When the Marketing Tail Wags the Research Dog: More on Medtronic and InFuse

I have posted a number of times on the case of Medtronic, its payments (bribes) to spine surgeons, and its product BMP-2 or InFuse:
http://brodyhooked.blogspot.com/2011/06/taking-professionalism-seriously.html
http://brodyhooked.blogspot.com/2010/12/in-defense-of-paranoia-suspecting.html
http://brodyhooked.blogspot.com/2011/08/in-praise-of-good-corporate-behavior.html

Our good friends at Health Care Renewal now inform us that the staff of the Senate Finance Committee has issued a report on this whole episode:
http://hcrenewal.blogspot.com/2012/10/marketers-systemic-influence-over.html

The Senate staff report itself can be found at:
http://www.finance.senate.gov/imo/media/doc/Medtronic_Report1.pdf
I'd caution you that the entire report is over 2300 pages, of which 22 pages is the report itself and the rest is "exhibits." (More on that later.) I am not sufficiently dedicated to have read all 2300 pages so what follows is based on the HCRenewal summary plus the first 22 pages of the Report proper.

The committee, no doubt at the urging of Sen. Grassley of Iowa, demanded internal documents from Medtronic regarding its clinical trials of InFuse, which is a biological product that makes bone grow. The basic idea is that when a surgeon wants to do a spinal fusion, in which two vertebrae are more or less glued together to stabilize the back, you can do it in two ways. You can take a graft of bone from the patient's hip and use that to bridge the two vertebrae; or you can use InFuse, put into a special metal cage made for the purpose, and it causes bone to grow in the same area and fuses the vertebrae. The problem is when InFuse makes bone grow where you don't want it, or escapes from its cage, or causes a variety of untoward reactions. The earlier posts describe the problems with InFuse, Medtronic's initial efforts to hide the problems, and the exhorbitant sum it paid to spine surgeons who did its bidding; the later posts show how Medtronic has changed its tune and promised a full and neutral investigation.

Now enter the Senate Finance Committee. They plowed through all those documents and concluded that Medtronic exerted an undue influence over the clinical studies and the way they were reported in scientific journals. I'll focus here on one specific anecdote included in the report, that probably add the most to what we have long known about how Pharma allows its marketing apparatus to control the scientific branch.

One study compared the use of InFuse with the standard hip bone graft method. The authors of the study first reported, "12 months after surgery, the patients [sic] graft-site pain had resolved...and no patients complained about the graft-site appearance." Medtronic employee Neil Beals, assigned to manage marketing programs and initiatives for biologic products like InFuse, inserted a comment in the draft: "ALTHOUGH THE PATIENTS DID NOT COMPLAIN ABOUT THE APPEARANCE DIDN'T SOME STILL EXPERIENCE PAIN AT THE DONOR SITE? SEEMS LIKE RESIDUAL EFFECTS OF DONOR SITE SHOULD BE NOTED." The supposedly "scientific" authors then dutifully inserted a sentence: "...even at the 24-month follow-up assessment, some patients continued to experience residual pain at the donor site, and rated the appearance of the site as only fair."

This seems quite a blatant example--the clinician-scientists report that pain and appearance of the donor site are not a problem. The marketing dude back at the company, who probably never laid eyes on a single patient, says, that can't be right, we'll never sell a lot of product that way. So the scientists meekly buckle under and change their report to make it come out like the marketing guy wanted. When you read further that one of the authors of this study was paid $22M in so-called consulting fees by Medtronic between 1997 and 2010, you might hazard a guess as to why the authors were so malleable.

Now let me switch-hit and say a word for the other team. If indeed the Senate Finance staff plowed through 2300 pages of documents, and the worst dirt they could find against Medtronic was the few anecdotes in the brief report, then maybe things were not all that bad. (Except, if you read my previous posts, they were.) But as I say I am not just now about to read all 2300 pages for myself, so we'll just have to leave it there.

Against Capitalism?

One of my most faithful pen-pals (if such a term can be applied to people who send me e-mails) shipped over this link:
http://dissidentvoice.org/2012/10/bad-pharma-bad-journalism/

Briefly, this blog post recounts the history of an exchange between Dr. Ben Goldacre, a British physician/journalist and author of a new book called Bad Pharma, and a dissident economist, Harry Shutt. Goldacre's book appears based on what I've heard so far to be same ol', same ol' for readers of this blog--he nails the drug industry and its medical hangers-on for their addiction to profits over science and health. Shutt's criticism was that all Goldacre calls for is improved regulation of the industry. How, he asked, can you assume that's any sort of adequate measure, when you've just compiled this huge body of evidence that the industry snaps its fingers at all the regulation previously put in place? Goldacre first sent a wimpy reply back, then ceased to respond at all as Shutt pressed him further.

