The residue of undue influence we call Conflict of Interest spreads like jungle vines in an deserted temple, and the longer the absence, the harder the restoration. In a recent [silly] JAMA Viewpoint article,
JAMAby Anne R. Cappola and Garret A.September 24, 2015
we were told Conflict of Interest was a pejorative term and should be changed to Confluence of Interest [in a bid to suggest something like synergy]. While our collective eyes rolled at the time [see a creative rationalization…,, selective inattention… have no place…], there’s a way in which the term is appropriate – as in a confluence of rivers, where contamination is guaranteed. And to push my analogy, the further you go downstream, the more muddied the distinctions. In following the Brintellix® for Cognitive Dysfuntion in Major Depressive Disorder story [a parable…], I ran into a examples where the COI laden literature is what seems headed downstream – into the future. Both of the supporting studies and a pre-emptory review article are available full text on-line – industry funded, industry designed, industry written, authors industry tainted or employed:
On the other hand, a well researched critique of the literature about Brintellix® and its approval are behind a $41 pay wall in an otherwise inaccessible journal [to have made it available Open Access would have cost ~$3000]:
by Lisa Cosgrove, Steven Vannoy, Barbara Mintzes, and Allen ShaughnessyAccountability in Research. 2016 Feb 18. [Epub ahead of print]
The relationships among academe, publishing, and industry can facilitate commercial bias in how drug efficacy and safety data are obtained, interpreted, and presented to regulatory bodies and prescribers. Through a critique of published and unpublished trials submitted to the Federal Drug Administration [FDA] and the European Medicines Agency [EMA] for approval of a new antidepressant, vortioxetine, we present a case study of the "ghost management" of the information delivery process. We argue that currently accepted practices undermine regulatory safeguards aimed at protecting the public from unsafe or ineffective medicines. The economies of influence that may intentionally and unintentionally produce evidence-biased-rather than evidence-based-medicine are identified. This is not a simple story of author financial conflicts of interest, but rather a complex tale of "ghost management" of the entire process of bringing a drug to market. This case study shows how weak regulatory policies allow for design choices and reporting strategies that can make marginal products look novel, more effective, and safer than they are, and how the selective and imbalanced reporting of clinical trial data in medical journals results in the marketing of expensive "me-too" drugs with questionable risk/benefit profiles. We offer solutions for neutralizing these economies of influence.
POINT 1: The Literature is what persists
In medicine, the thing that lasts is the published academic literature. Blog posts and press releases will evaporate sooner or later. So what will be available long term full text on-line will be those industry funded, industry designed, industry written, industry authored articles. In time, Cosgrove et al will require an archeologist to locate after a few years. It’s already hard enough. It’s because the industry funded ghosted studies come from deep pockets for whom the online fee is nothing, and because they’re in high impact journals. The critiques are hard to get published, usually unfunded, and there’s no loose petty cash to pay the Open Access fees. That’s one of the reasons for RIAT [Restoring Invisible and Abandoned Trials], to keep the other side of the story in The Literature [downstream]…
So what’s being passed to the future is the COI laden story, not the balancing independent, unfunded critique. Sooner or later, I’ll review their whole paper, but right now I wanted to focus on one particular piece of it. In looking over a new article, many of us reflexively look at the Conflict of Interest declarations and the funding to see if a clinical trial is industry funded and authored. A few years ago, we checked to see if the academic authors had COI and if it was ghost written. But they tightened the rules, and it hasn’t much mattered. The COI is now quickly apparent as well as the whatever-they-call the ghost-writer. Often they don’t even bother to have an academic author these days, just employees. And it doesn’t seem to make any difference except to cut down on the sponsors publication costs [which makes one wonder why an academician-free article is even in an academic journal anyway?]. We’ve apparently gotten enured to what was once taboo.
