Can You Test A Drug And Also Say Negative Things About It? 8

In my last post I raised the possibility that Steve Nissen, a highly influential cardiologist who has been an outspoken critic of industry influence in medicine, might have his own conflict of interest (COI) problem. In response, another cardiologist, James Stein, said that my post was unfair in its treatment of Nissen and failed to consider important distinctions and subtleties in the academic literature about conflict of interest.

Let me first of all confess that Stein– for whom I have the highest possible regard– makes some excellent points. And I further admit that my piece pretty much ignored some of these fine academic distinctions. But I also think it’s likely that we may have a forest and trees situation here and that by focusing on subtle COI distinctions it is possible to lose sight of the larger issue.

A Simple Test

Rather than focus on the subtle distinctions between different types of COI I’d like to propose a much simpler way to think about this problem as it exists in the real world. Here’s the test I would propose: can you imagine Nissen, or indeed anyone in a similar situation (running a large multimillion dollar trial of a drug) publicly saying something decidedly negative or critical about the drug?

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Steven Nissen, Conflicts Of Interest, And The New Cholesterol Drugs 6


Does Steve Nissen, an outspoken critic of inappropriate industry influence in medicine, have his own conflict of interest problem?

This week Nissen, the chief of cardiology at the Cleveland Clinic, was widely quoted in news reports about the FDA advisory panels evaluating two new highly promising cholesterol drugs from Amgen and Sanofi/Regeneron.

Nissen was broadly supportive of the drugs. Although he has been one of the leading voices against approving and using drugs based solely on their effect on surrogate outcomes, he was much more liberal about these drugs than some other experts and many of the panel members. Here’s what he told CNBC:

“I am somebody who generally is opposed to approving drugs on the basis of surrogate endpoints without the outcome data,” Nissen said by telephone Wednesday, referring to lowering of LDL cholesterol already shown by the medicine. “However, in this case, I actually support approval and I actually think the concerns of the committee are not on target.”

On the NBC Nightly News program he was even more effusive:

“These drugs are breakthrough drugs, they are blockbuster drugs that are very likely going to have a big impact.”

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Our Limitless Capacity For Self-Deception 10

I want to share with my readers a recent post and accompanying comment published on CardioExchange. The original post is by Eric Lindley, a cardiology fellow at the University of Utah:

Journal X: Not so Subtle Marketing Messages

I was the rare resident who thought that conflict of interest issues in medicine were a bit overblown. I did not find (or ignored) the evidence that pharma played a role in prescribing habits very persuasive, at least not when it came to my personal prescribing habits. I was not alone among the house staff, however, in appreciating an occasional “free” lunch, and the much rarer sponsored dinners at places I couldn’t afford as a physician-in-training.

Now I’m a fellow, and my attitudes about the pervasiveness of pharma influence have changed. Am I older and wiser? I’d like to think so. But I owe most of my conversion to the fresh perspective of my three-year-old daughter. She refers to most things by their color, including a majority of my medical journals. For instance, my JACC journals: blue for the mother journal, red for heart failure, green for interventions, etc. But then she started calling the original JACC the “X” journal. When I asked her why, she pointed to the “X” in Xarelto (rivaroxaban). I realized that every issue of JACC is covered front to back with the “X”. The message was subliminal to me, but quite obvious to her.

How do you think all of our pharma marketing looks with naive eyes?

This post prompted the following response from Siqin Ye, a cardiology fellow at Columbia University:

A story that I heard at ACC a few years ago goes something like this:

In a roomful of interventional cardiologists, the speaker asks, “How many of you have ever put in a stent that was unnecessary?”

Two or three hands went up.

The speaker then asks, “How many of you have seen someone in this room put in a stent that was unnecessary?”

About half the room raised their hands.

I think there is something similar with respect to our attitude towards pharma ads and gifts. I know plenty of residents and fellows who firmly believe that ads and dinners do not affect their personal practice patterns. Whether or not this is true for any given individual, the fact that pharma continue to spend so much on these activities suggest that as a whole, we are probably more susceptible than we believe.

 Thanks to Drs. Lindley and Ye for permission to reprint their words.


‘Bias in choosing the question is a much bigger issue than lying about the data’ Reply

Robert Califf takes questions about conflict of interest from Harlan Krumholz. Here are a few choice quotes. Read the entire Q&A on CardioExchange.

