The Milwaukee Journal Sentinel is at it again. Taking clinical data that has been thoroughly vetted through the FDA reviewers showing a drug which works remarkably well on patients and turning it into a negative story on that drug and potentially costing someone’s live.
More than 2 million Americans suffer from atrial fibrillation, a type of irregular heartbeat. To help treat this medical condition, Sanofi-Aventis manufactured Multaq (dronedarone), a drug that has been shown to reduce cardiovascular deaths. A very small group of critics however, believe that such claims are “shaky.” Of course they ignore the fact that dronedarone was designed to replace an existing generic drug amiodarone which has significant side effects several of which lead to death.
Leading the unfounded charge, a recent article in the Milwaukee Journal Sentinel has once again inappropriately attacked the hard work of physicians and researchers who have dedicated their time to improving atrial fibrillation.
One researcher Richard Page, MD now Chairman of Medicine at the University of Wisconsin had the misfortune of moving to Wisconsin this past summer only now to be greeted by a front page hit piece on his science and relationship with industry.
Seemingly, the Sentinel has chosen to ignore the fact that Multaq “has been studied in a clinical development program, including seven international, multicenter, randomized clinical trials involving more than 7000 patients with almost 4000 patients receiving Multaq.”
The Sentinel has also ignored the landmark ATHENA trial, the largest anti-arrhythmic drug trial conducted in patients with AF/AFL, which was designed by an independent steering committee along with Sanofi-Aventis, who collected and managed the data. Initially the study was supposed to stop at 4,300 patients, but at that number, there was not a significant benefit in reducing cardiovascular deaths. Consequently, the study enrolled an additional 328 for a total of 4,628 patients with atrial fibrillation with a follow-up of 30 months. The expanded version of the study included five deaths among those in the placebo group and one in the Multaq group,
This trial showed that Multaq, on top of standard cardiovascular therapy, significantly reduced cardiovascular hospitalization or death by 24 percent (p<0.001) when compared to placebo, meeting the study's primary endpoint. This result was entirely attributable to a reduction in cardiovascular hospitalization, findings that were significant enough for the FDA to approve Multaq, and report a significant cardiovascular death benefit.
These results were published in the February 2009 volume of the New England Journal of Medicine (NEJM), and included lead author Stefan Hohnloser, a German doctor, and Richard Page, who at the time of the Multaq study worked at the University of Washington School of Medicine, but then moved to chairman of the department of medicine at the University of Wisconsin School of Medicine and Public Health last August.
The study was reviewed by an FDA advisory panel according to a transcript of their meeting in March 2009, and eventually, the FDA panel disallowed the finding in the paper that the drug reduced cardiovascular deaths because the panel found “no significant difference in all-cause mortality on the drug or on the placebo.” Panel members criticizing Multaq included longtime drug industry critic Sidney Wolfe.
While the FDA got unanalyzed raw data for its later review and did its own analysis, Dr. Page acknowledged that he and the other authors did not get the original raw data from the 4,628 patients. The steering committee and the data monitoring committee however, had access to analyzed data, including reports of deaths, hospitalizations and adverse events.
Consequently, Dr. Page asserted that since the “FDA examined the original data and was satisfied with the conduct of the trial, any suggestion that the sponsor had any influence on the conduct of the trial interpretation is inaccurate."
Physician-Industry Relationships
Dr. Page coauthor of the 2009 NEJM study because he trusted the companies statisticians. He told the Sentinel that if these companies “were falsifying data, they wouldn’t be kept in business if that were found out.” Accordingly, since he “was satisfied and remains satisfied that the study was conducted in an appropriate way,” he vouched for the accuracy and completeness of the study despite not seeing the raw data.
Critics, such as Marcia Angell and Catherine DeAngelis and object to studies like the Multaq trial because it was paid for by Sanofi-Aventis. Despite two authors of the study working for the company and owning its stock, and four other authors serving as consultants or speakers, thus far neither Sanofi-Aventis nor Dr. Page have been accused of unethical conduct. Executive editor of NEJM Gregory Curfman published the article confidently and asserted that “clinical trial data belong to the drug companies, and 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 extraordinary finding, although no such wording is used in the article.” Curfman then noted that although another clinical trial must be done “before such a claim can be made, doctors understand what the finding means.”
