A U.S. Senate committee has launched an investigation into reports that doctors with financial ties to the medical device company Medtronic were aware of potentially serious complications with a spine surgery product made by the company yet failed to reveal those problems in published journal articles.
Citing news articles based on a Milwaukee Journal Sentinel/MedPage Today investigation, two powerful members of the Senate Finance Committee contacted Medtronic Tuesday demanding an extensive list of documents, including financial records and communications between the company and doctors who have received millions in royalties and other payments from Medtronic over the last decade.
Medtronic was warned not to destroy or make inaccessible any of the documents, data, or other related information in the letter signed by committee chairman Max Baucus (D-Mont.) and senior member Chuck Grassley (R-Iowa).
The Gathering Storm
The growing controversy involves Medtronic's spine surgery product Infuse, which was approved by the Food and Drug Administration in 2002.
Over the last year, an ongoing series of Journal Sentinel/MedPage Today investigations has raised questions about annual payments made to a core of prominent surgeons around the country who were involved either in the clinical testing of Infuse or co-authoring positive medical journal articles that failed to link the product to serious complications.
"We are extremely troubled by press reports suggesting that doctors conducting clinical trials examining the safety and effectiveness of Infuse on behalf of Medtronic were aware that Infuse, a treatment commonly used in spinal surgery, may cause medical complications, but failed to report this in the medical literature," Baucus and Grassley wrote. "This issue is compounded by the fact that some clinical investigators have substantial financial ties to Medtronic."
The letter was addressed to Omar Ishrak, who took over this month as chairman and chief executive of Minneapolis-based Medtronic.
Infuse, also known as bone morphogenetic protein-2, is a powerful biological agent used in spinal fusion surgery. The product stimulates bone growth and eliminates the need to harvest a small amount of a patient's own bone to create a fusion between two vertebrae. As a result, it is highly popular with spine surgeons.
Medtronic says Infuse has been implanted into more than 500,000 patients and it is used by more than 2,300 surgeons. Its sales amount to several hundred million dollars a year.
However, the product has been dogged by reports of financial conflicts of interest by researchers; serious -- unreported -- complications; and extensive off-label use. Moreover, evidence has accumulated suggesting that the superior clinical results reported by doctors with financial ties to Medtronic have not been replicated when the device was used by doctors who receive no payments from Medtronic.
Medtronic also has been under investigation by the U.S. Department of Justice on allegations of off-label marketing of Infuse. About 85% of Infuse use is off-label.
Sohail Mirza, MD, a professor of orthopedics at Dartmouth Medical School, said he was pleased that the Finance Committee was investigating the matter.
But, he added, "This is a sad failure of our profession. It's the Finance Committee doing public health work. Surgeons themselves or the FDA could have done the committee's work earlier. Our patients would have been better served if surgeons, our professional associations, and our scientific publications had established a culture or policies that prevented this circumstance."
In an emailed statement, Medtronic spokesperson Marybeth Thorsgaard said the company will respond to the senators' request.
She noted that three of the complications mentioned in the letter are listed as warnings on the FDA labeling for the product. Those complications involve retrograde ejaculation, which causes sterility in men; ectopic bone formation; and cervical complications such as swelling in the neck or throat.
She also said that Medtronic provided adverse event data to the FDA prior to its approval of Infuse "irrespective of any financial relationship between the company and the clinical investigator or study author."
As to concerns about Infuse and cancer, she said that in 44 clinical trials observed cancer rates were not statistically different between patients who received Infuse and those who did not.
"These reports that doctors conducting medical trials while on Medtronic's payroll may have hidden serious side effects for patients are deeply troubling," said Senate Finance Committee Chairman Baucus. "Information is one of the most important tools patients and doctors have when making medical decisions. Patients have a right to know the risks associated with their treatments and medical device companies have a duty to disclose this information. We need to do everything we can to ensure companies aren't concealing serious medical complications from patients just to increase profits."
Patients must rely on their doctor's knowledge of the risks and benefits of a medical device, Grassley added.
"If the medical literature has been written by those with financial ties to the device maker, the doctor and his patient should know that," he said. "A lack of transparency leaves doctors and patients in the dark on something any of us would want to know before surgery."
Other Voices Heard
Prompted in part by Journal Sentinel/MedPage Today stories, independent researchers at Stanford University last month found strong evidence that Infuse was linked to a complication that causes sterility in men, a connection that was not revealed in the medical literature. Their paper was published in the Spine Journal.
