Medtronic Shaped Positive Studies on Its Bone Graft Product The company helped write positive studies on its bone graft product.

Oct. 25, 2012 -- Highly positive studies published in peer-reviewed medical journals depicted Medtronic's spine fusion product as a major breakthrough in back surgery, but those studies drafted and edited with direct input from company employees, while the doctors listed as authors were paid millions, according to a U.S. Senate investigation.

The company's heavy, undisclosed manipulation of information about its bone morphogenetic protein-2 product called Infuse included removing and downplaying concerns about serious complications linked to the product and overstating its benefits.

Read this story on www.medpagetoday.com.

The Money Trail

Over the course of 15 years, Medtronic paid $210 million to a group of 13 doctors who co-authored the series of now-repudiated papers about the product. The payments also included two corporate entities associated with some of the doctors.

The investigation by Senate Committee on Finance was prompted in part by Journal Sentinel/MedPage Today investigations that showed how the practice of medicine has been corrupted by conflicts of interest involving doctors, drug and device companies and medical journals.

The Senate report, to be released Thursday, details how Medtronic employees, including some working in the company's marketing department, covertly collaborated with the academic physician authors in producing 11 different papers between 2002 and 2009.

Such "ghostwriting," though not illegal, has been condemned as a breach of integrity and transparency because doctors and patients rely on information in those articles to make medical decisions, not knowing that the papers may contain biased, inaccurate or potentially harmful information.

The Senate's findings highlight problems that should have been reported as at least a decade ago, said Dr. Ray Baker, a Kirkland, Wash., pain specialist who served on an advisory panel to Medicare and Medicaid on Infuse.

"I am just sad this happened," he said. "At every level when we thought, 'that wouldn't happen,' it happened. The integrity of our scientific literature is our foundation. It's what predicates our treatments."

Medtronic Denies

Medtronic disputed many of the findings in the Senate's report.

"Medtronic vigorously disagrees with any suggestion that the company improperly influenced or authored any of the peer-reviewed published manuscripts discussed in the report, or that Medtronic intended to under-report adverse events," a statement emailed by the company said.

The company said it reported the adverse events to the Food and Drug Administration and those risks also are listed the product label for Infuse. Medtronic also called the report's characterization of the payments to the doctors misleading and unfair.

"The vast majority of such payments were royalty payments made to compensate physicians for their intellectual property rights and contributions, not consulting payments," the company said.

In 2011, after the Spine Journal devoted an entire issue to repudiating Infuse research, the company, under its new CEO, Omar Ishrak, hired Yale University to oversee an independent review of the safety and effectiveness of Infuse.

"This sounds eerily familiar to many of the transgressions we've read about from the pharmaceutical industry," said Dr. Harlan Krumholz, a professor of medicine at Yale University, when told of the Senate report. "It paints a picture of a company very heavily involved in the science; marketing contaminating the science; and the medical profession and researchers being complicit.

The Public Trust

"It's no wonder the public has lost confidence in the drug and device industries."

Krumholz is overseeing Yale's review of Infuse. Those results are expected in January.

Medtronic's behavior also drew sharp criticism from two key senators on the committee.

"Medtronic's actions violate the trust patients have in their medical care," Sen. Max Baucus, (D-Mont.), chairman of the committee, said in a statement. "Patients everywhere will be better served by a more open, honest system without this kind of collusion."

Senior member Chuck Grassley (R-Iowa) said the findings support the Physician Payments Sunshine Act that he and Sen. Herb Kohl (D-Wis.) authored. That legislation will require drug and device companies to disclose such payments beginning next year.

"The findings also should prompt medical journals to take a very proactive approach...," Grassley said in a statement. "...The public will benefit from more transparency and accountability on their part."

In response to the Senate investigation, Medtronic turned over more than 5,000 documents, including emails involving the doctors and Medtronic employees as well as 14 years of payments from Medtronic to the doctors.

The Infuse Story

In January 2002, Dr. Hal Mathews spoke glowingly about Infuse to a FDA advisory panel that was considering whether to recommend approval of the product.

Mathews, then a Richmond, Va. spine surgeon who had taken part in the pivotal Infuse clinical trial, told the panel he had no direct financial interest in the product and that he was not being paid to appear at the meeting.

However, a 2001 email shows that Medtronic worked with the New York-based public relations firm, Ketchum, to prepare Mathews' speech to the panel, which went on to recommend approval of the product.

In addition, though Medtronic told the committee that Mathews was not paid for any activity undertaken in January 2002, Mathews was paid under consulting arrangements with the company in 2001.

In 2007, Mathews was hired by Medtronic as its vice president of medical and clinical affairs.

From the Pen of Medtronic

An email indicated that a Medtronic marketing employee, Julie Bearcroft, was involved in editing a 2005 Journal of Bone and Joint Surgery article and recommended against publishing a complete list complications related to the structural integrity of the fused area.

Those complications -- known as implant migration, subsidence and end-plate fracture -- had been observed in a clinical trial and had been formatted in a detailed table, according to an internal Medtronic email. But, following the advice of Bearcroft, that table was not included in the published paper.

"I personally think it is appropriate to simply report the adverse events were equivalent in the two groups without the detail," Bearcroft wrote in a note on a draft of the article.

After the editing change was made, the lead author of the paper, Dr. Ken Burkus, a Columbus, Ga. surgeon, sent a draft of the paper to his co-authors with the note, "this manuscript documents the superiority in clinical and radiographic outcomes with (Infuse)..."

Burkus, who got $6.4 million from Medtronic between 1998 through 2010, did not respond to an email seeking his comment.

