Pharma, Conflicts Of Interest And Fingerpointers
34 CommentsBy Ed Silverman // December 15th, 2009 // 9:32 am
The controversy over conflicts of interest is taking a twist as a former Merck executive and a medical journal are teaming up to lash out at doctors who have criticized drugmaker behavior in published studies, and have also served as expert witnesses in product-liability litigation.
To wit, Laurence Hirsch, a former vice president of medical communications at Merck, published a lengthy essay in a recent issue of Mayo Clinical Proceedings in which he lambasted the doctors and the journals that published their work for “selective and incomplete” disclosure. He points to Yale University professor of medicine Harlan Krumholz, who has reportedly been paid $200,000 while working for attorneys who are suing Merck, and David Egilman, a clinical associate professor of family medicine at Brown University, who has reportedly collected upwards of $2 million for similar consulting work.
One example that upsets him is their April 2008 article in the Journal of the American Medical Association, which examined journal articles about Vioxx and court documents from Vioxx lawsuits - and concluded Merck employees or ghostwriters were frequently involved in various articles, but the primary authors were often academics who had little to do with the studies or didn’t always disclose financial ties to Merck (see here). While the authors of the JAMA article did make disclosures, Hirsch maintains these were insufficient.
It shouldn’t be surprising that Hirsch is upset, because he oversaw the medical communications strategy at Merck during most of the Vioxx years. The Mayo essay is, essentially, a platform to strike back. Interestingly, Hirsch readily acknowledges his tenure at Merck, but failed to disclose his current employer, preferring to say only that he works for a medical device company with no financial conflict in Vioxx or the litigation (although it appears he works at BD, see here and here).
Merck, meanwhile, is distributing copies of Hirsch’s essay, according to The Chronicle of Higher Education, which quotes the Mayo editor, William Lanier, who penned a supporting editorial last September, as saying leading medical journals are fostering an anti-business bias that will stifle “creativity and productivity,” ultimately forcing R&D to go abroad.
For their part, a couple of the JAMA authors aren’t keeping quiet. Egilman, who settled with Eli Lilly after a judge found he leaked Zyprexa documents two years ago, long before Lilly paid $1.4 billion to settle civil and criminal off-label marketing charges (see here and here), wrote us that “Merck doesn’t need a pr team they have the Chronicle. Any mention of the fact that the drug (Vioxx) killed 100,000? That Merck took it off the market? That the NEJM accused them of hiding data? That we disclosed our funding? That Hirsch didn’t point to a single error (in his essay)? Details, details, details.”
And Krumholz wrote us that “he is unable to identify anything we did wrong in our articles – and it seems quite clear that there had been misdeeds with the Vioxx data (NEJM and the FDA also made the same points), that there was ghostwriting, that there was a major seeding trial, and that Vioxx increases risk – that is essentially what we have published.
“I was paid a substantial amount for my time – but it was at the standard rate and I worked hard to understand all the documents and be able to testify at the trial – nothing I said at the trial is in dispute – and was essentially that Vioxx increases risk (Merck had experts who said it did not).
“Hirsch also suggests that I should be precluded from commenting on any Merck products – trying to neutralize my comments about ezetimibe over the past couple of years. So even though I was testifying about a drug that is off the market – and at the time, I was talking about ezetimibe I was long done with the trial and had no financial arrangements with any company or lawyer - I spent hundreds of hours on that litigation. And the time I spent made a difference at the trial and ultimately gave me access to documents upon which I could do research, at a time when I was no longer being paid.
“I don’t mind disclosing the past relationship, but it is offensive to be targeted by someone who lead the messaging that promoted a drug that was increasing risk and suggesting that journals should be wary of my participation in the trial as if they were not. Of course they knew and as a result our work was scrutinized closely. They did not want to be sued over our work and wanted to be sure it was done well. And so did we.
“Ultimately, we are scientists who are trying to positively affect public policy. We are physicians who want our patients to have access to safe medications and to know where risks exist. We are trying to use our experience in the trial – with the veil lifted – to share information with the broader community. I don’t mind the debate, but this one with Mayo Clinic seemed like a concerted effort to neutralize us – marginalize us – and suggest that we did something wrong.
“And really I have nothing against Merck…I am really trying to get better transparency and avoid the distortions of information that marketing can introduce when it intrudes on the science. Both industry and academia need to find ways to have high integrity interactions and avoid those that are not in the best interest of the public and patients.”
Hirsch, meanwhile, is out stumping for “good publication practices” for medical journals. A co-founder of the International Society for Medical Publication Professionals, he recently co-authored - along with others who work for several drugmakers - an article in BMJ that offers new guidelines (see here).
Christopher
Hirsch’s current employer is not relevant to the article which was written about his experiences while at Merck.
The “good publication practices” referred to are not new but a further iteration of guidelines initiated and adopted voluntarily by various industry and medical communications companies in response to the need for better governance and more transparency.
