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.

Only one-quarter of U.S. medical centres ban ghostwriting

A new study released today shows only 26 per cent of top American medical centres have a ban on the use of ghostwriters by their researchers.

The study, released today by PLoS Medicine, surveyed 50 top medical centres across the United States, and found that 10 schools ban ghostwriting by name, while another three ban the practice without using the words "ghostwriting" or "ghostwriter."

Authors Jeffrey R. Lacasse and Jonathan Leo called ghostwriting a dangerous practice.

Medical ghostwriting, the practice of pharmaceutical companies secretly authoring journal articles published under the byline of academic researchers, is a troubling phenomenon because it is dangerous to public health. For example, ghostwritten articles on rofecoxib probably contributed to “…lasting injury and even deaths as a result of prescribers and patients being misinformed about risks”. Study 329, a randomized controlled trial of paroxetine in adolescents, was ghostwritten to claim that paroxetine is “generally well tolerated and effective for major depression in adolescents”, although data made available through legal proceedings show that “Study 329 was negative for efficacy on all 8 protocol specified outcomes and positive for harm”. Even beyond frank misrepresentation of data, commercially driven ghostwritten articles shape the medical literature in subtler but important ways, affecting how health conditions and treatments are perceived by clinicians. The ability of industry to exercise clandestine influence over the peer-reviewed medical literature is thus a serious threat to public health.

In 2009, the Institute of Medicine recommended that US-based academic medical centers enact policies that prohibit ghostwriting by their faculties. However, to date, there has been no systematic assessment of ghostwriting policies at academic medical centers. Since US-based academic medical centers generate biomedical research for a worldwide audience, we chose to conduct the first such investigation on elite US-based academic medical centers.

... When a pharmaceutical salesperson hands a clinician an article reprint, the name of the institution on the front page of the reprint serves as a stamp of approval. The article is not viewed as an advertisement, but as scientific research; the reprint is an effective marketing tool because peer-reviewed journal articles generated in academia are perceived to be the result of unbiased scientific inquiry. Deception regarding authorship prevents a discriminating audience from properly assessing the impact of bias in the published article. Importantly, this deception is impossible without the cooperation of faculty employed by academic medical centers. The practice of ghostwriting explicitly violates the usual norms of academia. We are not aware of any other academic fields where it is acceptable for professors to allow themselves to be listed as authors on research papers they did not write, or to purposefully conceal the contributions of industry coauthors in order to mislead readers.

The authors offer a possible wording for a ban on ghostwriting that they urge medical centres to adopt.

“All listed authors on a publication must meet the authorship criteria set by the International Committee of Medical Journal Editors. Making minor revisions to a manuscript does not qualify as authorship. Participating in the creation of ghost-authored manuscripts is not permitted. A ghost author is defined as someone who makes substantial contributions to writing a publication but is not listed as an author. All individuals who have made a substantial contribution to the manuscript must be listed as authors. Accurately reporting authorship is essential for maintaining research integrity, and violating any of these rules is considered research misconduct akin to plagiarism or falsification of data.”

No similar survey has been condiucted in Canada.

 

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.

More on salami slicing -- Cymbalta ads ordered pulled

Today, I had a story in the Toronto Star about an issue I touched on in this blog last week: Salami slicing, or the re-use of clinical trial data in more than one journal study.

I spoke to Glen Spielmans, who wrote a study on the practice after looking into claims made in TV ads by Eli Lilly about its antidepressant Cymbalta.

As he went through every study he could find on Cymbalta – which is also known by its generic name, duloxetine – Spielmans began feeling as if he was reading the same study over and over again, sort of an academic déjà vu.

"There just aren't that many data to do all these secondary analyses on," Spielmans said in an interview. "That raised a flag for me."

I also spoke to a cancer researcher that while salami slicing does happen, it's worth remembering that trials are often designed so the data can be sliced up later.

"I would be careful of anything that's given a folksy name," says Dr. Ralph Meyer, director of the National Cancer Institute of Canada's Clinical Trials Group at Queen's University. ...

"Clinical trials are a lot of work. They're a lot of expense," he says.

Trials that Meyer has run, for instance, have looked at such standard questions as the safety and effectiveness of a new treatment but have also used the opportunity to examine the cost-effectiveness of the procedure or the treatment's impact on a patient's quality of life. 

Jocalyn Clark, a researcher at the University of Toronto and an editor at the journal PLoS Medicine, says top journals like hers require all authors to declare if any part of the underlying research has been – or soon will be – published elsewhere.

