Healthy Skepticism Library item: 14209

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Publication type: news

Taylor P.
Health care, under the influence
Globe & Mail (Toronto, Canada) 2008 Apr 26A12
http://www.theglobeandmail.com/servlet/Page/document/v5/content/subscribe?user_URL=http://www.theglobeandmail.com%2Fservlet%2Fstory%2FLAC.20080426.DRUGS26%2FTPStory%2FspecialScienceandHealth%2Fcolumnists&ord=42162749&brand=theglobeandmail&force_login=true

Full text:

Can medical research be trusted? Can the scientists who sign their names to it, the journals that publish it?

These disturbing questions have been raised by a series of multibillion-dollar lawsuits against one of the world’s largest pharmaceutical firms.

Merck & Co. was forced to pull its top-selling pain medication Vioxx from the market in September of 2004, after research showed the drug increased the risk of heart attacks and strokes and may have contributed to thousands of deaths. The company agreed last year to pay $4.85-billion (U.S.) to settle the bulk of claims against it.

But the controversy won’t go away.

Internal Merck documents, filed as part of the litigation, are fuelling a debate over the role drug companies play in clinical trials – the process that underpins the testing and validation of modern medicinal treatments and new drug approvals.

This month, the influential Journal of the American Medical Association, or JAMA, published two damning studies based on those court documents.

One, led by Bruce Psaty of the University of Washington in Seattle, alleges that Merck did not disclose in a clear and timely fashion the full extent of the potential health risks posed by Vioxx. The other study, led by Joseph Ross of Mount Sinai School of Medicine in New York, could prove to be far more damaging to the reputation of the wider medical community.

Dr. Ross’s work explores the shadowy world of ghostwriting and guest authorships. Some Vioxx trials and promotional review articles were designed, executed and largely completed by drug company staff or hired hands, according to Dr. Ross.

With the manuscript in hand, the company would then search for doctors willing to lend their reputations to the work – for a fee. After they made minor contributions, their names would be added to the paper, giving it an air of arms-length objectivity. The completed article would be submitted for publication to a peer-reviewed journal, which would not be informed of the full extent of the true authorship, Dr. Ross said.

Merck denies any wrongdoing. “This is an example of trial-lawyer courtroom antics masquerading as scientific debate,” said company spokesman Kent Jarrell. He noted that most of the authors of the JAMA studies served as paid consultants to those suing Merck.

Even so, Catherine DeAngelis, the outspoken editor-in-chief of JAMA, said the lawsuits have opened a unique portal to view the inner workings of the drug industry. And, she said, the physicians and academics who become the guest authors of questionable studies and ghostwritten promotional articles are little more than “prostitutes.”

Dr. DeAngelis fears that the “manipulation” of medical research by the drug industry threatens to erode public confidence in the health-care system.

“The profession of medicine, in every aspect – clinical, education and research – has been inundated with profound influence from the pharmaceutical and medical devices industries,” Dr. DeAngelis and Phil Fontanarosa, JAMA’s executive deputy editor, wrote in an editorial that accompanied the two studies. “This has occurred because physicians have allowed it to happen and it’s time to stop.”

The editorial calls on the editors of other leading journals to embrace reforms that, Dr. DeAngelis believes, will prevent ghost authorships, expose conflicts of interest and guarantee the integrity of medical science.

“What she [Dr. DeAngelis] recognizes,” said Arthur Schafer, director of the Centre for Professional and Applied Ethics at the University of Manitoba, “is that all of modern medicine is floating on a sea of drug company money and the result has been utterly corrosive.”

a question of integrity

Modern medicine is supposed to be based on the principles of science and, in particular, the randomized double-blind clinical trial.

Patients are randomly assigned to receive either the drug under investigation or a placebo or possibly a competitor’s product. Neither the patients nor the front-line clinicians carrying out the research know who is getting the real thing – hence the term double-blind.

At the end of the trial, a statistician analyzes the results. The research team’s findings are then submitted to a peer-reviewed journal. If they pass muster, the paper is published so that results can be disseminated to the medical community.

