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.

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.




 

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.

 

 

 

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.

 

Glaxo loses Paxil lawsuit, more details

I have blogged about this verdict already today, but new details are beginning to emerge.

The $2.5 million (US) award granted by a Philadelphia jury in a verdict handed down this morning against GlaxoSmithKline in a lawsuit over its anti-depressant Paxil is more than twice what the plaintiff was seeking.

Michelle David, suing on behalf of her son Lyam Kilker, who turns four next week, had sought $1.2 million to cover future medical costs and other damages. The settlement granted by the jury in a 10-2 vote matches that awarded five years ago when the drug giant agreed to pay the state of New York $2.5 million to resolve claims that it suppressed research showing that Paxil may increase suicide risk in young people.

David's lawyer, Sean Tracey, hailed the verdict afterward, saying it was the first to "get a jury saying the drug caused the injury."

Business analysts following the company, however, were not so sure.

“I don’t think the link is proven, so there will likely be collective settlements which will keep costs low,” Navid Malik, an analyst at Matrix Corporate Capital in London with a buy rating on the stock, said in an e-mail. “If this was a threat to GSK, the first verdict might have been 100 times greater.”

Glaxo American depositary receipts, each representing two ordinary shares, fell 5 cents to $39.73 at 1:07 p.m. in New York Stock Exchange composite trading, after dropping as much as 1.4 per cent when the verdict was announced. Glaxo fell 14 pence, or 1.1 per cent, to 1,246.5 pence in London.

I have yet to see the full decision by the jury, but Bloomberg is quoting it as saying that the jury found that Glaxo officials “negligently failed to warn” the doctor treating Lyam’s mother about Paxil’s risks and concluded the medicine was a “factual cause” of the child’s heart defects.

On the other hand, the jury also found that Glaxo’s handling of the drug wasn’t “outrageous,” meaning the family couldn’t seek punitive damages against the British drug company.

In a statement after the verdict came down the company said it disagreed with the decision and will appeal.

GlaxoSmithKline disagrees with the verdict and will appeal. While we sympathize with Lyam Kilker and his family, the scientific evidence does not establish that exposure to Paxil during pregnancy caused his condition. Very unfortunately, birth defects occur in three to five per cent of all live births, whether or not the mother was taking medication during pregnancy.

I have called Glaxo for more comment, but have not yet heard back.

Glaxo spokesman Kevin Colgan called and read me the statement quoted above.
 

 

 

Glaxo loses Paxil lawsuit

Drugs giant GlaxoSmithKline was ordered this morning to pay $2.5 million (US) to the family of a young boy born with heart defects after his mother took the anti-depressant Paxil during pregnancy.

“The first win is always huge, especially when you get a jury saying the drug caused the injury,” Sean Tracey, Kilker’s lawyer, said in an interview after the jury reached its decision.

 It’s the first time a jury has considered claims that Glaxo, the U.K.’s largest drugmaker, knew Paxil caused birth defects and hid those risks to increase profits. The drug, approved for U.S. use in 1992, generated about $942 million in sales last year, or 2.1 percent of Glaxo’s total revenue.

“We’re disappointed with the verdict and I think we’ll be filing an appeal,” Joseph O’Neil, one of Glaxo’s lawyers, said in an interview.

Lyam Kilker, who turns four next week, was born with a rare heart deformity. During the trial, the first of some 600 filed against Glaxo, Tracey argued the company failed to warn doctors and patients about possible side effects to the drug.

Company lawyers presented studies and experts arguing that the drug is safe, despite warnings added to its label in 2005 (after Lyam was born) about the possibility of birth defects. Tracey countered by arguing before the jury that such researchers had close ties to the pharmaceutical industry.

The jury deliberated for seven hours. The Kilker case, brought by his mother Michelle David, was considered a test case for future lawsuits. The next will be heard in about a month -- also in Philadelphia, home to Glaxo's US headquarters.

Lawyers for many of those cases have been in Philadelphia monitoring the progress of the Kilker suit as part of their preparation for going to court.

First Paxil trial goes to the jury

The first of some 600 civil trials to be held alleging that GlaxoSmithKline's anti-depressant causes birth defects was put in the hands of a Philadelphia jury this morning.

Testimony in the state-court trial, which began in September, wrapped up yesterday. Jury deliberations have begun and a verdict is expected sometime in the coming days or week, court watchers said.

