InFuse – Part II
In its June 2011 issue, The Spine Journal (TSJ) critically reviewed the scientific underpinnings of 13 studies of BMP-2 which had appeared in peer review journals between 2002 and 2004. One of those studies received the 2002 Volvo Award. In its review, researchers led by Eugene Carragee, M.D., found the studies suffered from “serious potential design bias” and “unpublished adverse events and internal inconsistencies.”
This week, in part two of our review of TSJ’s BMP issue, we tackle some of the other issues raised by the Journal, notably corporate funding of the InFuse studies. We then look at the broader implications of TSJ’s review on innovation and self-regulation in the spine surgery community.
In part one of our review which we published last week, we created a table with information we took from TSJ. While we didn’t check all 13 studies, we looked at two—the 2002 Burkus et al. study and the 2006 Dimar et al. study. The 2002 Burkus et al. study did not list any adverse events from using BMP. But, the Dimar study did—contrary to two tables we found in Dr. Carragee et al.’s review. According to Carragee, Dimar et al., in the 2006 study did not report any complications from the use of BMP-2. When we read the same study (n=53 for the BMP group) we found this table.
Corporate Funding of the Infuse Studies
In Carragee’s critical review and accompanying editorial, he and his fellow authors raised the issue of corporate sponsorship of the studies and payments by Medtronic, Inc. to the study investigators. In editorial comments, which were supplied to The Wall Street Journal and The New York Times on Friday June 21—prior to being supplied to TSJ’s surgeon readers—the authors wrote the following:
“…the core of our professional faith is to first do no harm. 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. Yet harm has been done. And that fact creates a basic moral obligation.”
To illustrate the extent to which BMP study authors received payments from Medtronic, TSJ provided a Supplementary Appendix which listed the industry sponsorship and financial disclosures for all 13 peer-reviewed articles which were the subject of TSJ’s critical review. Here is a selection from that table.
Appendix 1: Disclosures of financial relationships between study authors and Medtronic Inc. at publication and at follow-up. (Electronic Publication only)
Disclosure of Financial Relationships at Publication
(in Whole, in Part, or with to Author).
Minimum Range of Total Financial Relationships of Any Type With Medtronic Inc.
Boden SD, Zdeblick TA, Sandhu HS, Heim SE. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine 2000 Feb;25(3):376-381.
Sponsored by Medtronic Sofamor Danek, Inc., Memphis TN.
$21, 025, 000
Boden SD, Kang J, Sandhu H, Heller JG. Use of recombinant human bone morphogenetic protein-2 to achieve posterolateral lumbar spine fusion in humans: a prospective, randomized clinical pilot trial: 2002 Volvo Award in clinical studies. Spine 2002 Dec;27(23):2662-2673.
Corporate and industry funds were received to support this work. One or more of the authors have received or will receive benefits (e.g., honoraria, gifts, consultancies) for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript.
$565, 000 - $1, 474, 000
Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech 2002 Oct;15(5):337-349.
$23, 121, 000 - $23, 581, 000plus additional $1, 500, 000, for Burkus cited in Wall Street Journal estimates. [J. Carreyrou, Wall Street Journal, 28 June 2011]
Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine 2002 Nov;27(21):2396-2408.
This study was sponsored by Medtronic Sofamor Danek, Memphis, Tennessee. Corporate/Industry funds were received to support this work. One or more of the author(s) has/have received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript, e.g., honoraria, gifts, consultancies.
$2, 532, 000 - $2, 592, 000 plus additional $1, 500, 000, for Burkus cited in Wall Street Journal estimates. [J. Carreyrou, Wall Street Journal, 28 June 2011]
Burkus JK, Heim SE, Gornet MF, Zdeblick TA. Is INFUSE bone graft superior to autograft bone? An integrated analysis of clinical trials using the LT-CAGE lumbar tapered fusion device. J Spinal Disord Tech 2003 Apr;16(2):113-122.
