Since 2002, Medtronic and a group of doctors with financial ties to the medical device company were aware that a new biological agent used in back surgery 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.

Prompted in part by Journal Sentinel stories, independent researchers at Stanford University looking at their own patients have found strong evidence connecting the lucrative product to retrograde ejaculation, a condition that causes sterility in men.

Though original data linking the product to the complication was included in information sent by the company to the Food and Drug Administration as part of the approval process in 2002, those doctors were still claiming there was "no relationship" between the product and the complication as recently as last year.

Medtronic and the doctors contend that the sterility complication was caused by surgical technique, not the product. But professional guidelines and independent doctors contacted by the newspaper say serious complications should be listed in published papers, regardless of what they assume to be the cause.

A new Journal Sentinel 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 papers about the product, known as Infuse, without cautioning that it was linked to male sterility. None of the royalty payments was for Infuse.

One of the authors, Thomas A. Zdeblick, is a University of Wisconsin School of Medicine and Public Health orthopedic surgeon. Zdeblick and Taz Consulting have received more than $23 million in various royalty payments from Medtronic since 2002. Zdeblick also is the editor of the journal where two of the Infuse papers that failed to mention the link were published.

Last year, a Journal Sentinel investigation found that doctors who had financial relationships with Medtronic produced substantially better results with Infuse in the clinical trial leading to its FDA approval than doctors who did not have financial ties to the company.

The newspaper articles documented growing concerns about Infuse side effects and how associated surgeons authored research that has been criticized as little more than marketing.

Meanwhile, Medtronic is under investigation by the U.S. Department of Justice on allegations of off-label marketing of Infuse, a case that could be settled in the near future with civil and criminal penalties, according to a Wells Fargo analyst's report issued last month. Companies are not allowed to promote their products for unapproved, or so-called "off-label," uses.

The Stanford study linking Infuse to increased risk of sterility, which is being published online Wednesday in the Spine Journal, a publication of the North American Spine Society, was done by independent surgeons.

"To have such strong evidence that a life-changing complication of sterility exists and then cover it up in my opinion is obscene," said Charles Rosen, an orthopedic surgeon and president of the Association for Medical Ethics who has read the Stanford study.

As a result, thousands of men may have become sterile without knowing that the product even posed such a risk, said Rosen, a clinical professor of orthopedic surgery at the University of California, Irvine.

In an email, Ken Burkus, a Columbus, Ga., surgeon who co-authored four of the papers, said the link between Infuse and the complication was not mentioned in the papers because it was not deemed to be "statistically significant."

But that claim was undercut by original data provided to the FDA that stated the sterility complication rates were at least five times greater in the Infuse patients. Stanford researchers found a similar outcome in their own Infuse patients.

Asked about his obligation to share such information with other surgeons and their patients, Burkus said in an email statement:

"These concerned physicians, surgeons and colleagues have several avenues to address these concerns. They can contact the FDA. They can contact the office of medical affairs at Medtronic. They can contact their local or national medical societies. They can write a 'letter to the editor' at the journal in which the manuscript was published."

Burkus, whose RBCK Research & Consulting was paid $782,000 in various royalties by Medtronic last year, declined to say whether financial relationships played a role in the failure of the papers to report the complication rate among the Infuse patients.

Under growing pressure from Congress, the Justice Department and the public, drug and medical device companies have recently begun listing payments to doctors.

"My co-authors and I made the appropriate and required disclosures for the journals in which the manuscripts were published," he said in an email. "I do not make the rules for these journals - I just try to follow the rules as best I can."

Latest issue

The sterility issue is the latest question raised about Medtronic's Infuse, known in the spinal field as bone morphogenetic protein-2, or BMP-2, a genetically engineered substance used in spinal fusion surgery. The product has generated annual sales of several hundred million dollars because it eliminates the need to obtain a small amount of a patient's own hip bone to create a fusion between vertebrae.

However, since its approval for use in some spinal fusion surgeries, a series of complications, including some that are life-threatening, have emerged .

A 2002 paper co-authored by UW's Zdeblick, Burkus and two others said there were no "unanticipated" adverse events related to Infuse in the clinical trial of the product. The paper was published in the Journal of Spinal Disorders & Techniques. Zdeblick has served as editor-in-chief of that journal since 2002.

Despite that conclusion, data from the Infuse clinical trial submitted to the FDA showed a link between the product's use and retrograde ejaculation.

That connection was never mentioned in at least four published papers by a group of doctors with strong financial ties to Medtronic, the Journal Sentinel found. In two of the papers the complication was attributed to surgical technique, not Infuse. In two other papers, the complication was not mentioned at all.

In an email responding to the Stanford paper, Zdeblick said different researchers can reach different conclusions.

"As a practicing surgeon, I would certainly want to know if Infuse leads to higher complications," he said. "Personally, I have not seen this. In my experience there is no direct link between Infuse and RE (retrograde ejaculation)."

In their findings, the Stanford School of Medicine researchers concluded that multiple lines of evidence strongly suggest that Infuse increases the risk of retrograde ejaculation.

The Stanford researchers went back and looked at 243 of their own patients who underwent spinal fusion surgery between 2002 and 2004, after Infuse was approved. They compared rates for the complication with or without the product. They also compared their findings with the original FDA data.

The review found that retrograde ejaculation occurred in more than 7% of Stanford's male patients treated with Infuse, compared with less than 1% of those who received a standard graft. The Stanford group's complication rate with Infuse was similar to the rate found in the unpublished clinical trial data submitted to the FDA.

Five of Stanford's 69 male patients treated with Infuse developed the complication, compared with one in 174 men who got a standard graft. After one year, the complication resolved in two of the five Infuse patients.

