Creating Waves of Awareness
The Whole Truth? Meta-Analysis of Reboxetine Trials Calls Into Question Veracity of All Industry-Sponsored Research
October 14, 2010 — Data from industry-sponsored trials published in peer review journals are misleading the public about the safety and efficacy of their drugs, according to 2 reports published online October 13 in the British Medical Journal (BMJ).
In a meta-analysis that looked at all of the published and unpublished data on the antidepressant reboxetine (Pfizer) for the short-term treatment of major depression, investigators concluded that the drug was not only ineffective but also potentially harmful. They also report that 74% of the data on patients who took part in the trials of reboxetine were not published because the findings were negative and that the data that were published about reboxetine overestimated its benefits and underestimated its harm.
"This meta-analysis provides a striking example of publication bias, in which the previously favourable risk-benefit profile of reboxetine shown in published trials is reversed by the addition of unpublished data," Beate Wieseler, MD, deputy head of the Department of Drug Assessment at the Institute for Quality and Efficiency in Health Care, Cologne, Germany, told Medscape Medical News.
"Overall, reboxetine is not effective for the treatment of major depressive disorder. It is ineffective and potentially harmful," she added.
"Striking Example of Publication Bias"
Reboxetine, the first selective norepinephrine reuptake inhibitor used in the treatment of depression, mainly acts by binding to the norepinephrine transporter and blocking the reuptake of extracellular norepinephrine. It has been approved for marketing in the United Kingdom, Germany, and other European countries since 1997 but did not win approval in the United States.
It has been claimed that the drug has superior efficacy compared with placebo and similar efficacy to other antidepressants, but its clinical relevance has been questioned. Dr. Wieseler and colleagues conducted their meta-analysis to assess these claims and also to measure the impact of potential publication bias in reboxetine trials.
We know that not all studies that investigate drugs are published. The published literature tends to overestimate benefits and underestimate harms...
"We know that not all studies that investigate drugs are published," Dr. Wieseler said. "The published literature tends to overestimate benefits and underestimate harms because positive studies are published more often and earlier than negative studies; therefore, the picture of a drug in the published literature may be biased."
The investigators analyzed 13 short-term treatment trials of reboxetine vs placebo or selective serotonin reuptake inhibitors (SSRIs) that encompassed a total of 4098 patients. They found that data on 3033 of these patients were not published.
Their analysis revealed no significant differences in remission between reboxetine and placebo (odds ratio [OR], 1.17; 95% confidence interval [CI], 0.91 – 1.51; P = .216) and that reboxetine was inferior to the SSRIs fluoxetine, paroxetine, and citalopram for remission rates (OR, 0.80; 95% CI,
0.67 – 0.96; P = .015) and response rates (OR, 0.80; 95% CI, 0.67 – 0.95; P = .01).
In the reboxetine treatment groups, there was a higher rate of patients affected by adverse events than with placebo and higher withdrawal rates owing to adverse events than with placebo and fluoxetine. "Published data overestimated the benefit of reboxetine vs placebo by up to 115% and reboxetine vs SSRIs by up to 23% and also underestimated harm," Dr. Wieseler said.
"If clinical guidelines are based on published literature only, they might overestimate benefits and underestimate harms of a drug. To solve the problem of inadequate information on treatment options, clinicians must insist on full transparency of all trial results. To be able to provide their patients with adequate treatments, clinicians should support mandatory publication of all trial results."
Need for Independent Authors
In a second report, Robert Steinbrook, MD, Dartmouth Medical School, Hanover, New Hampshire, and Jerome P. Kassirer, MD, Tufts University School of Medicine, Boston, Massachusetts, described recent examples that illustrate the problems of trusting drug companies to provide the complete picture about their own clinical trials. They propose that journals define full access to all trial data and mandate that investigators and journal editors have full access to these data. They also suggest that editors should take appropriate action if concerns about data arise after publication.
In an interview with Medscape Medical News, Dr. Steinbrook said that it is becoming very difficult to know what studies are trustworthy and what studies are not and to assume that industry sponsors are in a position to dispassionately evaluate their own products.
This is a multifaceted issue. It's not simply an issue for medical journals, it's an issue for physicians and also for regulatory agencies.
