Richard Page thinks Multaq is an excellent new drug for treating atrial fibrillation, a type of irregular heartbeat that affects more than 2 million Americans.

And Page, chairman of the department of medicine at the University of Wisconsin School of Medicine and Public Health, should know. He co-authored a large, international study that led to the drug's approval by the Food and Drug Administration last year, a move that could mean hundreds of millions in sales for Sanofi-Aventis, the company that makes the drug.

But in putting his name on the influential paper, Page allowed Sanofi-Aventis to dictate the terms. He vouched for the accuracy and completeness of the study despite not seeing the raw data. The company, which paid for the study, collected that information and performed the analysis without an external audit for accuracy or completeness.

Page says it comes down to trusting the drug company.

"These companies, if they were falsifying data, wouldn't be kept in business if that were found out," he said. "I was satisfied and remain satisfied that the study was conducted in an appropriate way."

But more and more critics say there is something wrong with the way medical research is done in America. They point to a growing number of scandals in which drug companies have been accused of suppressing or manipulating research and skewing results to make their drugs look better and safer.

In the Multaq case, Page and all six co-authors had financial ties to Sanofi-Aventis at the time of the study.

Two authors worked for the company and owned its stock. Page and the four other authors moonlighted as consultants or speakers.

Questions are being raised about a finding in the paper that the drug reduced cardiovascular deaths - a claim that was disallowed by an FDA panel.

A spokeswoman for Sanofi-Aventis said the company conducts its clinical trials to the highest scientific standards with rigorous analysis and accurate reporting of clinical data. That includes the Multaq trial, spokeswoman Carrie Melia said in an e-mail to the Journal Sentinel.

Yet studies paid for by drug companies are much more likely to have positive results than studies paid for by nonprofit organizations with nothing to gain from a drug's success in the marketplace.

For instance, with cardiovascular treatments, 40% of trials paid for by nonprofit sources showed favorable results, compared with 66% among drug industry-funded studies, according to a 2006 study in JAMA, the Journal of the American Medical Association.

When outside authors don't have complete access and control of data and protocol, manipulation is easier, said Eric Campbell, an associate professor at Harvard Medical School who researches conflicts of interest in medicine.

"If data are cut and shaved and trimmed and manipulated to make a point and that doesn't represent truth or the way a drug behaves, science is harmed and, more importantly, patients are harmed," Campbell said.

Consider the case of the popular painkiller Vioxx, which was pulled from the market in 2004 by its maker, Merck.

A 2008 analysis revealed that while Merck told the FDA in 2001 that the drug did not increase the risk of death, the company's internal documents showed the death rate of patients using Vioxx was three times higher than that of patients taking a placebo.

Under the microscope

The conduct of the pharmaceutical industry continues to come under the microscope.

This month, a new analysis of illegal pharmaceutical company behavior that was exposed by whistle-blowers identified 18 major cases leading to investigations by the federal government. The cases, which were brought from 2001 to 2009, resulted in nearly $9 billion in settlements, according to the report in the New England Journal of Medicine.

Many of those cases involved the illegal and potentially dangerous promotion of drugs for purposes for which they were not approved, so-called off-label use.

While it is illegal for drug companies to promote off-label uses for drugs, once a drug is approved, doctors can prescribe it for purposes other than for what it was approved. Such off-label drug sales can substantially increase pharmaceutical revenues without the typical cost of proving that a drug is safe and effective.

Multaq is an expensive drug. At the dose used in the study, the drug costs $290 a month, or about $3,480 a year, at a Milwaukee Walgreens.

Before it went on the market last year, it already was linked to serious problems.

In 2003, a separate trial of Multaq was stopped because more patients on the drug were dying than those on a placebo. That study was published in 2008.

Even so, Multaq was described as an agent that significantly reduced cardiovascular deaths in Page's study, which was published in February 2009 in the New England Journal of Medicine.

Less than a month later, FDA advisory panel members criticized that claim, according to a transcript of their meeting.

Indeed, concerns about off-label use of Multaq were voiced at that FDA advisory panel meeting in March 2009.

