At a rare meeting of the FDA’s Orthopaedic and Rehabilitation Devices Panel, most members voted to recommend FDA approval of VertiFlex Inc.’s Superion Interspinous Spacer (ISS).
Five of eight voting members voted on February 20, 2015 to recommend approval while two abstained and one voted against.
Spinous Process Fractures
The panel had concerns about spinous process fractures that showed up in the clinical trials comparing the Superion to Medtronic plc’s X-STOP. When asked at the end of the meeting if the probable benefits of the Superion outweighed the probable risks, half of the panel members could say yes, two voted no and two abstained.
The FDA approved X-STOP in 2005. Kyphon paid St. Francis Medical $725 million for the X-STOP in 2006 and Medtronic acquired Kyphon for $3.9 billion in 2007. Superion has been CE marked in Europe since 2007 and completed its pivotal IDE (investigational device exemption) trial in December 2011. It has been implanted in over 2, 000 patients worldwide.
“There were some general concerns with the comparative group and how the comparative group excelled at less than optimal results for our patients, ” said Panel Chair, Raj D. Rao, M.D.
At 24-months follow-up, according to FDA documents, 52.7% of the Superion group and 50.2% of the X-STOP group were considered successful. However, study data showed spinous process fractures developed after treatment in 16.3% of Intent-to-Treat (mITT) subjects in the Superion ISS group and 8.5% of X-STOP mITT subjects.
Possible Loss of Effectiveness
“The panel was asked to judge whether the spinous process fracture by itself was a substantial safety issue and I think the panel generally felt the spinous process fractures were not a substantial safety issue, but did raise concerns about the possible loss of effectiveness with the device in time, ” Rao said.
When asked why he voted “no” concerning benefits vs. risks, panel member S. Raymond Golish, M.D., Ph.D., an orthopedic and spine surgeon in private practice in Jupiter, Florida, reportedly said, “As I thought through it, I am not convinced we understand all of the probable risks, and so I could not say yes that the benefits outweigh the risks because I am not assured for myself that we have identified and properly assessed all of those risks. So, as a result of that, in question one, the safety, I could not then make a vote of yes for safety without better understanding the probable risks. So, I voted no.”
Fender: Panel Voted “Strongly” in Support
VertiFlex President and CEO Earl Fender said the panel “voted strongly” in support of the company’s pre-market approval application (PMA).”
“We are pleased with Panel’s support for PMA approval based on their thorough analysis of the level one evidence in our Superion IDE (investigational device exemption) trial. A study of this magnitude is a monumental effort. I am grateful for our dedicated team of researchers whose diligence and belief in minimally invasive surgery allowed us to collect such a strong body of evidence. Superion demonstrated clinical success of >80% in all components of the composite primary endpoint.”
The company submitted its final module of the PMA in April 2014.
The FDA’s ortho panel was supposed to meet in early December 2014, but postponed the hearing until February. Back in December, the company said the meeting was moved by the FDA because they were unable to complete their internal review of the PMA data in time for the December meeting.
Drs. Nunley and Blumenthal Present Evidence
One of the study investigators and panel presenter, Pierce D. Nunley, M.D., of the Spine Institute of Louisiana, said the Superion “Fits uniquely within the treatment continuum for patients who suffer from moderate lumbar spinal stenosis. Patients who have failed conservative care will have the option to receive a truly minimally invasive indirect decompression with Superion. This allows patients the potential to avoid traditional open spine surgery. Importantly, this can be performed without restricting options for future care.”
Scott Blumenthal, M.D., VertiFlex’s co-Medical Director and spine surgeon at Texas Back Institute also presented to the Advisory Panel. He pointed out that in the IDE study, Superion, “demonstrated durability of effect beyond the 24-month primary endpoint, continuing through 36 months, and also performed comparably to what is reported in published literature on traditional decompression surgery. Thus Superion becomes a very viable treatment option for both surgeons and patients.”
Superion Interspinous Spacer
The Superion spacer, according to the company, is for the treatment of patients with lumbar spinal stenosis. The IDE trial enrolled 470 patients between June 2008 and December 2012 at 31 centers across the U.S. Patients were randomized 1:1 to either the Superion or the commercially available X-STOP.
The device is designed to achieve indirect spinal decompression for patients suffering from neurogenic intermittent claudication due to moderate lumbar spinal stenosis. It is implanted minimally invasively through a cannula designed to be less traumatic to the patient. It can be implanted under general or local anesthesia.
Proposed Indications
The proposed “Indication for Use” for the device, as stated in the PMA, is as follows:
Treat skeletally mature patients suffering from pain, numbness, and/or cramping in the legs (neurogenic intermittent claudication) secondary to a diagnosis of moderate lumbar spinal stenosis, with or without Grade 1 spondylolisthesis, confirmed by X-ray, MRI and/or CT evidence of thickened ligamentum flavum, narrowed lateral recess, and/or central canal or foraminal narrowing.
