Long-awaited Yale study raises questions about integrity of previous studies of Medtronic's Infuse.

For years, spine surgeons praised Medtronic's Infuse in helping to speed healing and reduce pain after spinal fusion surgeries, saying it was better than alternatives. Turns out, they were wrong, according to a review by Yale University.

Medtronic Inc., the world's largest device maker, commissioned Yale researchers to oversee two independent reviews of its spinal fusion product after spine experts and U.S. lawmakers charged that Medtronic-sponsored studies had overstated benefits and downplayed the product's risks.

To blunt such criticism, Medtronic offered complete access to its data and paid $2.5 million to have Yale lead an independent review of its spinal product, called Infuse. Yale contracted with researchers at the University of York in England and at Oregon Health and Science University (OHSU) to conduct independent studies. Both concluded in a report published Monday in the journal Annals of Internal Medicine that there is little to no difference in effectiveness between Infuse and an older method for spurring bone growth.

"The review also found 'substantial evidence of reporting bias' in the previous studies on the product," officials at Oregon Health and Science University said in a statement. "The review found that Medtronic-sponsored publications analyzed or reported results in biased ways to indicate that it was more effective."

Medtronic said Monday that the analyses confirm what the company has long claimed — that Infuse is a safe and effective product for patients, though it emphasized that it poses some risks that must be considered by patients and physicians.

"We recognize that our products and therapies must have the public and medical community's trust, and so we will continue to create, test and explore new ways to make our clinical research available," Medtronic CEO Omar Ishrak said in a statement.

The FDA approved Infuse spinal fusion in 2002 for use in the lower back and it has been used on more than 1 million patients. The approach involves the removal of a degenerated disc and the fusing of adjacent vertebrae to improve stability. Since its introduction, sales of Infuse quickly soared, reaching nearly $1 billion a year before falling to $528 million, according to the most recent company report.

What remains to be seen is whether the Yale project's findings will further erode Infuse sales.

In fusion surgeries, doctors have typically used graft material taken from the patient's hip — called an iliac crest bone graft — to promote bone growth and improve stability.

Infuse uses recombinant human bone morphogenetic protein-2 (rhBMP-2), a genetically engineered protein, to stimulate bone growth instead. The bioengineered material is inserted into a thimble-like cage between the vertebrae.

The York and OHSU studies both determined that Infuse did not show significantly different results from the use of a hip graft. OHSU researchers concluded that Infuse has "no proven clinical advantage," while York researchers found Infuse increased fusion rates, reduced pain by "a clinically insignificant amount and increases early post-surgical pain." There may also be an increased risk of cancer associated with Infuse, although the risk was deemed very low.

Officials at the Spine Journal released a statement Monday, calling the Yale study the "latest shock" involving Infuse.

"The take-home message from this debacle … is that the public needs better safeguards against conflicted and tainted medical research," said Dr. Eugene Carragee, editor-in-chief of the Journal.

He added: "At present, Medtronic-sponsored surgeons may have to finally retire the line that 'this product is completely safe, don't worry about it,' but I would not count on it."

Chris O'Connell, Medtronic executive vice president and president of its restorative therapies group, said the company will continue to invest in Infuse and that the Yale results are consistent with Medtronic's original studies — studies that led to FDA approval of the product.

There remains an advantage to using Infuse, he said — the advantage of not having to do the second surgery to take bone from the hip. That often leads to more pain and longer recovery for patients, he said.

When asked what type of impact the Yale study could have on sales, O'Connell said he expects it to create a discourse among physicians "so they can use their expertise in the real world and apply it. Our belief is that this will generate a very balanced view."

Dr. Brian Zubac, a spine surgeon in Reston, Va., has used and researched Infuse.

"It has been the single greatest thing for my practice and my patients," he said. "It has revolutionized what I do."

It substantially increases the fusion rate for his patients who need multiple vertebrae fused, said Zubac, who added that he is not compensated by Medtronic and owns no stock. He has had good success using it on patients who have had poor surgery outcomes using a hip bone graft. Now, with the Yale results saying there is no difference between Infuse and the less expensive hip graft, he said he worries that insurance won't pay for it. That, he said, will take a tool out of his hands.

"I'm pretty sure I'm going to have to chop a lot more hip bone out," he said.

Trouble emerged for Infuse when allegations surfaced that Medtronic was coaxing doctors to use it in ways regulators hadn't approved — such as in neck surgery. In fact, Infuse was used more often in such "off-label" procedures, researchers said. In 2008, the FDA issued a warning after reports of excessive bone growth harming patients surfaced. While it isn't illegal for doctors to use devices as they see fit, companies cannot market unapproved uses.

Several former Medtronic employees, including the spine business' onetime general counsel, filed whistleblower lawsuits alleging that the company courted doctors with rich consulting deals and perks.

In 2006, Medtronic paid $40 million to settle with the Justice Department but admitted no wrongdoing. In May 2012, federal prosecutors closed an investigation of Infuse after finding no wrongdoing.

In the summer of 2011, a panel of spine experts reviewed the 13 original studies of Infuse and found that authors with financial ties to the company reported 10 to 50 times fewer complications with Infuse than were found in FDA reports and in other documents. Complications include different types of cancer, male sterility, infection and inappropriate bone growth. That review was published in the Spine Journal. Congress later launched an investigation.

In October, a U.S. Senate Finance Committee report alleged that Medtronic was heavily involved in shaping the content of medical journal articles about Infuse. The report raised questions about research conducted by physicians who received $210 million in royalties and consulting fees over 15 years from the Fridley-based company.

Medtronic denied it improperly influenced peer-reviewed reports or that it sought to underreport harm. Medtronic also called the report's characterization of payments to physicians "misleading and unfair." The company said most payments were made to compensate physicians for their intellectual property rights.

In August 2011, after the Spine Journal published its study, Medtronic agreed to grant Yale University researchers $2.5 million to determine the safety and effectiveness of Infuse. Dr. Harlan Krumholz, a nationally known physician and advocate of patient safety and transparency in clinical studies, led the effort as part of the Yale University Open Data Access (YODA) Project.

He said Medtronic's decision to share its data was unprecedented. The review raises questions over "how much we know and who is clearly benefiting from it."

Many clinical studies do not give the whole story about a product, Krumholz said. He hopes that Medtronic's action is repeated by others as a way to increase transparency and gain public trust.

"My hope is that this catches on. That this serves as a catalyst," Krumholz said. "My hope is that this can restore public trust in these companies."

In addition to giving access to its data, Medtronic agreed with Yale to develop a new program that would publish Infuse data on a website for use by researchers.

James Walsh • 612-673-7428