A Key Vioxx Study Was Really A ‘Seeding Study’
24 CommentsBy Ed Silverman // August 18th, 2008 // 6:10 pm
A 1999 Merck study of Vioxx, which was touted to participating doctors and patients as easier to stomach than another drug, was primarily a stealth marketing strategy, according to a report in The Annals of Internal Medicine, the Associated Press writes. Here it is.
The true purpose was to get lots of docs and patients in the habit of using Vioxx just in time for its launch, according to doctors who uncovered internal Merck memos behind the study, called ADVANTAGE. They did so while reviewing roughly a million Merck documents for plaintiffs’ lawyers preparing for trials in Vioxx lawsuits, the AP reports.
Drugmakers are widely suspected of doing many “seeding,” or marketing studies, but there’s been no “smoking gun” proving it before, according to the Annals of Internal Medicine, which published Merck’s original report on ADVANTAGE in 2003. Here it is.
An accompanying editorial, co-authored by Annals editor Harold Sox, states the journal was not told the true purpose of ADVANTAGE, which compared Vioxx with an older, cheaper pain reliever, naproxen, when it published results indicating Vioxx was better tolerated, the AP adds.
Jonathan Edelman, head of scientific affairs at Merck Research Laboratories, tells the AP that “the ADVANTAGE study was primarily a scientific study” designed and executed by the drugmaker’s clinical research unit and that any later use of data for marketing was a separate operation. Here is an open letter from Merck, the amended protocol for the trial, and Merck’s synopsis of the study.
But Kevin Hill tells the AP that he and colleagues, while working as paid consultants for lawyers representing plaintiffs who claimed Vioxx caused heart attacks or other harm, stumbled on documents indicating Merck’s marketing division designed ADVANTAGE and handled the data collection and analysis.
Using funding from the Robert Wood Johnson Foundation’s clinical scholars program, they searched further, uncovering items such as a memo from two top Merck executives nominating the study for an internal marketing award, according to the AP.
“The objectives were to provide product trial among a key physician group to accelerate uptake of Vioxx as the second entrant in a highly competitive new class,” the memo states.
ADVANTAGE used about 600 family docs new to clinical research, with each getting a stipend plus fees for recruiting a handful of patients each. Most clinical trials are run by a limited number of specialists at major teaching hospitals that each recruit hundreds of patients, the AP writes.
Hill, now a staff psychiatrist at McLean Hospital in Massachusetts, tells the AP he and his colleagues found documents indicating “ADVANTAGE was marketing framed as scientific research,” with an emphasis on how much Vioxx doctors in the study later prescribed. “I don’t think people would be willing to (risk side effects) if they knew that the aim of a clinical trial was to boost profits for a pharmaceutical company.”
The study’s name implied it had a scientific purpose: ADVANTAGE, or Assessment of Differences between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness. But Hill said docs participating in ADVANTAGE got a kit telling them how to talk to other doctors about Vioxx, and another Merck study running at the same time, called VIGOR, also examined how safe Vioxx was for people with gastrointestinal problems, so ADVANTAGE wasn’t needed. VIGOR’s results were published in 2000.
Merck spokesman Ron Rogers tells the AP that Hill and his colleagues have been critics of Merck and just cherrypicked “some documents to support their thesis.”
Bruce Psaty, a University of Washington epidemiologist, tells the AP that Hill and his colleagues had disclosed their conflict of interest in their report but that the ADVANTAGE trial wasn’t transparent about its purpose. “I would think that at some level this is standard practice,” he said of seeding studies, but they don’t come to light except during the discovery phase of litigation.
Ross McKinney, director of Duke University’s bioethics center, said seeding studies have been around for decades and usually are called postmarketing studies, meaning they’re for drugs approved for sale. He said most never get published, but this one did because it addressed an important scientific question, stomach tolerability, even though it was a seeding trial. But McKinney tells the AP seeding studies make the public skeptical about enrolling in clinical studies.
“It’s a serious violation of research ethics” and prevents patients from figuring out the risks and benefits of participating in the study, Arthur Caplan, who heads University of Pennsylvania’s medical ethics department, tells the AP.
Vioxx came on the market in June 1999, after Pfizer’s Celebrex, and both drugmakers claimed their painnkillers caused fewer stomach problems than other pain relievers. Merck yanked Vioxx in 2004, after its own research showed the med doubled risk of heart attack and stroke. Since then, Merck reaced a $4.85 billion settlement to end US personal injury lawsuits.
Sox, the Annals editor, and Drummond Rennie, the Journal of the American Medical Association’s deputy editor, wrote that the institutional review boards required to protect patients in clinical studies should ask whether an experiment is a seeding study, particularly when there are obvious clues. “Simply shining a bright light on their existence may have already sown the seeds of their destruction,” they write.