Patients with impaired physical function who experience relief in flexion from symptoms of leg/buttock/groin pain, numbness, and/or cramping, with or without back pain. The Superion ISS may be implanted at one or two adjacent lumbar (L) levels in patients in whom treatment is indicated at no more than two levels, from L1 to L5.
The data presented by the company included 190 subjects with the Superion and 201 with the X-STOP.
Success in the study was defined as an “individual with clinically significant improvement in outcomes compared to baseline for at least two of three domains of the Zurich Claudication Questionnaire and without any clinically significant confounding treatments, such as epidural steroid injections, nerve block procedures or spinal cord stimulators.”
Panel Questions
The FDA staff was seeking guidance from the panel on a series of questions.
Lower Overall Complication Rate for Superion
First, according to FDA documents, “11.1% of Superion subjects and 13.9% of X-STOP subjects experienced a major implant or procedure related complication. The majority of failures in the Superion cohort were due to spinous process fractures (n=31 at any time), while the failures in the X-STOP cohort were primarily due to migrations (n=16) and dislodgements (n=20). Spinous process fractures (n=17 at any time) also occurred in the X-STOP group.”
Agency staff wanted the panel to discuss the potential clinical impact of the different types or radiographic failure modes as well as the appropriateness of comparing them in determining radiographic success.
The panel believed that the spinous fractures “in and of themselves may have limited clinical consequences.” However, the panel noted the presence of fractures in conjunction with an interspinous spacer may suggest that the device is not achieving distraction of the intradiscal space, and the clinical effects of the loss in posterior disc height is not clear at this time.
The panel generally concluded that “migration and dislodgement of the device were a more significant concern than the spinous process fractures.”
Clinical Significance of Spinous Fractures
Secondly FDA staff asked the panel to discuss the clinical significance of the observed spinous process fractures, particularly given that “interspinous process devices rely upon intact spinous processes to exert their treatment effect.”
Generally, the panel believed that the patient outcome measures used in the study (ZCQ, ODI, VAS, etc.) may be useful for comparing performance metrics across studies, but noted that they lack sensitivity and enough patient focus to provide information on whether spinous process fractures have clinical consequences to the patient long-term.
The panel did express some concern that the Superion device was tested for non-inferiority against the X-STOP device, which some members of the panel considered exhibited “questionable performance and a device that does not have outstanding clinical results.” The panel recommended that longer term results are needed to see if the Superion device is a valuable “tool in the armament” of a spine surgeon.
Decompression (Gold Standard) vs Interspinous Device
FDA staff members noted it was aware of literature which has been published on interspinous process spacer devices including randomized, controlled, clinical trials (Moojen, BMJ, 2013; Moojen, European Spine Journal, 2015; Strömqvist, Spine, 2013), which suggest that decompression alone (the “gold standard” to treat lumbar spinal stenosis) results in comparable effectiveness outcomes compared to treatment with an interspinous process device alone, although use of an interspinous process device is associated with a higher reoperation rate.
In addition, the agency said it was aware of recent literature that suggests patients with degenerative spondylolisthesis should be considered as a distinct sub-population of spinal stenosis patients (Pearson, Spine, 2010), and the use of interspinous process devices to treat patients with degenerative spondylolisthesis is controversial (Kabir, Spine, 2010).
The FDA asked the panel to consider whether the literature referenced above is a fair representation of their current understanding of treatments available for this patient population and whether or not the findings are relevant to the device under discussion.
Panelists told the agency they believed that the literature presented was a good representation of the current body of literature but that it was only a small part of a greater body of published data and that there were many other publications which should be taken into consideration.
Post-Approval Plans
The panel generally believed that there is some lack of clarity regarding the duration of efficacy of interspinous process spacer devices. The panel generally believed that 24 months was an insufficient amount of time to measure the long term efficacy of these devices.
If the FDA approves the device, the company has proposed a post approval study to continue following the IDE subjects for up to five years, as well as an additional “actual conditions of use” post approval study which would enroll new subjects.
The panel believed that a decompression control group comparison should be the primary objective of the “actual conditions of use” study and a post approval study should be carried out beyond 24 months. They said cutting off the study at 24 months would bias the device. They also suggested that the a new enrollment Superion cohort should be compared to the IDE subjects at 36 months because of the increasing trend of revisions between 24 and 36 months.
Access for U.S. Patients
Fender said the company will continue to work closely with the FDA to complete their review of the PMA while the company finalizes plans for commercialization in the U.S.”
Given the FDA’s renewed emphasis on making sure U.S. patients get access to new and safe technology as quickly as possible, it would be a surprise if they don’t approve the Superion with some rigorous post approval requirements.