$22, 732, 000 - $23, 192, 000 plus additional $1, 500, 000, for Burkus cited in Wall Street Journal estimates. [J. Carreyrou, Wall Street Journal, 28 June 2011]
Source: The Spine Journal
According to TSJ, as of March 2011, of the 13 original studies, one study had no information available regarding the authors financial relationship with Medtronic while in the remaining 12 studies, the median-known financial association between the authors and Medtronic was found to be approximately $12, 000, 000–$16, 000, 000 per study (range, $560, 000–$23, 500, 000).
Payments listed in the table above were for ANY payments made ANY time for ANY thing—Carragee et al. did not check to see if the payments occurred before or during the time the studies were published or whether the payments were related to InFuse or implants related to InFuse or anything unrelated to the studies.
In fact, upon closer inspection, it appears that Carragee et al. chose payments that were made over a 15-year period and the referred-to royalty figures were paid for intellectual property and patents that occurred years after the studies were published. None of the authors, it turns out, received royalty payments for InFuse at any point in time.
So, for example, in the first study (Boden et al., Spine 2000, for $21 million) mentioned in Carragee et al.’s table, Boden and his colleagues did receive a nominal hourly consulting fee from Medtronic prior to the study being published. Furthermore, Dr. Boden specifically avoided participating in stock, options and royalties during that time period in order to remove any real or perceived potential conflict of interest. This was not mentioned by the Carragee et al. review.
Thomas Zdeblick, M.D., one of the investigators listed in a couple of the studies had coincidentally written a letter to the editor of TSJ and took issue with Caragee’s suggestion in a previous retrospective study of BMP adverse events, that conflicts of interest were poorly accounted for. Dr. Zdeblick wrote:
“…to suggest that the FDA trial data were somehow obscured by conflict of interest is misleading and inappropriate. No attempt was made to hide data. The results within the FDA trial concerning RE [Retrograde Ejaculation] and BMP-2 were not statistically significant, and therefore not in the initial report. Over 40 adverse events were tracked for the FDA, but did not lead to any significance, and were therefore not reported (e.g., nausea/vomiting, ileus, urinary retention). The beauty of a prospective, randomized, multicenter trial is that you get pooled concurrent data. I would rather trust this than a poorly performed historically controlled single report in making decisions regarding my patients.”
Dr. Zdeblick went on to say:
“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, which can be used with or without InFuse, was popular, and in use before InFuse.”
Dr. Carragee shot back:
“This is patently incorrect: The “FDA trial” found 12 RE events in the rhBMP-2 group (7.9%) versus 1 (1.5%) in the control group. (Fisher Exact p=0.05) Dr. Zdeblick declined to publish these rates for more than 8 years. In the RCT portion of the FDA trial, the rate of RE in the BMP-2 group was more than 4 times higher than the control group (6.4% of 78 patients compared to 1/5% of 68 controls); he also declined to report these rates for more than 8 years.”
Dr. Carragee went on to write:
“Dr. Zdeblick’s discussion regarding whether an RCT or a retrospective cohort-control trial provides more reliable evidence is also misleading. According to multiple sources on evidence-based medicine, retrospective cohort-controlled trials are most compelling as evidence when they reproduce the same effect, in direction and magnitude, as an RCT. These studies can provide strong evidence of the generalizability of an observation outside of the artificial RCT environment.”
Finally, Dr. Carragee specifically challenged Dr. Zdeblick’s claim that he had no financial interest in InFuse. He noted that it was a:
“…fascinating denial of what, in our opinion, is an obvious and enormous conflict of interest. The old saying “follow the money” and in this case, there is plenty to follow. Specifically related to InFuse, Dr. Zdeblick receives millions of royalty dollars from the Novus LT cage. He points out in his letter that his LT cage is the only device tested and approved by the FDA for spinal fusion with the InFuse product.” Continues Carragee : “To be clear, for the primary spinal fusion patient in the United States to receive the InFuse product in the tested and approved FDA manner promoted by Dr. Zdeblick in his letter, they must use Dr. Zdeblick’s device.”