…focusing exclusively on the medical products industry and failing to consider other sources of conflict of interest is a huge mistake and leads to sensationalism that then engenders reactive rules that add to bureaucracy rather than addressing the real issues.

…a despotic, egotistical principal investigator can be just as dangerous as a controlling funding organization. Like our constitution, trials need a balance of power…

Bias in choosing the question is a much bigger issue than lying about the data.

…lying about the data is rare. Lying by omission (not looking at aspects of the data) is much more common.

Guest Post: Why Is The National Library Of Medicine Still Indexing Reviews In Cardiovascular Medicine? Reply

The following guest post by Kevin Lomangino was originally published on Lomangino is an independent medical journalist and editor who is currently Editor-in-Chief of Clinical Nutrition Insight, a monthly evidence-based newsletter which reviews the scientific literature on nutrition for physicians and dietitians. He tweets as@Klomangino.

Why Is the National Library of Medicine Still Indexing Reviews in Cardiovascular Medicine?

by Kevin Lomangino 

Last week, a study looking at off-label drug promotion reported a finding that was considered “unsurprising and disturbing” by some observers: Only 15% of physicians and scientists touting such off-label uses disclosed that they had relevant financial relationships with the manufacturers who produced the drugs.

I’ll admit to some surprise at the extent to which these authors appear to have systematically hoodwinked their readers. But it’s true that the basic problem identified by the study – that scientific authors sometimes fail to disclose financial relationships that might influence their writing – is nothing new. In fact, the study brought to mind a troubling example of inadequate disclosure I wrote about here in February. And it inspired me to complete this follow-up post that I’ve been putting off for some time.

First, some background: The piece I wrote in February focused on a cardiology journal, Reviews in Cardiovascular Medicine (RICM), that engages in questionable editorial practices that promote commercial interests. The journal was first flagged by blogger Marilyn Mann for publishing an article, sponsored and reviewed prior to publication by pharmaceutical manufacturer Abbott, extolling the benefits of Abbott drugs for the prevention of cardiovascular disease.  After some more poking around, I found that the RICM editors also repeatedly failed to disclose—and in some cases, appeared to be actively concealing through misleading statements—relationships with other manufacturers whose products they were writing about in the journal. (I continue to welcome any attempt by these editors to explain the discrepancies identified, in case I’ve got the wrong idea.)

As far as I know, there haven’t been any negative repercussions for RICM or its editors stemming from my post or other critical coverage. (In fact, the editors are so unconcerned that they didn’t even bother to update their disclosure statements on the RICM website, which as I pointed out months ago are woefully out of date and inaccurate. ) This isn’t all that unusual, really, considering that even authors who participate in fraudulent research don’t face much in the way of consequences for their actions. It seems that the dollar value these authors bring to their institutions trumps any ethical qualms about their publishing activities.

If RICM were a subscription-based business, readers might have an opportunity to lodge a protest by refusing to renew their subscriptions. RICM, however, is sent out free of charge through support from industry sponsors. And it seems that companies are all too happy to have RICM’s editors serving as their pitchmen.

There is one organization, though, that I had hoped would have more than a passing interest in meting out some discipline to RICM: the National Library of Medicine (NLM).  As the curator of PubMed, the world’s foremost index of the scientific literature, the NLM has an obvious stake in assuring that the journals it indexes adhere to high editorial and ethical standards. And as it turns out, NLM even has a specific policy that seems designed to prevent the kinds of shenanigans that RICM engages in.
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Industry PR Efforts Influence Debate On Cholesterol Screening Guidelines For Children 4

Note: This post is accompanied by a separate guest post by James Stein.

What role should industry play in discussions about guidelines, especially when the debate about those guidelines includes allegations that industry may have influenced the final product of the guidelines? Should a public relations agency that represents a company with a product that would be affected by a guideline offer journalists a chance to interview an expert who has views that might benefit the company?

Let me first set the stage. An important debate assumed public form last November following the publication in Pediatrics of new NHLBI guidelines recommending universal cholesterol testing for children. The debate heated up earlier this year with two JAMA articles containing biting criticism of the guidelines, one of which was co-authored  by a dissenting member of the guidelines committee. Now the controversy has flared yet again, with the recent appearance of two articles in Pediatrics, one attacking the guidelines and the other a defense of the guidelines by several members of the committee.

