The Anulex Warning
In September 2006, the FDA informed Anulex Technologies, Inc. that the company's Xclose Tissue Repair System was substantially equivalent to existing anulex anchor band suturing systems and was therefore "cleared" through the 510(k) program to market the Class II device.
The cleared indication was "for use in soft tissue approximation for procedures such as general and orthopedic surgery." The company took that to mean they could use their device to stitch up the annulus after a spine surgeon was done performing a lumbar discectomy.
On February 11, 2011, the FDA sent Anulex a Warning Letter saying the company was conducting an unauthorized clinical trial and mislabeling the device for an indication not cleared by the FDA.
How did Anulex get on the wrong side of the FDA?
Xclose Commercialization and Randomized Study
According to the company's 510(k) summary, the Xclose consists of "two nonabsorbable braided surgical 3-0 suture and T-anchor assemblies, connected together with a loop of green 2-0 suture. The 2-0 suture loop is used to facilitate tightening, drawing the 3-0 suture assemblies together, thereby re-approximating the tissue. The device construct is composed of polyethylene terephthalate (PET) and conforms to USP requirements. The construct is provided sterile and preloaded on a disposable delivery instrument."
After receiving clearance from the FDA, the company began a study ("Randomized Study of Anular Repair with Xclose") in March 2007 to gather evidence that would be helpful in getting reimbursement. As required, the company posted the study on clinicaltrials.gov.
There are over 800, 000 lumbar discectomy procedures performed worldwide each year to treat disc herniation in the lumbar spine.
The prospective, randomized study enrolled 750 patients and compared anular repair to no-repair following a discectomy procedure. The purpose of the study was to evaluate the benefits of anulus fibrosus repair utilizing Xclose compared to a discectomy without anulus fibrosus repair. All patients were to have completed their two-year follow-up scheduled October 2011.
The company announced the commercial availability of the device in February 2010.
After the disclosure of the study and commercial release of the device, the FDA Minneapolis District Office inspected the company's facility in Minnetonka in August and September 2010. After the inspection the agency sent the company the Warning Letter. In summary, the FDA told the company it was mislabeling the Xclose device and needed an FDA approved IDE (Investigational Device Exemption) to test the device on patients.
If the device is mislabeled, as the FDA contends, then the company's post-market efficacy trial is out of compliance with FDA regulations. Being accused of using patients in an unauthorized, high risk clinical trial is a serious charge.
Until this is concluded, the development of the Xclose is under a regulatory cloud. This situation also gives the device industry a look into the new, kinder, gentler FDA that has promised to take its job of "promoting" public health as seriously as "protecting" the public health.
This is the second time in the last couple of years that a high profile spine company in Minnesota has gotten on the wrong side of the FDA. In 2008, Disc Dynamics threw in the towel after disagreements with the FDA. Both companies are part of the Split Rock Partners venture capital firm run by former Spine Tech CEO Dave Stassen. Split Rock is a well seasoned and regarded fund in the medical device industry and has participated in four rounds of financing to support Anulex. The total amount raised from all sources for Anulex has been about $48 million.
Anulex officials and consultants spoke to OTW to review technical issues about the device. The company issued the following statement on February 24:
"Anulex is steadfast in its commitment to conducting its business in full compliance with all regulatory and statutory requirements. While we respect the FDA’s perspective in this matter, we are disappointed to have received the FDA’s letter because we firmly believe our post-market activities related to Xclose have complied with FDA law.
"Patient safety has been, and continues to be, our foremost priority. The post-market study and wide usage outside the study has not resulted in reported occurrence of any patient safety issues or adverse events beyond those anticipated for procedures involving suturing in general and orthopedic surgeries. We have consulted with and sought guidance from the nation’s top medical device regulatory advisors, health professionals and orthopedic surgeons for every aspect of the development of Xclose, including our post-market activities."
The Warning and Appeal
The company is responding to the FDA and will request a meeting with the agency to try come to a resolution that meets both the FDA’s and company’s goals. If Anulex execs are unable to find a middle ground with the FDA then they'll have to appeal to the device division’s chief, Jeff Shuren, M.D., and ultimately the FDA Commissioner Margaret Hamburg, M.D. If the company is still unsuccessful after passing through Shuren and Hamburg, then the final recourse is to go to their congressional representatives in Minnesota. Involving Congress in dealings with the FDA has its own dangers as we reported in the ReGen Biologic’s situation.
Specifically, the FDA noted the following findings, among others, in the Warning Letter:
The FDA determined that the trial designed by Anulex for the Xclose, was for the purpose of "annulous fibrosus repair, " which the agency considers a Class III device and therefore needs to go through the PMA (premarket approval) process.
The agency says Anulex permitted "a significant risk device" to be implanted in the 750 subjects enrolled in this study prior to submission to FDA and approval of an IDE application.
The FDA considers the annulus fibrosus repair indication to be "investigational and outside the scope” of the 510(k) clearance.
Anulex was cited for “promotion an investigational device before the FDA has approved the device for commercial distribution and representation that an investigational device is safe or effective for the purposes for which it is being investigated.”
We asked individuals close to the company if the company had specifically identified "annulus fibrous repair" as an indication to the FDA in the 510(k) submission. The answer was no and the company believes such repair falls under the cleared indication of "for use in soft tissue approximation for procedures such as general and orthopedic surgery."
The FDA started an Innovation Initiative in February after marching orders from the White House to also focus on the agency’s “health promotion” mission.
Just a couple of weeks ago, the Financial Times reported that President Obama said his administration would focus on modernizing the FDA. "I've gotten a lot of commentary about the fact that... essentially their model was designed for the kind of medical devices you see in museums, " said Obama, according to the Times.
Mark DuVal, an attorney who has represented the company before the FDA says it's not unreasonable that scientists can disagree about these matters. What matters now is how reasonable the FDA is in dealing with Anulex's appeal.
He says the "hassle" factor has increased for his clients with the FDA in the last couple of years and noted that the Minneapolis FDA office has doubled in size to over 100 employees over that time.
Dennis Crane of Emerson Consulting in Minnesota told OTW that the FDA has a number of avenues which they can pursue in response to the warning letter to Anulex.
Typically, FDA will give the company an opportunity to make their own corrections. In the Anulex case, this would likely involve stopping enrollment in the clinical trial until such time as an IDE is approved. It would also likely involve stopping all promotion of the Xclose for use in annulus repair. Lastly, it would involve working to bring the clinical trial conducted up to IDE type standards.
If FDA does not feel that Anulex is taking sufficient action or is not taking it in a timely fashion, they can then implement any of their other options for dealing with violations, including (in order of most likely to least likely): recall of the product, seizure of the product, injunction or consent decree, civil penalties (up to $15, 000 per violation and up to $1, 000, 000 for all violations), withdrawal of approval of the product or criminal prosecution.
Since the Warning Letter, the company has removed references to the device from the company’s web site. Also missing from the site was any reference to the president and CEO of Anulex at the time of the letter, Richard Lunsford. Lunsford has resigned from his position. We were told he has relocated to Colorado for personal reasons.
At this point, the company is confident it will be successful in making its case to the FDA.
"Anulex takes this matter seriously, and we are committed to working cooperatively with the FDA so this matter can be fully and promptly resolved consistent with the applicable regulations, " concluded the company statement.