This exchange points out a basic feature of my book HOOKED as well as of this blog. I'm guilty as Goldacre is charged. I have clung to the position that I accept that we live in a capitalist society and that the drug industry is going to continue to be run as a for-profit endeavor. I have called for a lot of changes in how the industry, medicine, and government all do business, but have not called for nationalization of the industry or making it a public utility.

I may be accused of similar wimpiness in my recent book, The Golden Calf (see http://brodyhooked.blogspot.com/2011/11/shameless-commerce-division-new-book.html). I there attack economism, the belief in an unregulated free market as the solution to all human social problems. But to the extent that I offer a vision for an improved future, it's largely a return to the capitalism of the 1950s where the power of government and organized labor helped balance out the excesses of big business, and not the overthrow of capitalism.

I cannot honestly report that I have a deep philosophical commitment to capitalism, though I am persuaded by authors such as economist-philosopher Amartya Sen that basic respect for human rights and human liberty has to include respect for rights to participate in fair markets. My overall goal has been strategic rather than philosophical. I am trying to get the attention of readers, most especially my fellow physicians and health professionals. If the position from which I started is anti-capitalist, I could expect that hardly any of them would read beyond the first sentence. If I stay under the capitalist big tent and specifically detail the problems with medicine and Pharma, maybe at least a few more of them will pay attention.

Is that a coherent and responsible position to take? The beauty of a blog is that y'all get to decide.

Yet More from the Belly of the Beast: Pfizer's Campaign to Market Neurontin Off-Label

Thanks as so often to Dr. Roy Poses over at Health Care Renewal--
http://hcrenewal.blogspot.com/2012/10/when-clinical-trials-are-meant-for.html
--we are alerted to the recent publication by S. Swaroop Vedula and colleagues:
http://www.trialsjournal.com/content/13/1/136

These authors were part of the team that testified in lawsuits brought against Pfizer related to the drug Neurontin (gabapentin). As a result they had access to a trove of internal e-mails and documents. Here they report their analysis of these documents, from two separate legal actions in 2004 and 2008, providing a longitudinal account of how the company approached publication of clinical trial data on gabapentin for off-label uses. (The drug was approved by the FDA for two relatively narrow indications, epilepsy and post-herpetic neuralgia;and the company wanted to extend sales by showing that it worked also for migraine, bipolar disorders, neuropathic pain, and nociceptive pain.)

First the authors documented: "For each of the four off-label indications we included in our study, a document titled ‘marketing assessment,’ designed to examine the financial impact of seeking FDA approval for a new indication versus other methods of increasing sales for the indication, preceded clinical trials sponsored by Pfizer ..." That is, before the company or independent academic scientists had a go at designing and conducting a clinical trial, the marketing people already had their innings and decided on the overall strategy. In this instance, the key decision was not to try to gather data that would allow an aplication to the FDA to expand the approved indications for Neurontin, but to find data that would support off-label prescribing for that usage. And that key decision was made not based on the scientific results of clinical trials, but before the clinical trials were even begun. A critical difference is that if the company had approached the FDA, they would have been legally required to hand over all study results, both favoring the drug and not; while by going the off-label route, they could cherry-pick what they published, as we'll come to. (Reminder: a company cannot legally market a drug for off-label use directly, but its physician "key opinion leaders" are free to recommend off-label use so long as it seems to be at arm's length from the company. Today, drug reps can also hand out trial report reprints that support off-label use, hence the need to publish trials that are favorable.)

The other main reason, besides more control over publication, was that the patent on Neurontin was about the expire and it made no business sense for the company to expand its use just as the drug was about to go generic. In one instance, the decision as to publication of negative results seems to have been driven by the form's "evergreening" strategy, which was to roll out the "new" drug pregabalin as a me-too drug to replace gabapentin as their expensive, heavily-marketed brand-name drug. As pregabalin was about to be launched, the company may have wanted negative trials published about Neurontin, so as to lay the groundwork for later being able to claim that pregabalin was really head and shoulders better than its predecessor.

