BMP-2 Dispute Turns Nasty (MedPageToday)
Spine Journal Takes Aim at Infuse Research (MedPageToday)
Review faults Medtronic spine device studies (Minneapolis StarTribune Business)
SPINE EXPERTS SAY MEDTRONIC STUDIES BIASED (Memphis Commercial Appeal)
The dispute over adverse effects associated with bone morphogenetic protein-2 (BMP-2) in spinal fusion procedures has turned ugly for the editors of two leading orthopedics journals, with thinly veiled insults flying between them in an unusual public exchange of letters.
Squaring off are Thomas Zdeblick, MD, head of the University of Wisconsin’s orthopedics and rehabilitation department, and Eugene Carragee, MD, chief of spinal surgery at Stanford University.In the letters, Zdeblick hints that Carragee is a poor surgeon, while Carragee accuses Zdeblick of numerous falsehoods and pandering to the media.
The letters are to be published July 12 online in The Spine Journal, which Carragee edits.
A spokesperson for the North American Spine Society, which publishes the journal, said Zdeblick’s letter is slated for imminent online publication; Carragee’s response will be posted late next week.
However, both were quietly made available June 30 for downloading at the society’s own website.
The Bone of Contention
Zdeblick, who is editor of the Journal of Spine Disorders & Techniques, was a key figure in clinical trials of recombinant BMP-2, trade-named InFuse and manufactured by Medtronic, for spinal fusion procedures.
Those studies, and Zdeblick himself, have come under fire for under-reporting adverse effects — including retrograde ejaculation, a cause of male sterility, in which semen is forced into the bladder during orgasm — that appear increased with BMP-2.
A series of reports by MedPage Today and the Milwaukee Journal Sentinel revealed that Zdeblick and other researchers had lucrative financial ties to Medtronic that were not fully disclosed in the journal publications on those studies — including in Zdeblick’s own journal.
Those publications also failed to mention retrograde ejaculation as potentially more common with BMP-2 than with other spinal fusion methods, although data from the same studies submitted to the FDA pointed to a substantially greater rate with the InFuse product.
Prompted by these reports and by complaints from a Croatian orthopedic surgeon, Carragee and colleagues at Stanford recently published a cohort analysis of 243 procedures they performed from 2002 to 2004 — a period in which they used conventional fusion methods in some patients and BMP-2 in others — that found a rate of retrograde ejaculation with BMP-2 about four times as great as in patients receiving an alternative fusion procedure.
The Counter Offensive
Zdeblick’s Spine Journal letter attacked the analysis on several methodological fronts.
“Carragee used BMP-2 in an off-label manner, within a device never tested for dose or compatibility with BMP-2. He admits that he uses the same dose regardless of patient or implant size. We know BMP-2 to be very dose dependent,” Zdeblick wrote.
He also criticized Carragee’s use of femoral ring allografts in conjunction with BMP-2, citing “reports of increased inflammatory reaction and bone lucencies when allograft is combined with BMP-2,” including specifically a study at the University of California Los Angeles that found “an extraordinarily high rate of complication.”
Zdeblick went on to question the methods by which Carragee and colleagues assessed retrograde ejaculation in their cohort. “Unless the questionnaire used is specific to retrograde ejaculation and was unchanged over the years of the study, the data are suspect,” he warned.
Zdeblick also denied that the journal reports on the original Infuse studies had deliberately obscured the adverse event data.
“The results within the FDA trial concerning retrograde ejaculation and BMP-2 were not statistically significant, and therefore not in the initial report,” he wrote, noting that the same was true of ileus, urinary retention, nausea and vomiting, and many other adverse events.
The Wisconsin surgeon then suggested that the higher rate of retrograde ejaculation Carragee reported may have resulted from his technique.
“Certainly, retrograde ejaculation is very technique and surgeon related,” Zdeblick wrote.
“Maybe the specific techniques that Carragee uses should be compared with those of us that have not seen any difference. That would certainly educate patients and surgeons.”
