In late 2006, the FDA approved a clinical trial for Medtronic plc’s DIAM Spinal Stabilization System, a non-rigid interspinous spacer, to study patients with lumbar stenosis. The device, according to Medtronic, differs from other interspinous process spacers in its implant material, proposed indications and clinical trial study design.
The same year, the agency granted an Investigational Device Exemption (IDE) to the company to study the system for patients with lower back pain caused by degenerative disc disease.
On February 19, 2016, 11 members of the FDA’s Orthopaedic and Rehabilitation Devices Panel voted almost unanimously to recommend that the agency should not approve the company PMA’s (premarket approval) application.
The PMA Failure
PMA applications and panel meetings are rare occurrences. Medtronic is the second biggest medical device company on the planet with the biggest slice of the spine market. A panel rejection is a big deal when one considers Medtronic’s smaller competitors have been successful in shepherding their new spine systems through the regulatory maze.
Gaining FDA approval is something economists call “economic rent.” Such form of “rent” comes from receiving a government benefit that gives you a leg up with competitors. As the second largest medical device company in the world, one would expect Medtronic to be masters of this universe. With small competitors like VertiFlex, Inc. and Paradigm Spine, LLC gaining approval for their interspinous spacers, the overwhelming rejection of Medtronic’s application by the panel members is almost shocking.
To be fair, some of Medtronic’s large competitors like Stryker Corp. and Zimmer Spine have also failed with spinal devices at the FDA panel over the last five years.
Medtronic Spinal Challenges
But we wouldn’t want to be the executive that had to tell Medtronic CEO and Chairman, Omar Ishrak of such a major defeat, especially as the rejection by the panel comes on the heels of a quarterly report from Medtronic’s spine division which showed yet another drop in market share. Jeffries analyst Raj Denhoy wrote that Medtronic’s spine “has been losing share for so long (U.S. results were down low single-digits in 3Q) that claims that a turn is coming are difficult to reconcile.” Denhoy also noted last year that one reason Medtronic keeps its spine business because it generates a lot of cash and contributes to the parent company’s huge free cash flow.
So what happens now? Will the company shelve the system? Try to gain approval with some stringent post-approval requirements or try to convince the agency that their expert panel made an uninformed recommendation?
On March 15, 2016, a Medtronic spokesperson told us the company believes the data submitted in the DIAM system PMA application “supports safety, efficacy and benefit-risk ratio. While we’re disappointed in the result of the panel vote, we appreciate the panel’s review and feedback.”
Medtronic: Panel Didn’t Get Full Story
“Immediately following the panel meeting, our team began to diligently work on follow-up activities. Information responsive to some of the panel’s concerns, such as long-term patient data, is already included in the PMA application, but time limited our ability to fully address their questions within the context of the panel meeting.”
“The panel vote does not end our pursuit of PMA approval. We remain committed to the DIAM system and feel confident that we can work with the FDA to address the panel’s feedback. The DIAM implant is an important option for back pain patients—filling an unmet need that exists between conservative treatment and spinal fusion. We will continue our efforts to bring this device to market for U.S. spine surgeons and their patients, ” concluded the spokesperson.
Competitors Abound
As mentioned above, Medtronic is not alone in the interspinous field.
In February 2015, the FDA panel voted to recommended approval for VertiFlex’s Superion Interspinous Spacer device. In 2012, the agency approved Paradigm Spine’s coflex Interlaminar Technology implant. The coflex is a single-piece U-shaped titanium alloy dynamic stabilization device with pairs of wings that surround the superior and inferior spinous processes. This device was previously called the Interspinous U.
In November 2005, the X-STOP Interspinous Process Decompression (IPD) System (Kyphon, now part of Medtronic Spine) was approved by the FDA for treatment of patients aged 50 or older suffering from neurogenic intermittent claudication secondary to a confirmed diagnosis of lumbar spinal stenosis.
