GAITHERSBURG, Md. -- An FDA advisory panel was split over whether to recommend approval for the investigational Medtronic spine stabilization device called Amplify -- citing lack of data to prove that the benefits outweigh the risks for degenerative disc disease patients.
The FDA's Orthopaedic and Rehabilitation Devices Advisory Panel voted 6 to 5 (with three abstentions) that the benefits of the Amplify device outweighed its harms -- which may include a slightly increased risk for cancer compared with patients who underwent standard spinal fusion.
Medtronic is seeking approval for Amplify, which they say is superior at fusing vertebral bone compared with the current surgical standard for spinal fusion, which involves removing bone from the patient's iliac crest and grafting it to his or her spine.
Medtronic said the Amplify device is also less painful and safer than standard spinal fusion.
The device works by stabilizing the lower back vertebrae in patients with degenerative disc disease by using a compression resistant matrix and a metallic posterior spinal instrument.
Amplify contains rhBMP-2, a morphogenetic protein added to spur formation of new bone. The matrix acts as a carrier for rhBMP-2 as well as forming scaffolding onto which new bone can grow.
The split vote doesn't give the FDA clear guidance -- so the agency could go either way in its decision.
The FDA is not required to follow the advice of its advisory panels, but it often does.
The risk/benefit vote followed an advisory panel vote of 9 to 4, with one panelist abstaining, that the Amplify device is safe -- and a vote of 10 to 3, again with one abstention, that the device is effective.
While those votes would seem to indicate that the advisory panel thought Amplify was safe and effective, panel members did have concerns over the overall lack of data -- as well as troubling data suggesting a possible link between rhBMP-2 and cancer.
In documents released in advance of Tuesday's hearing, FDA reviewers had expressed concern that patients exposed to rhBMP-2 had a greater number of cancer cases than those who were not exposed to rhBMP-2.
An FDA analysis of Medtronic's clinical trials showed that after two years, 1.7% of patients exposed to rhBMP-2 had cancer, compared with 1.3% of patients not exposed to the protein, although the difference was not statistically significant (P=0.291).
There were 15 cancer cases among the Amplify group, which was almost triple the number in the control group; three-quarters of the cancer deaths during the study occurred among the Amplify group, according to an FDA presentation on Tuesday.
While this difference was deemed of "borderline" statistical significance, the findings "warrant further investigation," FDA researchers had commented in their advance briefing documents.
Still, the advisory panel couldn't seem to agree on the significance of the cancer data.
During their debate on Tuesday afternoon, the panel at first appeared in unanimous agreement that the increase in cancer cases appeared to be nothing more than a statistical fluke.
Panelist Alfred Neuget, MD, a medical oncologist who specializes in epidemiology, said that because the types of cancers varied -- and included ovarian, stomach, prostate, thyroid, and two pancreatic cancers and several skin cancers, among others -- it's likely just a random clustering.
"Clustering is a fact of life," Neuget said "In trials you're going to have instances like this. I'm not concerned."
However, the panel later revisited the debate and ultimately reached an agreement the cancer data are too inconclusive to rule out a cancer link.
The panel agreed that if Amplify is approved, Medtronic should run a five-year follow up registry trial to determine the potential cancer risk.
Some panelists were concerned with a possible immune response to rhBMP-2 that may affect fetal development. While the Medtronic's animal studies did not show a link between rhBMP-2 and fetal abnormalities, the company proposed a post-approval study in rabbits to further investigate a possible link.
Most female degenerative disc disease patients who would receive Amplify would be past childbearing age. However, panel member William Rohr, MD, an orthopedic surgeon, said that if the device was approved "there would be nothing to stop this from being used in scoliosis patients, who are virtually all of childbearing age."
The advisory committee based its votes on a number of clinical trials, including Medtronic's controlled, nonblinded, trial in which 463 degenerative disc disease patients were randomized to receive the Amplify system or posterolateral spinal fusion using autogenous bone.
The surgery was considered a success if the Amplify system was found to be non-inferior to spinal fusion.
"Success" was examined after two years and defined as: a verified fusion (defined as bridging the trabecular bone); no evidence of motion; more than 3 mm difference in translation on lateral flexion/extension radiographs; the absence of radiolucent lines through the fusion mass; no new permanent neurological deficits; absence of device-related adverse events; and no need for additional, nonelective surgical intervention.
The researchers found the Amplify group was statistically non-inferior -- but not statistically superior -- to the control group. After two years, the procedure was considered a success in 60.5% of Amplify patients, compared with 55.5% in the control group.
"This low success rate in both groups raises concerns about the overall effectiveness of this type of fusion surgery either with or without the proposed device," the FDA reviewers wrote.
However, members of the advisory panel were also concerned with the low level of success for both procedures.
Also of concern was the higher number of serious back and/or leg pain adverse events in the Amplify group compared with the control group (10% versus 8%).
Ultimately, the panel faced too many unanswered questions -- about the cancer data, about why so many patients were lost to follow-up, about possible fetal effects, and about the low overall success of the Amplify device or standard spinal fusion -- that they failed to endorse the device.
"I think the data are un-interpretable at this point," commented panelist Kathleen Propert, ScD, a professor of biostatistics at the University of Pennsylvania School of Medicine.
Another Medtronic spine device called Infuse also uses rhBMP-2, but Amplify is the first combination product utilizing rhBMP-2 for posterolateral fusion treatment of degenerative disc disease.