Lichtstrasse 35
If anyone thinks this wasn’t a marketing-driven study, why did they come up with the acronym ADVANTAGE? The days of trials with out a marketing name are long gone (4S, WOSCOPS, etc).
Common Behavior
These studies are apparently very commonplace for Merck. In Europe, I believe that their marketing divisions run the studies. In these cases, there is not even any medical or scientific input. Just wait until the investigative teams start looking at what Merck and Schering-Plough did overseas. Clinical trials with thousands and thousands of patients with the primary intention of driving prescriptions.
Doc
There have been many, many seeding trials - most are done post approval once the product is on the market.
Dan A.
Gotta share this again:
Published on http://www.brainblogger.com
The Human Injury of Lost Objectivity
If I were to rate the corruptive tactics performed by big pharmaceutical companies during my intimate experience with them , the intentional strategy of implementing fabricated and unreliable results of clinical trials performed by others possibly top the list, as they often were sponsored by a pharmaceutical company. By this atrophy of the scientific method absent of authenticity, harm and damage is possibly done to the health of the public. Most would agree that the science of research should be sound and as sterile and aseptic as possible- completely free of interference. However, it appears, money and increased profits can be a catalyst for reckless disregard for human health that is largely unregulated. This is particularly a factor on post-marketing studies of various pharmaceutical companies because others seem to be deliberately ignorant.
Decades ago, clinical trials were conducted at academic settings that focused on the acquisition of knowledge and the completely objective discoveries of meds and devices to benefit mankind. Then, in 1980, the Bayh-Dole Act was created, which allowed for such places with their researchers to profit off of their discoveries that were performed for pharmaceutical companies and others in the past. This resulted in the creation of for-profit research trial sites, called Contract Research Organizations that are often composed of primarily community patient care clinics absent of any research training compared with the former. Because of this structure, investigators of these pharmaceutical sponsored trials are likely void by sponsor design of necessary research experience or quality regarding their research purpose and ability to ensure its sterility, yet benefit it’s supporter. These quite numerous CROS are in fact for- profit, with some CROs making billions of dollars a year.
The trials conducted at such places again are sponsored by pharmaceutical companies that control and manipulate all aspects of the trial being conducted involving their particular med being studied in the trial. Etiology for their deception regarding this manipulation is because the pharmaceutical company that sponsors such a trial is basically creating a marketing tool for this studied drug of theirs. This coercion is done by various methods of deception in subtle and tacit methods. As a result, research in this manner ensures favorable results of the sponsor’s medication after the trial is complete. Their activities are again believed to be absent of true or applied regulation, and therefore have the autonomy to create whatever they want to benefit what may be a collusive relationship between the site and the sponsor; as such sites are largely unregulated.
Guest authorship has been known to be aggressively recruited by sponsors and usually the sponsors seek investigators to be recruited for this function in addition to being the lead investigator of their fabricated clinical trial. The trial manuscript and protocol design is prepared by those employed by the pharma sponsor upon specific direction of this pharma sponsor. The medical program coordinator of a particular sponsored trial is an actual employee of the sponsoring pharma company and also acts as the publisher, manuscript version reviewer and trial director who works with their pharma company’s hired CRO editors whose objectives are to benefit the sponsor. Typical and ultimate cost of the final manuscript of the trial to the sponsor created by the hired CRO exceeds 1000 dollars per page, some have said. Merck engages in this behavior, which shocked many, as they were always viewed as an ethical pharmaceutical company that always placed patients over profits. Apparently not.
Further disturbing is that once the creation of the trials is completed, the research paper is often composed with specific directions by the sponsor to writers known as ghostwriters. These people are not identified and acknowledged by the sponsor, and may not be trained in clinical research overall, as they are simply freelance writers, as one does not need research training or certification in order to perform this function. Rarely do trial ghostwriters question their instructions about their assignment, which is clearly deceptive and undocumented by the sponsor. Also, these hired mystery writers are known to make about 100 grand a year. This activity removes accountability and authenticity of the possibly fabricated clinical trial even further. The corruptive act is finally completed by the sponsor hiring an author to have their name be placed on the trial, while this hired author likely had absolutely no involvement with the trial, or even reviewing the trial is not asked by the hired author.
