The FDA Orthopaedic and Rehabilitation Devices Panel said “No” to Zimmer on November 4 and did not recommend FDA approval for Zimmer’s Dynesys Spinal System. It was the second panel “No” vote for a spine device in the past year. Earlier in 2009 the panel also declined to recommend approval for Stryker’s OP-1 bone growth product.
Dynasys Spinal System/ZimmerThe panel’s proceedings came to a stunning, if not also awkward, halt when panel member Edward Hanley, M.D., moved at the end of the long day that the panel recommend approval of the device with conditions. His motion was met with silence. No other panelists seconded the motion.
Panel member and spine surgeon John Kirkpatrick, M.D., then looked around the table at his colleagues and said, “I’ll be the heavy.” He then moved that the panel vote that the system is “not approvable” by the FDA.
Brent Blumenstein, Ph.D., the panel member who famously pointed out OP-1’s “Abuse of the Alpha”, seconded the motion. The panel then voted 5 to 1, with one abstention, in favor of Kirkpatrick’s motion.
Just like that, another spine device was shot down by the FDA’s independent group of surgeons and scientists.
Don’t Blame the FDA
Don’t blame the FDA staff for this recommendation. FDA reviewers said they thought the device was safe and effective in documents released before the panel meeting.
The reviewers said a Zimmer study of the device met its goals, showing results at least as good as the company’s older Silhouette Spinal Fixation System used as an adjunct to fusion. Patients implanted with Dynesys showed a 52% treatment success rate, compared with 40% for Silhouette.
“Zimmer Spine has developed a clinical option that is an alternative to fusion for stabilizing the lumbar spine. The data from this trial demonstrate that this device has been shown to be safe and effective for the treatment of patients with leg pain resulting from spondylolisthesis and/or stenosis, ” said the FDA summary.
“The patient outcome and radiographic data in the Dynesys Spinal System prospective, randomized, multi-center clinical trial support the conclusions that this device is safe and effective in this context and the results generated are not-inferior to those of posterior lateral fusion. The trial was designed and executed to ensure that the results can be generalized to the population with lumbar spinal instability from degenerative spondylolisthesis/retrolisthesis and/or independently, lateral or central stenosis.”
Flawed PMA?
So what happened?
“The [Dynesys] PMA (premarket approval) application may have done a disservice to the device, ” said panel member and a NASS (North American Spine Society) leader, Raj Rao, M.D., of the Medical College of Wisconsin in Milwaukee.
“The Dynesys is an intriguing concept that utilizes a well-established posterior pedicle screw platform. It intends to stabilize the motion segment, while preserving some degree of motion. The device is an attempt at addressing many of the questions that spine surgeons grapple with on a daily basis—what is the ideal pattern and range of motion at a spine segment, how much motion does a spine segment need following decompression procedures, and what motion at a spine segment is good for the adjacent segments, ” Rao told OTW after the meeting.
Raj Rao, M.D.
“The proposal submitted did not have a clear premise behind the workings of the device and this, in my opinion, led to a study design that did not allow these questions to be clearly answered. In addition, there were questions regarding the longer-term viability of the screw/construct within the body, ” added Rao.
The first warning of the day that panel members had trouble with the PMA occurred when panel member Sanjiv Naidu, M.D., Ph.D., of the Pinnacle Health System questioned discrepancies between lab and clinical outcomes for patients with leg pain.
Kirkpatrick said he didn’t understand the target population for the device and there were too many conflicting results without explanation. He cited the “paradoxical” results of patients with stenosis. He questioned sponsor presenters why leg pain results were different when researchers had expected the results to be the same.
Fog, Inconclusiveness and the Altar of Randomization
Blumenstein added that the “fog” of the clinical data left him in a “state of inconclusiveness.” He later said that he worships at the altar of randomization and noted that more than 25% of patients from the initial trial group were excluded from the final analysis. Rao noted a large discrepancy at some sites of Dynesys vs. Silhouette assignments.
When the sponsor’s presenters said their belief that all patients in the study were candidates for spinal fusion because of instability in the spine, Rao commented that instability of the spine for fusion candidates was defined by the pain generator. “But where was the source of the pain for the Dynesys patients?” asked Rao.
His question went unanswered.
Road to PMA
The Dynesys Spinal System was first introduced in Europe in the mid-1990s as a nonfusion pedicle screw system. The original technology was developed by Dr. Gilles Dubois of the Nouvelle Clinique St. Jean, France.
