Current regulations covering publication of clinical trials are insufficient, and drugmakers should be required to publish data on all drugs, even those that never get approved, say researchers.
A review published in the British Medical Journal (BMJ: October 13 issue) by researchers at the German Institute for Quality and Efficiency in Health Care (IQWiG) reports that 74% of the data on patients who took part in trials of Pfizer’s antidepressant Edronax (reboxetine) have not been published until now, and that the published data on the drug overestimate its benefits and underestimate the harms.
Edronax has been approved for the treatment of major depressive disorder in many European countries since 1997, but doubts have been raised about its effectiveness on the basis of recent studies and rejection of the US approval application in 2001. Published trials, however, show a favourable risk-benefit profile for the drug, the report notes.
In their study, IQWiG researchers led by Dr Beate Wieseler sought to assess the benefits and harms of Edronax compared with placebo or other selective serotonin reuptake inhibitors (SSRIs) for treating adults with major depression.
They analysed the results of 13 trials, including eight previously-unpublished trials from Pfizer, and found that while the overall quality of the trials was good, data on 74% of patients were unpublished. A further comparison of pubished and unpublished trials showed that the published data had overestimated the benefits of Edronax and underestimated harm.
Their review shows that Edronax is, overall, an ineffective and potentially harmful antidepressant, they conclude, and describe their findings as “a striking example of publication bias” which can affect health policy decisions and the content of clinical guidelines.
Current regulations on the publication of trial results are insufficient, they say, and call for: drugmakers to be required to publicly disclose data for all drugs – even for those which never get approved; public access to trials of older drugs not covered by current law; greater data-sharing between regulatory authorities; re-evaluation of a drug if its approval is declined elsewhere; and a legal obligation on manufacturers to provide all requested data to official bodies without restrictions to publication.
In an accompanying editorial, BMJ editors Dr Fiona Godlee and Dr Elizabeth Loder warn that “the medical evidence base is distorted by missing clinical trial data” and call for “urgent action is needed to restore trust in existing evidence.” It is important to re-evaluate the integrity of the existing base of research evidence and the BMJ will therefore devote a special theme issue to this topic in late 2011, they say.
IQWiG has described publication bias as one of the most important and dangerous sources of error in medicine. “Deception through concealment is no trivial offence – in extreme cases, patients may even receive useless or harmful treatments if information is incomplete,” it says.
It is particularly dangerous that doctors and researchers are often totally unaware that unpublished trials exist, says the Institute and, in order to solve this problem, it reached basic agreement on the transfer of such data with the German Association of Research-based Pharmaceutical Companies (VFA) in 2005. Also, in January that year, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) announced a voluntary commitment to disclose information on clinical trials.
However, IQWiG reported last November that “these announcements from the pharmaceutical industry cannot be relied upon. In recent years, companies have repeatedly refused to provide the Institute with study documents required for the benefit assessment of drugs. Frequently, clinical trial registries, which have been set up in recent years, do not contain these data either,” it said.
Responding to the IQWiG study, Pfizer stated that it discloses the results of its clinical trials to regulatory authorities around the world and that it would provide further comment on the report after reviewing it fully.
