Since it won FDA approval in 2002 for use in spinal fusions, recombinant human bone morphogenetic protein-2, or BMP-2, has generated annual sales of $800 million. Many of those sales represented off-label use, a trend that has lately stirred the interest of Congress and the media. 番茄社区 and the Milwaukee Journal Sentinel revealed many aspects of this marketing approach in an earlier special report; here, we report information gathered in our follow-up investigation.
A key factor in the BMP-2 success story is a cadre of prominent surgeons whose members have been enlisted by medical device-maker Medtronic to conduct clinical research or author articles about InFuse, the brand name for BMP-2.
This year alone, many of those doctors received payments of hundreds of thousands to millions of dollars each in royalties for a variety of other Medtronic spinal devices, according to a 番茄社区/Journal Sentinel analysis of newly released company payments. Medtronic began disclosing the payments this year, in advance of a federal requirement set to take effect in 2013.
Surgeons with no financial ties to Medtronic say the product's success is due largely to positive findings made by the surgeons affiliated with the company.
Publish and Profit
Doctors involved with two of the many research articles on BMP-2 published since it was approved -- one in 2002, the other in 2004 -- received a combined $6 million in royalties this year for other Medtronic spinal products, the newspaper found. The payments went directly to the doctors or business entities designated by them.
"There is no question, if you have a product, you want it to be published," said Dan Spengler, MD, former editor of a spinal medical journal and professor of orthopedic surgery at Vanderbilt University Medical School. "It carries weight."
There is no evidence any of the surgeons who have published articles on BMP-2 received royalties they did not deserve.
However, the spine surgery field has been plagued by troubling questions about transparency.
For years, published articles revealed scant information about the financial conflicts of authors, including not spelling out how much royalty money an author received. Critics say those articles have incalculable value to device-makers trying to increase sales of their products.
"That's really what delivers the most bang for the buck," said Charles Rosen, MD, a clinical professor of orthopedic surgery at the University of California Irvine and president of the Association for Medical Ethics.
But that impact is greatly diminished when doctors read that an author got a large amount of money.
"Compare the effect of reading, hypothetically, that one author received $5,000 last year from Medtronic versus reading he received $1 million," Rosen said. "The amount makes a difference."
In 2006, Medtronic agreed to pay $40 million to settle a U.S. Department of Justice lawsuit that alleged between 1998 and 2003 it paid kickbacks to doctors to induce them to use Medtronic spinal products. Among the forms of payments the government identified: sham consulting agreements, sham royalty agreements, and lavish trips.
In an e-mail, Medtronic spokeswoman Marybeth Thorsgaard said collaboration between doctors and the device industry was vital to medical technology innovation and has led to developments that have changed the lives of thousands of patients.
"Medtronic takes great care to ensure that all arrangements with physicians are fully compliant with the law and the industry's standards for such contracts," she said.
The company's relationships with doctors are transparent, she said, adding the company fully discloses those payments on its website.
At the time BMP-2 was approved in 2002, little was known about the financial connections between Medtronic and doctors associated with the clinical trial. Likewise, little was known that year when the Journal of Spinal Disorders & Techniques published the article reporting the trial results.
In that 2002 publication no mention was made of doctors getting royalties or having any financial connection to the company, but the four authors of the paper have received $2.8 million in Medtronic royalties this year, although those payments were for products other than BMP-2.
However, earlier this year Medtronic began listing payments to doctors on its website, a practice that will become law when the Physician Payment Sunshine Act goes into effect in 2013.
番茄社区 and the Journal Sentinel used that database to check payments made this year to a core of prominent doctors who have published research about BMP-2 since its approval.
Million Dollar Paydays
In 2004 The Spine Journal published what was to be a seminal article in the BMP-2 saga (Spine J 2004; 4: 527-539).
The paper described the use of BMP-2 for posterior lumbar interbody fusion, an off-label use because BMP-2 was approved for single-level spinal fusion involving the lumbar spine in which the operation was done from the front, or an anterior approach.
Moreover, the paper described a clinical trial that had to be stopped because the product was causing troubling bone formation in the spinal canal of patients. In the paper, that finding was downplayed, with the authors describing the results as "encouraging."
Three of the four authors of The Spine Journal paper have received a total of $4 million this year in royalties from Medtronic for a variety of spinal products other than BMP-2.
Spengler, the Vanderbilt orthopedic surgeon and former medical journal editor, said he doubted the paper would have been written in such positive terms by authors without financial ties to Medtronic.
He described the article as egregious, saying it "just blew off the complications. It's a horrible article."