She said universities and hospitals need to tell their researchers that slami slicing is not acceptable, and that academics taking part in the practice risk ruining their reputations with the journals they count on to publish their studies. In a part of the stroy that had to be cut for length, she equated the practice to ghostwriting, in that academics slicing up their data are not being fully honest with readers.

Meanwhile, the Food and Drug Administration in the U.S. has sent a letter to Eli Lilly ordering to pull its "misleading" print ads for Cymbalta.

Promotional materials are misleading if they fail to reveal material facts in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials. The Print Ad is misleading because it presents various efficacy claims for Cymbalta, but fails to communicate any risk information in the main part of the ad.




 

Few actually need antidepressants, study finds

It seems that despite the efforts of big drug companies to mass market their antidepressants -- turning them into blockbuster druggs as they pitch the pills to children and pregnant women -- only the severly depressed actually benefit, a new study says.

The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

Lead researcher Robert J. DeRubeis of the University of Pennsylvania said the study, published in the Journal of the American Medical Association, showed that those with only mild depression seemed to benefit from simply the added attention given to them by doctors during the drug trials -- and points to other ways such people can fight their depression.

“The message for patients with mild to moderate depression,” Dr. DeRubeis said, “is, ‘Look, medications are always an option, but there’s little evidence that they add to other efforts to shake the depression — whether it’s exercise, seeing the doctor, reading about the disorder or going for psychotherapy.’ ”

GlaxoSmithKline, the makers of Paxil, one of the drugs in the study, questioned the findings.

”The studies used for the analysis in the JAMA paper differ methodologically from studies used to support the approval of paroxetine for major depressive disorder, so it is difficult to make direct comparisons between the study results,” Glaxo spokeswoman Claire Brough said.

”Antidepressants are an important option, in addition to counseling and lifestyle changes, for treatment of depression.”

About 70 per cent of those taking such medications have mild enough depression that the medications may be of no use, the study found. The study could change how doctors approach depression with their patients, the New York Times said.

“I think the study could dampen enthusiasm for antidepressant medications a bit, and that may be a good thing,” said Dr. Erick H. Turner, a psychiatrist at Oregon Health and Science University. “People’s expectations for the drugs won’t be so high, and doctors won’t be surprised if they’re not curing every patient they see with medications.”

But Dr. Turner added, “The findings shouldn’t dampen expectations so much that people refuse to even try medication.”

The Star's mental health blogger, Sandy Naiman, also wrote about this study today, saying it "supports the strong contention I have about quick-fix, pill-popping approaches to mental health recovery."

 

 

 

 

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.

Medical journals act on conflicts of interest

The world's top medical journals, including the Canadian Medical Association Journal, have launched a beta version of a new financial disclosure form they will require future researchers to fill out before their studies can be published in their pages.

According to a joint editorial to be published in all the participating journals, the uniform disclosure requirements are meant to both make life simpler for researchers facing different reporting standards at each journal, and to ensure a standard measure of researchers' potential conflicts of interest.

We ask authors to disclose 4 types of information. First, their associations with commercial entities that provided support for the work reported in the submitted manuscript (the time frame for disclosure in this section of the form is the life span of the work being reported). Second, their associations with commercial entities that could be viewed as having an interest in the general area of the submitted manuscript (the time frame for disclosure in this section is the 36 months before submission of the manuscript). Third, any similar financial associations involving their spouse or their children younger than 18 years of age. Fourth, nonfinancial associations that may be relevant to the submitted manuscript.

Besides the CMAJ, the journals involved include the Journal of the American Medical Association, the New England Journal of Medicine, the Lancet and the Medical Journal of Australia.

The journals will meet in April to review the form and researchers' reaction to it, and may adjust the four-page form then.

 

Who best to regulate -- doctors or drug companies?

A move by New Jersey to become the first state in the US to regulate the relationship of doctors to drug companies is sparking a debate over the best way to counter the power of Big Pharma.

Last month, NJ Attorney General Anne Milgram released a 22-page report limiting the gifts doctors can accept from drug companies -- among other things saying they can no longer accept free lunches, gifts worth more than $200 (US) and banning them from putting their name on ghostwritten articles. It also calls for tighter controls on doctors' financial disclosure and limits on drug companies paying for doctor retraining.

All are methods used by drug companies to market their products to the doctors who write the prescriptions. New Jersey has one of the highest concentrations of drug companies in the U.S.

The Medical Society of New Jersey, however, says doctors should not be targeted.

Spokesman Daniel Klim said the task force's time could have been better spent on other issues.

"We don't believe that pharmaceutical gifts influence medical decision-making as much as, say, a patient's insurance plan," he said. Klim said that physicians follow a code of ethics and that real conflicts were rare.