The lawsuit involves allegations from Michelle David, who claims drug maker GlaxoSmithKline concealed negative study results linking Paxil to a life-threatening heart malformation in newborns of women who took the drug during pregnancy. The company marketed Paxil for treating pregnant women with anxiety, despite knowing about the apparent connection to birth defects, David contends.

David took Paxil while pregnant with her son, Lyam Kilker, who was born with life-threatening heart defects. The boy is now four and has fully recovered after being hospitalized as a newborn and undergoing multiple surgeries to repair his heart.

The trial is considered a test case for 600 such lawsuits expected to be heard the coming months in Philadelphia, where Glaxo's US headquarters are located. Lawyers for several of those upcoming cases have been in Philadelphia monitoring the David/Kilker case as they prepare their own arguments.

In his closing statement, David's lawyer Sean Tracey said Glaxo intentionally ignored the possibility that Paxil caused birth defects.

Glaxo researchers never followed up on studies showing Paxil posed a birth-defect risk for fear of harming sales, Sean Tracey, lawyer for a family suing over the drug, told jurors yesterday in state court in Philadelphia.

The London-based drugmaker “made a concerted effort” not to study Paxil’s links to birth defects, Tracey said. Glaxo executives sought to “avoid doing studies that would have revealed the truth about their drugs,” he said.

The drug, approved for use in the U.S. in 1992, generated about $942 million (US) in sales last year.

In her closing statement, Glaxo lawyer Chilton Varner urged jurors to “set sympathy aside and decide this case fairly,” adding that arguments that Glaxo “has acted improperly or unethically” in its testing and marketing of Paxil “don’t ring true.” 

She said the company isn't liable for Kilker's heart defects.

The company has set aside $2.8 billion to deal with legal and other non-tax disputes.

A second Paxil case, expected to begin next Tuesday, was settled out of court last weekend. The next is not scheduled to begin in mid-November.

 

Doctors fail to disclose conflicts of interest

A study in the New England Journal of Medicine today found that doctors, left to their own devices, do not always report potential conflicts of interest up to half the time.

The study led by Dr. Mininder Kocher of Children's Hospital Boston examined the issue of doctors disclosing conflicts by looking at the voluntary disclosures made by presenters at a 2008 conference of orthopaedic surgeons, comparing them with the records of payments made online.

Before the March 2008 annual meeting of the Academy of American Orthopedic Surgeons, physicians who were making presentations or serving on committees for the meeting were asked to list payments they received that could indicate potential conflicts of interest. About seven out of 10 physicians disclosed financial relationships that the device manufacturers had already made public, the authors concluded.

"The thrust has been voluntary disclosure from the physicians," Kocher said in an interview (with the Boston Globe). "Our study would suggest that that may not be so accurate and is difficult to validate."

The disclosure rate was higher for payments directly related to the topic the doctor was addressing at the meeting and lower for indirectly related topics. A talk about knee replacement results would be directly related to a physician's royalty payments for knee implants while a discussion of physical therapy regimens would not, Kocher said.

When contacted by Kocher's team about missing disclosures, the most common reason given was that the doctors felt the payments they received had nothing to do with the subject of their talks. The rate of non-disclosure ranged from 21 per cent to 50 per cent.

The doctors made presentations at the meeting or served as committee members, roles that required them to disclose the company payments. The five companies, which account for 95% of the market for hip and knee replacement prostheses, were forced to list the payments as part of a settlement of an investigation by the U.S. Justice Department.

About 30% of the time the doctors did not disclose their financial ties to the device firms, the study found. For payments that were directly related to their presentation, the non-disclosure rate was 21%. For payments that were deemed unrelated, the rate was 50%.

The doctors were required to disclose both related and non-related payments, although the system involved self-reporting.

The undisclosed payments totaled just over $12 million (US), and averaged about $151,000, Kocher said.

Te revelation comes as Republican Iowa Senator Charles Grassley pushes forward his proposal for a sunshine act in the US that would make the relationship between researchers and corporation more transparent.

 

'Serious danger' when doctors are paid by pharma

An editorial in the Boston Globe, which recently reported on 60 Massachusetts doctors who took $580,000 (US) in payments from drug companies over four years, calls for the practice to be banned outright.

The danger posed by this practice is serious: Research shows that getting money from the pharmaceutical industry can cloud doctors’ judgment when evaluating studies and side effects, as well as when they are prescribing medication. In addition, when reputed doctors rely on company material to promote a new drug to their colleagues, they also help broaden its use. Sometimes, the presentations end up encouraging the use of a drug for purposes beyond what it has been approved for by the Food and Drug Administration.