Before getting into the role of industry in this debate, I first want to emphasize that the  scientific and public health issues involved in this debate are of the highest possible importance. Cardiovascular disease remains the number one killer in the world, and although efforts to reduce cardiovascular disease have achieved remarkable success in recent decades, the rising tide of obesity and diabetes threatens to roll back much of this progress and is reshaping (literally and figuratively) childhood and adolescence. So prevention of cardiovascular disease, which starts in childhood, is a very major concern which deserves serious discussion.

An excellent example of the type of discussion we need is provided in an accompanying article by James Stein. His eloquent piece provides a thoughtful perspective and overview of the debate. I don’t have much to offer beyond what Stein writes, but in this piece I’d like to present a recent and highly relevant anecdote that might help illuminate the part of his discussion about the role of industry influence in this debate.

A few days after the publication of the Pediatrics papers, I received an email message from a public relations agency. Here it is (names and other identifying details redacted):
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Guest Post– Universal Screening for Dyslipidemia In Children: A Debate With Equipoise, But Tarnished By Industry Influence 2

Editor’s Note: CardioBrief is pleased to publish this guest post written by James Stein, a professor of medicine at the University of Wisconsin and the director of preventive cardiology at the University of Wisconsin Hospital and Clinics. This post is accompanied by a separate post by Larry Husten.

Universal Screening for Dyslipidemia in Children:  A Debate with Equipoise, but Tarnished by Industry Influence

 by James H. Stein, MD

As a strong proponent of heart and vascular disease prevention and a parent of two teenagers, I have watched closely the debate about the new Pediatric Lipid Guideline recommendation for universal lipid screening at ages 9-11 years (1-5).  The physicians and researchers on both sides of issue are intelligent, thoughtful, and honest advocates for their positions regarding universal screening, a question that truly has scientific equipoise.  In this post, I will briefly describe my position, and hopefully sound a clarion about the influence of the medical industry on this debate.  My discussion of industry’s role will emphasize evidence from the social science literature about conflicts of interest, so we can move beyond name-calling, moralizing, and emotional responses to this serious issue.

Universal Screening for Dyslipidemia in Children

I oppose universal lipid screening for children, primarily for the reason that Matt Gillman so eloquently described: because “the harms of screening fall disproportionately on the healthy” (2,5). To be clear, the potential harms of universal lipid screening in children, just like its potential benefits, have never been proven. So we are operating in a data vacuum and have scientific equipoise.  What are the potential harms?  First, increased medical costs, which are born by society, and second, the “medicalization” of lipid values that make children at no short- or even intermediate-term risk of cardiovascular disease (CVD) events, in some way, abnormal.   Risks of “medicalization” include stigmatization, labeling, and the practical inconvenience of having every 9-11 year child fast for 12 hours, twice, to get poked with a needle, when the most likely outcome is that they’ll be told that they need to eat a healthy diet and exercise.  Of more concern is the astute point raised by Newman et al. that girls have higher cholesterol levels and are more likely to get labeled and treated, but paradoxically are at lower CVD risk (2).  In regard to dietary interventions like the CHILD-1 diet, it is not clear to me why healthy eating patterns would not be recommended to all children and families, regardless of their lipid status. In regard to the safety of statins in children, I would argue that the evidence base is slim and likely biased.  What is known about their efficacy in children is limited to their effects on surrogate markers.  Although it is likely that long term use of statins will reduce CVD risk in children with hyperlipidemia, we have to be honest and recognize that changes in lipid levels and carotid intima-media thickness are not the same as reductions in CVD event rates.  The chain of evidence is present, but the links are weak.  Accordingly, we have scientific equipoise, not the scientific basis for a strong public health recommendation.

One good point for universal screening – previously raised by Marilyn Mann in a comment on – is that after kids leave home, they often drop out of medical care for a time, so it is easier to identify them when young, even if they do not get treated. It is a fair point, but in my opinion, does not justify screening all children, to find the small number of kids with familial hypercholesterolemia (FH) who would not have been identified by targeted screening. However, this is a question that could be addressed, in part, by mathematical modeling (2).  The guideline writers would have strengthened their case if they had presented an analysis of the number of new FH cases identified with universal screening,  the number of cases of “dyslipidemia”  identified, the number of true and false positives and negatives, as well as the costs and effectiveness of the screening program that they proposed.   It would be a challenging and imperfect analysis, but one that should have been done before the guideline was approved, rather than being left to future researchers.

