Vioxx Studies: Ghostwriters And Merck Sponsorship
16 CommentsBy Ed Silverman // April 15th, 2008 // 4:36 pm
So you thought all those Vioxx studies in medical journals were independent, hands-off affairs? Not necesssarily. An examination of medical journal articles about Vioxx and court documents from Vioxx lawsuits found that Merck employees or ghostwriters were frequently involved in various articles, but the primary authors were often academics who actually had little to do with the studies or didn’t always disclose financial ties to Merck.
That’s the finding of an article in the latest issue of the Journal of the American Medical Association by four academics who acknowledged they have served as expert witnesses for plaintiffs’ attorneys that have filed lawsuits against Merck. Among 96 relevant published articles, they found that 22 of 24 clinical trial articles published a disclosure of Merck’s financial support, but only 36 of 72 of review articles published either a disclosure of Merck sponsorship or a disclosure of whether the author had received any financial compensation from the drugmaker.
The article is likely to renew the controversy over ghostwriting and undisclosed financial ties between authors and drugmakers. “It almost calls into question all legitimate research that’s been conducted by the pharmaceutical industry with the academic physician,” James Ross of Mt. Sinai School of Medicine and one of the authors, tells The New York Times.
“By having no outside researchers look at data or be in control of a study allowed Merck to manipulate the trials,” David Egilman, a clinical associate professor in community health at Brown University and another of the study authors, tells Pharmalot. “They were able to use spin to create the impression that the drug didn’t kill people, which it did. They’d be less able to do this if independent academic researchers were evaluating data, writing drafts and were involved in final papers. Instead, they get to repackage their own data without any serious external review, publish in presitigious journals with presitigious authors and use it to market off-label by dropping papers that appear to be legit in doctors’ offices.”
In an editorial, JAMA’s editors write that “public trust for clinical research is in great jeopardy especially when the extent of how widespread such practices have become is unknown.” And they called for nearly a dozen immediate changes, including full disclosure of all financial ties and all study authors must fulfill certain authorship criteria.
Ironically, JAMA published one of the Vioxx studies that was cited in the article. In that case, a Merck scientist was listed at the lead author, but Cathy DeAngelis, JAMA’s editor, tells the Times that it was dishonest because the authors didn’t fully disclose the role of a ghostwriter. “I consider that being scammed,” she tells the paper.
In a statement, Merck called the article misleading, but acknowledged that it sometimes hires outside medical writers to conduct research and draft manuscripts before giving them to doctors who eventually are listed as authors. But the drugmaker contends it has “explicit policies” about disclosing financial ties and disputed the conclusion that the authors do little of the actual research or analysis.
The JAMA paper implies the authors of the VIGOR study were less involved than the Merck authors in the drafting of the paper. In fact, the outside authors, who are distinguished research physicians, were highly active in the drafting of the paper. Egilman, however, contends the authors apparently weren’t aware of data on heart attacks and deaths that were held in a locked database, suggesting less involvment than Merck insists.
In the case of one Alzheimer’s paper, study 078, the scientists whose names appear in the first, second and third position of the published article were intimately involved in the conduct of the study, having served as a protocol consultant, member of the endpoint adjudication committee or as a study investigator. Financial conflicts of interest were disclosed in the acknowledgement of the published article. The absence of their names on the draft document author list or in the acknowledgment section shown in the article in no way indicates that these scientists were guest authors on this publication.
But the JAMA article noted that, in 16 of 20 papers that reported on clinical trials, a Merck employee was designated as the author of the first draft of a manuscript, but an outside academic was listed as the lead author when the study was published, the Times notes. And one paper involved a study of Vioxx as a possible buffer against Alzheimer’s. The August 2003 draft identified the lead writer as “External author?” By the time the paper was published in 2005, the lead author was listed as Leon Thal, a well-known Alzheimer’s researcher at the University of California, San Diego, who the Times notes was killed in an airplane crash last year.
The second author listed, whose name had not been on the draft, was Steve Ferris, a New York University professor, who tells USA Today that he was unaware his study showed an increased risk of death among Alzheimer’s patients. “I can’t say that because I never had in my hands - I didn’t request it and I wasn’t given it - the reams of statistical analyses that gets digested into a draft manuscript.” He adds that he played a more limited role, serving on a committee that judged the accuracy of Alzheimer’s diagnoses.
Yet, Ferris tells the Times that he was substantially involved in helping shape the final draft. “It’s simply false that we didn’t contribute to the final publication,” he says. Huh? Meanwhile, Louis Kirby, the third outside author, sends an e-mail to the Times to say that “the fact that the draft was written by a Merck employee for later discussion by all the authors does not in and of itself constitute ghostwriting.”