The Spine Journal’s Editors as Advocacy Journalists
The editors of The Wall Street Journal and The New York Times (along with many other news outlets) received an email from TSJ with the headline “Years of Living Dangerously” late Friday, June 21—before any of TSJ’s subscribers received their issue.
The Wall Street Journal is the largest circulation newspaper in the U.S. with 2.1 million readers. The New York Times online version is the most popular web-based newspaper in the U.S. with 30 million unique visitors each month. Combined, it is fair to say, they far out strip TSJ’s ability to communicate a particular story.
One effect of TSJ’s pre-release to such large media outlets with a hyperbolic headline was to trigger global media coverage—the effect of which was to drown out any alternative point of view. I call it the megaphone effect.
OTW mentioned this to Dr. Carragee. His comment was, in effect, to say that everyone else does it including Medtronic so what’s the big deal? “We used the same embargo and press release deadlines, nearly to the hour, as is used for JAMA and NEJM. That is done every week of the year for major journals. It is interesting that I have never heard this complaint when an industry-sponsored trial has the same pre-release alert with embargo to the news media.”
Money Incentives and the Will to Win
There are few more powerful incentives for human behavior than money, particularly such large sums as those cited in the Carragee et al. review. Clearly, one of Dr. Carragee’s principal arguments, whether expressly stated or implied, is that the bias inherent in these kinds of payments from study sponsors or product suppliers has the power to overwhelm the peer review process at scientific journals.
While the specifics and timing of the payments, as we pointed out earlier, don’t match very well (if at all), with the narrative put forward by the Carragee et al. review, the point is nonetheless well taken.
In our view, it is almost impossible to underestimate the power of incentives. So the attention to this issue elicits strong sympathy from OTW. But getting it right is equally important.
Medicine Without Innovation
What if there had been no corporate funding of the studies? Would InFuse have been approved by the FDA?
Dr. Carragee’s answer to that question was: “Absolutely, but the more important question is whether the Medtronic studies need to be performed with the multiple design flaws and internal bias identified in order to demonstrate a valuable product—I do not think those design flaws were necessary, the product has value. Second, did it need to be presented in the manner it was in the published literature as being virtually perfect in all original trials, in order to be used by surgeons? Again, no, I do not think that was necessary either.”
Dr. Carragee makes several excellent points. But, in terms of the importance of corporate funding of the studies, recent trends would argue against his blanket assurance. According to an article in the January 13 issue of JAMA, the level of funding from the National Institutes of Health and industry has decreased by 2% in 2008, after adjustment for inflation. Subtract corporate funding and the picture is worse. “Adjusted for inflation, NIH contributions decreased by 8.6 percent from 2003 to 2007, ” according to the authors of the JAMA study.
What would life be like without research into more effective treatments, preventative measures and new commercial products? Without funding (corporate or non-corporate), how does such research occur? This is not a trivial question.
What Does Corporate Funding Pay For?
Hopefully, with greater sensitivity to the issues raised by Carragee et al.’s review, peer-review journals in orthopedics will be ever more diligent to squeeze out all forms of bias. >
But the issues at stake are greater than those raised by Carragee. Corporate funding is actually more vital and critical to all funding of biomedical research than perhaps Dr Carragee and his reviewers realize. One example in OTW’s backyard is Pfizer’s funding for research being done in a laboratory at the University of Pennsylvania (OTW is based in Philly). That money goes to the institution, not into the principal investigator's pocket.
According to Dr. Elliot V. Hersch, Professor of Pharmacology at Penn: "Without research money—whether it be from industry or the federal government—hundreds, if not thousands, of jobs would be lost at an institution like the University of Pennsylvania."