Eugene Carragee, MD, the lead author of that study and editor-in-chief of the Spine Journal, said his publication has received dozens of complaints over more than a year, suggesting serious concerns about Infuse studies published in various journals, including the Spine Journal.
Carragee, who is chief of spine surgery at Stanford, took over as editor of the Spine Journal in 2008.
"There has been a corrosive suspicion surrounding researchers' financial ties to Medtronic, possible company influence on data presentation and the basic safety reporting by some industry-sponsored surgeons," he said in an email to the Journal Sentinel/MedPage Today. "For the sake of our patients, I hope the Senate's investigation will lay the matter to rest so doctors, patients, and their families can find out whether they can have confidence in those Medtronic studies, as reported, or not."
Next week, independent researchers are expected to publish more papers revealing additional serious complications with Infuse -- complications that have not previously been reported in studies co-authored by doctors with financial ties to Medtronic. Those independent researchers said their research was also prompted in part by Journal Sentinel/MedPage Today stories.
The Baucus/Grassley letter noted that last year the Journal Sentinel (and MedPage Today ) reported on a Medtronic-funded study published in 2004 that found that 75% of patients who got Infuse developed ectopic bone, outside the targeted fusion area. The authors, several of whom had financial ties to Medtronic, concluded that "although not desirable" the bone formation in the spinal canal did not appear to have an ill effect on patients.
The paper was published in the Spine Journal. In a Journal Sentinel/MedPage Today story last year, doctors described the paper as an egregious article that was more of a marketing paper than a scientific article.
Last year alone, three of the paper's four authors got about $4 million in various royalty payments from Medtronic, the Journal Sentinel/MedPage Today reported.
However, a separate 2008 study by doctors without financial ties to Medtronic found neurological impairment from ectopic bone in five patients who got Infuse.
Mirza, of Dartmouth Medical School, credited the ongoing reporting of the Journal Sentinel/MedPage Today as a catalyst for the Senate Finance Committee action.
"It is a credit to the high-quality and public relevance of your reports," he said in an email.
The Baucus/Grassley letter also noted the male sterility complication.
Last month, the Journal Sentinel/MedPage Today reported that since 2002, Medtronic and a group of doctors with financial ties to the company were aware that Infuse was linked to sterility in men.
But that crucial information was not revealed in medical journal articles written by those doctors, including surgeons who would receive millions of dollars in various royalties from Medtronic.
A Journal Sentinel/MedPage Today analysis found that last year alone Medtronic paid more than $6 million in royalties to a handful of doctors who over the last nine years co-authored several Infuse papers without cautioning that it was linked to male sterility. None of the royalty payments was for Infuse.
One of the authors, Thomas A. Zdeblick, MD, is a University of Wisconsin School of Medicine and Public Health orthopedic surgeon. Zdeblick and Taz Consulting have received more than $23 million in royalty and other payments from Medtronic since 2002. Zdeblick also is the editor of the Journal of Spinal Disorders & Techniques, the medical journal that published two of the Infuse papers.
Zdeblick did not respond to a request for comment.
Casting a Wide Net
"We are also concerned that other severe side effects of Infuse and similar bone-growth products developed by Medtronic may have been unreported or under-reported in clinical literature," Baucus and Grassley wrote. "Reports have linked Infuse to potentially fatal swelling in the neck and throat and radiating leg pain."
The letter also cites a Journal Sentinel report from last August linking Infuse to cancer.
Last year, a Journal Sentinel/MedPage Today investigation also found that doctors with financial ties to Medtronic produced substantially better results with Infuse in the clinical trial leading to the FDA's approval of the product than doctors who did not have financial ties to the company.
In reports this year and last year, the Journal Sentinel/MedPage Today documented growing concerns about how Medtronic associated surgeons authored research that has been criticized as little more than marketing.
The Baucus/Grassley letter requested a variety of records, including a detailed account of payments made by Medtronic to all of the Infuse clinical investigators.
The names of the Infuse investigators and their financial disclosures have remained redacted in FDA files since before 2002 when Infuse was approved by the agency. In May 2010, the Journal Sentinel filed a Freedom of Information Act request for the information. While the agency acknowledged that information should be public, it has failed to release it.
Grassley and Baucus also requested documents and communications pertaining to adverse events and medical complications, including those involving medical journals, Infuse clinical investigators, the FDA, and Medtronic