As most anyone who read a morning paper today now knows, the current issue of JAMA contains two articles and an editorial based on documents released as part of the Vioxx lawsuits against Merck, showing evidence of ghostwriting and data manipulation. Little of this will be new to readers of HOOKED or this blog. Perhaps the most newsworthy point was the tone of JAMA's editorial, which might be describe as, "We're mad as hell and we're not going to take it any more." Or, as the editorial itself stated, "[Profound influence of the pharmaceutical and device industries over medical practice, education, and research] has occurred because physicians have allowed it to happen, and it is time to stop."
In news accounts Merck tried to minimize the damage by objecting that the authors of both papers had conflicts of interest because they had been employed by plaintiffs' attorneys in the lawsuits. (Funny how drug companies think that financial conflicts of interest are so damaging to one's credibility, as soon as the shoe is on the other foot.) JAMA makes no bones about these conflicts, acknowledging that only those involved with the lawsuits would normally have access to these documents in the first place. Just to assure that everything is kosher, JAMA took the unusual step of demanding that all of the original documents on which the authors relied be posted in publicly accessible websites that are referenced in the articles.
Ross et al. dealt with the issue of ghost and guest authorship, comparing correspondence between Merck and several medical communications companies regarding manuscripts being prepared for publication, with the actual publications in medical journals. (This is the same strategy Healy and Cattell employed in the best earlier paper on this topic, which made use of documents released by the Zoloft litigation.) When various drafts of the same article could be compared, they generally showed virtually no changes, thus negating any suggestion by the putative academic authors that they had carefully read and edited the manuscripts supplied for them by the ghostwriters. The practice most noted here, but not much discussed previously, is guest authorship, in which Merck in-house scientists wrote the paper but then added the names of academic scientists, often listing the academic as first or second author. Apparently, what has changed in recent years is that journal policies make it harder and harder completely to concal company sponsorship; indeed most of these articles disclose Merck funding. So the Merck scientists are listed openly as co-authors, only farther down the list, and the putative academic authors (who acually add little or nothing to the paper) are slipped in at the top.
Another tidbit in this paper is what the putative academic authors are paid for the use of their names. Ross et al. found fees of $750 to $2500 documented. In writing HOOKED, I could not find documented evidence of any fees of this sort greater than $1000, though when I mentioned that figure to several people closer than I am to the journal "biz," I received eye-rolls suggesting that I was on the low side. So it's nice to know what the going rate is for selling your integrity as a scientist.
Psaty and Kronmal recalculated the mortality rates from heart disease in two studies in which Merck tried to show that Vioxx would be good for preventing or reversing Alzheimer's--which flopped because it either did nothing or worsened the disease. They show that in both the published papers and in data submitted to the FDA, Merck managed to under-report the actual risk of heart disease deaths. Now that we know what we know, some of the data reported in the papers should have set off warning bells among journal editors and reviewers-- such as: "There were no drug-related deaths during the study. Non-drug related deaths occurred in 11 patients (9 in the rofecoxib group and 2 in the placebo group) while taking the study treatment or within 14 days of the last dose." Let's see--there were no "drug related" deaths, and purely by coincidence, more than four times as many patients who were taking Vioxx died compared to those taking placebo? Uh huh.
The editorial by DeAngelis and Fontanarosa lists a number of proposed reform measures, many of which are rather self-serving because they claim that if only all medical journals had the same stringent editorial policies as JAMA does, this sort of thing would not happen. The last in the list might easily be missed: "Individual physicians must be free of financial influences of pharmaceutical and medical devicde companies including serving on speaker's bureaus or accepting gifts." In other words, JAMA has belatedly come out in favor of the No Free Lunch pledge, AMSA's Pharm-Free campaign, and the National Physician's Alliance Unbranded Doctor campaign.
Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. JAMA 299:1800-12, April 16, 2008.
Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: a case study based on documents from rofecoxib litigation. JAMA 299:1813-17, April 16, 2008.
DeAngelis CD, Fontanarosa PB. Impugning the integrity of medical science: the adverse effect of industry influence. JAMA 299:1833-35, April 16, 2008.
Healy D, Cattell D. Interface betweem authorship, industry and science in the domain of therapeutics. Br J Psychiatry 183:22-27, 2003.
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The Human Injury of Lost Objectivity
If I were to rate the corruptive tactics performed by big pharmaceutical companies, the intentional corruption of implementing fabricated and unreliable results of clinical trials by pharmaceutical companies by hired third parties who manipulate these trials they sponsor because of their power to control others involved in such trials that is largely absent of regulation would be at the top of the list, and likely the most damaging to the requirement of authenticity and, more importantly, assuring the safety of the public health, as I understand that this does in fact occur.
Decades ago, clinical trials were conducted at academic settings that focused on the acquisition of knowledge and the completely objective discoveries of meds. Then, in 1980, the Bayh-Dole Act was created, which allowed for such places to profit off of their discoveries that were performed for pharmaceutical companies in the past. This resulted in the creation of for-profit research trial sites, called Contract Research Organizations, which is often composed of community research sites with questionable investigators possibly void of necessary research experience or quality regarding their research purpose and ability. Since they are for- profit, with some CROs making billions of dollars a year. The trials conducted at such places are sponsored by pharmaceutical companies that control and manipulate all aspects of the trial being conducted involving their med being studied in the trial. This coercion is done by various methods of deception in subtle and tacit methods. As a result, research in this manner has been transformed into a method of marketing, which includes altered results of the trial to favor the sponsor’s med. Their activities are 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.
Further disturbing is that once the creation of the trials is completed, they are then written by ghostwriters often, although no one seems to know how often. 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 be placed on the trial that likely had no involvement with the trial, and, along with others, was paid by the sponsor for doing this deceptive act.
To have the trial published, the sponsor pays a journal to do this in various ways, I understand, such as purchasing thousands of reprints of their study from the journal. Again, how often this process is performed is unknown, yet frequent enough to create hundreds of such false writers and research sites to support the pharmaceutical industry. So benefits of meds studied in such a malicious way potentially can harm patients and their treatment options and safety risks. The purchased reprints are distributed to the sponsor’s sales force to share the content with prescribers which may lack validity.
Such misconduct discussed so far impedes research and the scientific method with frightening ethical and harmful concerns, if in fact true based on reports by others. If so, our health care treatment with meds is now undetermined in large part with such corruptive situations, as well as the possible absence of objectivity that has been intentionally eliminated. Trust in the scientific method in this type of activity illustrated in this article is absent. More now than ever, meds are removed from the market are given black box warnings. 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 can interfere in such ways described in this article, requiring independent sites with no involvement with 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
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