In addition to the approvals of Paradigm Spine’s coflex and VertiFlex’s Superion, other interspinous systems currently undergoing clinical trials include the Wallis System (originally from Abbott Spine; currently from Zimmer Spine), introduced in Europe in 1986. The Wallis System is currently being tested in an FDA-regulated clinical trial. Other clinical trials underway at U.S. centers are DePuy Synthes’ In-Space and Globus Medical, Inc.’s Flexus devices; the comparator in these trials is the X-STOP device.
ExtendSure and CoRoent (both from NuVasive, Inc.) were launched in Europe in 2005 and 2006. The NL-Prow (Non-Linear Technologies), Aperius (Medtronic Spine), and Falena (Mikai S.p.A.) devices are in trials in Europe.
Ortho Panel Worries
So what happened at the panel meeting?
The focus of the panel meeting centered on the results of the clinical trial that compared the outcomes of a primary dataset of 97 patients who received the DIAM implant to 53 patients in a nonoperative control group.
According to the clinical trial results, 63.9% of patients in the DIAM group reached overall success at 12-months compared with 15.1% of the nonoperative control group, who received patient education plus either spinal injections, medications or physical therapy. Among the patients treated with the system, 69.1% achieved more than a 15 point Oswestry Disability Index (ODI) improvement, 4.1% of them experienced secondary surgery failures and 8.2% experienced an associated serious adverse event.
The panel had to answer three questions: Is it safe; is it effective and do the benefits to patients outweigh the risks?
On question #1 regarding reasonable assurance that the system is safe, the panel voted 7 to 4 against such assurance. On question #2 regarding effectiveness, the panel voted 8-2, with one abstention against effectiveness. On question #3 no panel members voted that the benefits outweighed the risks, with 7 members abstaining.
Panel member, Harvey Smith, M.D. of the University of Pennsylvania, told Healio.com after the meeting that he voted against the device because he did not think there was “substantial evidence to say it was definitively safe when we do not entirely understand the mechanism of the spinous process resorption, and given the fact that it was a relatively early follow-up and the nature of the device, that was a concern from the safety perspective.”
Data from an animal model showed a possible negative reaction to the foreign body of the implant, according to Smith.
“The Data Just Was Not There”
Said Smith, “I thought for an implanted device that was a new design, given the spinous process resorption, the animal model data showing a reaction to the implant and also some data showing that there was some wear debris, 12 months was not a sufficient follow-up time in my opinion. I think there is clearly an effect of the study, the sponsors did a lot of work they should be commended for, tackling a difficult disease, but within the rigors of the data, as they were presented, the data just was not there in their present form to be able to vote yes for it.”
Statistician Brent Blumenstein, Ph.D., of Trial Architecture Consulting in Washington, D.C., who is rarely satisfied with statistical evidence presented by sponsoring companies, said at the meeting he voted no on all three questions due to “serious issues with the information we got from the trial. I think the primary endpoint, as I pointed out, is mixed up and flawed with respect to its applicability to both arms. The proper emphasis on the intent-to-treat analysis was not done.”
The trial data show the device is safe at the 12-month follow up, but more data are needed to show the implant’s long-term safety and efficacy, panel member Leonard Topoleski, M.D., of the University of Maryland, said at the meeting. He also voted no on the three questions.
The DIAM System
The DIAM system, according to the PMA documents submitted to the FDA, is indicated for “skeletally mature patients that have low back pain (with or without radicular pain) with current episode lasting less than 1 year in duration secondary to moderate lumbar degenerative disc disease (DDD) at a single level from L2-L5. DDD is confirmed radiographically with one or more of the following factors: (1) Patients must have greater than 2 millimeters of decreased disc height compared to the adjacent level; (2) scarring/thickening of the ligamentum flavum, annulus fibrosis, or facet joint capsule; or (3) herniated nucleus pulposus. The DIAM device is implanted via a minimally invasive posterior approach.”
The device is implanted between the spinous processes of the patient’s affected level. It has a stiff silicone core that reportedly transfers some of the axial spinal load through the device. This design is meant to load share with the posterior disc, annulus and facet joints, according to a presentation by Kathryn Simpson, Ph.D., director of Regulatory Affairs at Medtronic.
The system has had CE Mark approval in the EU for at least 10 years and Medtronic is not giving up.
There is work to do.