To have the trial published, the sponsor has been known to pay a journal, and the sponsor bribes the journal in a few ways, such as the sponsor purchasing from a selected journal thousands of reprints of their study from the journal, for example. Again, how often this process is performed is unknown, yet frequent enough to create hundreds of such false writers mentioned earlier and progressively growing research sites to receive the support the pharmaceutical industry. So benefits of meds studied in such a malicious way potentially can harm patients and their treatment options along with clear safety risks. The purchased reprints bought by the sponsor of the study are distributed to the sponsor’s sales force to share the content with prescribers, with the sales force completely unaware about this manipulation. As a bonus, the sponsor may pay this journal to advertise their products to be placed in this journal as well.
Such misconduct discussed so far impedes research and the scientific method with frightening ethical and harmful concerns, as stated previously. If so, our health care treatment options with meds are now undetermined in large part due to such corruptive situations, as well as the absence of objectivity that has been intentionally eliminated with trials produced in this way. Trust in the scientific method in this type of activity illustrated in this article is absent and replaced with what could be harmful to others.
More now than ever, meds are removed from the market or are given black box warnings, which is basically eliminating future growth of the black box drug. Now I understand why this may be occurring.
Transparency and disclosure needs to happen with the pharmaceutical industry for reasons such as this as well as many others, in order to correct what we have historically relied upon for conclusive proof, which is the scientific method. More importantly, research should not be conducted in a way that the sponsor cannot in any way interfere in such ways described in this article, which would require independent clinical trial sites with no involvement of the drug maker. And clearly, regulation has to be enforced not selectively, but in a complete fashion regarding such matters. Public awareness would be a catalyst for this to occur, after initially experiencing a state of total disbelief that such operations actually are conducted by such people, of course. We can no longer be dependent on others for our optimal health. Knowledge is power, and is also possibly a lifesaver.
“Ethics and Science need to shake hands.” ……. Richard Cabot
Dan Abshear
Author’s note: What has been written was based upon information and belief.
Paul G
You people make me laugh.
The same people who keep screaming about how much we need to do more studies of absoluteley every combination and permutation, to look ate every single possible comparison, before and after the drug is approved, are the same people who complain when a study may have been had dual purposes.
I read all the documents Ed linked and from what i can tell, this was a scientific study managed by the science people but that also had the practical aspects of being based in the community — where real products get used and where things can be more realistic than in an academic center study.
Personally, I would like to see more of these studies.
Alina Piacentino
Thought you might be interested in this open letter from John Edelman, M.D. of Merck Research Labs:
August 18, 2008
An Open Letter to the Editors of The Annals of Internal Medicine
In this open letter to the editors of The Annals of Internal Medicine, Merck would like to put in perspective the latest article by four authors who served as paid consultants to plaintiffs’ lawyers in the VIOXX litigation against Merck. We are troubled by the biased article, which contains numerous inaccuracies, and wonder about the motivation behind this attack on Merck’s scientific excellence and integrity.
It is unfortunate that the authors and journal editors chose not to contact Merck before finalizing these publications. Had any of these individuals contacted Merck, factual errors could have been avoided.
The ADVANTAGE clinical trial was designed, conducted, analyzed, interpreted and published by the scientific department of Merck’s U.S. Human Health (USHH) organization, Clinical Development (CDP), in conjunction with participating investigators. CDP was part of the Medical and Scientific Affairs department of USHH and was separate from the marketing department within USHH.
In the article, the authors erroneously claim that the objectives of the ADVANTAGE study were not scientific, and base this spurious conclusion on their review of a limited selection of documents produced in the VIOXX litigation. The authors appear to purposely fail to distinguish between the various departments of Merck’s USHH organization, including its scientific research and marketing departments.
There’s no doubt that the ADVANTAGE clinical trial had a legitimate scientific purpose. That purpose was to assess the gastrointestinal tolerability of VIOXX compared to naproxen – a commonly used arthritis medicine with known tolerability problems – in the treatment of patients with osteoarthritis in a primary care setting, and for the first time allowed patients taking concomitant aspirin to participate.
ADVANTAGE was a double-blind, randomized, controlled clinical trial with a legitimate scientific purpose designed to answer previously unanswered questions about the use of VIOXX in osteoarthritis in a primary care setting. It was not a seeding study.
The study assessed GI tolerability by seeing whether VIOXX or naproxen, at the highest approved doses for long-term treatment of osteoarthritis, caused fewer adverse events like abdominal pain, epigastric discomfort, diarrhea, heartburn, nausea, and dyspepsia.
ADVANTAGE was important because although the earlier VIOXX clinical trial program provided extensive data on efficacy and safety, it did not include naproxen as a comparison medication, and did not conduct research in the primary care setting, where patients with osteoarthritis would likely be seen by physicians who would consider VIOXX as a treatment option.
