ARTICLE IN BRIEF
The Department of Justice and the Senate Finance Committee are seeking company information from Medtronic amid concerns over potential side effects and allegations of financial ties between the company and prominent researchers who authored studies supporting its popular spinal fusion bone growth product Infuse.
The Senate Finance Committee sent a letter to Medtronic, Inc., on June 21, seeking company information amid concerns over potential side effects and allegations of financial ties between Medtronic and prominent researchers who authored studies supporting its popular spinal fusion bone growth product Infuse, or bone morphogenetic protein-2 (rhBMP-2).
Since its approval for lumbar procedures by the FDA in 2002, the spinal fusion system has become widely used. It incorporates a steel bracket and a matrix of recombinant human bone growth factor that helps fuse damaged lumbar vertebrae, eliminating the need for collecting bone from other parts of the body.
The US Department of Justice (DOJ) recently launched its own investigation to determine if the Minneapolis-based Medtronic has promoted off-label use, which is prohibited by law. According to the DOJ, more than 80 percent of revenues from the product come from off-label applications. Since its approval, the rhBMP-2 product has been used in some 500,000 patients by more than 2,300 surgeons, according to the company.
The Senate committee, which oversees Medicare and Medicaid, said it is “extremely troubled” by emerging allegations that physicians who conducted clinical trials on rhBMP-2 were aware of potential complications but failed to report this in the medical literature, and that some have received substantial payments from Medtronic. According to a June 29 article in the Wall Street Journal, based on an analysis of Medtronic documents and disclosures made on the Medtronic website, over the past decade, “15 of those surgeons have collectively received at least $62 million for unrelated work.”
Last week, the Senate Finance Committee began investigating whether Medtronic‘s large payments to the surgeons played a role in the fact they didn‘t report the complications, after seeing an advance copy of the study.
In a statement issued by Medtronic, the company, which is not commenting otherwise, said that it will cooperate with the Senate request for documents associated with the studies and financial payments to researchers. But the statement noted that these potential side effects were made known to the FDA in the clinical trial documents that led to the product‘s approval and are listed on the product‘s warning label.
A series of investigative articles by the Milwaukee Journal Sentinel and the online news site MedPageToday uncovered the payments to doctors and surgeons. According to documents obtained by the newspaper, Thomas A. Zdeblick, MD, chairman of the department of orthopedics and rehabilitation at the University of Wisconsin-Madison, for example, allegedly received nearly $23 million from Medtronic since 2002. Dr. Zdeblick is also the editor of the Journal of Spinal Disorders & Techniques, which published two major favorable rhBMP-2 studies, neither of which mentioned any of the sterility risks associated with its use.
More recently, reports of excess cancers in rhBMP-2 graft recipients have also been reported. Last July, the FDA Orthopedic and Rehabilitation Devices Advisory Panel met to consider pre-market approval of Medtronic‘s second-generation rhBMP-2 spine stabilization system, called Amplify. The panel was deadlocked 9-4 for recommending approval.
An FDA review of clinical data collected in a multi-center, randomized, controlled clinical trial and presented at the hearing found slightly higher cancer incidence in rhBMP-2 patients. And while the difference was not statistically significant, significance was “borderline,” it concluded.
Medtronic‘s own clinical trials reported that after two years, 1.7 percent of patients exposed to rhBMP-2 developed cancers compared with 1.3 percent of controls, but the multicenter study found cancers in 3.8 percent of treated patients over 24 months versus 0.9 percent in untreated controls. Moreover, a 60-month review found cancers occurred in 5.0 percent of patients and in 1.8 percent of controls.
In a telephone interview with Neurology Today, Richard A. Deyo, MD, Kaiser Permanente Professor of Evidence-Based Family Medicine at Oregon Health and Science University in Portland, noted that the North American Spine Society dedicated its June issue of The Spine Journal to rhBMP-2, including nine research papers and several editorials critical of the original studies submitted by Medtronic.
The appendix of one paper lists lead authors of the early studies and the amounts they have received from Medtronic, many of them in the tens of millions of dollars. Several of the new studies also report on adverse events, including a paper indicating a significantly increased risk of sterility from retrograde ejaculation in treated patients, co-authored by the journal‘s editor-in-chief Eugene Carragee, MD, professor of orthopedic surgery and chief of the spine surgery division for Stanford University Hospital and Clinics in Redwood City, CA.
“I think the [revelations] in the new series of studies is alarming,” Dr. Deyo told Neurology Today. “We have to wonder about conflicts of interest in the research process and thorough reporting of side effects. The disclosures made in clinical journals are often obscure, and while the FDA puts information about side effects on its website, it is often difficult to find and interpret. I think this calls for greater access to FDA review documentation in a more accessible format than currently exists.”
He said the dollar amounts reportedly received by the researchers and surgeons in question are “breathtaking.”
“To argue that it did not influence them boggles the mind. I think the industry views these financial incentives as business as usual, and if problems later arise, they sometimes pay settlements or fines, but it is rare for individuals to be held accountable.”
He said it will “be interesting” to see how the surgical community responds to this new information, but that the procedure is altready established.
“I believe there is a place for BMP-2 for the approved indication, but probably much less for off-label use. We will have to wait and see.”
INACCURATE RISK ESTIMATES
Dr. Carragee told Neurology Today in a telephone interview that many more adverse events — some quite serious — have been reported but have either been downplayed or omitted from major studies authored by the researchers with financial ties to the company.
“Three or four of the major published papers failed to mention any possible sterility risk associated with rhBMP-2, even the information has been coming in from early on,” he said.
In an editorial in the June issue of The Spine Journal, he and four co-authors also criticized the lax reporting of financial conflicts of interest in published studies.
“We find ourselves at a precarious intersection of professionalism, morality, and public safety,” they wrote. “As the review points out, none of the original estimates of safety for any of the rhBMP-2 applications…proved accurate. More disturbingly, published reports underestimated the risks of rhBMP-2 use despite indications from the earliest trials that inflammatory reactions, adverse back and leg pain events, radiculitis, retrograde ejaculation, urinary retention, bone resorption, and implant displacement may be problems associated with rhBMP-2 use.”
A systematic review by Dr. Carragee and his colleagues, also published in the June issue, show that complications and adverse events documented in FDA reports and subsequent publications “are perhaps 10 to 50 times the original estimates calculated from industry-sponsored studies,” he told Neurology Today.
GUILT BY ASSOCIATION
Although some of the major authors of the original studies received millions of dollars, many others who were co-authors were unaware that the senior authors had any financial ties with Medtronic, Dr. Carragee said.
“This is a very important point that seems to have been overlooked — many of them were fellows and residents at the time, and had no idea about the money. The majority received nothing and were in the dark, and now some of them are promising young academic neurosurgeons and have suddenly found their careers unfairly jeopardized.”
Dr. Carragee said that this is very clear if one looks at the appendix of the analysis of the 13 studies in his study in the June issue of The Spine Journal. “We list all of the authors and whether they had financial relationships with the company, but most of them got nothing.”