Autism and snake oil

For me, one of the most interesting things about the retraction last week by the Lancet of its discredited 1998 study linking vaccines and autism was the consensus that those who have believed the study will continue to have faith in it, despite the retraction.

That's why, with the help of Star health reporter Megan Ogilvie, who wrote the paper's original story on the retraction, I began asking around why people clung to scientific studies long after they have been discredited. The result was a story in Tuesday's paper.

I spoke with Jeanette Holden, a geneticist at Queen's University specializing in autism and whose brother is autistic.

As a scientist, Holden knows every rational reason why a discredited 1998 study, by Andrew Wakefield of London's Royal Free Hospital, linking autism to vaccines is poor science – vaccines have no connection to autism, she says – but can find little fault in the families of autistic children who remain loyal to it.

"This does provide some sort of an answer," she says.

I also spoke with Paul Offit, a Philadelphia pediatrician whose book Autism's False Prophets takes aim at the anti- vaccination movement, who said that people such as Wakefield offers patients and their families the glimmer of something he and other scientists so far cannot: hope.

And hope can be a powerful thing. "They love him because he offers them something," Offit says.

The story has generated some e-mails to Ogilvie and I, with one reader from the United States this morning passionately defending Wakefield and assailing his critics.

Offit, he says, has a conflict of interest because he created a vaccine and stands to lose financially if vaccines are shown to cause autism. However, Wakefield had his own conflicts of interest, having been paid by a law firm suing vaccine makers to conduct the study. The firm also provided some of the research subjects.

Wakefield was the lead author of the report. He wrote that the parents of eight of the 12 children blamed MMR: they said symptoms of autism had set in within days of vaccination. The Sunday Times has now established that four, probably five, of these children were covered by the legal aid study. And Wakefield himself had been awarded up to £55,000 to assist their case by finding scientific evidence of the link.

Wakefield did not tell his colleagues or medical authorities of this conflict of interest either during or after the research.The children were subjected to a battery of invasive procedures, including colonoscopies and lumbar punctures.

In the months that followed the examination of the first children, many more were channelled through the hospital. The parents of many were clients of one solicitor, Richard Barr, of King's Lynn, Norfolk, who was leading the legal attack and had organised Wakefield's funding from the Legal Aid Board (now the Legal Services Commission).

The writer also disputes the description in the story that autism as "relatively rare," pointing out that diagnoses of the condition have been increasing rapidly. I have no way of knowing, however, if that's due to more cases, or better diagnostics. The write ends the e-mail by saying that parents love Wakefiled because he listens to them, which is essentially what Holden and Offit said.

Holden said the only way such family members might finally break with the vaccine study is if Wakefield himself disavows it. She doesn't, however, expect that to happen.

Peering over the edge into assisted suicide

In today's Toronto Star, I address the issue of assisted suicide -- and the argument that euthanasia is practiced so often in hospitals in all but name, that we should consider simply legalizing it.

Starving to death in a hospital bed is a horrible way to die, says an expert on the ethics of death, and it may be time to allow more overt ways of ending the lives of the terminally ill.

Wayne Sumner, a University of Toronto philosophy professor writing a book on assisted suicide, says while euthanasia is illegal in Canada, terminally ill patients or their families can refuse food, water and life-sustaining treatment.

"We tip-toe up to the barrier," says Wayne Sumner, who will speak about assisted suicide at UofT's Joint Centre for Bioethics on Wednesday afternoon.

"We peer over the edge, but seem reluctant to take that next step."

Sumner says there is no practical difference between letting someone starve to death, as is now done when feeding tubes are removed, and the more overt act of instructing a doctor to inject a lethal dose of medication to hasten death.

"If someone is refusing food and water, it's hard to see that the intention is anything but death," he says.

As such, he says, Canada should consider taking euthanasia out of the Criminal Code.

The peg for the story is a seminar to be given this afternoon by the University of Toronto's Joint Centre for Bioethics at their new home at 155 College St., Ste. 754, in Toronto. The centre often webcasts its seminars. Sumner will outline how he came to his conclusions, by addressing the agruments against allowing assisted suicide. Dr. Lawrence Librach of the Temmy Latner Centre for Palliative Care at Mount Sinai Hospital will provide commentary.

Moira McQueen, director of the Canadian Catholic Bioethics Institute, does not agree with Sumner that taking the next step to allow euthanasia would be the compassionate thing to do, as a way of alleviating suffering for both patients and family under the current system.

Every patient, she says,  has the right to refuse treatment or food, and let nature take its course.

"With euthanasia, you're not letting anything take its course," she says.

It is too big a leap to say that because people can refuse treatment or nourishment, they should actively take their own lives, she says.

"We all want to be compassionate, but we want to make sure we're doing the right thing, too."