A separate article in the same issue of JAMA, which was by Bruce Psaty and Richard A. Kronmal of the University of Washington, concluded that in the years leading to the Vioxx recall, Merck wasn’t fully candid in submitting data to the FDA about Vioxx heart attack risks, the Times adds. In its statement, Merck argues their analysis was misleading, because the FDA was aware of concerns over cardiovascular risks associated with Vioxx and had been discussing this with Merck.
Dan
About ghostwriting clinical trials:
Data used to construct such trials is typically obtained from embellished data created by the pharma company. The author names on such a study is paid for by the pharma company, and rarely did such an author have anything do do with such a study. The pharma company sponsors such trials from start to finish, with supervision by others largely absent. It’s a corruption of science and all that others depend on for reliable data.
Doc
“In some cases, Merck’s marketing department was involved in
developing plans for manuscripts, the article said.”
The quote above from the NYT article says it all. As the public’s understanding of the level of marketing involvement in the ’science and medical’ side of pharma grows, the public’s low view of pharma will continue to slide and rightly so.
Pharma Industry
How Pharma Stacks the Deck with Medical Journals…
Some once-friendly ghosts may be getting Merck in trouble all over again.
The ethereal beings in question are ghostwriters — the nameless, faceless freelancers paid by drug companies to draft up medical review papers, usually well before theyR…
Justice in Michigan
The role of corrupted physicians should not be underplayed in ghost/guest-writing, which, of course, has been going on for a long time.
I understand the hundred rationalizations we hear each time this comes up: “I read it,” “I agreed with the conclusions,” “It saved time so I could do research,” “Grad students often write first drafts signed by more senior people,” etc.
So, I have to ask one of my usual questions. Is there anyone for whom this authentically “goes down well”?
B. Martin, MD
In the full spirit of disclosure, why don’t the authors identify the plaintiff firm(s) that they’ve been retained by and the dollar amounts they’ve received as a result of their input on the Vioxx litigation?
Although some of the concluding points by Ross et al may be valid, I am troubled by the fact that they did not seek direct responses from Merck scientists or the academic authors before publication of the piece–which is really more of a journalistic-type expose than any report of scientific merit. It’s as if JAMA’s turning into a medical equivalent of Out magazine.
Former pharma Marketing Exec
This is just the tip of the iceberg…
Ghost writing is something that has been going on for quite some time. This is why I have said, will continue to say, and will never change my position - if you sue a drug company because of mis-leading data, harm caused by off label use of drugs or even that data was withheld, you must go after the authors of these papers.
Whether that entails filing a separate suit, I do not know, anyone with legal savvy here can tell us. But until these doctors who allow their name to be used in this manner realize that they too can be held accountable, this isn’t going to stop.
I was at a meeting last summer where a panel concluded that their members should no longer allow their names to be used on papers unless they were privy to all the raw data and could fully corroborate the results. It was music to my ears!
Doc Martin, in full spirit of disclosure why don’t we find out who was paid what - i.e. the ghost writers, the doctors, everybody. They should make public the true cost of something like this. John Q public would really like to know!
Is there any other profession that allows its members to access such graft, politics not-with-standing?
anonymous
The notes refer to the internal clinical trial in the use of Vioxx in an Alzheimer’s study. It would appear to be linked to increased deaths.
I have concerns with the off-label use of Etanercept (Enbrel) for Alzheimer’s patients by a dermatologist who with his “patented Perispinal” (in the neck)administration which is based on his hypothesis that administration in this area, followed by tilting the head back to help the flow of Etanercept toward the brain area to tackle inflammation caused by overproduction of Tumour Necrosis Factor alpha (TNFalpha). AntiTNF drugs lower the immune system. Is it right that Alzheimer’s disease patients with their existing health issues should be exposed to a drug which will lower their immune system and leave them exposed to the serious adverse events listed on the now Black Box label for Etanercept (Enbrel). The extraordinary claims in this hypothesis by a dermatologist, of instant improvement in Alzheimer’s patients on this unique patented administration of Etanercept has attracted worldwide press and tv interest, which has resulted in people seeking out this treatment. This hypothesis must not be ignored. It warrants intense scrutiny to whether this intervention is safe.
ENBREL is a type of protein called a tumor necrosis factor (TNF) blocker that blocks the action of a substance your body’s immune system makes called TNF. People with an immune disease, such as rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, or psoriasis, have too much TNF in their bodies. ENBREL can reduce the amount of active TNF in the body to normal levels, helping to treat your disease. But, in doing so, ENBREL can also lower the ability of your immune system to fight infections.
Serious infections, including tuberculosis (TB), have happened in patients taking ENBREL. Some of these serious infections have been fatal. Many serious infections occurred in people prone to infection. Serious infections have also occurred in patients with advanced or poorly controlled diabetes. Do not start ENBREL if you have an infection or are allergic to ENBREL or its components. Once on ENBREL, if you get an infection or have any sign of an infection, including fever, cough, or flu-like symptoms, or have open sores, tell your doctor. Your doctor should test you for TB before starting ENBREL and should monitor you closely for signs and symptoms of TB.
