Since 2002, the medical device company Medtronic and a group of doctors with financial ties to the company were aware that its new biological agent used in back surgery was linked to a serious complication: sterility in men.
But that information was not revealed in published manuscripts written by those doctors, a group that included orthopedic surgeons who would receive millions of dollars in various royalties from the company, a Milwaukee Journal Sentinel/MedPage Today investigation found.
Now, prompted in part by earlier Journal Sentinel/MedPage Today articles, independent researchers at Stanford University conducted a retrospective review of outcomes of patients treated at Stanford and published the findings today in The Spine Journal. The Stanford team found that in their patients use of recombinant human bone morphogenetic protein-2, or BMP-2 -- marketed as Infuse by Medtronic -- was associated with a measurable rate of retrograde ejaculation, a condition that causes sterility.
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Indeed, in the main arm of the clinical trial that led to the approval of BMP-2—data that were submitted to the FDA in 2002—five of 78 men treated with BMP-2 developed the retrograde ejaculation 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 percent) treated with BMP-2 also developed retrograde ejaculation.
Yet, as recently as last year the BMP-2 investigators with financial ties to Medtronic claimed there was "no relationship" between the product and the complication.
And the doctors' denials fly in the face of a Medtronic statement included in a 16-page document obtained by the Journal Sentinel/MedPage Today from publicly available FDA files. In that document company states that retrograde ejaculation is a potential adverse event that may occur with Infuse.
And when contacted by the Journal Sentinel/MedPage Today Medtronic and the doctors contended the sterility complication was caused by surgical technique, not the product, which they said was why the sterility data were not included in the published papers
But professional guidelines and independent doctors contacted by the Journal Sentinel/MedPage Today say serious complications should be listed in published papers, regardless of what is believed to be the cause.
A new Journal Sentinel/MedPage Today analysis found that last year alone Medtronic paid more than $6 million in royalties for various products to the physicians who co-authored the BMP-2 studies, but the company and the authors note that none of those royalties were for Infuse.
One of the authors, Dr. Thomas A. Zdeblick, is a University of Wisconsin School of Medicine and Public Health orthopedic surgeon who, along with Taz Consulting, has received more than $23 million in various royalty payments from Medtronic since 2002. Zdeblick also is the editor of the journal that published two of the papers that failed to mention the link.
In an email, a spokesperson for the Univeristy of Wisconsin said that Zdeblick "neither owns equity in Medtronic nor receives royalties or any other payments for the sale of Infuse, either now in the past."
A previous Journal Sentinel/MedPage Today investigation found that doctors who had financial relationships with Medtronic reported substantially better results using BMP-2 in clinical trials leading to its approval than did doctors who reported no financial ties to the company.
Independent of the ongoing Journal Sentinel/MedPage Today investigation, the company is being investigated by the U.S. Department of Justice for possible 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.
The emergence of sterility as an adverse event associated with BMP-2 suggests a worsening scenario for the device.
"To have such strong evidence that a life changing complication of sterility exists and then cover it up in my opinion is obscene…" said Dr. Charles Rosen, an orthopedic surgeon and president of the Association for Medical Ethics who was not a part of 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, Dr. Ken Burkus, a Columbus, Ga. surgeon who co-authored four of the papers, said the link between BMP-2 and the complication was not mentioned in the papers because it was not deemed to be "statistically significant."
But that explanation was undercut by the original data provided to the FDA data which stated that the sterility-causing complication rates were at least five times greater in the BMP-2patients.
In their analysis, the Stanford researchers found a similar outcome in their own BMP-2 patients.
Asked about his obligation to share adverse event information with other surgeons, and therefore 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 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 address the issue of whether financial relationships played a role in the failure of the papers to report the complication rate among the Infuse patients.
"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."
The sterility issue is just the latest question raised about BMP-2, which has generated annual sales of several hundred million dollars since its approval. The rapid uptake of the product was not surprising 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, a series of complications, including some that are life-threatening, have emerged.
In a 2002 paper co-authored by UW's Zdeblick, Burkus and two others said there were no "unanticipated" adverse events related to BMP-2 in the clinical trial of the product. The paper was published in the Journal of Spinal Disorders & Techniques. Zdeblick has been editor-in-chief of that journal since 2002.
But prior to its approval, data from the BMP-2 clinical trial submitted to the FDA showed a link between it and a condition known as retrograde ejaculation, which causes sterility.
Retrograde ejaculation was never listed as a treatment associated adverse event in at least four published papers authored by BMP-2 investigators who had financial ties to Medtronic, the Journal Sentinel/MedPage Today found.
In two of the four papers the retrograde ejaculation was mentioned but was attributed to surgical technique..
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 [BMP-2] 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)."
Writing in the Spine Journal, the Stanford surgeons concluded that multiple lines of evidence strongly suggest that BMP-2 increases the risk of retrograde ejaculation.