"This is a drug that killed a lot of people in this first trial, and so there is a huge amount of concern," said panel member Sidney Wolfe, a longtime drug industry critic who became a member of FDA's Drug Safety and Risk Management Committee in 2008.

"We know this drug is toxic. We know this drug, in certain kinds of circumstances, has killed people, and we know, from every marketing experience we've ever looked at, that off-label use is guaranteed - and it's guaranteed all over the lot."

Melia, spokeswoman for Sanofi-Aventis, noted the trial had an independent data monitoring committee to keep tabs of deaths, hospitalizations and adverse events. The trial was designed by an independent steering committee along with the company.

She acknowledged that the company collected and managed the data but said both the steering committee and the data monitoring committee had access to analyzed data. They did not, however, have access to the raw data.

Neither Sanofi-Aventis nor Page has been accused of unethical conduct in the Multaq clinical trial.

Questionable methods

But critics are zeroing in on studies in which companies collect and control information from clinical trials, then disseminate it to researchers hired by the firms to write the studies.

Before the 1980s, drug industry money for clinical trial research at academic institutions gave complete control to university researchers, wrote Marcia Angell, a former New England Journal editor, in 2008. But now the companies often design the studies and do the analysis, sometimes without giving university researchers access to the original data.

Doctors must be able to trust what they read in published medical articles and know that the findings have not been manipulated, said Catherine DeAngelis, a physician and editor of JAMA, the Journal of the American Medical Association.

Studies in which drug companies control the data without an independent analysis open the door to manipulation, she said.

"Our primary role is to protect patients," she said. "If you can't trust what you are reading, then where are you?"

The Multaq trial is a good example of questionable studies, DeAngelis said.

At JAMA, such studies are no longer accepted for publication, she said. If drug company employees perform the data analysis, there must be an independent analysis by someone with no ties to the company before JAMA will consider it, she said.

DeAngelis instituted the requirement in 2005 after she received a clinical trial manuscript and asked for an independent analysis. The company refused. She declined to name the company or the product.

"It told me they were hiding something," she said.

The study later was published in another journal. Recently, she said, there have been reports of side effects with the product.

If regulators find that data was manipulated, she said, she will identify the case publicly.

The New England Journal of Medicine, which published the Multaq study, does not have such a policy.

Clinical trial data belong to the drug companies, said Gregory Curfman, executive editor of the publication.

"We are living in the real world here," he said. "They own it. It's their data."

He defended his journal's decision to publish the finding that Multaq reduced cardiovascular deaths 29%, calling it an exploratory finding, although no such wording is used in the article.

Before such a claim can be made, another clinical trial must be done, he said. He said doctors understand what the finding means.

But Campbell, of Harvard Medical School, said drug companies use such findings to increase sales of their drugs.

"Everyone has known for a long time that drug companies use publications in academic journals to stimulate off-label use (of a drug)," he said.

Campbell said it is inappropriate for academics to put their names on such studies.

Page said he and the other academic physicians were directly involved in protocol management and data analysis.

"Based on the direct involvement in design, management, analysis and manuscript preparation, it is appropriate for the steering committee to be authors on the report," he said.

A common practice

At the time of the Multaq study, Page worked at the University of Washington School of Medicine. He joined the University of Wisconsin in August.

Page said his work as a paid consultant to Sanofi-Aventis and other companies ended in May 2008 because he became president of a medical society that did not allow financial ties to industry.

"This partnership of physicians with industry serves the public by providing expertise and oversight in industry-sponsored trials," he said.

It is common for academic experts such as Page to sit on steering committees of drug company-funded trials.

In an interview, Page acknowledged that he and the other authors did not get the original raw data from the Multaq trial, which involved 4,628 patients with atrial fibrillation from around the world.

He did get reports of deaths that were provided in a blinded fashion, meaning that he did not know whether the person was getting Multaq or a placebo.

He said he and other members of the study's steering committee used the blinded data to make judgments.