But Cosgrove et al added something that hasn’t occurred to me, and I haven’t noticed before. In looking at the COI, they went beyond the listed authors:
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In eleven of the thirteen publications, the majority of authors were employees of the manufacturer, and in four of the thirteen published studies, all authors were company employees.
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In all of the trial reports, the authors explicitly thank an employee of the manufacturer for “assistance in the preparation and writing” of the manuscript or note that assistance with preparing and writing the article was provided by an employee.
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In nine of the thirteen published articles, the following issue was disclosed:
“[the manufacturer] was involved in the study design, in the collection, analysis and interpretation of data, and in the writing of the report.” -
The thirteen published studies were published in seven academic journals. The editors of five of these journals had financial ties to vortioxetine’s manufacturer…
Below is a summary of the industry-publishing relationships of the eight published studies submitted to the FDA and one additional study submitted to the EMA that was published…
POINT 2: The Editors control The Literature
It’s number 4. They looked into the financial conflicts of interest of the Journal Editors. Of course we should’ve been doing that all along. It’s the Journal Editors that control the gateway into The Literature. It was Editor Myna Dulcan who opened the door to Paxil Study 329 and it is Editor Andres Martin who has kept it there for 15 years. It’s Jeffrey Drazen who wants to relax COI restrictions at the NEJM and thinks people who want to check articles are "parasites." If there’s any place where COI is a more important parameter, I don’t know where that might be. I would’ve naively assumed they didn’t have COI. Silly me.
So, while I believe that the idea of RIAT [Restoring Invisible and Abandoned Trials] remains a good solution for articles that are found to be questionable, there are lots of articles that can be identified almost from the get-go as in need of a strong counterpoint which is one part of what Cosgrove et al did in their article. So for POINT 1, we need more of those, but we also need some way to give people access to them – whether that means publishing in an Open Access journal, establishing journals for that specific purpose, or raising some money to give authors of those articles scholarships to pay Open Access fees. Contemporary criticism needs to travel alongside questionable literature as it rides into the future. And as for POINT 2, point taken! In any article that appears to be COI-laden, we need to make the COI declaration of the Editor[s] a public part of any critique…
“The motives of the people working on DSM 5 have often been questioned. They have been accused of having a financial conflict of interest because some have (minimal) drug company ties and also because so many of the DSM 5 changes will enhance Pharma profits by adding to our already existing societal overdose of carelessly prescribed psychiatric medicine. But I know the people working on DSM 5 and know this charge to be both unfair and untrue. Indeed, they have made some very bad decisions, but they did so with pure hearts and not because they wanted to help the drug companies. Their’s is an intellectual, not financial, conflict of interest that results from the natural tendency of highly specialized experts to over value their pet ideas, to want to expand their own areas of research interest, and to be oblivious to the distortions that occur in translating DSM 5 to real life clinical practice (particularly in primary care where 80% of psychiatric drugs are prescribed).”
https://www.psychologytoday.com/blog/dsm5-in-distress/201212/dsm-5-is-guide-not-bible-ignore-its-ten-worst-changes
Drs. Dulcan and Martin have made poor decisions that have done a disservice to the clinician members of AACAP and clinician readers of JAACAP. The absence of financial COI is immaterial. Hubris, bias, and favoritism need not necessarily originate from financial interest.
http://carlatpsychiatry.blogspot.com/2010/05/hot-city-empty-exhibit-hall-and-stern.html
And then there are the Marty’s
http://www.healthyskepticism.org/files/docs/gsk/paroxetine/study329/20000627Dulcantokeller.pdf
As you reference here:
http://1boringoldman.com/index.php/2011/05/07/retract-study-329/
“JAACAP represents a collaborative effort designed to disseminate research findings and facilitate discussion within our community. The scientific process is one of continual evolution – a cycle that advances with each new replication, refinement, or rejection of past findings. Under the vast umbrella of scientific research and reporting, we must always make room for opposing views and varying interpretations. There can be no final word on any subject, but our common goal must be the same: to advance the science of pediatric mental health and to promote the care of youth and their families.”