A private member's bill by Bloc Quebecois MP Francine Lalonde to allow doctor-assisted suicide is currently before Parliament. Assisted suicide is allowed in three U.S. states – Oregon, Montana and Washington state – and in Belgium, Luxemburg, the Netherlands and Switzerland.

A Swiss clinic, Dignitas, has become a destination for people around the world seeking physician-assisted suicide, with more than 1,000 people travelling to Zurich since the clinic opened 12 years ago – including 10 from Canada. The Swiss government is now considering restricting suicides by foreigners, with Justice Minister Eveline Widmer-Schlumpf saying last October, "As a country, we aren't interested in attracting suicide tourism."

Sumner said the move could put political pressure on other governments to allow assisted suicide, since people will soon no longer have the option of flying out of the country for the procedure.

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.

Garden State crackdown on drug marketing

Any doctor wanting to practice medicine in New Jersey may soon have to refuse lunches from drug industry representatives and any gift worth more than $200 (US), if new rules proposed by the state's attorney general are adopted.

The proposals were among 22 recommendations included in a Dec. 3 report to Attorney General Anne Milgram

While a handful of states have fought financial conflicts in medicine by regulating drugmakers and threatening hefty fines, the proposals would make New Jersey the first to make doctors the targets of enforcement.

The proposed regulations "are designed to ensure that patient care is guided by the unbiased exercise of doctors' best judgments," Milgram said in endorsing the report's proposals. "It is critical to minimize the potential for conflicts, and it is critical that patients are made aware of any financial relationship between a physician and a pharmaceutical company or medical device manufacturer. Such relationships could bias medical decision-making."

The report calls on the state medical board to require that 25 per cent of continuing medical education credits come from "evidence-based educational programs" that refuse industry grants. The report also targets ghostwriting, a widespread practice in the drug industry, by recommending that doctors be barred from claiming authorship for articles they did not write. The report also aims to stop doctors from misrepresenting their financial interests on disclosure forms.

On the industry side, the report recommends tight controls on what is known in the pharmaceutical industry as “data mining,” or tracking physician prescription information. All physicians would have to be notified when renewing their licenses that they can opt out of having information about their prescriptions sold by pharmacists to healthcare information organizations, which collect information on prescriptions for pharmaceutical company marketing.

As well, the report recommends that pharmacies be required to maintain documentation that doctors have consented to the sale of their prescribing information. The report calls for legislation to restrict the use and sale of prescriber information for commercial purposes.

 

 

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.

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.

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.

Canadian named in ghostwriting

Writing in the Toronto Star this morning, I look at the case of a McGill University psychology professor, Barbara Sherwin, whose name appeared atop an article prepared by ghostwriting firm DesignWrite as part of its contract to promote Wyeth Pharmaceutical's HRT drugs.

A top Canadian researcher studying hormone replacement therapy was part of a ghostwriting scheme paid for by drug giant Wyeth Pharmaceuticals to promote its products, court documents obtained by the Toronto Star indicate. 
The article in question appeared in the April 2000 edition of the Journal of the American Geriatrics Society and listed McGill University psychology professor Barbara Sherwin as author. 
It argued that estrogen could help treat memory loss in older patients, while offering other benefits. 
Sherwin is the first Canadian implicated in an ongoing scandal in the United States, where court documents – unsealed recently after a successful motion by The New York Times and the journal PLoS Medicine – have lifted the veil on the extent of ghostwriting in the pharmaceutical industry. 
The university is investigating. 
"McGill University is committed to the highest standards of honesty and integrity in research and scholarship and takes substantiated allegations of research misconduct very seriously," said provost Anthony C. Masi in a statement yesterday.
"The university has an established process for investigating and dealing with such allegations, (and) will look into this matter and take appropriate action." 

Sherwin's article examined treatments for memory loss in aging patients. It favoured estrogen, used in hormone replacement therapy, saying the hormone could also help prevent cardiovascular disease and osteoporosis, as well as reduce the risk of colorectal cancer and "all-cause mortality in postmenopausal women." 

"Since estrogen has been used for nearly 60 years, its effective dosages, side effects, and influences on other organ systems are well known," the study says, describing estrogen as "relatively safe." The study, a copy of which remains in the stacks of the University of Toronto's medical school library, lists Sherwin as the sole author. 

But court documents now indicate that New Jersey ghostwriting firm DesignWrite, hired by Wyeth to promote its products, actually penned the article. 

The danger of ghostwriting, said James Szaller, a Cleveland lawyer leading a large class-action suit against Wyeth, is that doctors rely on such articles when caring for their patients. 
"It puts patients at risk, and doctors are relying on marketing materials and not truly clinical studies or unbiased reviews of the medical literature," he said. "It's insane."

