A Milwaukee Sentinel/MedPage Today investigation into the use of Medtronic’s Infuse device in spinal fusion surgery has uncovered a scandal that is bound to shake up the cozy relationship of device manufacturers and the orthopedic profession.
What is Medtronic’s Infuse?
Bone growth and repair are regulated by, among other factors, by bone morphogenetic factors, or BMP. These factors, there are about 20 of them so far, have many other regulatory functions, but all of them have to do with the formation of the correct architecture of a variety of tissues. Bone is the most prominent among them.
The vertebral column is comprised of the bony vertebra and the cartilaginous disc that separates them. When the rim of the disc is weakened it bulges, or even herniates. This impinges on a spinal nerve, causing pain.
In most cases pain resolves spontaneously when the bulging recedes. But sometimes the pain is unrelenting or the anatomic defect may progress to a permanent functional impairment. In this case, surgery is indicated. The common procedure is removal of the damaged disc and fusion the adjacent vertebra. Fusion is accomplished by removing a piece of bone from the patient’s hip and implanting it in the space between the vertebra. And here is where Medtronic’s Infuse comes in. It is basically BMP-2 adsorbed on a purified collagen matrix ,which is implanted in the site of the fracture. The BMPs eluted slowly off the collagen gel and helps accelerate bone healing. So on the face of it, this is a major advance over the autograft procedure.
So what’s the problem?
Research into major failures, be it in engineering or policy decisions, showed that most of them did not come about because of a single major factor; rather, a chain of small failures eventually reached a tipping point and a catastrophic failure ensues. The disaster of Apollo 13 and the intelligence failures of 9/11 are prime examples.
John Fauber, an investigative journalist shined a disturbing light on the approval process back in 2010.
“The querulous advisory panel member, Stephen Li, PhD, pointed out that nine of the doctors who authored the BMP-2 research submitted to the FDA had a financial stake in the product. Moreover, the studies by those nine all had findings that were twice as good as studies from researchers who did not have a financial interest in the product. Why the discordant findings, Li asked.”
Did anybody from the FDA have an answer? Did they pursue the issue? The answer is no, and no. They just let it slide. Here are some disturbing facts that apparently were not deemed important enough to halt approval of Infuse.
One surgeon, a lead author on four of these research papers, did not disclose any financial ties while with the company on three of the papers; he was paid over $4 million by Medtronic. In another study, the lead author did not disclose any financial ties to Medtronic; he was paid at least $11 million by the company. In a series of 12 publications, the median financial ties of the authors to Medtronic were $12–16 million. In those studies that had more than 20 and 100 patients, one or more authors had financial ties of $1 million and $10 million, respectively. Early clinical trials using recombinant human BMP-2 underreported adverse events associated with treatment. In the 13 original industry-sponsored publications related to safety, there were zero adverse events in 780 patients. It has since been revealed that potential complications can arise from the use including implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation.
Something smells fishy
Zero adverse events? Only a bunch of orthopedic surgeons ignorant of basic human biology would make such a claim. Any interference in the intricate web of cell signals is bound to have profound effects on the target cells. Furthermore, anybody who has had minimal experience in collagen gels as carriers of protein molecules knows that the elution rates of the adsorbed proteins are highly unpredictable and poorly controlled. So is it any wonder that one of the common adverse event is formation of ectopic bone, meaning excess bone. And the result: impingement on the spinal nerve causing severe pain, or complete strangulation of the nerve, resulting in paralysis.
Many biological substances are used as drugs nowadays. Testing of new biologic agents generally requires clinical trials with 1,000 to 3,000 people. But in allowing Infuse on the market, the FDA treated it as a combination device, rather than as a biologic agent, with only 277 patients in the clinical trial. Furthermore, perusal of the trial protocol shows that in the randomized arm of the clinical trial of Infuse, only 143 people were implanted with the product. All of those who got Infuse were compared with 136 people who got their own hip bone in traditional spinal fusion surgery.
In addition, Infuse was approved in a “noninferiority” trial, meaning Medtronic did not have to prove it was any better than the traditional treatment.
As a result, Infuse got on the market with less safety testing than other biologic drugs.
Where was the FDA? Many of the reports of adverse events submitted by treating orthopedists to the FDA, via Medtronic, mention “ectopic bone” as the cause. Did anybody at Medtronic or the FDA read those reports?
Who will be held accountable?
Journal Sentinel/MedPage Today analysis of U.S. Food and Drug Administration data found more than 6,500 reports of Infuse-related problems have been registered with the agency’s medical device reporting system since 2002, the year Infuse was approved.
Roughly half of those — some 3,300 — were filed last year alone.
Last week, the company told investors it will pay $22 million to settle about 950 claims and is setting aside $140 million to settle an anticipated 3,800 additional claims.
Sounds like finally somebody will pay, right? Not so fast.
The ones who will pay are the shareholders of Medtronic. Not the executives of the company: they in fact habitually vote fat bonuses for themselves. Not the greedy Orthopedic surgeons who published false data for a bribe of millions of dollars; not the FDA officials of the Devices branch; who are notorious for a cozy relationship with the industry they are supposed to regulate.
Just like in the aftermath of the financial disaster -nobody will go to jail. And we will be left wondering, yet again: is the system rigged?