Questions raised about Avandia tests

Despite government investigations into the safety of diabetes drug Avandia, test subjects are still being recruited for studies into the controverial drug, according to a report.

That has some researchers scratching their heads, since regulators in Canada and the US are grappling with what to do about the drug.

"Exposing thousands of people to this drug for many years, just to see if existing studies are right, doesn't make a lot of sense," says Dr. David Juurlink, the scientist who was the lead investigator in the ICES study that compared Avandia and Actos.

"The idea that you would enroll tens of thousands of patients into a study and give them this drug for years just to see if it is really more dangerous, that to me that is something you might do to guinea pigs, not to patients," he says.

Prof. Jonathan Kimmelman, of the Biomedical Ethics Unit at McGill University in Montreal has reviewed the research so far and says he too is concerned.

"You are randomizing patients to a drug that has an unfavourable risk-benefit balance. That is not right," he said.

Three studies in as many years have raised concerns about the safety of the drug.

Avandia's potential to raise the risk of heart attacks in some patients was brought to light in a 2007 New England Medical Journal article that reported a 43 per cent higher risk of heart attacks among Avandia patients when compared with those taking other diabetes drugs, including Actos.

Then last June, scientists working on a large study called RECORD, concluded that Avandia did increase heart failure risk in some patients, but didn't increase the risk of cardiovascular death compared with standard diabetes drugs.

The pendulum swung again last August when a Canadian study published in the British Medical Journal concluded that Avandia carried a higher risk of heart failure and death than Actos.

Dr. Hertzel Gerstein of McMaster University in Hamilton and lead Canadian investigator of one study, defended the research. "The question we are asking on the trial is overall, are the benefits such that they outweigh the risks of the drug?" he said.

 

 

 

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.




 

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.

 

 

Pfizer conflict controversy continues

The controversial appointment of Pfizer Canada executive Bernard Prigent to the Canadian Institutes of Health Research was the lead item on the CBC's national morning radio show, The Current.

A podcast of the show is available.

In the show, Francoise Baylis, Canada Research Chair in bioethics at Dalhousie University, says it is impossible for Prigent to avoid a conflict of interest in the new posting because his job as a Pfizer vice president is to sell as many drugs as possible. The job of the CIHR, however, is to ensure public safety. The two are not always the same thing, she said.

Dr. Jean Rouleau, dean of medicine at the University of Montreal and a member of the CIFR's governing council told the CBC's Anna Maria Tremonti that the group needs to hear from people in the pharmaceutical industry.

Baylis said such input, when needed, could be had by calling Prigent and other industry executives to make submission to the CIHR, without giving them a voice in the decisions made by the group.

Meanwhile, a former member of the CIHR, Saskatchewan researcher Steven Lewis lashed out at the appointment, citing the industry's past marketing scandals and saying the appointment gives Pfizer a competitive advantage over other companies.

"The industry's greatest innovations have occurred outside the lab," he wrote. "Expensive junkets for docs-for-hire to shill for their products to their peers; the purchase of previously distinguished academics to affix their names to ghostwritten papers; the suppression of unfriendly clinical trials and adverse effects data; the publication of the same data in different journals to bias systematic reviews and meta-analyses; etc. ad infinitum."

Lewis said it is "hardly irrelevant that the company to which Dr. Prigent owes his livelihood and his allegiance has owned up to sleaze that stands out even among its shady peers."

Since 2004, Pfizer, the world's largest drug company, has paid $2.75 billion in criminal fines and penalties, Lewis said. "Most recently (Pfizer paid) a whopping $2.3 billion for fraudulently marketing Bextra, a painkiller withdrawn from the market in 2005, and three other drugs."

He questioned how Prigent would respond if the council were asked to support research showing a Pfizer drug is dangerous or identifies the massive public subsidies that flow to drug companies.

As a member of the governing council, Lewis said Prigent will have access to information that his competitors do not and "he can exert a steering effect where they cannot."

CIHR president Dr. Alain Beaudet, who recommended Prigent for the appointment, has said he will bring a private-sector voice to the council and help ensure wise spending.

An online petition against the appointment has now collected almost 4,000 names.

 

 

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.