Ouch.
And Countering That …
Carragee wrote a response that picked apart Zdeblick’s assertions one by one.
On the issue of BMP-2 dosing, he agreed that he had used the same dose in all patients, but pointed out that it was the lowest dose — 4.2 mg — used in any of the original Infuse studies.
“Dr. Zdeblick claims we used too high a dose of [BMP-2] in smaller patients or implants. Apparently Dr. Zdeblick … did not read the article closely, as the issue is clear: only the smallest dose was ever used,” Carragee wrote.
Regarding the combination of allograft bone and BMP-2, Carragee noted that the UCLA study had relied exclusively on the combination to achieve fusion, whereas in his patients, “all had supplemental rigid fixation.”
Alluding to similar criticisms Zdeblick had shared with journalists, Carragee wrote that “although these made additional neat talking points for Dr. Zdeblick to justify to the press our ‘numerous flaws’ and ‘irresponsible’ behavior, all were simply made up. It may be important for Dr. Zdeblick to consider that this type of PR gambit only works if you can be sure no one will actually read the article or supporting documents.”
Carragee took another swipe at Zdeblick’s reading comprehension in responding to the question about evaluation of retrograde ejaculation, noting that the paper had stated explicitly that “specific data collection on retrograde ejaculation was included for follow-up of all subjects.”
He then expressed astonishment that any researcher would report serious adverse events in a trial — calling retrograde ejaculation not just serious but “catastrophic” — only if there was a statistically significant difference in rates.
Despite a more than four times greater rate in BMP-2 patients in Dr. Zdeblick’s randomized controlled trial, Dr. Zdeblick refused and continues to refuse to follow the standard CONSORT [Consolidated Statement of Reporting Trials] recommendation for reporting complications in clinical trials.”
Carragee contended that the failure to state the number and type of adverse events in the trial is a “poor reporting practice for harms-related data” according to CONSORT standards published in 2004.
He also quoted the CONSORT statement as calling it inappropriate to summarize adverse events with “statements about whether data were statistically significant without giving the exact counts of events” — which is “precisely the reporting technique used by Dr. Zdeblick,” Carragee charged.
Finally, Carragee took aim at a disclosure statement Zdeblick included with his letter.
It read: “I have absolutely no financial interest in InFuse (BMP-2). At no time have I had a financial incentive related to the approval or use of InFuse. I do receive royalties for the LT Cage [a Medtronic device used in the BMP-2 spinal fusion studies], which can be used with or without InFuse, was popular, and in use before InFuse.”
However, Carragee pointed out that Zdeblick had received a total of $23 million from Medtronic over the years in royalties on the LT Cage and that the device is the only one approved by the FDA for use with BMP-2 in spinal fusion.
“To be clear, for a primary spinal fusion patient in the United States to receive the InFuse product in the tested and FDA-approved manner promoted by Dr. Zdeblick in his letter, they must use Dr. Zdeblick’s device. If surgeons wish to use InFuse in this tested and FDA-approved manner, Dr. Zdeblick directly profits,” Carragee wrote.
He called Zdeblick’s position “a fascinating denial of what, in our opinion, is an obvious and enormous conflict of interest.”
Carragee concluded, “There is nothing wrong with making money or even lots and lots of money. But surely it is a very reasonable concern that Dr. Zdeblick’s arrangement gives him a simple, obvious, and compelling financial interest in the fortunes of Medtronic and their InFuse product. Dr. Zdeblick’s claim, ‘At no time have I had a financial incentive related to the approval or use of InFuse,’ is, in the opinion of many observers, hardly credible.”
Zdeblick also criticized Carragee for taking an 18-month break from spine surgery for active military service and claimed Carragee’s problems with InFuse might really reflect a dulling of his surgical skills due to time away from the operating room. Carragee said he served two short tours, but both occurred after the cases reported in his study. Full details of this aspect of the dispute appear in an accompanying article by John Fauber, Milwaukee Journal Sentinel/MedPage Today