Serious nervous system disorders, such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes have been reported. There have been rare reports of serious blood disorders (some fatal).
In medical studies, more cases of lymphoma (a type of cancer) were seen in patients taking TNF blockers compared to similar patients who were not taking TNF blockers. The risk of lymphoma may be several-fold higher in people with rheumatoid arthritis and psoriasis; the role of TNF blockers in the development of malignancies is unknown.
INDICATIONS
Moderate to Severe Rheumatoid Arthritis (RA)
ENBREL is indicated for reducing signs and symptoms, keeping joint damage from getting worse, and improving physical function in patients with moderate to severe rheumatoid arthritis. ENBREL can be taken with methotrexate or used alone.
In medical studies, ENBREL was shown to be effective in about 2 out of 3 adults with RA who used it, and has been shown to begin working in as few as 2 weeks, with most patients receiving benefit within 3 months. In an RA medical study, 55% of patients had no progression of joint damage. The claims of instant improvement in this off-label use of Etanercept in Alzheimer’s disease is clearly at odds with the two week period before any improvement in approved indication such as RA.
Common side effects in adult clinical trials were injection site reaction, infection and headache.
The unique injected patented site which the inventor calls a Perispinal injection is part of this procedure. This in the neck area, then tilt the head back to encourage the flow of Etanercept toward the area of the brain. The FDA site guidelines for administration are; thigh, abdomen but not near navel and top shoulder. TNF has its role to play as part of defense of our immune system. Etanercept lowers the immune system. Should Alzheimer’s disease patients be exposed to an off-label drug which exposes them to serious infections and possible adverse events associated with Etanercept, an immune lowering drug. This is all based on a hypothesis that is full of extraordinary claims without the standard pre-clinical into clinical trials or availability of basic research papers. If somebody claims a breakthrough in the treatment of Alzheimer’s disease as these claims do in the use of Etanercept by perispinal administration, this in the field of neuroscience which is full of claims without merit. We all want to aid better treatments, but that does not mean having to accept extraordinary claims of improvementin an off-label use, yet the science tells us of the associated severe risks with this drug from the clinical trials, which did not include the effects of this drug on Alzheimer’s patients. I want the Alzheimer’s disease patient to get the best treatment, but I cannot agree that a hypothesis from a dermatologist should go unchallenged just because of it’s extraordinary claims and its anticedents
Paul
Believe me, I am no lover of the industry. But I think that JAMA has gone overboard.
Where are the ethics of rehashing totally one-sided plaintiff lawyer stuff? Plaintiffs did not get the zillions of dollars they thought they’d made with Vioxx and now are just rehashing things for public embarrassment.
I got an idea. Let’s have: Grassley, JAMA, the plaintiff’s bar and a few other naysayers manage all medical innovation, clinical studies, publications, drug development and medical education. They ought to do a fine job.
If I sound tired of all this, it’s because I am. Let’s move on to talk about bigger issues like how are we going to ensure at least a minimum amount of healthcare for most americans, or how we are going to put our forces together to cure cancer.
anonymous
http://www.agec.org/programs/conferences/BP_Alzheimers/schedule.asp
2:15-3:00 pm Perispinal Etanercept for Alzheimer’s Disease
Edward Tobinick, MD
Anyone up to challenge the claims of the dermatologist on breakthrough Alzheimer’s disease treatment. Etanercept hypothesis presentation at:
Best Practices in the Continuum of Care: Advances in Alzheimer’s Disease Management. April 16, 2008 Double Tree Hotel, Little Rock, Arksansas
2:15-3:00pm CT presentation
Perispinal Etanercept for Alzheimer’s Disease
Edward Tobinick, MD
Paul
From early 2007, but still current.
The tortious ties of the Prescription Project
Robert Goldberg
As we noted The Prescription Project is ” an initiative of the Boston-based nonprofit healthcare advocacy group Community Catalyst, which made headlines a little over a year ago when it sued Pfizer over its marketing claims for Lipitor. The Prescription Project is being conducted in partnership with the Institute on Medicine as a Profession (IMAP) and is funded by a USD 6 million, two-year grant from The Pew Charitable Trusts and money from George Soros.
In addition, the group has assembled a prestigious advisory committee whose members include Cathy DeAngelis, the editor-in-chief of JAMA; Steven Nissen, the president of the American College of Cardiology; and Philip A Pizzo, the dean of the Stanford School of Medicine.”
Part of this campaign includes class action lawsuits initiated by the Prescription Action Litigation Project which in turn is comprised of Trial Lawyers Inc (large trial firms that seek huge monetary damages by suing corporations) and their public advocacy front, Public Citizen and various state organizations.