Eugene Carragee, who headed the Stanford study and performed all the surgeries in the Stanford review, said he could not speculate on why the complication was not reported in the published articles.

"It is certainly strange," said Carragee, chief of spinal surgery at Stanford and editor-in-chief of the Spine Journal. "The data was there. You don't have to be 99% certain before you say there can be a problem."

Reporting standards

The Consolidated Standards for Reporting Trials endorsed by many medical journals in 2004 say failing to list serious harms found in clinical trials, regardless of statistical significance, constitutes poor reporting of clinical trial results.

"With the serious possibility that RE (retrograde ejaculation) is associated with (Infuse) use in the lower lumbar spine, it is important that men be counseled about this risk and advised that avoiding (Infuse) in favor of alternative grafting methods may minimize the risk," Carragee and his co-authors wrote.

Marybeth Thorsgaard, a Medtronic spokeswoman, said the company disclosed to the FDA that retrograde ejaculation is a potential complication related to anterior surgical procedures.

She said the company also includes information about the complication in package inserts with Infuse. The insert shows higher rates of the complication with Infuse than with the control group.

"Medtronic has been transparent about this issue on its labeling and in its PMA (premarket approval) submission (to the FDA)," she said.

Thorsgaard also pointed to a 2010 letter published in the Journal of Bone & Joint Surgery. The letter was co-authored by Burkus, Zdeblick and two other doctors who have received Medtronic royalties.

The letter was a response to a letter written by three doctors in Croatia who had raised concerns about Infuse causing sterility. The two letters were published together.

In their letter, the American doctors flatly denied any relationship between the complication and Infuse. They also noted that the complication eventually had resolved in five of 11 patients.

Retrograde ejaculation occurs when sperm and semen enter the bladder instead of the urethra.

It is believed that Infuse, a potent biological protein that stimulates bone growth, may have an inflammatory effect on nerves and soft tissue surrounding the spine, including on the nerves that control whether semen enters the bladder or the urethra.

While scientists know a lot about how Infuse affects bone, not much is known about its effects on other tissues, especially with the doses used for bone fusion, said James Kang, an orthopedic surgeon at the University of Pittsburgh School of Medicine, in a commentary that accompanies the Stanford paper.

Concerns in Croatia

In early 2010, the Croatian doctors began raising questions about the failure of medical journal articles to tie Infuse to retrograde ejaculation.

Tomislav Smoljanovic, an orthopedic surgeon at the Zagreb University School of Medicine, and his colleagues sent a flurry of letters to various medical journals raising concerns about retrograde ejaculation and other complications associated with Infuse.

One of the letters, which Smoljanovic shared with the Journal Sentinel, was sent to Zdeblick in February 2010. Less than a month later, Zdeblick, as editor of the Journal of Spinal Disorders & Techniques, rejected it for publication.

Smoljanovic's concerns and questions raised by Journal Sentinel stories prompted the review by researchers at Stanford.

In the main arm of the clinical trial that led to approval of Infuse, five out of 78 men who got Infuse developed the complication compared with one of 68 men who received the standard hip bone graft, according FDA records. In another arm of the clinical trial, an additional six of 57 men (10.5%) who got Infuse also developed retrograde ejaculation.

The associated doctors' denials of a connection between Infuse and the complication is at odds with other data filed with the FDA by Medtronic prior to the 2002 approval of Infuse.

In that 16-page document obtained by the Journal Sentinel from FDA files, the company states that retrograde ejaculation is a potential adverse event that may occur with Infuse.

'Dramatic difference'

Several independent doctors contacted by the Journal Sentinel say that while the surgical technique may be a factor in the development of the complication, the Medtronic authors should have stated Infuse also was linked to the condition.

"I'm concerned that the published reports don't match up with the FDA data," said Sohail Mirza, a professor of orthopedics at Dartmouth Medical School. "Our standard in medicine is to use the published literature to counsel patients."

Dan Spengler, a professor of orthopedics and rehabilitation at Vanderbilt University Medical Center, noted that the rate of retrograde ejaculation in the Infuse clinical trial was about five times higher among patients who got the product.

"It was a pretty dramatic difference," Spengler said.

"I have no idea why they didn't do it. You have to seriously question whether it was a willful thing and whether it was linked in any way to the finances."

Richard Deyo, a professor of evidenced-based family medicine at Oregon Health and Science University, said Infuse is an example of medical industry-funded studies showing a product in the most favorable light.

"I have to be worried that conflicts of interest are playing a role here and that the reports have been written in such a way that minimize undesirable effects and maximize the benefits," said Deyo, who has done research on spinal surgery. "No one wants to bite the hand that feeds them."

For public health reasons, he said, the data about retrograde ejaculation and Infuse needed to be put in those published reports.

Kang, of the University of Pittsburgh, questioned how two groups of researchers - the Medtronic-funded surgeons and the Stanford surgeons - could find similar rates of retrograde ejaculation in their Infuse patients yet come to completely different conclusions.

He said the only rational explanation is that the Stanford researchers had no commercial conflicts of interest and the Infuse studies were corporate sponsored.

In an era of public scrutiny of surgeons' conflicts of interest, "We must come to the hard realization that data analysis and interpretation in such studies can be biased in favor of funding sources," Kang wrote. "After all, it is against our nature to publish a negative result or an adverse event that condemns a product that is being studied if we are being funded by the sponsors of the product."



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Coming Thursday

A look at the Croatian doctor who sent a series of letters to various medical journals raising concerns about complications associated with Medtronic's Infuse.

This article is part of an ongoing series about how money and conflicts of interest affect medicine and patient care. John Fauber reported this story in a joint project of the Journal Sentinel and MedPage Today. MedPage Today provides a clinical perspective for physicians on breaking medical news at medpagetoday.com.