Medtronic Infuse on the Hot Seat a Case of Research Malfeasance or Legal Maneuvering?
Late last month, I recieved several "breaking news" alerts the U.S. Senate Finance Committee had begun an investigation regarding whether doctors with financial ties to medical device maker Medtronic were aware of serious problems with a widely promoted spinal fusion product, known as Infuse, but never disclosed potential health complications in articles in medical journals.
Infuse, which the Food and Drug Administration (FDA) approved in 2002, contains a genetically engineered version of a naturally occurring protein that can stimulate bone growth. It is an alternative to procedures like autologous grafting, where bone is taken from elsewhere in the patient's body. Those procedures can cause lasting pain. Since its approval, Infuse has been implanted in more than 500,000 patients by more than 2,300 surgeons, and has Earned Medtronic millions of dollars in annual sales.
However, three years ago, concerns about unapproved use prompted the U.S. Department of Justice to issue a subpoena. In addition, the Finance Committee and the Senate Special Committee on Aging submitted their own inquiries into Medtronic. Since then, a series of reports in the Milwaukee Journal-Sentinel revealed ties between Medtronic and doctors who allegedly failed to disclose Infuse problems.
In July 2008, the FDA issued a warning letter about off-label use of the protein in InFuse. The agency said there had been reports of life-threatening complications associated the protein. “The reason why doctors saw fit to use the product off-label was because of heavy promotion activity from the company," said Salvatore Graziano, who was lead counsel in a shareholder lawsuit filed in 2008. "The FDA actually approved InFuse for a very, very narrow application because of concerns for serious side effects.”
Article in Spine Journal
The main analysis, which was led by editors of the Spine Journal, found a systematic failure to report serious complications with Infuse, bone morphogenetic protein-2 or BMP-2, which is used in spinal fusion surgery. The researchers found complication rates that were 10 to 50 times greater than the estimated complication rates revealed in the medical literature.
The 13 papers criticized by the Spine Journal were co-authored by doctors who received a median of at least $12 million to $16 million per study from Medtronic, the journal reported. The article in Spine Journal asserted that in each of the 13 studies, “conflicts of interest were either not reported or were unclear.” Six of the 13 papers were published in Spine, a publication that has no relation to The Spine Journal, while 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. For a summary of the articles click here.
An article from Medpage Today recognized that Infuse represents an “unprecedented event in medicine: the entire issue of a medical journal devoted to a scientific and financial expose of a product, the practices of the company that markets it, and the financially conflicted doctors who tested and promoted it.”
Jeffrey Fischgrund, MD, editor-in-chief of the Journal of the American Academy of Orthopaedic Surgeons and a spine surgeon at William Beaumont Hospital in Royal Oak, Michigan, said he had never seen “a whole journal devoted to a product.” Marcia Angell, MD, the former editor of the New England Journal of Medicine also said she had “never seen a journal publish an issue devoted to debunking a popular treatment, and, by implication, the authors of the studies that promote the treatment."
The studies co-authored by the Medtronic-associated doctors indicated there were no complications related to Infuse when it was known that the product was linked to several serious problems, ranging from excess cancers and serious inflammatory reactions to fertility problems caused by retrograde ejaculation and radiating leg pain.
In an interview with the Journal Sentinel/MedPage Today, Medtronic officials said they now are looking into the issue of whether published articles failed to properly report various complications linked to Infuse. Richard Kuntz, Medtronic's senior vice president and chief scientific, clinical and regulatory officer said the company will do a “full analysis of these papers.”
Kuntz and Christopher O'Connell, an executive vice president who oversees the Medtronic division that includes Infuse, also said they will provide a full accounting of royalties and other payments to doctors who authored Infuse papers.
In a prepared statement, Medtronic chairman and CEO Omar Ishrak said he strongly believes in the safety of Infuse as it is described in data submitted to the FDA and is summarized on the product's label.
"Integrity and patient safety are my highest priorities," Ishrak added. "While the Spine Journal articles raise questions about researchers' conclusions in their peer-reviewed literature, the articles do not raise questions about the data Medtronic submitted to the FDA in the approval process in 2002 or the information available to the physicians today through the instructions for use brochure attached to each product sold."
Senate Finance Letter
In a letter written by Finance Chairman Senator Max Baucus (D-MT) and Senator Charles Grassley (R-IA), the Senators expressed their concern with “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.” They added that, this “issue is compounded by the fact that some clinical investigators have substantial financial ties to Medtronic.”
The letter cites reports that have linked Infuse to potentially fatal swelling in the neck and throat, and radiating leg pain, as well as a potential link to cancer. For instance, an article from the Journal Sentinel noted that, “a Medtronic-funded study published in 2004 found that 75 percent of Infuse patients experienced ectopic bone growth, where potentially harmful bone growth occurs outside of the fusion area. The authors, who had financial ties to Medtronic, ‘concluded that, although not desirable,’ the ectopic bone growth ‘did not appear to have an ill effect on the patients.’
The Journal-Sentinel writes that names of Infuse investigators and their financial disclosures “have remained redacted in FDA files since before 2002 when Infuse was approved by the agency.” Last year, the paper filed a Freedom of Information Act request, but the agency never released the info.