For instance, one mainstay of the PALP is the law firm Hagens Berman Sobol Shapiro (HBSS) which has been going after Pfizer for what is alleges are “false marketing claims by pharmaceutical giant, Pfizer. We are investigating claims made for its cardiovascular disease drug Lipitor, that encouraged doctors to prescribe the drug for patients when it was not necessary or healthy to do so.” The firm is claiming that Pfizer encouraged doctors to prescribe the cholesterol drug for hypertension, chronic kidney disease, and many other unapproved illnesses besides the prevention of cardiovascular disease. …
Hagens, Berman is famous for suing Starbucks for unbridled competition and being slapped with a $10 million penalty for violating their “.. duty of loyalty to three small water bottlers that in 2003 were close to settling a claim with Nestle Waters North America, the owner of Poland Spring Water Co.” “Seattle law firm told to pay $10.8 million”, Seattle Post-Intelligencer, Mar.24; Lattman, Mar. 24).
Public Citizen and the U.S. Public Interest Research Group (PIRG) works closely with Hagens Berman and other tort firms through Community Catalyst and TPP and other conduits to attack off label prescribing via fishing expeditions, testimony and now legislation at the state level to force doctors to either disclose or disgorge any money obtained from drug or biotech firms for any purpose.
This is not an effort to ‘clean up’ medicine. This is a witch hunt, a Stalinist effort to purge medicine of any relationship between academia, private industry and clinicians. And it is an effort to presume that off-label prescribing is both hurtful and possibly criminal behavior. Let’s be clear: the goal is to create another opportunity for shaking down the drug industry and physicians. All you need are RiskMaps that prohibits and limits off-label prescribing and you have a whole new source of revenue for tort lawyers…..
Sort of like shorting currencies and buying them up. No wonder Soros is involved.
Doug Bremner
My comment on this study was that pharma could take the money that has been used to pay for ghostwriters and author honorariums and pay the patients to take these medications.
http://www.beforeyoutakethatpill.com/blog.html
With the Vioxx studies there was a quote from a pharma exec to the effect of him asking marketing why they did this post approval study that exposed them to the risk of finding out about a new adverse side effect.
Doug Bremner
In other words even Merck was saying that the value of many of these clinical trials is dubious. If you look at some of them the list of ’study investigators’ strings into the thousands. i.e. the studies were performed to hook the doctors on the medications who were the ’study investigators’. A dubious use of resources at best.
Chris
Ghost writing has been around for years and serves a purpose in providing expedited publication of data provided guidelines are followed. Lead authors do not always write their own drafts - some use external services paid by the sponsoring company and some use members of their departments. The JAMA article ignores many aspects of this relationship including a voluntary initiative between selected medical journals, pharma companies and medical writing companies which, in 2003, resulted in published guidelines which set out good publication practice.
http://www.controlled-trials.com/news/Good_Publication_Practice_for_pharmaceutical_companies_2355-Article.pdf
The authors of the JAMA article selectively referred to articles, many of which were written prior to the guidelines’ (to which Merck and other leading companies contributed) publication in 2003. As they surely know leadtime from submission to publication in many journals can exceed 12 months, and so many of the cited articles pre-dated the voluntary and endorsed guidelines referred to here.
It is easy to adopt a position and find data to support it especially with agenda as obvious as this. Unfortunately the public - including the NY Times - too easily seizes on yet another pharma industry horror story coming from an apparently unbiased source.
I could go on: I don’t have time; but I am angered by the relentless, political onslaught led by these self-appointed vigilantes of the ‘truth’.
Nathan
In case anyone is interested, Derek Lowe commented on this topic today on his MedChem blog.
http://pipeline.corante.com/archives/2008/04/18/cut_it_out_cut_it_out_now.php
HorusCat
“The quote above from the NYT article says it all. As the public’s understanding of the level of marketing involvement in the ’science and medical’ side of pharma grows, the public’s low view of pharma will continue to slide and rightly so.”
Yet when the public contracts cancer or Alzheimer’s or Crohn’s or Parkinson’s, they will be demanding the pharmaceutical cures from their physicians. And the public will continue to smoke and overeat and sit on its 1-19-19 watching TV, content in the knowledge that it can take a pill to lower its cholesterol, blood pressure and hypertension, and suck on an inhaler to help with the COPD. Maybe the public should look in the mirror.
HorusCat
Chris,
I’m with you! I got kind of caustic on my post above…I’m a little manic because of the nice spring weather after all the RAIN. I am glad that most of my doctors appreciate what I do….for instance the doc today that said a patient couldn’t afford the co-pay for his biologic, and I pointed out that we have a program that severely limits the co-pay for a year (giving him time to find alternatives). The doc got on the phone, called his nurse in the other office, and I will drive 2 hours to get there on Tuesday to show her the form and explain the program. I have told the doc about the program, BTW, every time I have seen him for the last 6 months.