In recent months, the controversy surrounding Medtronic Inc.’s Infuse bone growth product has gained momentum. Not only has the device maker been accused of downplaying the serious side effects associated with Infuse, but most recently, a prominent researcher warned that Infuse may be associated with a higher risk of developing cancer. Not surprisingly, Medtronicâ€™s spine business is suffering, and it appears Infuse is to blame. According to Medtronic press release, its core spinal revenue declined by 3 percent in the second quarter compared to last year. At the same time, the biologics portion of Medtronic’s spine business declined by 4 percent, thanks to a drop in Infuse sales.
Medtronic’s Infuse bone graft system consists of the LT-Cage Device â€“ a small, hollow metal cylinder â€“ which is filled with genetically engineered material, known as rhBMP-2 (recombinant human Bone Morphogenetic Protein-2), which stimulates bone growth. In 2002, the U.S. Food and Drug Administration (FDA) approved the Infuse system for use in one type of spine surgery â€“ anterior approach lumbar fusion. While Infuse was later approved for use in two types of dental surgeries, it was never approved for any other spine surgery.
Since its approval, Infuse has been at the center of several controversies. Most recently, questions have been raised about Medtronic-sponsored research that may have downplayed serious side effects. And earlier this month, new research linked Infuse to an increased risk of cancer. Both of those issues were raised by Dr. Eugene Carragee, a Stanford University orthopedic surgeon and editor of The Spine Journal.
Over the summer, Carragee authored an article for The Spine Journal in which he disclosed that Medtronic-paid surgeons had failed to report serious complications from Infuse, including cancer, sterility in men, infections, bone dissolution and worsened back and leg pain. The article said complications occurred in 10 to 50 percent of patients who got the product in 13 Medtronic-funded clinical trials between 2000 and 2010. Dr. Carragee’s article appeared in the June issue of The Spine Journal, which was devoted, in its entirety, to a review of rhBMP. Carragee’s review examined payment data from Medtronic to doctors who co-authored the Infuse studies, and found that, the median amount to the company paid to doctors was at least $12 million to $16 million per study (though it should be noted that none of the royalty payments related to Infuse.)
Earlier this month, Carragee again made news when he presented a study at the North American Spine Society that raised serious questions about a possible association between Infuse and an increased risk of cancer. Carragee’s analysis of a Medtronic study for its Amplify product, a higher-dose version of rhBMP-2, found that the study failed to identify a significant cancer risk though both the research team and Medtronic were aware of data linking the product to cancer. Again, the researchers had received millions in royalties from Medtronic (though again, the payments were not related to rhBMP-2 products). The study was submitted to the FDA in order to obtain approval for Amplify; however the FDA declined to approve Amplify, citing the product’s association with a higher incidence of cancer.
The study analyzed by Carragee involved 239 patients who got the Amplify product and 224 who got a conventional graft of their own hip bone. After three years, 5% of those who got Amplify, or 12 patients, were diagnosed with a new cancer, compared with 1.3%, or three patients, who got a graft of their own hip bone. The difference was statistically significant. In an interview with The New York Times, Carragee said the cancer findings could have serious implications for people receiving Infuse. Doctors often administer Infuse off-label at levels significantly above the recommended dosages, ones that approach or exceed the amount of rhBMP-2 found in a dose of Amplify, he said.
Unfortunately, it does appear that Infuse is frequently used off-label. In 2008, the FDA warned that Infuse Bone Graft and similar products had caused serious problems when they were used off-label in cervical spine (neck) surgeries. Injuries associated with off-label use of Infuse can include ectopic or uncontrolled bone growth at or near the site of the surgery; ongoing or chronic radiating pain in the legs or arms (i.e., neuritis, radiculopathy, or radiculitis); sterility, retrograde ejaculation, or other uro-genital injuries in male patients; nerve injuries causing severe and chronic pain. In cervical spine surgeries some patients experience acute severe neck swelling several days after surgery resulting in death or permanent injury.
The U.S. Senate Finance Committee has been investigating Infuse for several years, and recently â€“ thanks to Carrageeâ€™s Spine Journal article â€“ demanded Medtronic turn over records detailing payments made to infuse researchers. Meanwhile, the U.S. Justice Department is investigating off-label use of Infuse.