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Posted on Friday 20 May 2016


Under the Influence: the Interplay among Industry, Publishing, and Drug Regulation.
by Lisa Cosgrove, Steven Vannoy, Barbara Mintzes, and Allen Shaughnessy
Accountability in Research. 2016 23[5]:257-279.
[full text on-line ?]

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 Through a critique of published and unpublished trials submitted to the Food and Drug Administration [FDA] and the European Medicines Agency [EMA] for approval of a new antidepressant, vortioxetine, we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.

This article differs from the others in this series in that it is primarily a perspective/opinion piece about the intersection of industry, the medical literature, and the regulatory processes that uses the recent FDA approval of Vortioxetine [Brintellix®] as an exemplare. It’s a well-framed discussion of a complex issue, offering suggestions for reform. While some may not agree with their emphases or solutions, it’s an excellent "big picture" article – a thoughtful contribution. But specific to the Vortioxetine theme from the last post [publication bias II – close encounters of the second kind…], their research into the Vortioxetine RCTs is definitely value-added to the other reports. And it’s another example of a contrarian article that they had a really hard time getting published.

Cosgrove et al looked at all the Vortioxetine trials, published and unpublished, and introduced a term I hadn’t run across before – Ghost Management. Just saying an article is ghost-written doesn’t tell the whole story, because the ghost-writer is employed by the RCT’s sponsor. Ghost Management is much more accurate in that it conveys the extent of the sponsor’s control over the entire RCT process. I found some of their findings jarring, even after my years of reading these reports. For example, the extent of industry COI:
Vortioxetine is typical of virtually all new drugs in that the pre-market RCTs were all sponsored by the manufacturer. However, congruent with commercialized publication planning, every author in all of the published short term RCTs, as well as one longer term randomized drug withdrawal study, had significant commercial ties to the manufacturer, well beyond research funding [e.g., they were employees, participated on advisory boards, and/or had received consulting monies or honoraria]…

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:
  • 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.
  • 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.
  • 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…
It had never occurred to me to look at the COI of the journal editors. Another finding – one of their suggestions is that the FDA consider all trials instead of the best ones, and take the performance against comparators into account. They produced this meta-analysis across trials:
At this point, my usual M.O., having highlighted a few "teasers," would be to suggest you read the whole article yourself. There’s plenty more I haven’t mentioned. But, in this case, you can’t read it. I can’t either. My usual resource for access is through my faculty connection to our library. But lthough the journal is indexed, it offers no provision to read the article [unusual]. On-line, it’s not Open Access but behind a $41 pay wall. Making it Open Access would’ve cost the authors ~$3000, a mighty stiff fee for any academic [but trivial for PHARMA]. I had written Dr. Cosgrove to ask if she had cataloged or written about their Hegira looking for a publisher. She hadn’t, but she mentioned in passing that they were disappointed with the response to their article. I don’t doubt that, since the only people who can read it are subscribers to Accountability in Research, rich people, or those who have written the authors for a copy. It’s hidden under a bushel, or so I thought. But then I discovered ResearchGate! And got to the paper full text even before I joined [which I later did]. That’s where that [full text on-line ?] link came from. Definitely check out ResearchGate if you haven’t already. And however you get this article, it’s well worth the trouble.

So back to the main theme here. This is a solid article that shouldn’t be hard to publish. Credentialed authors. Well researched. Thoughtful analyses. Certainly relevant. But it’s contrarian. It swims upstream against the conclusions the original authors presented. And those articles are [to say it yet again] hot potatoes, just like Juriedini, Amsterdam, and McHenry’s paper. In this case, the research on the Vortioxetine [Brintellix®] trials adds an essential dimension to those papers mentioned in the last post. This is just not an Impact Factor 0.826 article. So is this a form of publication bias? Close enough for me, but I’m open for any other name as long as it says that it’s not right. Well documented dissent is [and has always been] an integral part of the scientific process…

Publication bias is the term for what occurs whenever the research that appears in the published literature is systematically unrepresentative of the population of completed studies. Simply put, when the research that is readily available differs in its results from the results of all the research that has been done in an area, readers and reviewers of that research are in danger of drawing the wrong conclusion about what that body of research shows…
  1.  
    Joseph Arpaia
    May 21, 2016 | 10:14 PM
     

    You know I have never understood why new drugs don’t have to compete with competitors, only against placebo. Well I understand the reason from the drug-company’s perspective, but there is no one else who benefits. And no other product is tested that way.

    Toyota doesn’t test a new model care against a bicycle.
    Apple doesn’t test their new computers against an abacus.
    The army wouldn’t test a new tank armor against cardboard that looked like tank armor (placebo armor).
    We don’t test antibiotics against placebo either, or at least I haven’t seen any such studies.

    I know studies against a comparator can be fudged but it seems like it would raise the bar a bit.

  2.  
    Bernard Carroll
    May 23, 2016 | 7:14 PM
     

    I just love this comment. It gets to the guts of the FDA’s role, which was gutted out by Congress. Just a de minimis proof of efficacy is all they are allowed to demand. That means 2 pivotal trials against placebo, no matter how many failed trials also were conducted.

    The humbug reason given by Pharma and the KOLs for licensing me-too drugs with no therapeutic advantage is the mantra that a larger number of therapeutic options is better in the long run (because patients may not tolerate the standard agents).

  3.  
    James OBrien, M.D.
    May 24, 2016 | 10:24 AM
     

    FDA is the TSA of American medicine.

    They’re managed to do the impossible, have minimal standards, yet make the process extraordinarily long and expensive.

    Kind of like TSAs long wait lines, lots of cost and inconvenience, but they fail to actually make things any safer for the public.

    I know this is a quaint notion, but how about eliminating the FDA and let the states handle this issue like they do with medical licensing? Constitutionally, the federal government has no business in this area. I know they don’t care, but how is that working out?

    Some states will do a better job than others. That’s what is supposed to happen.

    It’s not a perfect idea. California will certainly screw it up, because, well it’s California where vaping is the devil’s work and marijuana is the cure for everything.

  4.  
    James OBrien, M.D.
    May 25, 2016 | 11:43 AM
     

    I’m going to respectfully disagree and support me-too drugs on two principles.

    1. No therapeutic advantage in populations does not mean no therapeutic advantage in an individual. Though the NNT is about the same for all antidepressants since 1988, we’ve all had patients who can’t tolerate one but do well on another. Let’s not fall into the trap of thinking like UR on this.

    2. I think pretty much everyone here agrees the monopolies are bad. See the Shkreli threads. The way who beat a monopoly is to allow a competitor.

    What’s a lot worse than slightly effective but overrated SSRIs is a world where Prozac is the only one, which would be the case if the newer drugs had to “beat” it in Phase 3.

    “Me too” is a problem, but there are better ways to address it. I’ve suggested having a national or international prize which is how England solved the Longitude Problem.

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