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| Medtronic Infuse |
Surgeons who conducted clinical trials to test a Medtronic Inc. (MDT) bone- growth protein widely used in spine surgery didn't report serious complications that arose in those trials in their research papers, a new study says.
Over the past decade, 15 of those surgeons have collectively received at least $62 million from the medical-device company for unrelated work, according to a Wall Street Journal analysis of Medtronic documents and of recent disclosures made on the company's website.
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. The product, called Infuse Bone Graft, has already been the subject of a series of inquiries by the Senate committee, as well as an ongoing investigation by the Justice Department into its use beyond its official Food and Drug Administration indication. Infuse represents about $700 million in annual sales for Medtronic.
The new study, published in the Spine Journal, reveals that serious complications, including cancer, sterility, infections, bone dissolution and worsened back and leg pain occurred in 10% to 50% of patients who were administered Infuse or a sister product in 13 clinical trials funded by Medtronic and conducted by the surgeons between 2000 and 2010. Yet these complications weren't reported in the research papers the surgeons wrote on those trials, even though the papers were peer reviewed. Some of the complications are mentioned on the product's label.
Eugene Carragee, the study's lead author and a professor of orthopedic surgery at Stanford University School of Medicine, says that in retrospect, the medical journals that published the Infuse papers should have been more suspicious of their claims. "You wouldn't be able to do a clinical trial of aspirin without having some side effects," he says.
Six of the 13 papers were published in Spine, a publication that bears no relation to the Spine Journal, which is publishing the new study. The other seven papers were published in the Journal of Spinal Disorders & Techniques, the Journal of Bone and Joint Surgery, and the Journal of Neurosurgery: Spine. The Spine Journal itself published one of the papers.
Christopher Shaffrey, an editorial board member of the Journal of Neurosurgery: Spine, said the complications "should have been reported" in the papers. "This is an important article that calls attention to the need for full disclosure and full reporting" by study authors, he added. The other journals didn't immediately comment.
In a written statement, Medtronic's new chief executive, Omar Ishrak, conceded that Carragee's study raised "questions about researchers' conclusions in their published peer-reviewed literature," but added that it didn't tarnish the credibility of the clinical-trial data Medtronic submitted to the FDA. For his study, Carragee went back and examined that data and found some of the unreported complications in it.
Ishrak, who took the company's helm just two weeks ago, added that Medtronic would "investigate questions surrounding researchers' potential conflicts of interest, refine our policies as warranted, and strive to lead the industry in ethical and transparent business practices." In a phone interview, Richard Kuntz, Medtronic's chief scientific officer, said Ishrak asked him to put together a team of internal and external researchers to review all the issues raised by Carragee's study and report back to him within 90 days.
Infuse, which for some patients dispensed with the need to harvest bone from the hip to help vertebrae fuse, was approved by the FDA in 2002 for use in one particular type of spinal fusion surgery. But it became widely used off-label-- or for uses not officially approved by the FDA-- in other types of spinal surgeries that were the subject of some of the papers Carragee reviewed. Research indicates that at least 85% of Infuse use is now off-label. Doctors are free to use drugs beyond their official indications.
"Medtronic paid millions to doctors and those same doctors, oddly enough, published the 'science' Medtronic needed to sell a product," says Paul Thacker, a former aide to Sen. Charles Grassley (R., Iowa) who was involved in the Senate Finance Committee's past investigations of Medtronic and now works for the watchdog group Project On Government Oversight.
One of the off-label uses that the papers contributed to popularizing was in fusions of the cervical spine. The Justice Department launched its investigation into Infuse in late 2008 following reports of serious adverse events associated with that usage, including some patient deaths. In its annual 10K filings to the Securities and Exchange Commission, Medtronic said it was "fully cooperating" with the investigation.
In one of the study's findings, Carragee and his co-authors found that a research paper published two years ago in the Journal of Bone and Joint Surgery about Medtronic's sister Infuse product called Amplify failed to discuss what they calculated was a 90% to 95% probability that there was a link between Amplify and cancer.
The cancer link took up 15 pages of a 68-page FDA summary discussing Amplify when it was up for approval earlier this year, but received no mention in the 2009 Medtronic-sponsored paper. The FDA declined to approve Amplify in March because of the cancer concerns, but Medtronic is appealing the decision and still hopes to get the product to market. Medtronic's Kuntz says the company remains unconvinced of the cancer link.
Three of the spine surgeons involved in the Amplify trial, John Dimar, Steven Glassman, and Kenneth Burkus, have together received at least $10 million in royalty and consulting payments from Medtronic since 2001, the Medtronic documents and its website disclosures show. In an email, Glassman said he recently published an article on bone grafting in the Spine Journal that he said was "clearly adverse" to Infuse, "which seems to contradict the theme of" Carragee's study. Burkus didn't respond to calls seeking comments. Dimar couldn't be reached. Glassman and Dimar were featured in a page-one Wall Street Journal story last December about payments Medtronic made to spine surgeons for their participation in the development of company products.
Burkus, a spine surgeon in Columbus, Ga., was the lead author on four of the 13 Infuse papers examined by Carragee. In three of those four papers, he disclosed no financial ties to Medtronic. Burkus has received more than $4 million from Medtronic since 2001.
Email correspondence obtained independently by The Wall Street Journal between Burkus and Medtronic shows he sought company input into his research results. In an email dated July 3, 2004 to which he attached a draft of one Infuse paper he was lead-writing, Burkus wrote his co-authors and Medtronic executives: "Come in off the porch and put down the sparklers, bottle rockets and M-80s. This manuscript will start the real fireworks." He then solicited from them " additions/criticisms/changes" and "deletions."
"This seriously undermines the stated claim of the authors that they were completely neutral observers and reporters of that clinical trial," Carragee says of the email. But Kuntz says there's nothing wrong per se with Burkus's email. "It's very common practice for researchers to solicit a wide range of input, as long as they maintain final editorial control," he says.
The medical journal that published two of the four papers on which Burkus was lead author, the Journal of Spinal Disorders & Techniques, was edited by Thomas Zdeblick, an orthopedic surgeon at the University of Wisconsin School of Medicine and Public Health who has received more than $24 million from Medtronic since 2001. Zdeblick was a co-author on both papers, but disclosed no financial relationship with Medtronic in the papers. He didn't respond to calls seeking comment.
In a forthcoming letter to the editor he recently sent to The Spine Journal, Zdeblick said that none of the payments he received from Medtronic were directly related to Infuse but that he receives royalties for a cage that Infuse is placed in when it's inserted in the spine. Kuntz says Medtronic now prohibits researchers who receive royalties from it to conduct clinical trials aimed at obtaining FDA approval for Medtronic products.
The issues raised by the Spine Journal study present Ishrak, the new Medtronic CEO, with his first public-relations challenge. He joined the company on June 13 from General Electric Co. (GE), where he headed GE's $12 billion-a-year health- care business. Ishrak's predecessor, Bill Hawkins, announced plans to retire last December after a challenging four-year tenure that included the recall of defective heart defibrillator leads. Medtronic has struggled to increase its revenues and has seen its stock price stagnate. Medtronic shares rose 43 cents to $39.01 in 4 p.m. EDT composite trading Tuesday on the New York Stock Exchange.
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