Science as marketing

A new peer-reviewed study paints a disturbing picture of the use and abuse of science by pharmaceutical companies to help them sell drugs.

Published in the latest edition of the Journal of Bioethical Inquiry, the study goes through several case studies of big drug companies using questionable science to boost the apparent effectiveness and/or safety of their products. Authors Glen Spielmans and Peter Parry sifted through internal court documents released to the public through lawsuits against the drug companies in one of the first peer-reviewed studies to rely on such documents.

They outline several ways they say that companies used science improperly to market their drugs, including selective use of trial results (or "data fishing") to suppress or spin negative results, and ghostwriting -- in which a report written by or for a drug company to give a psitive review to one of its products is then published under the name of a respected academic or research who had little (if anything) to do with its preparation.

In most cases, the study says, the "authors" are not even allowed to see the raw data -- a fatal flaw, the authors say, because the raw data can sometimes point to a different conclusion that the data the company has selected to share with the outside world, or its "authors" of ghostwritten articles.

By participating in such schemes, Spielmans and Parry say, "honorary academic authors are not just padding their vitae, they are also potentially harming public health when they fail to carefully review data presented in studies on which their names appear as authors."

They outline GlaxoSmithKline's ghostwriting program for its anti-depressant Paxil, dubbed CASPPER, for "Case Study Publications for Peer Review." 

The authors also offer an example of how data fishing can work, again from GSK, but not from the CASPPER program. In the example, data from a "wash-out" period before the formal trial -- during which past medications use is washed from the participants' bodies to ensure a clean trial -- is included, which alters the study's conclusions.

Instead of showing a higher chance of suicide, the eventual study showed the opposite.

Placebo-controlled trials often include a placebo wash-out phase, in which all participants initially receive placebo prior to some participants then switching to the drug under investigation. For example, a study may use a 3-week period of placebo washout, followed by 8 weeks of patients receiving either drug or placebo. It should be obvious that the comparison of efficacy and safety between drug and placebo should begin during the fourth week, when half of the participants have started receiving active medication. Yet some manufacturers of antidepressants counted suicidal behaviour in the placebo wash-out phase against placebo in their comparisons of drug to placebo. Comparing suicidal acts on 11 weeks on placebo to 8 weeks on a drug helped to drive up apparent rates of suicidal behaviour on placebo, which made the drugs appear safe in comparison. Indeed, an article was published in 1995 allegedly showing that paroxetine reduces suicidality. The academic author admitted that he had not seen the actual raw data; rather, he had been provided data tables by the manufacturer, which he then helped to convert into an article (Glenmullen 2007). However, the data in the article included suicide attempts which occurred during the placebo washout phase, though this was not stated in the manuscript. GSK has since posted its own analysis online, in which it notes an increased risk of suicidal behaviour among patients taking paroxetine relative to placebo (GlaxoSmithKline undated). Nearly anyone reading a journal article will assume that the named authors had access to raw data rather than misleading data tables provided by a drug firm. While not technically ghost authorship, the manner in which the data were translated into final form is clearly outside of the norms of science.

The authors call for more access to raw data, and recommend that perhaps journal articles should be read with a grain of salt.

The article also provides links to several web site containing internal drug company files made public due to lawsuits: furiousseasons.com/ zyprexadocs.html, furiousseasons.com/ zip/seroqueldocs.zip and healthyskepticism.org/ documents/Antipsychotics.php. There is also the Drug Industry Document Archive at the University of California, San Francisco, which has a searchable database of company files from several court cases.

A thin slice of (antidepressant) salami

A new study is casting a light on the controversial practice in academic publishing of "salami slicing" -- or the publication of several studies from just one set of clinical data.

Blogger and award-winning reporter Ed Silverman defines salami slicing this way: "Simply put, this involves publishing separate, but similar articles that rely on the same set of data. Researchers may slice the salami to increase their publishing output and drugmakers may view this as a way to promote useful findings for their meds.

The study, in the journal Psychotherapy and Psychosomatics, says the practice does little to advance science, but can help boost drug sales and feed a researcher's need to publish or perish.