"This is a multifaceted issue. It's not simply an issue for medical journals; it's an issue for physicians and also for regulatory agencies. Looking at medical journals and the peer-reviewed medical literature, we recognize the many steps that journals have taken to tighten their standards over the years, but we suggest that more needs to be done," he said. Specifically, there should be a more explicit definition of what is meant by full access to all the data. There should be an author who is independent of the sponsor take responsibility for the integrity of the study and the accuracy of the data analysis, and finally the responsible author should be prepared and able to provide the data to the journal if requested before acceptance and for a period of time after publication — perhaps 5 years, Dr. Steinbrook said. "Our view is that the requirement for the availability of the data would be important. We don't view this as a routine exercise to look at primary data; it's not a trivial undertaking; it's meant to be done for specific well-defined reasons," he said. "But it is our view that the mere requirement of availability of data for independent examination by journals would be an important safeguard."
In an accompanying editorial, BMJ Editor Fiona Godlee and Associate Editor Elizabeth Loder write the reboxetine story and similar episodes "must call into question the entire evidence synthesis enterprise. Meta-analyses are generally considered the best form of evidence, but is that a plausible world view any longer when so many of them are likely to be missing relevant information?"
Meta-analyses are generally considered the best form of evidence, but is that a plausible world view any longer when so many of them are likely to be missing relevant information?
Because of the seriousness of the problem, the BMJ plans to devote a special theme issue to the topic in late 2011. "We are especially interested in high quality original research that aims to uncover previously unavailable data and re-evaluate treatments and practice in light of that new evidence."
They add that restoring trust in existing evidence is the most important thing. "To that end, the BMJ is more interested in constructive use of data than finger pointing or blame. We encourage drug companies and device manufacturers, as well as academic researchers, to take advantage of the
opportunity afforded by our upcoming theme issue," they write. "Full information about previously conducted clinical trials involving drugs, devices, and other treatments is vital to clinical decision making. It is time to demonstrate a shared commitment to set the record straight."
A Threat to Big Pharma: Comparative Effectiveness Research
A new model of research may help us sort out this messy collusion between science, government and Big Pharma. Comparative effectiveness research takes existing treatments and compares them to determine which are the most effective. Unfortunately, fear mongering and lobbying by the pharmaceutical industry for “rationed care” convinced the Senate to leave a critical provision for funding comparative effectiveness research on the cutting room floor. Apparently, independent comparisons of medical therapies, including a comparison of new expensive drugs to older, proven, cheaper drugs, was considered bad for business.
This is all the more tragic given recent findings using this model of research. A large independent comparative effectiveness study conducted in July 2010 found older high blood pressure drugs such as water pills or diuretics to be more effective in reducing heart attacks and strokes at dramatically lower cost than “new and improved” blood pressure medication. Comparing pharmaceutical treatments to lifestyle or integrated approaches to health is even more dangerous, lest we find that lifestyle treatment for heart disease and diabetes which cost our health care system $750 billion a year works better and costs less than drugs and surgery and has good side effects such as improved quality of life. Unfortunately, in our health care system, business trumps science every time.
Such confusion is not accidental but intentional. The more confusion about medication, the more Big Pharma sells. Propagating doubt is big business. These are the same kinds of techniques Big Tobacco used to great profit, claiming that scientific links between smoking and cancer were “not proven.
Take the recent Avandia debacle. For 10 years Glaxo Smith Kline, based on their internal research, knew their blockbuster diabetes drug increased the risk of heart disease. But they hid the data. Even though it was legally required, they did not submit the data to the FDA or post it on their website. After legal action forced them to publish the data on a public website, independent scientists analyzed the data, showed it to be harmful and reported their findings. Despite this the drug became the biggest selling diabetes drug with sales of over $3 billion a year through corporate lobbying at the FDA, medical deception and intense pharmaceutical marketing.
From 1999 to 2009, it is estimated there were over 47,000 unnecessary deaths from Avandia. 600,000 American still take it today. Glaxo Smith Kline was fined a few billion dollars for their deception–a fraction of their profit from the drug–and a small penalty to pay for the mass murder of almost 50,000 people. The Europeans have removed it from the market, but the FDA avoided clear action until this month. However, rather than take the drug off the market, which would have been the responsible thing to do, it is still allowed for limited indications and patients still on it may continue using it (if they haven’t had a heart attack yet and know the risks). Would you want to take it? Would you want your mother or father to take it?