In addition, ADVANTAGE was the first study of VIOXX conducted by Merck that allowed the concomitant use of aspirin by patients participating in the trial. Indeed, the very journal that published the article that is the subject of this letter previously published the results of the ADVANTAGE study back in 2003, and at the time acknowledged that physicians would be interested in the type of results ADVANTAGE produced.
In the end, ADVANTAGE showed a different gastrointestinal profile between VIOXX and naproxen that was unaffected by concomitant use of aspirin. This was an important medical result for physicians. In addition to measuring the GI tolerability of VIOXX, investigators also monitored patients for adverse events, which were required to be submitted to the FDA. Therefore, in ADVANTAGE, Merck was further evaluating any potential risks of VIOXX.
It is important to emphasize that ADVANTAGE met all the Merck requirements for clinical research. All studies sponsored by Merck must have a protocol that describes the scientific, administrative, and regulatory aspects of the study in a manner that is consistent with currently accepted scientific methodology, FDA’s Good Clinical Practice guidance and worldwide regulatory requirements.
We also want to underscore that the scientific purpose of ADVANTAGE was properly disclosed to physicians-investigators, participants, and institutional review boards, and Merck’s business interests were clearly understood. As is always the case, a scientifically sound and properly conducted study that further demonstrates the benefits of a drug would have a favorable impact on patients with debilitating arthritis, doctors searching for ways to treat their pain, and the pharmaceutical company that produced the drug. Such studies also further our understanding of the drug’s potential risk.
Merck firmly believes there is great value in understanding questions physicians want answered and in conducting rigorous, scientific clinical studies to address those questions. We believe we acted appropriately with respect to the ADVANTAGE trial, and stand behind our strong beliefs in the principles of scientific integrity. In publishing the paper and accompanying editorial in question, without further investigating readily available information, we believe that the Annals failed to act in the best interests of their readers or the scientific community.
Sincerely,
Jonathan M. Edelman, M.D.
Executive Director, Global Center for Scientific Affairs
Merck Research Laboratories
Ed Silverman
Hi Alina,
Thanks, although I have a link to Edelman’s letter in the post. It’s in the fifth graph and can be accessed by clicking on the phrase ‘here’s an open letter from Merck.’ I also included links to the trial protocal and Merck’s summary review of the trial.
Regards
ed
Justice in Michigan
I can’t judge the credibility of the above letter in general.
But the reference to “debilitating arthritis” strikes me as the typical over-the-top manipulative use of language with which we’ve all become familiar.
The vast majority of people to whom Vioxx was marketed did not have “debilitating arthritis” but everyday aches and pains that made it a little more difficult to figure skate or walk the dog as easily as twenty years earlier. And Vioxx was never shown to be more effecctive for aches and pains, let alone OA, than any other NSAID.
So, at least in this regard, it’s the same old S.
Supremacy Claus
No specific harm. No invalidating practice or method. No data to show biased, wrong conclusions.
The Left just picks on lawyer gotcha about a secondary advantage of a study. All studies have secondary advantages, especially by Left wing ideologues.
“I may be doing this study. However, my real aim is to get a promotion, to show my mother how smart I am, to practice writing grants.”
This article is Yale inspired, Left wing ideologue garbage. Its hidden motive is the hidden corporate bashing agenda. I would like its Yale twit to publish all internal memos about the article.
Why Not
SC - You will have to explain why Art Caplan, head of Penn’s medical ethics center (which has significant industry ties and funding) condemns the study as “a serious breach of medical ethics.”
Are they, too, part of the conspiracy? “They” include some Chief Medical Officers in the inustry along with academic bioethcists.
atlex
WN,
Journalists know that they can always go to Art Caplan and get him to say that anything and everything is “a serious breach of medical ethics.” It’s like going to Sidney Wolfe to get a quote on why everything is bad for you. I’m not arguing the ethics of this study (although I don’t find it particularly offensive, but just because Caplan says something is unethical doesn’t make it so.
Atlex
Former Big Pharma
Paul, Alina and Supremacy,
Get your heads out of the sand and accept reality. There are no ethics in the business of pharma. They left when MBAs took over and the companies started their downhill slides. I’ve been there and it really does stink from the head down. Top management is greedy and corrupt. The marketing people don’t care about patients other than them getting on as many drugs as possible to raise their profits. It’s not liberal to think this way, it’s moral!
Supremacy Claus
Why Not: When you cite Art Kaplan, you cite a laughed-at buffoon, derided in his own field, respected only by left wing media for his agreeable bashing of clinicians and drug companies.
Find someone else for rebuttal, and I will take it seriously enough to consider. In reading the comments, I note Atlex has made this widely held point already, only more eloquently. Atlex reflects the medical community view, as well as the medical ethics specialist view.