Such findings can also be used in the government approval process for a new drug application.

But what if drug companies, which finance most trials, can skew the results in their own favour and bury negative findings? And what if peer-reviewers and government regulators are unable to detect the trickery? The entire scientific process then becomes little more than a “web of deceit, dishonesty and deception,” Prof. Schafer said. He added that “the crisis in research integrity” is becoming increasingly apparent.

In January, for instance, the New England Journal of Medicine published a study showing that a lot of negative research on antidepressant drugs never sees the light of day. The study was led by Erick Turner of the Oregon Health & Science University in Portland. He used to work in the drug approval branch of the U.S. Food and Drug Administration.

Through his inside knowledge, he was aware that drug companies had to file detailed records of their clinical trials with the federal regulator. He also came to realize that the findings from many trials were never made public. After leaving the FDA, Dr. Turner, along with research colleagues, used the U.S. Freedom of Information Act to pry open the confidential corporate files that the FDA had on 12 antidepressant medications.

“I was going to get this dirty little secret out into the public domain,” he recalled in a recent interview.

The study revealed that 88 per cent of clinical trials showing the drugs didn’t work weren’t published or were spun to make them look positive. Doctors are left with a skewed view of the effectiveness of the drugs if the medical literature is filled with only rosy results, Dr. Turner said. That means they could be prescribing medications that are of limited value or even harmful.

But pharmaceutical companies don’t have to engage in shell games to boost the amount of medical literature in their favour. They can also stage trials that will likely give them results they want, according to a landmark Canadian study led by Paula Rochon.

“I was looking at all these studies and I started to see some interesting patterns … they were always positive,” recalled Dr. Rochon, a scientist at the Baycrest Centre for Geriatric Care in Toronto.

So Dr. Rochon and her research colleagues collected all the industry-funded trials for non-steroidal anti-inflammatory drugs, which are used for treating arthritis. In total, they looked at 56 trials. Not one of the studies came to a conclusion that was unfavorable to the drug company sponsoring the research, said Dr. Rochon, whose revealing findings were published in the journal Archives of Internal Medicine in 1994.

On closer examination, it became apparent that the trials were stacked in favour of the corporate sponsors right from the start.

“It would always be set up in a way that the drug of interest – meaning the company’s drug – was likely going to be …[better] than the one they were comparing it to,” she explained.

And there are many ways to skew the results, she said. For instance, a drug could be compared against too low a dose of a competing brand, making the trial sponsor’s medication appear superior. Or the duration of the trial can be relatively short, if there are concerns about long-term safety issues with the sponsor’s product. Furthermore, the raw numbers can be cherry-picked so only the most flattering findings are eventually reported.

“This stuff is really clever,” she said, referring to the subtle methods used to make one drug seem better than another.

So, when assessing the validity of a study, it’s critical to know who designed it and who analyzed the results. Even when university professors and private physicians are involved, they may have played only a minor role and not had full access to the complete data.

Potential conflicts of interest need to be stated up front, said An-Wen Chan, a physician and clinical epidemiologist at the University of Toronto. And yet, many times the names of key company scientists and statisticians are left off the final papers submitted for publication, he noted.

Only in recent years have the major medical journals required study authors to declare their financial dealings with drug companies and list potential conflicts of interest. However, the entire system still depends on people being honest.

“Unless I stand over them and watch them write it,” acknowledged Jeffrey Drazen, editor-in-chief of the New England Journal of Medicine, “I have no way of knowing whether they are telling me the truth or not.”

Preregistering drug trials

In order to gain greater transparency, some journal editors and independent experts have been lobbying more than a decade for the public preregistration of all clinical trials. Anyone planning a trial would have to provide details of the methodology and research goals before the first patient is recruited.

Public preregistration doesn’t guarantee drug companies will release all their bad news, said Ida Sim, who led a World Health Organization effort to set up national drug trial registries. But if there is an overabundance of bullish studies for a particular medication, independent experts can check the public record for all the drug’s trials to see if some results have been withheld, said Dr. Sim, an associate professor of medicine at the University of California, San Francisco.

