January 28, 2017 – One could call it a scandal. The dire reality is that what is described here could be widespread practice in the business of clinical trials performed and outcomes reported by Pharma, namely that only half of the truth may be told to patients, treating physicians and hospitals, the research community, and the public at large.
The point in case is made here with Study 329, concerning paroxetine, a common antidepressant drug thought safe for teenagers which actually has to be judged ineffective and worse, has been linked to suicidal and self-harming behaviours of adolescents.
Paroxetine is prescribed for depression, anxiety, panic attacks, post-traumatic stress disorder (PSTD), obsessive compulsive disorder (OCD), and most recently, for symptoms of menopause. It is currently marketed under more than 100 different names worldwide, including, Aropax, Brisdelle, Casbol, Denerval, Eutimil, Frosinor, Isoxatine, Motivan, Paxil
(in the US), Pexeva, Seroxat, Tagonis, and Zwapar.
The conclusions on the ineffectiveness and inducing suicidal and self-harming behaviours of adolescents of Paroxetine come from the re-evaluation of an infamous study, known as “Study 329”. Study 329
, which was funded by the pharmaceutical company GlaxoSmithKline, was performed in the 1990s, was published in 2001
, and concluded that Paroxetine was effective and safe for adolescents. It reported that six young people became “emotionally labile” on Paroxetine, without explaining what that meant, and did not report any problems of dependence.
A retrospective new analysis named “Restoring Study 329” of now publicly made available data from Study 329, and performed by independent team members of the RIAT initiative, shows that not only the original conclusions were wrong but that the drug has worrying side-effects. The research was published in the British Medical Journal (Noury et al., 2015
In this context it is important to understand that RIAT stands for “Restoring Invisible and Abandoned Trials” and is intended to re-author studies by independent teams where there is access to data from studies that have not been published or have been misleadingly published. For example, currently, if a company runs 50 trials and 48 show negative results but two show slightly positive results, the company can use only the two positive studies to try to get its drug approved and can choose to publish only these two positive studies, giving the impression that the findings of the two are representative. The RIAT proposal aims at publishing some or all of the data from the other 48 trials to give a truer, more balanced picture of a drug in question. The concept behind RIAT has been published in the British Medical Journal (Doshi et al., 2013
) and been commented upon in the PLOS One Blog in 2013
Upon reanalysis of the now more competed data, the authors found that the efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.
In contrast to the original claims neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.