Medtronic officials inserted into papers language that attempted to portray Infuse as a better, less painful alternative to the standard technique of using a small amount of a patient's own hip bone for fusing vertebrae, a claim that has been questioned by independent spine surgeons.

Giving Infuse the Edge

In 2001 and 2002, after viewing early drafts of a 2002 Infuse paper, Neil Beals, a Medtronic marketing official recommended that the physician authors make "a bigger deal" out of the supposed pain reduction with Infuse.

Subsequently, a sentence was inserted in the paper stating that Infuse spared patients from being exposed to problems associated using their own bone for the fusion.

In its review of Infuse last year, doctors writing in the Spine Journal said the often-cited donor site pain was less frequent and serious than Infuse proponents suggested.

In addition, in a draft of a 2003 paper the authors said that any pain at the site of the hipbone graft site had been resolved in the study subjects within a year of the surgery. But Beals questioned that and inserted language saying residual effects of the donor site should be noted.

The final article appears to have adopted his suggestions, noting that even 24 months after the surgeries "some patients continued to experience residual pain at the donor site and rated the appearance of the site as only fair."

Downplaying Safety Concerns

The company also tried, unsuccessfully, to adopt weaker patient safety rules for a clinical trial testing the effectiveness of Infuse in the cervical spine, a use that remains unapproved and which has been linked to life threatening swelling in neck.

In 2008, the FDA warned doctors against using Infuse in cervical spine fusions, citing 38 cases of swelling in the neck and throat leading to compression of the airway. Some of those cases required emergency tracheotomies.

The weaker safety rules sought by Medtronic would have allowed the company to continue the clinical trial even if patients experienced severe swelling in neck.

Infuse is a powerful biological agent that stimulates the growth of new bone, but excess bone growth can be a serious problem when the product is used in certain off-label surgeries. It was approved in 2002 for lumbar spine fusions in which the surgical approach is from the front.

The unapproved use has caused serious problems for Patricia Caplinger and hundreds of other spine surgery patients like her, according to a lawsuit filed earlier this year against Medtronic in federal court in Oklahoma.

The complication experienced by Caplinger was the subject of a 2004 paper written by doctors who have received millions of dollars from Medtronic. That paper involved a clinical trial of Infuse that had to be halted five years earlier because of excess bone growth in the spinal canals of 70 percent of the patients.

That clinical trial used Infuse in a surgery similar to what Caplinger underwent in 2010.

The surgeons who wrote the article said that patients weren't harmed by the excess bone growth. But that claim that was refuted by an Oklahoma surgeon who took part in the trial and told the Journal Sentinel/MedPage Today last year that he had two patients who developed painful, excess bone growth that required additional surgeries. Caplinger who lives in Missouri was not one of those patients.

A Helping Hand in the OR

Caplinger says that her doctor and others surgeons were persuaded by Medtronic and its "paid physician promoters" to use Infuse in dangerous, off-label surgeries, according to her lawsuit.

In Caplinger's case, a Medtronic representative actually was present during her surgery and "was actively involved," providing information about use of Infuse in Caplinger's procedure, according to the lawsuit.

Because of the excess bone growth, Caplinger suffers continuous pain in her back and legs and developed a condition known as foot drop, which, in turn, led to a ligament tear in her right knee. She also has required revision surgery on her back and will need another revision surgery because the bone growth is continuing.

In an email, Caplinger, a nurse, said she is worried that the pain eventually will prevent her from doing what she loves the most, working in the emergency department.

"I live with pain every minute of every day," she said. "I have forgotten what not being in pain feels like."

A Medtronic spokesperson said the complaint lacks and the company has the court to dismiss the case.

Medtronic Had Answers

The Senate report and accompanying documents also show Medtronic employees -- in addition to editing drafts of a paper -- at times covertly drafted responses to questions raised by other doctors who were examining the work as part of medical journal peer review.

Case in point: A 2004 paper was published in the Spine Journal where co-author Dr. Charles Branch Jr. also served as deputy editor. Branch, chairman of neurosurgery at Wake Forest University, received $3.1 million from Medtronic from 1998 to 2010. His royalty payments have been split with the university.

That article also was subject of a 2011 Journal Sentinel/MedPage Today investigation.

The Senate documents include a 2003 email, as the article was being drafted, in which Bill Martin, the company's vice president of spinal marketing, wrote: "We may want to steer clear of calling it a flawed technique. There are still quite a few surgeons utilizing this technique..."

About a week later, Rick Treharne, another Medtronic executive, wrote to one of the paper's authors: "In looking over the data, I was impressed with how well the BMP (Infuse) patients actually did. So much so that I added a few paragraphs at the end that you may not agree with."

As peer reviewers for the journal looked over the paper, they raised concerns that it was a slanted, advertising piece.

"This manuscript is full of biased statements that are a reflection of the data evaluators -- the company that markets the product," wrote one reviewer.

"Unless the authors can discuss the results in this study in an unbiased manner, which they have been unable to do in its present form, this data should not be published," wrote another.

Treharne then sent one of the co-authors a draft of a letter to be sent to the editor of the journal addressing the concern. Another Medtronic executive also helped formulate a response to the editor.

The letter that ultimately was sent to the journal's editor sought to reassure him, claiming that three of the co-authors were independent, the Senate investigation found.

But between 1997 and 2003, two of the "independent" authors had received $8.5 million from Medtronic.

"We were falsely reassured that there were independent people looking at the data," said Dr. Eugene Carragee, who took over as editor of the Spine Journal in 2009. "It's a violation of the fundamental trust of peer review."

When published, the paper described the results of halted clinical trial as "encouraging."