Why Not
Atlex - Bringing in Art Caplan was not to invoke divine authority but only to suggest that the world may be more complicated than the conspiracy theories that preeocupy SC.
Why Not
SC - No doubt you see Harold Sox, Editor of the Annals, also part of the vast left wing conspiracy. Have you read the Annals editorial linked in Ed’s piece?
Ed Silverman
Hi Folks,
For the record, I’ve contacted U Penn’s Art Caplan many times over the years and he hasn’t always confirmed for me that a particular situation has an ethical issue, at least in his view. In other words, it’s not the dial-a-quote situation inferred here.
Why does the media contact him as often as it does? Usually, he’s accessible and he takes the time to walk through situations. That can be very helpful. Of course, there’s nothing to say other ethicists can’t or shouldn’t be contacted. I agree that including a mix of views is a good thing.
I’m not writing this, by the way, because I belong to his fan club, or anyone’s fan club. I just thought I’d share one journalist’s thought after reading the comments.
Regards
ed
Why Not
Thanks for input, Ed. One of the reasons Caplan has lost credibility among his peers (other bioethicists) has been his and his centers ties with the industry. I know some of the CMOs with whom he’s worked.
That was my point - that the conspiracy theory doesn’t work very well when you have so many “conspirators” from otherwise very different worlds.
atlex
Ed,
Your statement regarding Caplan may indeed be true, but in those cases where he doesn’t confirm a (lazy) journalist’s predisposed opinion regarding the ethics of a situation, his opinion is usually left out. Maybe I’m mistaken, but if you Google his quotes from the general press, almost all contain the same type of statement(although some do have longer discussions). Again, that doesn’t mean he is wrong (or right), but each of these types of stories seem to have the same pattern. That leaves one to at least consider that he is a “dial-a-quote” like Sydney Wolfe.
Atlex
Ed Silverman
Hi Atlex,
I understand your point, but can’t really speak for other journalists, in so far as I’ve not been privvy to their conversations.
As to me, I’ve included comments that, I thought and hoped, shed light on whatever issue I was probing. And I’ve tried to use whatever remarks were then appropriate. Ethics discussions can be slippery sometimes. But my reason for calling an ethicist, Caplan or someone else, is because I think there may be an ethical issue. Maybe they agree - based on what I present them (if they’re not familiar with the subject) - or maybe they don’t. Or maybe there are shadings in between. I try to include remarks - from any source - that I think will help readers/viewers.
Again, I can’t speak for other journalists, although I do know that accessibility is important, and not only on deadline (if only most people understood this point). But as I indicated earlier, I agree that a wide mix of experts or expert views is good to have, and I’ll keep that in mind myself.
Cheers
atlex
Ed,
I think you know my comment wasn’t directed at you. And, ultimately, having heard Caplan in an open forum, I think his opinions are well-thought out and, most often, quite nuanced (as ethical discussions tend to be). Thus, in many cases his statements tend to get shortened to a pithy condemnation that probably doesn’t reflect the full extent of his opinion.
Atlex
Ed Silverman
Hi Atlex,
I know, but since you raised the topic and it’s on this site, I figured some people may want to know what I do or how I go about things. So I’m happy to provide insights if it’s somehow helpful.
Best
ed
Why Not
Atlex writes; “I think his opinions are well-thought out and, most often, quite nuanced (as ethical discussions tend to be). Thus, in many cases his statements tend to get shortened to a pithy condemnation that probably doesn’t reflect the full extent of his opinion.”
Well, I guess this moves us beyond the buffoon caricature (not Atlex’s) and into something that is, indeed, more nuanced.
Former pharma Marketing Exec
Supremacy Claus - you have got to be kidding me!
You think Altex represents the medical ethicist point of view? When did the promotion happen?
Seeding trials on un-approved drugs is an will forever remain un-ethical. It impedes the patient’s ability to informed consent and therefore obstructs the patients ability to make appropriately informed decisions on their health care treatment. These patients did not realize that they were taking an un-approved drug,
This is yet another reminder of why I chose to leave this business. Unfortunately quite a few of you “newcomers” seem to be totally inept at reading your moral compass. I invite you to visit this site: http://www.moralcompass.com/index.php Please do us all a favor and click on the “learn more” it would be additionally benefiting to many of us if you would take the free self assessment test.
This type of seeding trial breeds miss trust - the PERFECT STORM…
Kim Klausner
The nine Merck documents cited in the Hill paper, and others, can be viewed at the University of California, San Francisco’s Drug Industry Document Archive (http://dida.library.ucsf.edu) by entering “cs:humeston” without the quotations in the query box.
Kim Klausner
Digital Libary Manager