Thanks to Ben Goldacre and Vaughan Bell, I learned this morning of an interesting paper in British Medical Journal that analyzed substantial unpublished data from Pfizer on their norephinephrine reuptake inhibitor antidepressant, reboxetine. Sold in Europe as a pair of enantiomers under the trade name Edronax, reboxetine’s US application was rejected by the FDA in 2001 for “lack of compelling evidence of efficacy.”
The authors, all from the Institute for Quality and Efficiency in Healthcare in Köln, Germany, requested from Pfizer all unpublished clinical data on the antidepressant from trials comparing its efficacy and safety to either placebo or active SSRI drugs. (The institute is better known by the acronym, IQWiG, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG).) An accompanying analysis of the article discusses the role of the IQWiG.
The paper stemmed from a report the Institute had conducted in 2009 for the German Federal Joint Committee (G-BA) for efficacy and safety of reboxetine, mirtazepine, and bupropion given acutely, generally eight to ten weeks. Both Essex Pharma and GSK provided IQWiG investigators with all unpublished data for the analysis of the latter two drugs but Pfizer had not (PDF, English translation).
The retrieval of previously unpublished trials was hampered by the fact that during preparation of the preliminary health technology assessment report, the manufacturer of reboxetine did not provide a complete list of unpublished trials as requested by IQWiG. Secondary publications clearly indicated that further potentially relevant unpublished trials existed. As the preliminary report showed that reboxetine had been tested in at least 16 trials including about 4600 patients, but data on almost two thirds of these patients were not accessible, the institute initially concluded that no meaningful assessment of reboxetine was possible.
After the publication of the preliminary report, the manufacturer decided to cooperate and provided most of the missing data (one venlafaxine controlled trial was not available as a full publication).
Indeed, roughly three-quarters of the data had not been published (from 3,033 of 4,098 subjects). When now pooled with published data, the analysis revealed that reboxetine was no better in remission and response rates than placebo and was inferior to SSRIs such as fluoxetine, paroxetine, and citalopram. More concerning was the finding that reboxetine was 1.8-fold more likely than fluoxetine to cause trial withdrawals due to adverse events.
Note, however, that the adverse events were pooled and not analyzed separately – suicidal ideation, attempts, and deaths were too low in incidence to make any comparison and this was not an intent of the meta-analysis. (For the record, the investigators reported, “A total of 18 serious adverse events related to suicide (suicidal tendencies, suicide attempts, or completed suicides) were noted (six for reboxetine; four for placebo; eight for SSRIs).”)
As one might expect, the authors hammer on the concept of publication bias, where trial sponsors publish only the most favorable data and call for international regulatory requirements that all clinical data be considered in regulatory approvals and be made available to health assessment organizations.
Look for more discussion today on the release of clinical outcomes and safety data by drug manufacturers.
Eyding, D., Lelgemann, M., Grouven, U., Harter, M., Kromp, M., Kaiser, T., Kerekes, M., Gerken, M., & Wieseler, B. (2010). Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials BMJ, 341 (Oct 12) DOI: 10.1136/bmj.c4737
Wieseler, B., McGauran, N., & Kaiser, T. (2010). Finding studies on reboxetine: a tale of hide and seek BMJ, 341 (Oct 12) DOI: 10.1136/bmj.c4942
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