The Stanford researchers went back and looked at 243 patients of their own who underwent spinal fusion surgery between 2002 and 2004 after BMP-2 was approved. They compared rates for the complication with or without the product. They also compared their findings with the original FDA data.
The Stanford review found that retrograde ejaculation occurred in more than 7 percent of its male patients treated with BMP-2, compared with less than 1% of those who received a standard graft. The Stanford group's complication rate with BMP-2 was similar to the rate found in the unpublished clinical trial data submitted to FDA.
Five of Stanford's 69 male patients treated with BMP-2 developed the complication, compared with one of 174 men who got a standard graft. After one year, the complication resolved in two of the five BMP-2 patients.
Dr. 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 that came out after the product was approved.
"It is certainly strange," said Carragee, chief of spinal surgery at Stanford and editor-in-chief of the Spine Journal. "The data were there. You don't have to be 99 percent certain before you say there can be a problem."
First report all harm
Serious complications such as sterility that are linked to a treatment should be reported in published articles, according to independent doctors interviewed by the Journal Sentinel/MedPage Today.
In addition, the Consolidated Standards for Reporting Trials endorsed by many medical journals in 2004 state that failing to list serious harms found in clinical trials, regardless of statistical significance, constitutes poor reporting of clinical trial results. The group also endorsed a similar standard for reporting such harms in 2001.
"With the serious possibility that RE (retrograde ejaculation) is associated with (BMP-2) use in the lower lumbar spine, it is important that men be counseled about this risk and advised that avoiding (BMP-2) in favor of alternative grafting methods may minimize the risk," Carragee and his co-authors wrote.
In an email response to the Journal Sentinel/MedPage Today, Medtronic spokeswoman Marybeth Thorsgaard said the company disclosed to the FDA that retrograde ejaculation was a potential complication related to anterior surgical procedures.
Moreover, she said the company included information about retrograde ejaculation in the package insert for Infuse. That insert, she said, acknowledges a higher rate of retrograde ejaculation with BMP-2 compared with control groups.
"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 and Joint Surgery.
The letter, which was co-authored by Burkus, Zdeblick and two other doctors who have receive Medtronic royalties, was a response to a letter written by three doctors in Croatia who had raised concerns about whether BMP-2 was a cause of the complication.
In their letter the American doctors flatly denied there is any relationship between the complication and Infuse. They also noted that the complication eventually had resolved in five of 11 patients.
In early 2010, the Croatian doctors began raising questions about the failure of those medical journal articles to tie BMP-2 to retrograde ejaculation.
Tomislav Smoljanovic, MD, 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/MedPage Today more than a year ago, was sent to Zdeblick in February 2010.
Less than a month later, Zdeblick rejected it for publication in his journal.
Carragee said the Milwaukee Journal Sentinel/MedPage Today articles about BMP-2 and concerns raised by Smoljanovic caused Stanford researchers to investigator whether BMP-2 caused retrograde ejaculation.
Reporting all complications
The explanation offered by Zdeblick and his colleagues, i.e. that retrograde ejaculation is a complication caused by surgery rather than by BMP-2, does not hold up to scrutiny according to several independent doctors contacted by the Journal Sentinel/MedPage Today.
While acknowledging that surgical technique may be a factor in the development of the complication, doctors interviewed by the Journal Sentinel/MedPage Today, agreed that the Medtronic authors should have stated that BMP-2 also was linked to the condition, regardless of what they thought was the level of statistical significance.
"I'm concerned that the published reports don't match up with the FDA data," said Dr. Sohail Mirza, a professor of orthopedics at Dartmouth Medical School. "Our standard in medicine is to use the published literature to counsel patients."
Dr. Dan Spengler, a professor of orthopedics and rehabilitation at Vanderbilt University Medical Center, noted that rate of retrograde ejaculation in the BMP-2 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 (mention the link between the complication and BMP-2). You have to seriously question whether it was a willful thing and whether it was linked in any way to the finances," Spengler said.
Dr. Richard Deyo, a professor of evidenced-based family medicine at Oregon Health and Science University, said BMP-2 was another 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."
But for public health reasons, he said, the actual data about retrograde ejaculation and BMP-2 needed to be included in the published manuscript.
Retrograde ejaculation occurs with sperm and semen enter the bladder instead of the urethra.
It is believed that BMP-2, 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 researchers know a lot about the how BMP-2 affects bone, much is not known about its effects on other tissues, especially with the doses used for bone fusion, James Kang, MD, an orthopedic surgeon at the University of Pittsburgh School of Medicine, said in a commentary that The Spine Journal published along with the Stanford paper.
Kang also questioned how two groups of researchers -- the Medtronic-funded surgeons and the Stanford surgeons – could find similar rates of retrograde ejaculation in their BMP-2 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."