Medtronic's FDA Data on Infuse Contradict Published Studies

Ken Terry

June 28, 2011

June 28, 2011 — Several harmful side effects of using Medtronic's Infuse Bone Graft in spinal fusion surgery went unreported in the published articles supporting the safety and efficacy of that product, according to a new review article in The Spine Journal.

Clinical trial data submitted to the US Food and Drug Administration (FDA) make it clear that the product, recombinant bone morphogenetic protein 2 (rhBMP-2), was associated with a significant number of adverse events, The Spine Journal review points out. Yet none of the 13 industry-sponsored studies reflect these results.

"The Medtronic-sponsored studies failed to report even 1 single adverse event of any type," Eugene Carragee, MD, editor-in-chief of The Spine Journal and the lead author of the new study, tells Medscape Medical News. "And the FDA data are completely different. The FDA data show there was increased radiculitis, an increased number of leg pain events, increased infection rates, and an increased chance of sterility. It's astounding. But it was completely under the radar initially."

Dr. Carragee, who is also chief of the Spine Surgery Division at Stanford University Medical School in California, is especially concerned about the incidence of retrograde ejaculation, which causes sterility. A separate retrospective controlled trial done by Dr. Carragee and colleagues and reported just last month showed that the incidence of retrograde ejaculation was much higher in patients who received rhBMP-2 in fusion surgery than in those who didn't.

Similarly, he says, the full Medtronic study data submitted to the FDA show that 11 patients in the study group had retrograde ejaculation, compared with just 1 in the control group. In the randomized trial section, 5 had complication in the BMP-2 group vs 1 in the control. Extrapolating to all patients who have been treated with rhBMP-2, he said, "it's possible that hundreds of men may have been sterilized due to the use of this product."

Off-Label Use

The FDA-approved product, Infuse/LT-Cage, comprising rhBMP-2 combined with a threaded bone cage, is used to promote the growth of bone tissue in the healing process after surgery. The FDA approved Infuse in 2002 for use in anterior lumbar fusion surgery on skeletally mature patients, excluding pregnant women, but it has been applied widely off-label. In 2008, after receiving reports of serious complications, the FDA warned that the off-label use of Infuse in cervical fusion procedures was unsafe.

Nevertheless, it continued to be used in lumbar and cervical operations. Partly because bone tissue no longer had to be harvested from patients for this purpose, the number of complex fusion procedures in Medicare patients increased 15-fold from 2002 to 2007, according to a study released last year in the Journal of the American Medical Association. Today, Infuse generates about $900 million in annual revenues for Medtronic.

More recently, another product using rhBMP-2 but a different matrix device (Amplify) went before the FDA's Orthopedic and Rehabilitation Devices Panel in July 2010. The panel gave a reserved endorsement for approval for spinal fusion in degenerative disk disease, provided follow-up be performed to monitor particularly for cancer risk. In March this year, however, FDA declined approval, citing this latter risk.

In their new review, based on the FDA data and more recent studies that also include data on the Amplify device, Dr. Carragee and his colleagues point out that no adverse events related to rhBMP-2 use were reported in any of the studies; the overall rate was 0%, with a 99% confidence interval of less than 0.5%.

However, comparing the FDA documents and subsequent publications, they write, "we suggest an estimate of adverse events associated with rhBMP-2 use in spine fusion ranging from 10% to 50% depending on the approach. Anterior cervical fusion with rhBMP-2 has an estimated 40% greater risk of adverse events with rhBMP-2 in the early postoperative period, including life-threatening events."

Use of rhBMP-2 in anterior interbody lumbar fusion was associated with higher implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation than among controls; in posterior interbody lumbar fusion procedures, the rhBMP-2 groups had radiculitis, ectopic bone formation, osteolysis, and poorer global outcomes than controls.

"In posterolateral fusions, the risk of adverse effects associated with rhBMP-2 use was equivalent to or greater than that of iliac crest bone graft harvesting, and 15% to 20% of subjects reported early back pain and leg pain adverse events; higher doses of rhBMP-2 were also associated with a greater apparent risk of new malignancy," the study authors note.

"Level I and Level II evidence from original FDA summaries, original published data, and subsequent studies suggest possible study design bias in the original trials, as well as a clear increased risk of complications and adverse events to patients receiving rhBMP-2 in spinal fusion," they conclude.

In an editorial accompanying the review of trials, Dr. Carragee and colleagues, including Alexander J. Ghanayem, MD, of Loyola University Medical Center, Maywood, Illinois, Bradley K. Weiner, MD, of The Methodist Hospital, Houston, Texas, David J. Rothman, PhD, of Columbia University College of Physicians and Surgeons, New York, and Christopher M. Bono, MD, of Brigham & Women's Hospital, Boston, Massachusetts, review the current spine care research climate and clinical trial history of rhBMP-2.