 

Researchers ask NIH to fund ethics research

In the wake of growing scandals over conflicts of interest and ghostwriting in medical research, more than 100 top researchers from around the world -- including several from Canada -- wrote to the U.S. National Institutes of Health this morning asking it to fund ethics research.

We are writing to ask NIH to fund studies on medical ethics, conflicts of interest in medicine and research, and prescribing behavior. NIH funds a substantial portion of the generation and dissemination of evidence, but the uptake of that evidence and its translation into clinical practice is strongly affected by the complex web of relationships that exists among industry, academicians, medical educators and clinicians.

There is growing evidence that each strand of this web is compromised by ethical lapses and financial conflicts of interest. The recent disclosure of ghostwritten articles, physician payoffs, and the use of academic opinion leaders to increase markets for FDA-regulated products indicate that ethical lapses may permeate biomedical research. A PLoS Medicine editorial in September called ghostwriting “The dirty little secret of medical publishing” and notes “the systematic manipulation and abuse of scholarly publishing by the pharmaceutical industry and its commercial partners in their attempt to influence the health care decisions of physicians and the general public.” An October 1 editorial in the Boston Globe called for a ban on industry speaker fees to physicians. Last month, a commentary in JAMA called for physicians to pay for continuing medical education (CME), citing a recent Institute of Medicine report4 that criticized physicians’ reliance on industry-funded education.

The letter to NIH director Francis Collins says the NIH "is the best place to launch and support a scientifically rigorous inquiry into the state of research ethics, industry-academic relationships, and the effect of these relationships on human health."

It notes, however, that there is currently no mechanism in place for the NIH to conduct such a study, but asks to meet face-to-face with Collins to discuss the issue.

The 10-page footnoted letter co-ordinated by PharmedIOut, a physician-run organization researching conflicts of interest, contains more than eight pages of signatures from top medical and ethics researchers from around the world.

Signatories include several Canadians, including Sharon Batt of Dalhousie University, Pierre Biron of the Université de Montréal, Alan Cassels of the University of Victoria, Carol Kushner a health policy consultant in Toronto, Joel Lexchin at York University, Barbara Mintzes at the University of British Columbia, David L. Sackett at McMaster University and Sergio Sismondo at Queen's University.

 

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.

Payments to doctors going online

Merck will soon become the largest drug company to post its payments to doctors online in the wake of costly lawsuits in which such payouts have become a big issue.

Richard Clark, chairman and chief executive of the second-largest US drugs group by sales, told the Financial Times that “the system needs to be totally transparent.” He also questioned whether there was a need for an annual ceiling on payments.

The group will begin publishing regular details in the fourth quarter.

His comments mark the latest escalation in efforts by drugs companies scrambling to seize the initiative on reforms to a system that has come under intense criticism for potential conflicts of interest, triggering growing legislative and regulatory pressure for change.

Critics claim tens of millions of dollars a year paid by drug companies in consultancy, speaking and writing fees as well as free drug samples given to influential doctors and medical academics are leading to prescriptions of medicines that are not justified by scientific evidence.

Merck isn't the first to do this Eli Lilly has alread set up its online registry, listing some $22 million (US) in payouts to 3.400 doctors and researchers in the first quarter. It was required to make the information publc after a $1.4-billion settlement in January over illegal promotion of its anti-psychotic drug Zy-prexa.

I took a quick look through the Lilly list. It's a bit overwelming. The doctors and researchers are listed alphabetically. The list is searchable, but it can be tough to find information unless you've got a good idea of what you're looking for.

The registry only includes US doctors, howsever, so there are no Canadians listed.

The Boston Globe, however, has used the list to find 60 Massachusetts doctors who received payments from Lilly.

At least 60 Massachusetts doctors collectively have earned more than a half-million dollars this year as speakers paid by pharmaceutical giant Eli Lilly & Co. - including two Boston Medical Center physicians whose participation is being reviewed for possible violation of a hospital policy against marketing activities by its doctors.

After learning of the doctors’ company-sponsored talks from the Globe, Boston Medical Center said it would investigate the matter and directed the physicians not to make any further presentations on behalf of Lilly in the meantime

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.