Was Hirsch offered the chance to comment for this piece so that his point of view could be included alongside the rebuttals of Krumholz and Egilman?
taller yet today
GOING OFF THE DEEP END
elmore
Those publication practice are baloney. Pub plans are for marketing. An author who wants to include something not approved by the sponsor because it casts a less than glorious light on the drug or device lose funding and are considered “unfriendly.” Which means, good-bye funding. This is common knowledge.
Ed Silverman
Hi Christopher,
Thanks for the questions. I don’t know that working at BD is relevant, but why not just mention it anyway, so it doesn’t raise any further questions? At least that’s the thought that ran through my mind.
And I have call into Hirsch. Although I look at this as the end of a round - he published his thoughts and two of the authors responded. So maybe any reply would signal a new round. Perhaps. The never-ending cycle of rebuttals is always welcome. In any event, I’m happy to include anything he has to say, should he respond.
Cheers
ed
Condor
Excellent perspective, Ed!
Just linked yours, on mine — and I will be watching the comment-box here, closely, for notable quotes. Should be a barn-burner!
Namaste
Carey
Christopher, Hirsch put together the ghost writing program on Vioxx. It’s not like we’re all sitting around wondering what his position is. Are you confused?
Casper the Friendly Ghost
I support anything written (or not) by Laurence Hirsch
Condor
H i l a r i o u s, Casper!
Spot-on!
Namaste
bill franklin
wild wild west!
Atlex
I’m stunned by the “thou dost protest too much” response from both Egilman and Krumholz. Clearly, Hirsch hit a sensitive spot. Without comment on Merck’s conduct (that’s been thoroughly discussed innumerable times), it is clear that tort bar money can create as many conflicts of interest as drug company money. What these two authors need to recognize is that while their conclusion maybe correct (or not), the fact that they received substantial remuneration($300K for one and $20M+ for the other)from tort attorneys is an important fact. The size and scope of these conflicts should be disclosed in a more complete fashion, similar to the requirements placed on authors with ties to manufacturers.
Christopher
Hi elmore,
You are right that publication plans are marketing tools but if you read the publication practice guidelines it should be evident that they are not the same thing at all. In fact they were developed to provide more tranparency about how articles are written, by whom and under what conditions.
Casper the Friendly Ghost
Altered Atlex: Be skeptical of lawyers at DOJ. They were paid off by taxpayers to prosecute Merck for ripping off and killing taxpayers with Vioxx.
Atlex
Casper,
I said nothing about DoJ lawyers. I specifically referred to tort lawyers, such as Mark Lanier. I’m not going to spend time explaining the difference since it would clearly go over your head.
Atlex
bill franklin
atlex, you playing?
Justice in MI
Aren’t medical writers who have served as consultants, experts, etc. in litigation already obliged, via most journal policies, to disclose that?
Is it the specific amount that should be at the bottom of every author note, whether from industry, law firm, or similar? And other perks, like dinners, chotckes, etc. over the course of the writer’s career?
That would be fun!
vince
And the lawyers representing Merck in this action; does that make them tort lawyers ? Where all unpaid agents in pursuit of the truth.Perhaps Casper the ghost perhaps personally address this matter ?
anon
Arrogance: sheer arrogance of the pharma industry execs to cry about their shameful deeds that have been exposed in countless court cases.
Isn’t time now for Congress to finally investigate this corrupt industry that preys upon the American public like a hungry wolf?
Carey
Lawyers working for Merck work for truth and transparency. And Laurence Hirsch works for them.
Justice in MI
Without getting into particulars of Hirsch, etc., I do believe that consultants, expert witnesses, etc. ought to disclose that in relevant places. Didn’t intend to sound as glib about the issue.
Noel
Would anyone be able to provide a link or two with regard to the good publication practices?
Noel
Santa
Noel - in Ed’s piece above there are two links. The second, to BMJ, offers a link to an article which early in the piece contains a list of relevant guidelines with weblinks.
Big Pharma Watch
Hirsch is so full of crap. The things that he must have been aware of at Merck and he has the testicular fortitude to call somebody else out. He should be ashamed when he looks at himself in the mirror in the morning and see the horns coming out of his head!
Joel Lexchin
In his article Laurence Hirsch waxes eloquent about Merck’s commitment to register clinical trials and to disclose the results of clinical trials. Here is the same Laurence Hirsch in an article in the Canadian Medical Association Journal in February 2004: “Hence we [Merck], like
others, do not concur with calls for mandatory registration
of all clinical trials at their inception to redress publication
bias; rather, we commit to publish trials as noted above.” The commitment was to publish the results of hypothesis-testing trials regardless of outcome, a very limited set of the trials that Merck and other companies undertake.
Keith ATL-L-14475-M06 #615
I need an attorney for my upcoming vioxx trial. The issues of influence peddling and and stistical errors(?) will be addressed; as the prescribing Senator (Dr.) is withholding medical records taken at a Research Laboratory. My attorney withdrew rather than address this issue.