Massachusetts General Hospital, Brigham and Women’s Hospital, and McLean Hospital - all of which also employ doctors who have received money from Eli Lilly this year - will prohibit their doctors from receiving speakers’ fees from the pharmaceutical industry starting today. Other hospitals in Massachusetts and around the country should follow their lead immediately.

Efforts by Eli Lilly to set up an online registry of such payments are not enough, the editorial says. Merck plans to set up a similar registry in the coming months.

While transparency is a good first step that exposes doctors’ financial relationships to the broader medical community, it is unlikely to affect how patients view their doctors. More important, it will not address the subtle ways the payments influence and interfere with patient care.

Patients trust doctors as stewards of their health. They revere them as scientists who can exercise sound, independent judgment. Allowing doctors to promote drugs for pharmaceutical companies takes advantage of that trust and reverence. It also compromises doctors’ most important work: treating people who are ill.

The Lilly registry details $22 million (US) in payments to American doctors in just one fiscal quarter -- providing, it seems, a slice of just how big an issue this is.

Meanwhile, the University of Wisconsin, which has been rocked by revelations of the close ties of many of its researchers to medical device companies and ghostwriting, has backed off plans to ban its professors from collecting fees from the companies whose products they are supposed to be researching.

University of Wisconsin officials have watered down proposed conflict of interest rules, allowing orthopedic surgeons and other doctors who implant devices to earn large sums of money making presentations for medical device companies.

The new policy would keep in place a ban on UW doctors giving talks about medications for drug companies.

Not addressed in the policy is the university's own relationship with the drug industry, which has come under scrutiny in a series of stories this year by the Journal Sentinel.

The university receives several million dollars a year from drug-makers to sponsor doctor education activities, some of which have been criticized as promotional efforts to sell expensive brand name drugs.

But it is the exemption for the device-makers and the ban on drug-only talks that is riling up doctors at UW as part of a high stakes ethics battle simmering at medical schools across the country.

At issue is whether doctors should be free to hire themselves out as promotional speakers and consultants to drug and medical device makers and how much financial influence those firms should wield at academic medical centers.

"It's the subject of animated hallway conversations and nasty e-mails," said a UW doctor who asked not to be identified. "The fever pitch is high."

The university declined comment.

A medical writer's perspective on ghostwriting

Montreal-based medical writer Kate Johnson has weighed in on her blog about the ongoing ghostwriting scandal, saying a distinction needs to be made between anonymous writers hired by drug companies, and those hired by the researchers themselves.

It's a fair point, and Johnson goes to lengths to explain how academic journal articles can have several authors, named and unnamed.

Obviously, if four names appear on a paper, it is unlikely that all four people sat down and typed individual sections. As a medical editor I strongly discourage this degree of “co-operation” because of the disjointed and chaotic results. But it is when an additional, unnamed person is responsible for the writing, that the notion of ghostwriting takes shape.

The ghostwriting scandal revealed in August by the New York Times hinges on this type of ghostwriting, but here a further distinction should be made regarding the definition of ghostwriting.

Although the JAMA study does not make this distinction, the Times focuses on ghostwriters who were hired by drug companies to spin the science in favor of their products. This is clearly a corruption of science and an indisputable attempt to mislead doctors and the public.

Few medical academics could see anything except extreme dishonesty in this practice.

The only point I might quibble with Johnson is on her use of the word "obviously" at the beginning of the excerpt. I am not sure this is obvious to most people, but I could be wrong.

She is right, though, that there is a difference between ghostwriters paid by a drug company and those paid by a researcher -- especially since the drug companies have made clear in their internal documents (made public in court cases) that paying ghostwriters is part of their drug marketing strategy. One would expect that ghostwriters hired by the researchers themsleves would be more attuned to the researchers' findings than to the marketing needs of Big Pharma.

Johnson has pointed out before that many top researchers, for all their brilliance and innovation, are not the best writers -- so turn to people like her for help. As a reporter who has had to sift through many scientific reports, I appreciate that contribution.

But I would also like to know that such a contribution has been made. From a reporter's point of view, there's no such thing as too much information when it comes to such things. It also erodes a researcher's credibility if, and when, it is revealed that a ghostwriter has been used and not acknowledged.

Perhaps researchers, when considering how much (if any) credit to give to ghostwriters should ask themselves one simple question: would I accept such behaviour from one of my students?