Salami publications may be included as part of a pharmaceutical firm’s publication plan. When supportive and highly similar points about a drug’s efficacy and/or safety from a single clinical trial are published in a variety of journals, a wide audience of potential prescribers and key opinion leaders is reached. Thus, in addition to padding the curricula vitae of researchers, salami publications may lead to the results of a successful trial being disseminated across several publications, likely helping to boost product visibility and reinforcing the product’s key marketing messages. Because various researchers and clinicians read differing journals, they may not notice that redundant findings are being presented in multiple publications.

The study found that six clinical trial were sliced thin enough to be used in 20 or more different published studies.

Pfizer Canada facing two conflict fights

Drug giant Pfizer Canada finds itself at the centre of two conflict of interest controversies after one of its executives was appointed to the Canadian Institutes of Health Research and it signed a deal to provide $780,000 for the Canadian Medical Association to set up educational programs for doctors.

The controversies have also touched the Canadian Medical Association, which is coming under fire for taking $780,000 from Pfizer to set up the education programs.

“My feeling is that the pharmaceutical industry has no business at all educating doctors,” said Arnold Relman, professor emeritus at Harvard Medical School and former editor of the New England Journal of Medicine. “There's no question that if you're paying the piper, you influence the tune that the piper is going to play.”

Heather Bisset, Pfizer Canada's manager of corporate communications, said it simply wants to “improve education that's provided for doctors across Canada.”

Meanwhile, as of this writing, more than 3,100 people had signed an online petition against the appointment of Dr. Bernard Prigent, vice president and medical director of Pfizer Canada, to the governing council of CIHR.

Francoise Baylis, Canada Research Chair in bioethics at Dalhousie University calls Prigent's appointment "an intractable conflict of interest."

To quote from one of the signatories, “You don’t put the rooster in charge of the hen house.” The duty of pharmaceutical companies (e.g., Pfizer) is to make money for their shareholders. The duty of CIHR is to promote the public interest. The interests of shareholders and the interests of Canadians are not one and the same.

CIHR was created in 2000 as an arms-length federal agency responsible for funding health research in Canada. The 2009-2010 total budget for CIHR was just under a billion dollars. This is a lot of money and it is important that Canadians understand how their tax dollars are being spent.

CIHR president Alain Beaudet said Prigent's experience in innovation and commercialization will “fill a major expertise gap” on the board.

 

Top journals boost conflict standards

The top medical journals in the world, including the Canadian Medical Association Journal, will soon start demanding more stringent and uniform conflict of interest declarations from researchers than they have in the past.

The requirements will go beyond existing disclosure rules at many medical journals to include items such as financial relationships involving spouses, partners or minor children. Also required will be disclosure of nonfinancial conflicts, such as religious and political affiliations. Such disclosures are used in medical journals to alert readers to potential biases in research.

At least a dozen publications have agreed to use a new, standardized disclosure form, which will be phased in over the next several months.

By standardizing what researchers report to different medical journals, the editors are attempting to address complaints about the existing system for disclosing conflicts of interest. Researchers say medical journals' differing policies are confusing and lead to inadvertent omissions. Advocates for better reporting of financial conflicts say a researcher's potential conflict may be listed in one publication but not another.

The new standards are the products of the International Committee of Medical Journal Editors, and are signed by the editors of 14 leading medical journals around the world, including Paul Hebert, editor-in-chief of the CMAJ, as well of editors of such respected journals as the Lancet, The Britich Medical Journal, the Journal of the American Medical Association and the New England Journal of Medicine.

Under the new rules, researchers will have to fill out a form detailing their possible conflicts of interest. The ICMJE says the standardized form will make the process of disclosure simpler for all involved. "Our goal is to make the process of disclosure uniform and easy; the new form should eliminate the need to reformat disclosure information for specific journals," reads an association editorial on the new standards.

The Scientist magazine, meanwhile, has opened a discussion forum asking researchers what they think of the new form. The ICMJE says the form may be adjusted next spring, depending on how well it works out in the initial "beta" run.

A recent study in the New England Journal of Medicine found that up to half of researchers fail to properly discloe all potential conflicts of interest.

Wyeth ghostwriting documents now searchable

Recently released court documents in a lawsuit against drug giant Wyeth, thanks to a court action by the New York Times and PLoS Medicine, are now searchable at a University of California, San Francisco web site.