For example, recently the University was awarded a $250, 000 grant to do a study of a Liqui-Gel pain reliever in which each of 210 subjects, who'd had impacted wisdom teeth surgically removed, swallowed two Liqui-Gels and two caplets. (Neither the subjects nor the researchers knew who received active medication and who did not.) The study sponsor, Whitehall Pharmaceuticals (now a part of Pfizer), wrote the checks out to the Trustees of the University of Pennsylvania. About $60, 000 went for indirect costs, such as for lights, heat, and use of Penn facilities.
The rest of the money was used to pay:
Hersch's research coordinator's salary and benefits for almost two years
Part of the salaries of Hersch and the Penn oral surgeons involved in the study
Study participants, who spent about eight hours filling out various pain questionnaires
And for travel to present study data at a research meeting.
But the stakes go well beyond such U.S. institutions as the University of Pennsylvania. As we illustrated earlier, medical product companies supply the largest proportion of total research spending (58%)—U.S. only.
Worldwide, approximately 70% to 80% of all biomedical research and development is sponsored by U.S.-based corporations, foundations and government agencies. As a proportion of total health care spending, the U.S. invests 4.5% on R&D, an amount higher than any other country in the world. U.S. spending on biomedical R&D (corporate and non corporate) supports the planet.
“Do No Harm”
"In surgery, as in anything else, skill, judgment and confidence are learned through experience, haltingly and humiliatingly. Like the tennis player and the oboist and the guy who fixes hard drives, we need practice to get good at what we do. There is one difference in medicine though: we practice on people."— Atul Gawande
One casualty that may well come from the unmasking of the flaws of the early InFuse studies is that ad hoc experimentation, off-label use of, not only InFuse, but potentially, screws, plates, other biomaterials, will be deemed too dangerous to allow, if not also reimburse. That would be tragic.
One of the reasons orthopedic science experiences such rapid advances during war time is because ad hoc experimentation increases and in the process new techniques and tools are discovered. External fixation. Intermedullary nails. Pedicle screws. Even hip arthroplasty. These and thousands of other procedures and implants emerged from ad hoc experimentation by real surgeons on real patients.
There are no virgin births in medicine. All healthcare providers learn by practicing and making mistakes on real patients. All products used to care for patients are tested and fail on real patients. Which means; to “do no harm” is also to “do no experimentation.” No experimentation will mean no innovation. No innovation will do the greatest harm.
To allow for ingenuity is to allow space for failure. Innovative products (and biomaterials are no exception) are not born fully understood. Should have we waited 20-30 years before approving hip replacements in order to more fully understand wear rates? Should we have waited an additional ten years before approving InFuse in order to better understand its complications? If we had waited, how many hundreds of thousands, perhaps millions of patients would have been harmed by the omission of these products from the medical armamentarium?
Honestly, OTW gives Dr. Carragee and his colleagues their due. Published clinical studies have long suffered, in our view, from poor enforcement of the disclosure rules and reported outcomes that too loosely translate into general practice. Furthermore, that view of ours is, we think, held as well by the majority of rank and file spine surgeons. Dr. Carragee’s kind of critical, meticulous review gave rise to this special issue of TSJ and it will, we hope, raise the overall quality of peer review and financial disclosures among all scientific journals.
But Dr. Carragee and his colleagues are also advocates for a particular point of view and that prompted them to put TSJ into a position of campaigning for that point of view and impugning or drowning out alternative points of view. Why, for example, didn’t TSJ use its edition to create a point/counterpoint dialogue between Dr. Carragee and his colleagues on one side and the authors of the 13 studies on the other? (Without The Wall Street Journal or The New York Times or The Milwaukee Journal Sentinel mucking about.)
The stakes in this debate are extremely high. How the FDA and others internalize TSJ’s characterizations of the role of corporate funding, of experimentation and of off-label use of medical products could well determine the manner in which spine patient care progresses in the U.S.