Hiding evidence is only one tactic Pharma uses to illegally promote and profit from medication. Another is illegal marketing practices. Yet another Big Pharma company, Novartis, was fined $422.5 million this week for criminal activities. They were illegally marketing their drugs to doctors. Drugs can only be marketed for the conditions for which they were approved. If a medication, such as Trileptal (one of six illegally marketed Novaritis drugs) is approved for seizures, it cannot be marketed for chronic pain. This is exactly what Novaritis and others do.
This is not an oversight, a mistake or unintentional criminal activity on the part of drug companies, ut a deliberate and focused strategy that feeds profits. Perhaps, they think of these criminal “fines” as part of their marketing budget. Novaritis earned nearly $10 billion per year for the drugs it marketed illegally. The $422.5 million fine is a small “marketing expense,” a slap on the wrist. They should be fined the entire amount they earned from the illegal marketing of those drugs. Or better yet, the company executives that approve these policies should serve jail time. If an individual knowingly harms or kills another human being, they are convicted and serve time. Pharma just pays a “fee” that is insignificant in the face of their total profits.
Novartis is not alone. They are in good company. Here’s how much the top Big Pharma companies were fined for the exact same illegal practices for which most pleaded guilty.
Getting the Science Wrong: Misleading Media Reports
To get beyond this kind of industry deception, doctors and health care consumers need to be wary and read between the lines. In an era of sound bites and sensationalism, we do not receive intelligent and critical analysis, and most importantly a coherent synthesis of scientific research. The data in any one study is part of a scientific story of how the world works, and medical research is the story of biology. Each study must be evaluated in the context of what we know, existing data, and what makes sense from a biological perspective. We won’t always be right, but we can stop the ping-pong game of what’s good and what’s bad for you that facilitates the newest, not necessarily the best, treatment, and provides fodder for journalistic sensationalism that fuels the 24/7 news cycle.
Often headlines are taken from the abstracts or summaries of research articles. Studies show that half the time, the abstracts don’t accurately represent the findings of the research. Even when the summary is correct, studies show that the media incorrectly reports the research findings or doesn’t
place them in the historical context of other key research on the subject. No wonder patients and doctors are confused. Business interests and the incestuous relationship between scientists and industry have corrupted the landscape of medical research. The media doesn’t do a good job of investigative journalism. But there are things you can to do change protect yourself.
How to Protect Yourself From the Spin Doctors
1. Follow the money: Be a detective and look up the articles mentioned in the news. Find the study, see who wrote it, and determine what financial conflicts of interest they have. Also check who
funded the research.
2. Do your homework: Be suspicious of media reports of scientific findings. Does the finding make sense in the context of other studies and is it the best possible approach. Educate yourself by
learning to use PUBMED (the National Library of Medicine) and reviewing different perspectives.
3. Does it pass the “sniff test”: Is the treatment suggested just a “me too” drug that has not been proven to be any better than existing treatments? Does it make sense to you or does something
smell rotten? Trust your intuition.
4. Advocate for an arm’s length relationship between industry and academia. Write your Senators and Congressmen to develop new regulations and legislation that will build a fire-wall to protect
us. Grants are fine, but Pharma should have no participation in study
design and should not be allowed to interpret or publish results.
5. Demand a no revolving door policy between industry and government regulators. Former drug company executives should not be on FDA committees or involved in regulation or
6. Advocate for comparative effectiveness research. Preventing this research allows Pharma not to play fair.
7. Campaign for finance reform: If done effectively, can limit the influence of industry on government.
Don’t let yourself be confused by poor reporting in the media. Learn to see through the collusion between Big Pharma and medicine by staying ahead of the medical spin doctors using these steps. For more information on the extant comparative effectiveness research between lifestyle medicine and pharmaceuticals see my recent blog posts on drhyman.com.
To your good health,
Mark Hyman, MD
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Dr. Wieseler is employed by the Institute for Quality and Efficiency in Health Care. Dr. Steinbrook, Dr. Godlee, and Dr. Loder have disclosed no relevant financial relationships.
BMJ. Published online October 13, 2010.