Opponents also disagree with industry support of research by pointing “to a growing number of scandals.” Although 18 major investigations by the federal government have occurred between 2001 and 2009, resulting in nearly $9 billion in settlements, many of those cases involved the illegal promotion of drugs for off-label use, not industry funded clinical trials.
Another concern for critics was Dr. Page’s work as a paid consultant to Sanofi-Aventis and other companies, which ended in May 2008 because he became president of the American College of Cardiology and the Heart Rhythm Society, which did not allow financial ties to industry. But the society itself raised an issue this year when a lecture sponsored by Sanofi-Aventis touted off-label uses for Multaq, without a physician disclosing his payments by the company. Subsequently the lecture was taken down and later re-posted, with the financial disclosure information, and now the society will include written disclosures for such activities, including verbal disclosures for audio programs.
Conclusion
Companies like Sanofi-Aventis “conduct clinical trials to the highest scientific standards with rigorous analysis and accurate reporting of clinical data.” Consequently, without any charges of unethical conduct assumptions and accusations created by biased media sources must be avoided so as not to damage the important partnership that physicians and industry serve the public for by providing expertise and oversight in industry-sponsored trials.
Articles like this are a disservice to the commitment and time physicians like Dr. Page spend trying to bring new treatments to millions of patients. Using a close minded, anti-industry approach, the Sentinel has disregarded numerous indications that Multaq is a safe and effective drug. Considering FDA approved Multaq because clinical trials conducted by Sanofi-Aventis showed reduced cardiovascular hospitalization or death by 24%, the suggestion by the Sentinel that the company had any influence on the conduct of the trial interpretation is inaccurate.
If the writer or his mother had persistent AFIB, he would be writing a story about how Multaq changed her life for the better.
With Sanofi-aventis set to initiate a 10,000 Patient Study With Multaq(R) in Permanent AF, sensationalist articles such as those found in the Sentinel will do more harm than good, by scaring away potential participants from clinical trial using smoke and mirrors. This trial is of major significance because no anti-arrhythmic drug has ever been shown to reduce major morbidity and mortality in permanent AF patients in a large scale clinical trial. As a result, the unsubstantiated claims made by the Sentinel and other anti-industry critics must be disregarded so that physicians like Dr. Page can continue their duty to continue helping 2 million people.
You will be hard pressed to find ANYBODY more bullish on MULTAQ
than me. I was one of the first 400 volunteers to test it. I was on it for 14 months in 2003 and 2004. It allowed me to get away from the super toxic Amioderone, and I flourish for 23 months of blisfull good (Sinus Rhythm) health. An overtaxing
European trip, sent me back to severe AF, and of course I could
no longer obtain the needed research drug. My health spiralled downweard into AFIB hell, permanently for the last 6 years! Then, just last monday a near miracle occured. After taking the recently approved MULTAQ for a year, a smart cardiologist
at the VA hospital scheduled a new electro-zapping of my heart, I’d had 5 previous failures, lacking the magic drug as a catalyst, but this time I was primed by the “wonder-med”!
I was even given final comment by the doctor in charge of the
proceedure, not to get my hopes up very high, as I faded out
under the anesthesia. Boy… did it turn out differently!? I awoke to a proceedure room full of smiling lady doctors and nurses. There amazed smiles, showed me we’d just hit a home run! NORMAL SINUS RHYTHM after 6 years of hellish suffering.
My hugely swollen feet and ankles began to shrink within hours.
a full 14 pounds of edema fluid, was excreted in 2 days. My
partial right eye blidness, went away, as my pain and slow-wittedness disapated like a misty vapor. I was back with a
healthy and non-invaded heart, sans surgery of any kind. Just
brought about by the same medicine that I had volunteered to test so many years ago, a few thousand volts of micro-shock
aplied to my heart, while under a general anesthesia. Folks
I feel wonderful so far, almost like my body had compensated
so much to keep me functioning, that a normal heart would almost give me and edge over others my age. I’m finding it a
kick to have SO MUCH unexpected vitality!