"I think in any industry you could find negativity," he said.

Milgram defended the report, saying the state has greater jurisdiction over doctors. "It really is, at the end of the day, each individual doctor's conflict of interest as much as it is the industry's."

Other states, such as Massachusetts and Vermont, put the reporting onus on industry instead of physicians.

Daniel Hoffman, president of the consulting firm Pharmaceutical Business Research Associates in Glenmoore, Pa., supported the restrictions, saying small gifts lead to bigger benefits, such as free education courses.

"It's sort of the opening gambit to a one-hand-washes-the-other relationship that I think has to be broken, to which this kind of ban can be useful," he said.

Industry groups agreed with Klim, however.

Dave Knowlton, president of the nonprofit New Jersey Health Care Quality Institute, said the state should be wary of putting new regulations on doctors who already have too many hoops to jump through.

"I really think that we should be diligent about saying, 'Let's not put another hassle on them unless we really think there's a need for it,' " he said.

Knowlton was on the task force and said he was frustrated that he and other members were left out of much of the process.

He wanted proof that the regulations were needed, arguing that many of the abuses of years past had been remedied through voluntary actions by manufacturers and federal regulations controlling such things as payments to physicians during drug and product trials.

The US federal government is working on regulations governing the drug companies, but Milgram said action is needed now: "To me, the argument of 'please just wait [for a federal plan]' isn't fair to the consumer, because people go to the doctor's every day."

The report makes 22 recommendations in all.

 

 

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.

 

 

The video Pfizer doesn't want you to see

Pharmaceutical giant Pfizer has asked a judge to order that a video be take off YouTube, saying it could prejudice juries in upcoming court cases.

It's the latest twist for a company caught for months in allegations of ghostwriting.

The video, entitled Prempro News Segment, was made by the law firm behind a $78 million (US) court-ordered settlement in the fall of a lawsuit brought against the company. The Philadelphia jury found that Wyeth, a division of Pfizer, failed to warn women that taking its hormone drug Prempro could cause breast cancer.

“Plaintiff’s counsel should be compelled to remove this video from the Internet and refrain from making any further inflammatory and prejudicial public statements” until the litigation is resolved, Pfizer’s lawyers said in a motion filed yesterday in Philadelphia Common Pleas Court.

More than 6 million women have taken hormone-replacement medicines to treat menopause symptoms such as hot flashes, night sweats and mood swings. Until 1995, many patients combined Premarin, an estrogen-based drug made by Pfizer’s Wyeth unit, with progestin-laden Provera, made by Upjohn, another subsidiary of Pfizer, the world’s largest drugmaker.

Wyeth scientists later combined the two hormones in its Prempro pill. The drugs are still on the market. New York-based Pfizer completed its $68 billion purchase of Wyeth in October.

The video was produced by lawyer Zoe Littlepage, who had her staff post it to YouTube. It is made to look like a TV news segment. In it, she accuses Wyeth of hiding the drug's dangers.

“Wyeth chose to not do studies, and even worse, chose to downplay and suppress any evidence of breast cancer and these drugs,” Littlepage says on the video, which doesn’t include a response to the allegations from Pfizer.

The video also features a man identified as a jury foreman in an already-concluded trial over the menopause drugs who calls Wyeth “despicable” and declares that the company is more concerned about profit than about the health of patients.

Documents in the case, filed by Connie Barton, a medical office assistant in Peoria, Ill., have now been unsealed, and used by the New York Times to track the marketing of hormone replacement therapy to women.

The documents that have surfaced in the Wyeth cases offer a rare glimpse inside the file cabinets and hard drives of a major drug company. And the cases demonstrate the importance of litigation in detailing exactly how drug makers operate their businesses, says Dr. Jerome L. Avorn, a professor of medicine at Harvard Medical School who has written about the subject in The Journal of the American Medical Association.

“The information coming out in litigation helps us understand how a belief in a ‘protective benefit’ of estrogens on the heart was able to spread like wildfire through the medical community,” says Dr. Avorn, who is not involved in the Wyeth litigation.

“Thousands of doctors prescribed the drugs for millions of women on that basis,” he says, adding that studies later contradicted the belief. “It will be very interesting to see whether the courts are able to connect the dots and make it clear whether this was a kind of medical ventriloquism on Wyeth’s part.”

Chris Loder, a Pfizer spokesman, says Wyeth acted responsibly by including a clear warning about a breast cancer risk on Prempro labels and by updating the warning as new evidence emerged. He said Pfizer plans to appeal every product-liability case on menopausal drugs it loses, including Barton’s.