The next major finding from the authors was, "According to the internal company documents, 'affiliate-driven manuscripts' were written for Pfizer ... by [Medical Action Communications, a medical communication company] and sent to the authors for approval. Each article was coordinated by a manuscript team, consisting of representatives from the medical and marketing divisions of the company." This suggests that ghostwriting--having paid writers spin the research papers the way the company wanted them, and only then letting the scientific "authors" see the drafts of the papers--was simply standard operating procedure within the company. The entire process showed that Pfizer, and especially its marketing division, kept everyone involved in the publication of a paper on a short leash.

Finally, the authors demonstrated that the journals in which papers were published, and the timing of publication, were also chosen for maximum marketing impact--for instance, with positive results published in high-impact journals and published quickly, and with negative results showing up in low-circulation journals years later.

As the authors summarize: "In this study we also observed that publication occurred in journals with higher or lower circulations related to statistical significance of findings; delay in publishing statistically non-significant findings; tailoring of publication content to reflect key marketing messages; adding spin to scientific publications such that conclusions favoring gabapentin were emphasized and conclusions that did not favor gabapentin were explained away; and indicators of ghost authorship. Each form of bias, and spin, on its own, could be seen as a relatively minor issue. The value of our findings is in the overall picture that emerges from what appears to be the simultaneous use of many forms of reporting bias and spin, all within the context of a pharmaceutical company’s publication strategy, implemented for marketing purposes."

So-- it's all about the marketing, and not about the science. No big surprise here, but further documentation of what we've had reason to believe from all previous reports of this type.

Now, I sort of hate to keep beating up on editor Jeffrey Drazen of the New England Journal:
http://brodyhooked.blogspot.com/2012/09/nejm-overly-defensive-or-just-naive.html
--who as previously reported said we should not judge articles based on who sponsored the research but on the quality as depicted in the published paper. What Dr. Vedula and colleagues show us is that if a paper that's positive about a new drug shows up in Dr. Drazen's high-impact journal, we can be reasonably sure that there are 3-4 other studies with much less impressive, or even negative results, which are kept aside to be not published at all, or else published in much-lower-circulation journals many years later--or at least that's the standard business plan within the industry. And of course there's no way on this green earth that even the most fastidious reader of NEJM could ever know that. So much for being able to read a paper in the journal and then draw your own conclusions.

More on Sponsorship of Studies in Medical Journals

In my last post: http://brodyhooked.blogspot.com/2012/09/nejm-overly-defensive-or-just-naive.html
--I took off after an editorial in the New England Journal defending industry sponsorship of trials, saying that you should decide whether a trial is trustworthy based on reading its methods, not based on who sponsored it. My rebuttal is that many of the features that make results untrustworthy simply cannot be gleaned from reading the published report in the journal.

Here's the other side of the coin--things that make results untrustworthy that the alert reader can spot.

Again tipping my hat to Rick Bukata and Jerry Hoffman's Primary Care Medical Abstracts, I come across a study by Drs. Michael Hochman of UCLA and Danny McCormick of Harvard:
http://www.springerlink.com/content/8h66774155415128/

These guys looked at several ways of reporting results that overestimate benefits:

• Reporting relative vs. absolute risks
• Reporting surrogate endpoints rather than significant changes in health
• Reporting composite endpoints instead of reporting each endpoint of interest separately
• Reporting only disease-specific mortality instead of all-cause mortality

If people write in and request I'll explain why each of these overestimates benefit from drugs.

Drs. Hochman and McCormick then compared how likely it was that a study would report results in these ways, based on who sponsored the study. They found significant differences in two categories. Exclusively industry-sponsored studies were more likely than studies with at least some non-commercial support to report surrogate endpoints (45% vs. 29%) and disease-specific mortality (27% vs. 16%).

Now, if you wanted to defend the NEJM editorial position, you could say that readers of studies can readily see how the data are reported according to these criteria and can be wary of any study, regardless who funds it, that reports data in the less desirable way. But let's give the last word to Drs. Hochman and McCormick, in their final recommendations: "These findings highlight the need for educational efforts to ensure that readers understand the complexities of these endpoints and of relative risk reporting. ... In addition, Institutional Scientific Review Committees and regulatory agencies (e.g. the FDA) must closely examine the endpoints used in clinical trials and discourage the inappropriate use of surrogate and composite endpoints, and endpoints involving disease-specific mortality. Finally, medical journals may consider instituting editorial policies mandating the reporting of results in absolute numbers."


In other words, rather than asking readers to sift through whether the results are reported in a useful and valid fashion, medical journals like NEJM could simply refuse to publish papers that don't adhere to the highest standards. Of course, if they did, they might lose revenue as drug companies would not buy so many expensive reprints of papers that are really useful for marketing drugs--which may be one of the roots of the problem.