Consequently, based on these concerns, Senators Baucus and Grassley asked Medtronic to provide the Finance Committee with the following information and documents by July 11, 2011:
- All documents and communications (with 1) medical journals; 2) clinical investigators 3) FDA and 4) physician consultants) pertaining to adverse postoperative events and/or medical complications relating to the use of recombinant human bone morphogenetic protein 2 (rhBMP-2) treatments
- A detailed account of payments that Medtronic made to all Infuse clinical investigators, including payments to corporate entities in which Medtronic-sponsored Infuse clinical investigators are principals
- For each individual and organization identified above, the following information for each payment in table format:
- Date of payment
- Payment description (CME, royalty, honorarium, research support, etc.)
- Amount of payment
- Year end or year-to-date payment total
In an email response, Medtronic spokesperson Marybeth Thorsgaard said that before the clinical trial started, patients were told that ectopic bone was a possible complication. "It was listed as an anticipated adverse event in the trial design and patients were made aware in their signed consent forms," she said in an email. "The article makes the point that there were no adverse events in the trial that we did NOT recognize as a potential risk."
A Medtronic spokesperson explained to the Sentinel in a written statement that three complications mentioned in the Senate letter are listed as warnings on product labeling - retrograde ejaculation, which causes sterility in men; ectopic bone formation; and cervical complications such as swelling in the neck or throat.
She added that Medtronic acknowledged complications to the FDA before approval, “irrespective of any financial relationship between the company and the clinical investigator or study author.” She also wrote that cancer rates were not statistically different between patients who received Infuse and those who did not in 44 clinical trials.
She also said there was an early report about the ectopic bone that was presented at a spine-related medical meeting in October 2001 and that when Infuse came on the market in 2002, product labeling warned of potential ectopic bone, especially if it was used in manner similar to the halted clinical trail described in the 2004 paper. She added that, financial ties between the authors of the paper and Medtronic were mentioned in the paper.
The same Sentinel article however, noted that a separate 2008 study conducted by physicians without ties to Medtronic found ‘neurological impairment occurred’ in five patients who had the same ectopic bone formation.
Thomas Zdeblick, an orthopedic surgeon at the University of Wisconsin School of Medicine and Public Health, authored two of the Infuse papers published in the Journal of Spinal Disorders & Techniques, where Zdeblick has been editor-in-chief since 2002. According to Medpage, “neither of those papers linked Infuse to a complication that causes sterility in men, though that information was known to the authors.”
Although Zdeblick has received more than $23 million in royalties from Medtronic since 2002, None of Zdeblick's royalties are for Infuse, though he has received royalties for a product that is used with Infuse. Zdeblick told the New York Times that he did not have a “direct financial interest in the success of Infuse or Medtronic.” Zdeblick invented an LT Cage: two racetrack-shaped pieces of titanium that revolutionized spine surgery by reducing recovery time.
Zdeblick asserted that, “No one who uses any of my products at this hospital makes any money for me. I’ve done a really good job, I think, of firewalling what I do as an inventor and what I do as an academician and what I do as a surgeon.”
Another report describing a study in which men treated with Infuse developed a condition that causes ‘temporary or permanent sterility at a far higher rate than men who received a bone graft.’ However, the link was not reported in the original Medtronic-funded study. The report was created by independent researchers at Stanford University who found 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, lead author of that study and editor-in-chief of the Spine Journal, says his publication has received many complaints for more than a year, suggesting serious concerns about published Infuse studies. Carragee is chief of spine surgery at Stanford. He also raised concerns about the trial design used by Medtronic for the FDA studies, which he claimed were based on fundamental design flaws, biased in favor of the company’s products.
Zdeblick asserted that, “the complications, other than sterility, were in what’s called off-label use of Infuse, different operations than he used it in.” Zdeblick said he only co-authored one study on Infuse, the one that led to its FDA approval for use inside his LT cage. Five out of every 500 men became sterile because of Infuse, just 1 percent, so there was no reason to include the information in his report because it wasn’t statistically significant, according to Zdeblick. Although he said he did send the information to the FDA. “I know that’s hard for people to understand, but in science, if something’s not statistically different, it’s the same,” Zdeblick said.
“As a crusader, I think (Carragee’s) on that path to get people to go back in time to less expensive days. I don’t want to go back there. I’d rather do what we do now because the results we get from spine surgery now are better than they’ve ever been,” said Zdeblick. One of the study’s co-author, a Chicago spine surgeon, said he knows Dr. Zdeblick and feels the UW surgeon has made full disclosure, but other doctors studying infuse have not. Zdeblick said that he hasn't made any money off infuse or any surgeries at UW, only his inventions.
This latest incident involving potential unreported financial conflicts of interest, while concerning, should remain focused on the facts of this case and this case alone. Generalizing and stereotyping the medical device or pharmaceutical industry based on the actions of one product, researcher or company is inappropriate and will only further cause unnecessary confusion for patients and physicians. While it is certainly important that patients get the right treatment and are properly informed about the risks of any given treatment, this concern must be carefully balanced against the need for medical innovation to progress and find new cures and treatments.
While a Journal-Sentinel analysis found that Medtronic last year 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 infuse was linked to male sterility which the original researchers note was not statically significant, none of the royalty payments the original researchers received in the Journal Sentinel was for work on Infuse.
Since all the “data” was submitted to the FDA, one would think that their analysis would show a serious problem with the product if there was one. Several articles mention pending lawsuits, it would not be out of the realm of possibility that all this press and related noise on this issue at this time is an attempt to force some sort of legal settlement.
It will be interesting to get both sides of this story as it unwinds and not rush to judgment as media has done, in this case with tremendous zeal.