For the record, I have declined to have my kids screened, even though we are in a purportedly higher risk group (Ashkenazi Jews).


The Influence of Industry on the Universal Screening Debate

The debate about universal screening is a fair and important one, but the influence of industry interferes with our ability – indeed, our obligation – to honestly debate and discuss this important public health issue.  It is amazing that every time the specter of conflict of interest is raised, doctors and researchers get pretty edgy.  You can literally see the hairs rise on their backs. And of course, everyone is an expert on this issue and no one is biased.  That is unfortunate, because a strong social science literature has taught us that everyone is biased (6). To illustrate this point, let’s focus on some of the guidelines writers’ responses.
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Industry Supported Editorial Assistance: The Debate Continues 3

Editor’s Note: Here is the latest installment of a debate over industry-sponsored editorial assistance between Tom Yates, a UK-based physician critical of the role of industry in medical publishing, and Karen Wooley, who owns a medical education company and is a representative of the the Global Alliance of Publication Professionals (GAPP). (The previous installments of the debate can be found here and here.)

Karen Wooley responds to questions raised by Yates in the earlier posts:
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A Defense of Professional Medical Writers 2

Updated on February 16 with a response by Tom Yates to Karen Woolley.

Editor’s Note: In response to a recent guest post by Tom Yates on industry sponsored editorial assistance, the following comment was submitted  by Karen Woolley on behalf of the Global Alliance of Publication Professionals. This thoughtful statement deserves attention, but I would point out that Woolley does not actually address the problems raised by Yates about industry sponsorship of articles. Specifically, I would invite Woolley and her group to respond to these questions posed by Yates:

  • What expertise do publications professionals have have in the field about which they are writing?
  • Can Woolley point to industry-sponsored publications that do  not recommend prescribing a drug manufactured by the sponsor?
  • Will the industry sponsor or the communications company make public the details of their contract?

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Guest Post: Industry Sponsored Editorial Assistance 4

Editor’s Note: The following guest post by Tom Yates is reprinted with permission from his blog Sick Populations. Yates is a UK-based physician with an interest in epidemiology and population health.

Industry Sponsored Editorial Assistance

by Tom Yates

The September 2011 edition of the Quarterly Journal of Medicine contained two review articles which dealt with the use of new oral anticoagulants in patients withatrial fibrillation.

The first was by Prof Richard Hobbs and Isabelle Leach, who works for a reputable sounding organisation called Chameleon Communications. The funding and conflict of interest statements read as follows.

F.D.R.H. received no funding for this work. Bayer AG and Johnson & Johnson Pharmaceutical Research & Development, LLC, through funding of the professional medical writing services provided by IL. The sponsors were not involved in writing or editing the material. The authors take full responsibility for all content…F.D.R.H. has received occasional speaker fees or sponsorship from a variety of pharmaceutical companies, some with interests in AF including Boehringer Ingelheim, Pfizer, and Bayer. I.L. is an employee of Chameleon Communications International which received funding from the sponsors for her time on this manuscript.

Bayer, who funded the editorial assistance, make Rivaroxaban, one of the drugs discussed in the article. Many of the companies from which Prof Hobbs has received money also make new oral anticoagulants. Chameleon Communications has been involved in preparing several other manuscripts in other journals on new anticoagulants over recent months.

The second, by Prof Joerg Kreuzer, was that edition’s “Editor’s Choice” article. Prof Kreuzer’s funding and conflict of interest statement read as follows.

This work was supported by Boehringer Ingelheim. The author was fully responsible for all content and editorial decisions. The author received no financial support or other compensation related to the development of the paper. Editorial support was funded by Boehringer Ingelheim…Conflict of interest: None declared… The authors would like to thank Rebecca Gardner of PAREXEL, UK, for editorial assistance in the preparation of this article.

Boehringer Ingelheim, make Dabigatran etexilate, a drug promoted in the article’s conclusion.

Concerned about these clear conflicts of interests, I wrote a letter to QJM arguing that the involvement of industry in the funding of review articles generates bias, probably above and beyond the mere choice of topics on which they focus. I requested answers to these four questions:
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