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.

 

Research ethics need an overhaul: report

A report out this week calls for an overhaul of the way academic research is done in this country, and for an ombudsman to be appointed to oversee everything.

The report, the Montreal Gazette points out, was well underway before the question of academic integrity broke wide open in Canada last summer with a Toronto Star story about the use of ghostwriters by McGill University professor Barbara Sherwin in an academic article about hormone replacement therapy.

A university inquiry into Sherwin is still several months from completion, the schools says, and likely won't be finished until the new year. The school's provost office blames the long investigation on the huge repercussions for whatever it decides and the complexity and rarity of the case itself.

The new report, however, makes the point that academic misconducts are not all that rare -- though Canada is better than many. The drug sector is particularly bad.

Breeches of research integrity are a problem in some parts of the private sector, notably in the pharmaceutical industry. The existence of companies, including some in Canada, that “ghost write” papers for academic researchers is but one visible manifestation of research misconduct in the private sector. These companies craft research papers in support of a particular drug and seek out researchers willing to be listed as authors in exchange for money and other benefits.

The study, The State of Research Integrity and Misconduct Policies in Canada, prepared for the Canadian Research Integrity Committee by consulting firm Hickling Arthurs Low, says ghostwriting is only part of the problem.

The existence of companies, including some in Canada, that 'ghost- write' papers for academic researchers is but one visible manifestation of research misconduct in the private sector. These companies craft research papers in support of a particular drug and seek out researchers willing to be listed as authors in exchange for money and other benefits.

The report also looks at fabrication of data, falsification of data, plagiarism, conflicts of interest and abuse of power or retaliation towards colleagues and assistants. The 29 academic institutions surveyed, which represent about 60 per cent of the research done in Canada, reported investigating about 39 such incidents a year.

The report says that number is probably low.

This estimate should be treated with the appropriate caution given the challenges associated with collecting this information. In addition to research institutions having little incentive to share this information, there is a strong likelihood that misconduct cases go unreported by researchers due to an unwillingness to risk one’s own reputation or sour relationships with colleagues, or simply an unwillingness to engage a process that can lead to frustration and additional work stress. Under-reporting also comes about when allegations are reported but are then ‘swept under the carpet’ at some level of the institution. Anecdotes from interviews conducted for this study attest to all of these instances.

 

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.

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.

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

Wyeth ghostwriting documents now searchable

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

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

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

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

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

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

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

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