The Wyeth documents are the latest made searchable at the Drug Industry Document Archive, or DIDA, which archives the documents from several high-profile cases. Here's a blurb on what the site is all about, how it got started, and how it is funded:

The Drug Industry Document Archive (DIDA) was created by the Center for Knowledge Management at the University of California San Francisco Library in collaboration with faculty members C. Seth Landefeld, MD and Michael Steinman, MD to house material pertaining to United States of America ex rel. David Franklin vs. Parke-Davis, Division of Warner-Lambert (now owned by Pfizer, Inc). Filed by former Parke-Davis employee David Franklin, the lawsuit alleged that the company violated federal regulations by engaging in systematic efforts to promote the drug gabapentin (Neurontin) for uses not approved by the U.S. Food and Drug Administration. Drs. Steinman and Landefeld were unpaid expert witnesses on behalf of the plaintiff and wrote an expert report for the court regarding marketing practices for gabapentin and its potential impact on physician prescribing.

Documents were obtained from public-access files of the United States District Court for Massachusetts and other sources including the plaintiff's law firm. These include materials written by Parke-Davis and companies with whom it worked which were entered as evidence, and legal documents outlining the progress of the litigation.

Documents from additional sources, including court cases and US government committee investigations, have been added to DIDA over the last few years. For a full listing of these sources, see The Documents.

The archive was founded with the support of a gift made by Thomas Greene to The Regents of the University of California in February 2005. Mr. Greene's law firm represented Mr. Franklin in the litigation from which many of the archived documents were obtained.

The Wyeth documents detail the use of ghostwritiers by Wyeth to promote its hormone replacement therapy drugs over the last decade. Last month, MecGill professor Barabara Sherwin was implicated in the case, when documents showed she used the services of a ghostwriting company on at least two occassions. Sherwin has denied any wrongdoing.

The documents were first made available last month on the PLoS web site, but were not searchable and difficult to sort through. The DIDA site now make it possible to search for documents by name, type or content.

Ghostwriting -- why they do it

A prominent hormone replacement therapy researcher exposed by the New York Times last December to have put his name on ghostwritten studies for estrogen drug company Wyeth Pharmaceuticals has broken his silence to say he's sorry.

Seattle blogger William Heisel, a former award-winning health reporter for the LA Times, managed to reach Australisn researcher John Eden by e-mail, where others had failed.

He was surprisingly forthcoming and said he regrets the decision.

"We academics are under some pressure to 'publish or perish,'" Eden wrote. "Performance evaluation of at least Australian academics includes the number and quality of publications per year. In retrospect, I was probably naïve and I wouldn't do it now."

His comments cut to the heart of what observers have said is at the heart of ghostwriting -- professors are under pressure to publish papers, and to publish often, or see their careers suffer. So when someone comes along to help them get more publishing credits to their name, they agree.

In a column by Peggy Curran, the Montreal Gazette wondered if the pressure to publish was behind the involvment with ghostwriters by McGill University professor Barbara Sherwin.

In a written statement last weekend, Sherwin said she “made an error in agreeing to have my name attributed to that article without making it clear that others contributed to it.” Sherwin said she was not paid for the article, and believes the article reflected “sound and thorough scholarship.”

So was Sherwin duped or simply sloppy, so desperately keen to publish she was willing to blur the lines of ethical conduct? If, as she says, the article went through a peer review, why didn’t she mention the other authors? How often do academics, under pressure to deliver on deadline, rely on a ghost for hire?

Jocalyn Clark, a University of Toronto assistant professor of medicine and a senior editor at PLoS, says universities have a responsiblity to get tough on ghostwriting. PLoS, along with the New York Times, managed to get 1,500 court documents on ghostwriting made public, and then put them online.

Canadian named in ghostwriting, part 2, and what can be done

In a story in this morning's Toronto Star, I explore the ties between McGill University professor Barbara Sherwin, alleged in court documents to have used a ghostwriter for an April 2000 study, and New Jersey ghostwriting firm on a second study published three years later.

Sherwin vehemently denies there was any ghostwriting involved in the 2003 article.

Here is her complete statement to the Star on the matter:

"Concerning the article in question, published in Endocrine Reviews in April 2003, I had refused to submit material offered by DesignWrite personnel. The article eventually published in Endocrine Reviews was entirely my own work. I cannot emmphasize that strongly enough."

"In my previous statement, I maintained that I had never - either prior to or following the publication of an article in the Journal of the American Geriatric Society in April 2000 - submitted work other than my own. I stand by that statement."