Pharmaceutical companies have vigorously resisted preregistration, arguing that it reveals trade secrets and tips off competitors to their plans. Dr. Sim said this is a hollow industry objection because companies are well aware what each other are doing by the time a drug reaches the clinical trial stage – and only the public is left in the dark.

In September of 2004, the International Committee of Medical Journal Editors, which includes the cream of the medical publishing world, finally took a stand. It agreed to print the results of only those studies that had been preregistered. So if a drug company wanted its findings to appear in the pages of the most prestigious journals, it would have to go along with the process.

Governments are also requiring drug companies to be more open. Legislation passed last year by the U.S. Congress calls for the preregistration, on a publicly accessible website, of human trials conducted in the United States. Recently proposed changes to Canada’s Food and Drugs Act would lead to regulations that impose similar conditions on studies in this country.

The New England Journal’s Dr. Drazen believes it will take about five years to know whether preregistration has led to more transparency in research. Meanwhile, JAMA’s Dr. DeAngelis remains convinced that more reforms are needed to truly protect the integrity of medical science.

For instance, she would like to see independent statisticians at academic institutions reviewing the raw data of industry-sponsored trials before the final results are published. In fact, that’s already a requirement for studies printed in her journal. Dr. DeAngelis says she is under no illusion that a university-based statistician is any smarter or more honest than one employed by a drug company.

“But if anybody raises a question about the statistical analysis, I can pick up the phone and call the dean who can do the investigation,” something that is beyond the powers of a medical journal, she said.

Despite her harsh criticism of the industry and especially collaborating physicians, she strongly believes pharmaceutical companies, over all, make a major contribution to public health.

“We absolutely need the pharmaceutical companies, at least in the United States, and I know this is also true in Canada, because the government … doesn’t put money into clinical trials for developing new drugs,” Dr. DeAngelis said.

But the University of Manitoba’s Prof. Schafer isn’t so sure. “I think he who pays the piper calls the tune,” he said, adding that major changes are needed in the way clinical trials are funded. “So long as the careers of researchers hinge on pleasing drug companies, and so long as the drug companies’ success hinges on bottom-line profitability, the crisis will be aggravated. It is bound to get worse.”

The name game

Clinical trials and promotional articles about Vioxx were researched and written by Merck & Co. staff or hired hands. Merck would then recruit high-profile academics willing to lend their names and reputations to the largely finished papers for publication in medical journals, according to researcher Joseph Ross.

1. A draft study investigating the effects of Vioxx (whose clinical name is Rofecoxib) on Alzheimer’s patients appears with the names of Merck employees, or paid consultants, on the title page.

The phrase “External author?” is typed in the spot normally reserved for the first author.

Dr. Ross takes this to mean that an outside, big-name author had not yet been found for the company-sponsored trial. (A separate JAMA study alleges Merck played down the health risks posed to Alzheimer’s patients who took part in this trial.)

2. In the published version, Leon J. Thal and Steven H. Ferris are listed as the first two authors. Dr. Ferris, a psychiatry professor at New York University, disputes Dr. Ross’ interpretation. Dr. Ferris told Reuters News Agency he had an active role reviewing binders of patient data while “over the years the study was ongoing.” Dr. Thal, who was a respected Alzheimer’s researcher at the University of California San Diego, died in a private plane crash in 2007.

“We were not paid to be authors,” Dr. Ferris said.

THE GLOBE AND MAIL: SOURCES: JOSEPH ROSS, MOUNT SINAI SCHOOL OF MEDICINE, JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, REUTERS

ptaylor@globeandmail.com

Source Citation:Taylor, Paul. “Health care, under the influence.(Health)(BAD MEDICINE).” Globe & Mail (Toronto, Canada) (April 26, 2008): A12. CPI.Q (Canadian Periodicals). Gale. University of Manitoba CPIQ. 3 June 2008
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Gale Document Number:A178301586

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