‘Like us, you have probably grown accustomed to the steady stream of revelations about incomplete or suppressed information from clinical trials of drugs and medical devices. If so, this issue of the BMJ features a pair of papers that will dismay but not surprise you‘.
‘Researchers for an official German drug assessment body charged with synthesising evidence on the antidepressant reboxetine encountered serious obstacles when they tried to get unpublished clinical trial information from the drug company that held the data, an experience from which they draw several lessons….
‘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?” continue reading…’
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In a meta-analysis that looked at all of the published and unpublished data on the antidepressant reboxetine (Pfizer) for the short-term treatment of major depression, investigators concluded that the drug was not only ineffective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the previously favourable risk-benefit profile of reboxetine shown in published trials is reversed by the addition of unpublished data,” Beate Wieseler, MD, deputy head of the Department of Drug Assessment at the Institute for Quality and Efficiency in Health Care, Cologne, Germany, told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,” 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. 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?”
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.”
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.