Orthopedic surgeon Rosen said the paper was biased, calling it "more of a marketing paper than an objective scientific study."
Good Idea, Most of the Time
Although marketing has certainly boosted BMP-2, it is important to note that its blockbuster status was also driven by the fact that it eliminates the need for doing a bone graft as part of spinal fusion -- it has revolutionized the field because of its ability to essentially turn whatever it touches into bone -- a good thing if confined to the tiny space between vertebrae.
However, there have been concerns about serious side effects, especially when the product is used in what are known as off-label surgeries, that is, purposes other than for what it originally was tested and approved.
About 85% of BMP-2 use now is off-label, according to recent studies.
Said Spengler: "It (the 2004 article) seems to be totally aimed at promoting BMP-2 off label without really saying so."
The article described three of the authors as consultants to Medtronic, though it did not disclose that any of them were receiving royalties at the time.
Regis Haid, MD, lead author of the article and an Atlanta neurosurgeon, told 番茄社区/Journal Sentinel he was getting royalties for other Medtronic products. Haid noted disclosure rules for medical journals have become more stringent in recent years.
Asked to describe the benefit of BMP-2, he said it provides excellent benefit to patients, adding he had it implanted in his own neck in an off-label procedure. "I have BMP in me, and I would put it in you."
From January through September 2010, Haid and Spinal Engineering LLC received about $2 million in royalties. During the same time period, co-author Ken Burkus, MD, a Columbus, Ga., surgeon and RBCK Research & Consulting, received $573,000.
"Very importantly, you cannot assume that such royalty payments were made prior to 2010," he said in an e-mail, declining to say whether he got royalties at the time the paper was written. "I follow the rules to my fullest ability as put forward by the specific journal."
He took issue with criticism that the paper put a positive spin on a troubling clinical trial.
"I believe the words used were appropriate . . . ," Burkus said. "I believe the words used were neither 'positive nor negative' but rather were representative of the data presented."
Tell the Editor
He said if other doctors have problems with the paper, they should take it up with the editor of the journal: "They can write a letter to the editor."
Co-author Charles Branch Jr., MD, chairman of neurosurgery at Wake Forest University, and the university itself have received $1.2 million in Medtronic royalties this year.
A spokeswoman for the university said it owns the intellectual property rights to Branch's patents and that royalties generally are split with 35% to the individual and 65% to the university. None of those royalties involved BMP-2, university media relations manager Bonnie Davis said in an e-mail.
She said Branch and Wake Forest were getting royalties at the time the paper was published, but not when the trial was going on.
In a separate e-mail, Branch said use of the term "encouraging" in the paper "was not a strong endorsement," but, rather, recognition that patients getting BMP-2 had superior results to those receiving a traditional bone graft.
The Pivotal Trial
The clinical trial that ultimately led to FDA approval of BMP-2 focused on spinal fusion using an anterior approach.
Burkus, was an author of both the 2002 paper on the pivotal clinical trial and the 2004 paper on off-label use. When asked about the 2002 paper, he again declined to say if he was receiving royalties from Medtronic or if he had some other financial connection with the company at the time the 2002 paper was published. He got $573,000 through September.
Curtis Dickman, MD, a Phoenix surgeon, a co-author of the 2002 paper, did not respond to phone calls and e-mails. He and Vantage Investments LLC received $306,000 in royalties.
The third author of the 2002 paper, Matthew Gornet, MD, a St. Louis surgeon, and Gornet Enterprises got $591,000 in royalty payments
Gornet said he did not have a financial connection with the company at the time of the study, though he developed a relationship as a consultant right after the trial, an arrangement that ended after about a year.
He said his patent rights with Medtronic did not begin until 2003 and none of his royalties involved BMP-2.
The last author listed on the 2002 was Thomas Zdeblick, MD, an orthopedic surgeon at the University of Wisconsin School of Medicine and Public Health. Through September, he and Taz Consulting received $1.4 million in royalties for a variety of products.
Other records show Zdeblick has received more than $23 million in royalties from Medtronic since 2002.
In an e-mail, Zdeblick said he had no financial interest in BMP-2. He does receive royalties for the invention of the LT-Cage, which was used in the BMP-2 clinical trial, but the two products are sold separately.
Another surgeon, Thomas Kleeman, MD, of New Hampshire, was not an author the 2002 paper, but co-authored a 2009 paper on the BMP-2 clinical trial and also is listed as an author on an abstract on the clinical at the 2007 North American Spine Society meeting.
Kleeman, who did not return phone calls, received $56,000 in royalties this year.