Sherwin declined comment, but issued a statement regretting her work with DesignWrite.

"I wrote a portion of the article, but not all of it, although only my name was listed as its author. Other parts of that article were written with the assistance of DesignWrite, a firm which, it turns out, was employed by a pharmaceutical manufacturer to assist in the development of academic articles," she said in the email statement. 
"I made an error in agreeing to have my name attached to that article without having it made clear that others contributed to it. It is an error I regret and which had never occurred before or since. I received no remuneration for the article in question. I believe the article, which was peer-reviewed, represented sound and thorough scholarship and in no way could be construed as promotion for any particular product or company." 
Szaller, who for four years has sifted through internal DesignWrite documents, said Sherwin seems to have offered "a fair amount of editing" suggestions to the writers, compared with others working with DesignWrite. 
"There are some who simply seemed to glance at it and make one- or two-word changes," he said.

Ghostwriting documents put online

PLoS Medicine, the medical journal that paired up with the New York Times last month to convince a US court ot unseal documents in a class action suit against Wyeth, put the court documents online this morning. These are raw documents, and so numerous they're tough to sort through.

The documents include internal correspondence, reports, and tracking documents relating to interactions between the pharmaceutical company Wyeth and a medical communications firm, to promote Wyeth’s hormone drugs. These documents show in considerable detail a coordinated and carefully monitored campaign of “ghostwriting” by Wyeth and medical writing companies for a number of products marketed by the company.

Ghostwriting, which involves using medical writers to produce articles that are then nominally authored by an academic not substantially involved in the writing process, has been condemned as an unacceptable practice by medical journals and editors. Nonetheless, the practice appears to persist and by placing all the documents for scrutiny in the public domain, the editors of PLoS Medicine hope that they will help guide the way to identifying reforms that will eventually stamp ghostwriting out.

In order to make these documents available, PLoS Medicine, represented by public interest law firm, Public Justice (http://www.publicjustice.net), and The New York Times intervened in an ongoing court case in which women were suing Wyeth, the manufacturers of Prempro, a hormone replacement therapy. During the discovery process for this case, one of the lawyers representing injured women in the litigation, Jim Szaller of Cleveland, Ohio, had become aware of many documents that laid out in detail the company’s (mostly successful) attempts to publish papers written by unacknowledged professional medical writers in which the message, tone, and content had been determined by the company but the paper was subsequently nominally “authored” by respected academics.

In an accompanying editorial to be published in the September issue of PLoS Medicine, but put online today, PLoS condemns ghostwriting as medical publishing's "dirty little secret" and calls on journals to immediate retract any ghostwritten articles and to ban the authors involved from future publication. Universities are urged to investigate any professor implicated "as a matter of urgency. Shareholders should worry about whether the companies they are invested in could be in for a financil hit.

But more than that, it says, much soul searching is also needed.

Medical journal editors need to decide whether they want to roll over and just join the marketing departments of pharmaceutical companies. Authors who put their names to such papers need to consider whether doing so is more important than having a medical literature that can be believed in. Politicians need to consider the harm done by an environment that incites companies into insane races for profit rather than for medical need. And companies need to consider whether the arms race they have started will in the end benefit anyone. After all, even drug company employees get sick; do they trust ghost authors?

Ghostwriting called bad medicine

Over the weekend, I had a story in the Toronto Star looking at ghostwriting in medical journal, beginning with the case of a woman diagnosed with breast cancer after two decades of using hormone replacement therapy.

Jackie Smith thought she was doing the right thing.

With an asthmatic 4-year-old boy at home and a sick father a world away in Australia, she had no room in her life for osteoporosis or early menopause. It was 20 years ago, and when her gynecologist suggested hormone replacement therapy to stave off the effects of aging, she agreed.

"I was having these awful hot flashes," the 62-year-old recalls. "I found it really hard to deal with. There was a lot of stress in my life."

It's a moment she is revisiting now, with news that the company behind her treatment used ghostwriters to promote HRT in academic journals and play down any health threats, including breast cancer and stroke.

Last month, Smith, who was on HRT for 13 years, was told she has breast cancer. "The hardest part was telling my son," she says, adding that her boy, now living in British Columbia, flew home immediately.

News of ghostwriting has been seeping out for years, with lawsuits in the U.S. forcing drug companies to admit to the practice.

But a lawsuit against HRT manufacturer Wyeth Pharmaceuticals has gone further, finally pulling back the veil on the shadowy world of academic publishing and laying out how ghostwriting works.

In the story, I compare ghostwriting to students who hire essay-writing companies to prepare their term papers -- except the money involved is a lot bigger, and the professors get promoted for having more articles published, while students get expelled.

It hardly seems fair.In fact, Smith says she would fail any student who uses such a service.