BY JOHN CARREYROU
A report by the Senate Finance Committee based on thousands of documents it subpoenaed from Medtronic Inc. raises new questions about the integrity of the medical research underpinning one of the medical-device maker's products.
Medtronic was "heavily involved in drafting, editing and shaping the content of medical journal articles" about the product—a bone-growth protein used in spine surgery called Infuse—even as it was paying the physicians who wrote those articles a total of $210 million for unrelated work, the Senate report alleges.
In one instance, a Medtronic employee recommended to one of the physicians not publishing a list of side ...
...effects associated with Infuse in a 2005 journal article, company emails show. Medtronic marketing officials also urged inserting language into other journal articles touting the use of Infuse as better for patients than using bone harvested from their pelvises because of the pain associated with the latter, other company documents show.
Medtronic's influence extended to preparing a physician's 2002 speech to a panel advising the Food and Drug Administration on whether to approve the drug, the report alleges. The physician's disclosure to the panel at the time suggested his testimony was independent, but the company had in fact helped him draft it and paid him as a consultant the previous year, company documents show. Medtronic later hired the physician as an executive.
In response to the Senate report, Medtronic issued a statement saying it "vigorously" disagreed with any suggestion that "it improperly influenced or authored any of the peer-reviewed published manuscripts." The company also denied that it "intended to under-report adverse events" associated with Infuse.
Infuse, which is used to spur the fusion of vertebrae to reduce back pain, once brought up to $800 million in annual sales for Medtronic. But the drug has been a source of controversy for the company since 2008, when reports began surfacing of patient deaths linked to its use in the neck.
The FDA approved Infuse in 2002 only for use in one particular type of surgery involving the lower spine. But it became widely used in other types of surgeries, including neck procedures, after a series of medical-journal articles depicted those other uses as safe and effective. Doctors are free to use drugs beyond their official uses, but companies can't promote such "off-label" uses.
Those journal articles have since come under a cloud. Last year, Eugene Carragee, a professor of orthopedic surgery at Stanford University School of Medicine, published a study showing that 13 of the articles failed to report serious complications associated with Infuse and a sister drug called Amplify that hasn't been approved by the FDA. Dr. Carragee's study prompted the Senate inquiry that led to Thursday's report.
Although it was known that Medtronic had financial relationships with some of the physicians who wrote journal articles, the scale of the payments and how far back they went in time had not been fully disclosed until now.
Medtronic says the payments weren't connected to the journal articles. Rather, it said, "the vast majority" were "royalty payments made to compensate physicians for their intellectual property rights and contributions" to other company products.
The documents obtained by the Senate committee show that Medtronic paid four of the article authors—Scott D. Boden, Regis W. Haid, Volker Sonntag and Thomas A. Zdeblick—between $22 million and $34 million each from 1996 to 2010. Medtronic also paid a limited liability company connected to two other authors, John R. Dimar and Steven D. Glassman, nearly $65 million over the same period.
All six are spine surgeons with current or former university affiliations. Drs. Boden and Haid are based in Atlanta, Dr. Sonntag in Phoenix, Dr. Zdeblick in Madison, Wis., and Drs. Dimar and Glassman in Louisville, Ky.
Another 27 physicians who shared authorship of the medical journal articles received payments from Medtronic ranging from a few hundred dollars to $6.4 million over the same 15-year span, the Medtronic documents show.
Dr. Sonntag didn't respond to attempts to reach him for comment.
Dr. Zdeblick said he was "a minor author" on two of the Infuse articles and "saw those manuscripts only in their later stages and have no knowledge of their early preparation." He said the $34 million he received from Medtronic was "related to the spinal implants I have designed and hold 22 patents on." He added that he received no royalties for Infuse itself. However, some of his royalties were for a device that Infuse is encased in when it's inserted in the spine.
Dr. Haid said the $25.5 million he was paid by Medtronic was for patented contributions he made to a variety of Medtronic products, though not Infuse. He said the money didn't influence his judgment with regard to the two journal articles he participated in. "I hold myself to high standards of integrity," he added.
Dr. Boden said he wrote two early articles about Infuse without input from "any Medtronic personnel." He acknowledged receiving consulting payments from the company at the time, but said he disclosed them to his university and took "steps to manage potential conflicts." He added that most of the $28.8 million he received from Medtronic came later and was related to "intellectual property for future biologic products." However, Dr. Boden was also a co-author on a 2007 article about Amplify, by which time he had begun receiving large royalty payments from Medtronic.
Drs. Glassman and Dimar said their journal articles "were edited and published by ourselves" and added that they have reported Infuse's adverse effects "in numerous peer-reviewed publications." They said the money their limited-liability company received from Medtronic was royalties shared with three other surgeons.
In most of the medical journal articles, the authors didn't disclose their extensive financial relationships with Medtronic.
For instance, in the 2007 Amplify article, which was co-authored by Drs. Boden, Glassman and Dimar, the disclosure read in part: "No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript."
That year, Drs. Dimar and Glassman's limited liability company received $9.7 million in royalties for a system of rods, hooks and screws they used in conjunction with Amplify in the study, Medtronic documents show. The study also failed to report a probable link between Amplify and cancer that ultimately led the FDA to decline to approve the drug.
Medtronic's role in shaping the medical journal articles was similarly not disclosed. In June 2004, a Medtronic marketing executive recommended to a surgeon author not listing all the adverse events associated with Infuse in the manuscript of one article. That article was published the following year in the Journal of Bone and Joint Surgery without a table detailing the adverse events.
Dr. Carragee says the omission had serious health implications because the adverse events included instances of inflammation, neurologic problems and bone weakening that could have been forerunners of the problems some patients would later die from when Infuse was used off label in their necks.
In another example of Medtronic's role in molding what was supposed to be independent medical research, another of the company's marketing executives encouraged the authors of two medical journal articles to emphasize the pain experienced by a control group of patients who received pelvic-bone grafts instead of Infuse. A "bigger deal should be made of elimination of donor site pain with Infuse," the executive wrote in a 2001 email to one of the surgeon authors. "I would put that front and center in results, discussion and conclusion so that 'equivalent' results aren't received as a letdown."
In some instances, Medtronic employees drafted responses for the authors to concerns expressed by peer reviewers before publication, the company documents show.
In January 2002, Hallett H. Mathews, a spine surgeon based in Richmond, Va., appeared before an FDA committee tasked with advising the agency about whether to allow Infuse onto the market. Before giving his testimony, which was favorable to Infuse, Dr. Hallett told the committee: "I have no direct financial interest in the product under review here today and am not being paid for my participation in this meeting."
Though technically correct, the disclaimer didn't disclose that Dr. Mathews had been paid consulting fees by Medtronic in 2001 and that Medtronic had worked with the public-relations firm Ketchum to prepare his testimony to the committee that day. Dr. Mathews later went to work for Medtronic as an executive. He left the company last year. Dr. Mathews didn't respond to an attempt to reach him.
In an attempt to address concerns about the science behind Infuse, Medtronic has given a $2.5 million grant to Yale University to oversee two independent reviews of all of its clinical data on the drug. The company expects those reviews to be completed sometime next year.
Write to John Carreyrou at firstname.lastname@example.org