McGill continues to investigate. Here is the university's complete statement yesterday from provost Anthony C. Masi:

"As I said last week, McGill University takes academic integrity very seriously. We have policies and procedures in place that require us to investigate serious allegations of academic misconduct."

Jocalyn Clark, a Toronto-based senior editor for PLoS Medicine, which last month managed with the New York Times to get the court documents released to the public. says universities need take the lead in stamping out ghostwriting.

Academic institutions, she says, use a professor’s publishing record as the basis for promotions, grants and deciding who gets tenure – so have a responsibility to ensure those records are beyond reproach.

“Publications are the main currency in academic institutions,” Clark, an assistant professor at the Unviersity of Toronto medical school, said in an interview.

As such, the schools need to send a clear message that using ghostwriters will hurt an academic’s career, not help.

“Stamping out ghostwriting will only happen when academic institutions, their medical schools and their faculty declare that this is not acceptable,” she says.

PLoS, which in a recent editorial referred to ghostwriting as "the dirty little secret of medical publishing," has also called on medical journals to retract all ghostwritten articles, to notify the universities where the authors of the articles work and to ban those authors from publishing with that journal again.

Such measures, Clark says, could damage a researcher’s career. At that, she hopes, would be a powerful incentive for them to stay away from ghostwriters. 

PLoS has also made the court documents available online.
 

Ghostwriting documents a wealth of information

Court documents put online last week by PLoS Medicine give the public an unprecedented look into the world of academic publishing and the extent to which big drug companies used ghostwriters to market their products.

The 1,500 documents -- internal memos, meeting agendas and minutes, project tracking report, faxes, cover letters, draft manuscripts and more -- detail the efforts by Wyeth Pharmaceuticals to use top academic journals as marketing tools for its hormone replacement therapy drugs, and to enlist top researchers from around the world to be "authors" of the studies.

The documents were made public last month after PLoS and the New York Times convinced a US court ot unseal documents in a lawsuit to release them to the public. PLoS put them all online last Friday.

Toronto-based senior editor told me yesterday that the public needs access to these document so they can see for themselves what happened.

"The thing that strikes me about the documents is how the campaign is so co-ordinated, so deliberate," Jocalyn Clark says. "Which implies it is a normal course of business."

One document, a May 15, 1997 proposal by DesignWrite to produce ghostwritten articles for Wyeth, bluntly states three main goals for the partnership: boost physician awareness of HRT, “diminish the negative perceptions associated with estrogens and cancer” and lessen the competitive threat of another company’s similar drug.

The proposal, which won DesignWrite a seven-year contract to produce up to 30 articles at up to $25,000 per article, offers Wyeth (referred to as “the client”), full control over the content of the articles.

“After the client has reviewed and released the manuscript for submission, DesignWrite will see it through the necessary production stages – creating camera-ready figures and tables and the text according to journal guidelines and submit the package (manuscript, art cover letter, and any required forms and checklists) to the appropriate journal editor.”

Depositions by several DesignWrite and Wyeth executives are also among the doucments available.

In one such deposition, Karen Mittleman, senior medical writer at DesignWrite, explains the general process for ghostwriting: Wyeth sends data to DesignWrite to be used in a ghostwritten article. An outline is prepared by DesignWrite and sent to Wyeth for review. It then goes back to DesignWrite to prepare a first draft, which takes between four to eight weeks. The draft is sent to Wyeth for review and to a respected researcher in the field, who will also review it and attach his or her name as author.

In many of the documents, a distinction is drawn between “writers,” the anonymous people who pen the articles, and “authors,” the academics who lend their names and reputations to the finished product.

Beyond ghostwriting, the documents indicate, DesignWrite was also hired by Wyeth produced PowerPoint slides to be used by academics when making presentations at industry conferences. Wyeth paid $10,000 for this service.

Trudo Lemmens, a professor of law and medical ethics, has said such help with presentations is often the beginning of the slippery slope drawing academics into a pharmaceutical company’s sphere.

DesignWrite also wrote articles for academic journal supplements at $25,000 apiece, the court documents indicate. Wyeth could then by up multiple copies of the supplements for distribution to doctors’ offices and to give to its sales force to use as evidence of the effectiveness and safety of hormone replacement therapy.

