense that it is unique to X-Stop - was it would make sense for us to try to get ... a real-world experience to make sure the academic and well controlled study experience follows through if you do the same thing in a broader or different population."

The study approval order calls for 240 patients to be enrolled in COAST. The estimated completion date is 2014, CDRH said.

According to the agency, the primary effectiveness endpoint for both postmarket studies is treatment response, defined as clinically significant improvement in symptom severity and physical function as measured by the Zurich Claudication Questionnaire; patient satisfaction; no additional surgery for lumbar stenosis; no dislodgement of the implant; and no device-related complications.

Medtronic also plans to gauge the two-year post-operative outcomes of surgeons who have participated in a postmarket physician training program. The endpoint is non-inferiority to success rates seen in the premarket trial, Sehra said.

Additional Financial Burden, But Some Positives

While the relatively long post-approval studies are "obviously an additional financial burden on the company, there are some positives," Sehra said.

The extra study time will allow the firm "to find out more quickly if there are any new adverse events. I think, in a way, that's positive, because otherwise, we'd just have to hear from doctors or hospitals if bad things are happening."

"But for the most part, it is an increased burden, both in terms of finances and in terms of organization to do this."

He added that CDRH's increased postmarket rigor is forcing the company to "think very carefully" about the budgeting and planning process for getting a device to market.

Sehra advised other companies to be "open and broad" in their initial investigational device exemption discussions with FDA, "so they get a very good perspective, in advance, of what's going to be expected - not just to approval, but beyond approval."

- Sue Darcey