Self-righteousness and pomposity go a long way.
With or without financial COI.
http://study329.org/wp-content/uploads/2015/09/Mina-Dulcan-Interview-Transcript1.pdf
Starting on page 2 with “Well, if you were a lay person, yes, it would, but if you were one of us reading that you don’t read that sentence.” and ending with
“If you were say a general practitioner you might not.” on page 4.
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That is not a financial COI. It more so appears to bespeak hubris and a lack of clarity of thought. Which seems a poor combination in an editor in chief.
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There is a particular irony to that last quote from Dulcan when you consider:
“Q: Do you think the prescription of antidepressants by family MDs and pediatricians are part of the problem?
A:No. I think it is critical that we find treatments that primary doctors can use. They are the 1st line of therapy for uncomplicated depression.”
https://lists.ufl.edu/cgi-bin/wa?A3=ind09&L=PSYCHIATRY-L&E=quoted-printable&P=106066&B=–0016e648084270a1ff046cf4f923&T=text%2Fhtml;%20charset=windows-1252
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Also note the last paragraph of the first page of Varley’s commentary here: http://jama.jamanetwork.com/article.aspx?articleid=197154 It helps illustrate the clarity of what Dulcan chose to publish, even for “one of us” who would “perfectly well understand it.”
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This is behind a paywall I can’t access today. Wonder if in the NEJM the 2001 Keller paper was represented, unlike those lay people might, as “not actually a thrillingly positive study.”
http://www.nejm.org/doi/full/10.1056/NEJMcp012249
Or here for that matter:
http://www.tandfonline.com/doi/abs/10.3810/pgm.2002.09.1300
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Limitations section is on page 9 of the pdf at this link:
https://www.justice.gov/sites/default/files/opa/legacy/2012/07/02/complaint-ex2.pdf
It discusses the high placebo response rate and that the trial was not a direct comparison of imipramine and paroxetine.
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The Editors control The Literature.
Dr. Dulcan was editor in chief of JAACAP for 10 years.
Hubris, close mindedness clothed in pompous statements, would appear to be just as dangerous as financial COI.
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The contrast between the reality in that interview above, and the hyperbole below, is saddening.
http://psycnet.apa.org/psycinfo/2007-18374-001
Sometimes it feels like the more often the phrase “the science” is used, the less often that is really what is being referenced.
Without openness to replication at all levels, there can be no science. What passes for science in large sectors of biomedical research–especially the variety that leads to FDA market approval–fails the basic test of Karl Popper’s falsifiability doctrine for distinguishing between empirical science and non-science.See: https://en.wikipedia.org/wiki/Karl_Popper#Falsifiability.2Fproblem_of_demarcation
Your critique amply documents the antics and accompanying corrupt motivations of debased biomedical researchers, the industry and government that lend financial support, and the true parasites amidst it all–the editors of biomedical research journals. It’s ironic that all of this plays out in the name of contributing to “the future good of society.” But perhaps not ironic as much as predictable . . . charlatans typically appeal to the loftiest of ideals in when working a scam.
And please don’t forget that those compromised studies will be endlessly recycled into review articles, textbooks, practice guides, and the “common wisdom” to which most physicians refer for “evidence-based” decision-making.
1bom,
May be of interest:
http://www.economist.com/news/science-and-technology/21695381-too-many-medical-trials-move-their-goalposts-halfway-through-new-initiative
1bom,
Know you’ll see this/have seen this. But, seemed relevant enough to the topic at hand to mention:
http://blogs.plos.org/mindthebrain/2016/03/31/remission-of-suicidal-ideation-by-magnetic-seizure-therapy-neurononsense-in-jama-psychiatry/
http://blogs.plos.org/mindthebrain/2016/03/24/getting-realistic-about-changing-the-direction-of-suicide-prevention-research/