Anon
“Leading medical journals are fostering an anti-business bias that will stifle “creativity and productivity,” ultimately forcing R&D to go abroad.”
What a joke. Merck was severely rationing access by its scientists to essential drug discovery information tools such as SciFinder, Crossfire, etc. while Hirsch was there.
All to save a few million $ a year. Talk about “stifling creativity and productivity.”
Condor
H I L A R I O U S!
Merck just named the “Fosamax® Guy” as its Chief Medical Officer, and new executive vice president.
Well, at least we can tell this particular tiger — by its stripes — eh?
I congratulate Merck for being so bluntly honest — it will save the shareholders money, by making this guy an “on-staff” (fixed cost) expert witness in its defense of what will likely grow to be more than 1,000 Fosamax bone death lawsuits.
“Crafty,” eh?
[With my tongue firmly in cheek.]
Namaste
pharmavet
There is an easily understood reason why Pharma-sponsored trials have a higher reported frequency of positive outcomes, and has to do with the expense of conducting trials, as anyone on this board will tell you. In Phase III trials, a trial with a power (probability of success in layman’s terms)of 80 or 90% often requires many thousands of patients and is extremely expensive. Few entities other than Pharma can afford to properly design a trial with adequate power. Many if not most non-Pharma sponsored trials are underpowered because they are underfunded, and thus have a higher likelihood of failure. This has nothing to do with “publication bias” and everything to do with properly designed, properly powered and properly funded clinical trials, which Pharma is simply better at because it can afford to be better.
Justice in MI
It’s an interesting perspective, pharmavet. As you know, less complimentary explanations include changing endpoints post hoc, choosing inappropriate comparators, etc..
But I think there is a logical flaw in your explanation, even if one were to accept your premise.
Why would a “properly designed, properly powered and properly funded” trial favor _either_ a positive or negative outcome? Wouldn’t either outcome be equally likely, if more reliable, in such a trial?
Conversely, why would a less well designed trial favor a negative outcome?
Atlex
JiM,
If a study sponsor has done a good job of determining treatment hypotheses through previous research, a large, well-designed trial should work a majority of the time. Small trials are used to weed out poor prospects and large trials are then conducted on the products that have the greatest likelihood of success. Of course, from a statistics perspective, it is more likely to reach a definitive outcome with a larger trial. An underpowered trial, common outside of pharma because of budgetary constraints, may directionally show successful treatment, but may not reach statistical significance. Thus, it did not prove successful treatment and is often termed a treatment failure.
In a related issue, many (I’m not saying all) times, pharma companies early smaller trials in order to develop or test hypotheses. These more commonly fail and can make up a significant portion of the trials that go unpublished.
Atlex
Chris
Justice -
One can have a “properly designed, properly powered and properly funded trial” versus placebo which would tend to favor a positive outcome. If you compared the drug to standard of care, the results might be substantially different.
Not sure the converse is true. It would seem to depend on your definition of ‘well designed’. If well-designed means that you are fairly sure of the outcome, then perhaps a less well designed trial leaves more uncertainty as to the results and thus might increase the risk of a negative outcome.
Justice in MI
Thanks Chris and Atlex–
I can understand why industry would have the means, and the incentive, to fund high-powered trials.
But, from the same motives, there would be incentives to fund trials that have bias built into their design.
So I suppose it ultimately comes down to the issue of trust and a review of specific cases. My guess would be one would find, in whatever proportion, confirmation for both views. Personally, I have no idea what that proportion would be, but this has been a useful exchange.
pharmavet
Thanks Chris and Atlex for explaining how hypotheses generated from preliminary data in Phase II trials are used to design and power Phase III trials. When the hypotheses are not confirmed in Phase III it is usually a result of overestimation of presumed effect size, larger than expected variance, or both. As for post hoc analyses or data dredging, those tactics might get something published, but will not pass muster with FDA reviewers. A good journal should require the author to state which were the prespecified endpoints so that the reader will know which analyses were done post hoc. A good reviewer should be able to spot design bias, such as when dose of a comparator is deliberately low to widen the treatment difference. The government says it wants to do comparative effectiveness trials. If so, they will soon learn that such studies (i.e. non-inferiority trials) are very expensive, even for Pharma. If the taxpayers want to bear the costs then that’s a decision society will have to make.
Chris
If certain pharma companies would just publish the comparative effectiveness trials they have already conducted, then we would be at least part way there.
Justice in MI
re: ‘vets’ point on post hoc anlyses, Peter Honig–who was then at Merck but previously at FDA–was quoted in 2004 as follows:
“When I was at the F.D.A.,” Dr. Honig said, “I would read peer-reviewed articles in journals and realize that the endpoints weren’t the original ones from the study because I had reviewed the original protocols myself.”
At that time, at least, it was clear that FDA would say nothing about post hoc spin in journals, and journals themselves were soft targets.
That may have changed some, but most rx’ers will go by what the journals say anyway, regardless of what is or isn’t on the label.