"The core of our professional faith...is to first do not harm," they write. "It harms patients to have biased and corrupted research published. It harms patients to have unaccountable special interests permeate medical research. It harms patients when poor publication practices become business as usual," they write. "Yet harm has been done. And that fact creates a basic moral obligation."

"The history of rhBMP-2 research is a cautionary tale for all medical professionals, researchers, and patients," Dr. Bono, editorial coauthor and acting editor in chief of this issue of The Spine Journal, said in a statement. "As this matter demonstrates, the spine care field is currently at a precarious intersection of professionalism, morality, and public safety. As physicians and journal editors, we felt an obligation to present a thorough examination of this controversial issue."

Conflict of interest?

Compounding the problem, the Wall Street Journal reports that 2 authors of studies purportedly demonstrating the safety of rhBMP-2 received millions of dollars from Medtronic; the paper reports that the company paid Dr. Thomas Zdeblick, an orthopedic surgeon at the University of Wisconsin School of Medicine and Public Health, Madison, $19 million from 2003 to 2007 and Dr. Kenneth Burkus, another orthopedist, more than $1.5 million between June 2001 and June 2006.

Both physicians have denied that the money they received from Medtronic was related to their work on Infuse or influenced their research on the drug, the Journal reports. The company states, "Medtronic provides PMA clinical study adverse event data to the FDA irrespective of any financial relationship between the company and the clinical investigator or study author."

Nevertheless, Dr. Carragee notes, the internal documents obtained by the Journal indicate that Dr. Burkus received Medtronic payments during the period when he was researching rhBMP-2. Dr. Carragee said he does not recall seeing any reference to Dr. Burkus' involvement with Medtronic in the published studies on the product.

Moreover, he says, Dr. Burkus stated on several occasions that Infuse had produced no adverse side effects, although the FDA data supplied by his research team contradict that position. "I don't think that's an accurate reflection of the problem," Dr. Carragee says.

The controversy has now generated ripples wide enough that the Senate Finance Committee is getting involved. Committee chairman Max Baucus (D-Montana) and Sen. Charles Grassley (R-Iowa) sent a letter to Medtronic, dated June 21, expressing concern that the researchers in the rhBMP-2 clinical trials might have been aware of but did not report evidence that the product may cause sterility and potentially harmful bone growth and might not have mentioned it in their papers.

The senators have demanded that Medtronic send them copies of all communications with medical journals, the FDA, the clinical investigators, and the physician consultants who looked at postoperative events. In addition, they want records of all payments made to the researchers and have given the company until July 11 to respond.

Public Health Problem

Dr. Carragee says he would continue to use rhBMP-2 for patients who have no alternatives, including men who have received radiation treatments or are taking steroids. "These guys just can't heal their bodies," he says, because it's hard to get their bones to fuse. "But for a 25-year-old guy who has 2 disk herniations and is having a fusion, this is an awfully powerful and hazardous drug to use on that kind of a person."

Only about 10% to 20% of patients currently receiving it really need rhBMP-2, he estimates. Unfortunately, he adds, about half of all patients undergoing fusion surgery now receive the drug, with its attendant side effects. "The idea that 40% of the spinal fusions in the country are now using this is a real public health problem."

Senator Baucus placed the issue in a wider context in a press release he issued with Senator Grassley on June 22.

"These reports that doctors conducting medical trials while on Medtronic's payroll may have hidden serious side effects for patients are deeply troubling," he said.

"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."

All rhBMP-2 studies reviewed were funded (in whole or in part) by Medtronic or had authors with significant financial associations with Medtronic. No funds were received to support the critical review article. "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," the study authors declare. Dr. Carragee reports stock ownership including Intrinsic Spine (<1% ownership, options only), Cytonics (unknown number of options, <1% ownership); private investments: Simpirica (unknown number of stocks (D); consulting: US Department of Justice (D), Kaiser Permanente (D); research support (investigator salary): National Institutes of Health (C, paid directly to institution/ employer); other office: NASS The Spine Journal (E); fellowship support: OREF (E, paid directly to institution/employer), AO Foundation (E, paid directly to institution/employer); Trips/Travel: US Army (B), Department of Defense (A), Orthopaedic Trauma Society (A), OREF (B), AAOS (A), NASS (A), The Spine Journal (A). CMB: royalties: Wolters Kluwer (B), Informa Healthcare (B); other office: Intrinsic Therapeutics (B); other: JAAOS (B), The Spine Journal. Disclosures for other authors appear in the paper. The disclosure key can be found on the Table of Contents and at www.TheSpineJournalOnline.com.

Spine J. 2011;11:471-491, 463-468. Links to these papers can be found here.

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