"Furthermore, the FDA examined the original data and was satisfied with the conduct of the trial," Page said. "Any suggestion that the sponsor had any influence on the conduct of the trial interpretation is inaccurate."

Working on a clinical trial in which the drug-maker controls the data is not a problem if you trust that the company is going to do the right thing, Page said.

"We knew how it was analyzed," he said. "We just didn't do the analysis ourselves, and we didn't go out and hire other statisticians to do that. This was a trial sponsored by Sanofi-Aventis and they paid for the statisticians. There is a sense of trust that they won't falsify data."

FDA advisory panel members have raised questions, not about falsified data, but about how the study was conducted.

Data differences

Unlike the academic authors in the Multaq trial, published by the New England Journal of Medicine, the FDA got unanalyzed raw data for its later review and did its own analysis.

One FDA panel member questioned differences between the information included in the published February 2009 study and what was submitted to the FDA

The published paper concluded that the drug reduced cardiovascular deaths when in reality that benefit was not significant under the original study design, said advisory panel member Sanjay Kaul, who also serves as director of the vascular physiology and thrombosis research laboratory at Cedars-Sinai Heart Institute.

Determining the rate of cardiovascular death was a secondary measure of the study. The main measure was a combination of two things: hospitalization for a cardiovascular reason or death. On that count, there was 24% benefit with Multaq. It was on that basis that the drug was approved by the FDA.

Kaul said it worked like this:

The study was supposed to stop at 4,300 patients. At that number, there was not a significant benefit in reducing cardiovascular deaths.

But the study was extended beyond its planned cutoff date and an additional 328 patients were enrolled.

The expanded version of the study included five deaths among those in the placebo group and one in the Multaq group. The company and study authors determined that was enough to report a significant cardiovascular death benefit.

That's what was published in the New England Journal study.

But the FDA did not allow the claim.

"It is not proper to change the rules in the middle of the game," Kaul said.

Page declined to respond to Journal Sentinel questions about who made the decision to add additional patients. The lead author of the study, Stefan Hohnloser, a German doctor, also would not respond to those questions.

Some doubts

The claimed benefit of cardiovascular death reduction was not valid for another reason, Kaul said.

Cardiovascular deaths were part of a larger category of death from any cause. Because there was no significant difference in all-cause mortality on the drug or on the placebo, the claimed reduction in cardiovascular death also was not valid.

"These observations raise questions about the quality of the data and ultimately the reliability of the findings," Kaul said.

At the time of the FDA hearing, other panel members also questioned the claim.

"The cardiovascular death claim is on shaky ground," panel member William Calhoun, a physician with the University of Texas in Galveston, said at the March 2009 hearing.

In an interview, Kaul said Multaq was only modestly effective at best and had no clear safety benefit.

Kaul raised the questions after Sanofi-Aventis paid for a controversial lecture this year in which off-label uses for Multaq were touted by another doctor who has worked as a consultant to the company.

The lecture was posted on Afibprofessional.org, a site launched by the American College of Cardiology and the Heart Rhythm Society. UW's Page is the president of the society.

In the lecture, the doctor claims a dramatic reduction in cardiovascular deaths with Multaq.

But when the lecture initially was posted, it did not disclose that the doctor received undisclosed consultant fees in excess of $10,000 from Sanofi-Aventis, according to the CardioBrief blog by medical writer Larry Husten.

In March, the lecture was taken down and later re-posted, this time with the financial disclosure information.

Page said he supported the creation of the website but was not aware of its content, which was managed by the staffers.

Because of concerns raised about the lecture, his society now will include written disclosures for such activities, including verbal disclosures for audio programs.

Melia, spokeswoman for Sanofi-Aventis, said the doctor's comments were his independent view.

"Sanofi-Aventis U.S. does not engage in or endorse the off-label promotion of any product, including Multaq," she said.

John Fauber reported this story in a joint project of the Journal Sentinel and MedPage Today. MedPage Today provides a clinical perspective for physicians on breaking medical news at www.medpagetoday.com .

***

About this series

This article is part of an ongoing series about how money and conflicts of interest affect medicine and patient care.