The firm was also instrumental in putting together a patient information handout for doctors to give their patients if they had questions about HRT. The 2001 handout, written by DesignWrite writer Bernadette Janas and sent to Wyeth for approval, reassured women that “HRT does not increase breast cancer risk.”

No mention was made of the role DesgnWrite or Wyeth played in putting the handout together.

Making academic fraud a crime, have your say

A story in the online version of The Scientist is sparking calls from readers that academic fraud be criminalized, with the journal now polling readers.

The original story documentedsome $23 million (US) in grants handed out to researchers at the University of Alabama at Birmingham who lied about their methodology and falsified data in at least 16 journal articles. The story is based on records from the US Department of Health's Office of Research Integrity.

The scientists, Judith Thomas and Juan Contreras, formerly at the University of Alabama at Birmingham (UAB), falsely reported that they performed double kidney removals on several rhesus macaques in experiments designed to test the effectiveness of two immune suppressing drugs -- Immunotoxin FN18-CRM9 and 15-deoxyspergualin (15-DSG) -- in preventing rejection of the a single transplanted kidney.

The experimental protocol was to remove one intrinsic kidney, replacing it with a transplant and starting the monkeys on immunosuppresants, and then remove the other intrinsic kidney a month later, according to Richard Marchase, UAB's vice president of research. "What occurred in a good number of these animals was that [Contreras and Thomas] never performed the second surgery," Marchase told The Scientist. In a statement emailed to The Scientist Marchase called the misconduct "a very serious offense."

Thomas's and Contreras's research was funded with more than $23 million in grants from the National Institutes of Health. UAB officials learned that Contreras and Thomas had left one native kidney intact in at least 32 animals -- which allowed those animals to live and inflated the apparent effectiveness of the drugs -- on January 27, 2006, when Thomas reported that she found an experimental monkey with one of its native kidneys intact and blamed Contreras for the mistake.

The scale of the fraud and the implications of the falsified results -- patients could have ended up getting dangerously wrong treatment -- led to readers of the original story going onto the Scientist web site to call for criminal fraud charges to be laid, prompting the journal to poll readers for their thoughts.

Feel free to join in.

 

Real journal, fake credentials

The ongoing scandal in the medical publishing world took on a new twist today with news that Chiming Wei, founder and editor of a journal on the fledgling field of nanotechnology, appears to have exaggerated his credentials -- claiming to head a program at Johns Hopkins University that doesn't exist and starting a professional society with himself as president and chairman.

Indeed, an investigation of his credentials reveals that he claimed to hold a directorship of a non-existent program, co-authored only two original papers in Nanomedicine (one of which, a co-author says, he contributed to only editorially), and was accused of mismanaging the professional society to the point that some board members resigned and began a new professional group.

"I think that this individual is a good example of a field that is poorly- or under-regulated," Summer Johnson, executive editor of The American Journal of Bioethics, told The Scientist. "Everyone trusted the fact that he appeared to have high quality credentials."

Chiming Wei, president and founder of an organization called the American Academy of Nanomedicine (AANM), has the equivalent of a PhD from a Japanese institution and is a researcher in cardiothoracic surgery, but is not currently affiliated with any university. He started the group in 2005, when he was an associate professor at Johns Hopkins University in Baltimore, MD. The AANM's website lists Wei as Director of the Cardiothoracic-Renal Nanomedicine Program at Johns Hopkins, but according to the university, there is no such program. The Johns Hopkins press office was "unable to find evidence that this program exists," a university spokesperson wrote in an email.

Wei was also accused by experts in the field of adding his name to their journal articles, without permission or contributing in a meaningful way to the articles, in order to bolster his credentials.

Wei denied the accusations.

The journal, Nanomedicine: Nanotechnology, Biology, and Medicine, was established by Elsevier four years ago at Wei's urging.

The Scientist reports that Elsevier, however, did not check Wei's credentials before installing him as editor of a peer reviewed journal.

An Elsevier spokesperson said the publisher never checked Wei's publication record in nanomedicine before giving him the job of editing a nanomedicine journal. "Based on the discussions we didn't feel a need to read through [Wei's] papers, as he was quite knowledgeable on the subject," the Elsevier spokesperson added.

Elsevier has been at the centre of a controversy in recent weeks after revelations that it published several journals that were little more than paid promotional items for pharmaceutical giant Merck & Co.