This technology was subsequently transferred to Zimmer GmbH (formerly Centerpulse) where the design and development continued. The product was first used in the European Union in 1994 as a pedicle screw system for non-fusion applications. It received the CE mark in 1999.
Through March 2009, there have been over 40, 000 patients implanted and the device was also cleared by the FDA for posterior fixation as an adjunct to fusion.
Zimmer Reaction
David Dvorak, CEOThis has to hurt at Zimmer headquarters in Warsaw. Just a few weeks ago CEO David Dvorak told Wall Street analysts during a quarterly earnings conference call that the majority of “headwind” at the company’s spine division, stemmed from Dynesys’ financial performance.
“We’re heading for a panel review of the Dynesys product with the broader indications coming up next month. So that’s going to be telling to the future of that product line, but we are big believers in the clinical success of that product and believe that it’s really a product that can make a big difference for patients, ” said Dvorak.
After the panel’s vote, the company, through its spokesperson Brad Bishop, said,
Following today’s decision, Zimmer Spine will continue to work with the FDA to determine necessary next steps. Zimmer Spine remains committed to the Dynesys system, which has a proven clinical track record over 14 years in more than 42, 000 cases globally.
“The system is used in fusion applications in the United States and non-fusion applications outside of the United States. This recommendation by the FDA panel does not impact use of the product outside of the United States. The company continues to believe the Dynesys system has the potential to become a valuable treatment alternative in a non-fusion application for Americans suffering from lumbar degeneration, ” added Bishop.
Potholes on the Approvability Road
With the device panel once again voting against recommending approval of a device because they believed that the clinical trials were poorly designed, we asked Mark N. Melkerson, Director, FDA’s Division of Surgical, Orthopedic, and Restorative Devices immediately after the meeting if initial IDE (investigational device exemption) study designs developed collaboratively with sponsors and the FDA were out of touch with device panel standards?
The FDA works with sponsors in designing the clinical trials and identifies milestones that must be met to reach “approvability” for the device. By the time the device panel sees the results of the clinical trials, many years have passed since those milestones of approvability were defined and agreed upon by the sponsor and FDA.
Melkerson said the agency was not ready to answer that question. He said he told the company immediately after the vote that there would be a review of the transcript of the panel meeting and the agency would get back together with the company to see if there were opportunities to continue to work towards approvability. The FDA is not obligated to follow the recommendations of the panel and could grant Dynesys approval with a significant post-market study requirement.
Some long-time FDA panel observers told OTW that they would not find it out of the question for the FDA to approve the previously cleared device. They reminded us that the FDA pays as close attention to the answers given by panelists to the questions posed by staff members as they do to the final vote. It was also noted that St. Francis Medical went through a similar ordeal with the agency following a negative panel vote, before receiving final approval for the X-STOP.
Investigator Bias and Financial Disclosure
While the drama of another “No” vote by the panel took center stage, there was another notable item raised by Bob Durgin, J.D., the panel’s industry representative from Biomet.
Durgin asked FDA staff why their summary document was highlighting an analysis of possible bias that could have been introduced through the financial interests of investigators. Investigators are always required to disclose their levels of financial interest in devices under panel consideration.
An analysis of those interests in the Dynesys showed that “no statistically significant treatment-by-compensation” was found in this case. A second analysis examined the correlation between compensation and clinical success rates for the Dynesys treatment, Silhouette treatment and both cohorts combined.
The FDA summary stated, “The correlation was positive for the Dynesys treatment and negative for the Silhouette, which are the anticipated directions if there were to be an effect of compensation. Therefore, there is only a trend which suggests the possibility of bias from compensation with no statistically significant evidence of such an effect.”
Durgin wanted to know why this was being highlighted if it was determined that it was statistically irrelevant?
After repeated inquiry from Durgin, Mark Melkerson told the panel that pressure from Congress was behind this new emphasis. Some FDA staffers told us that the experience of Synthes’ ProDisc, where allegations of investigator bias due to financial interests were made, contributed to this new focus.
Clearing the Fog
In the end the panel members could not overcome their doubts of approving this cleared device for a new indication. The fog was too thick and comparisons for indications and patient selection too unclear. Whether or not Zimmer can find its way through the fog to eventually approval of the device is unknown.
