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An analysis of a controversial study into the use of paroxetine in adolescents has re-ignited the debate over the importance of full disclosure of clinical trial data.
An international team of researchers say their close analysis of results from Study 329 show that the drug, for the treatment of depression and anxiety, was neither safe nor effective in teenagers — a complete contradiction of the way in which the research was presented in 2001.
Research funded by GlaxoSmithKline (GSK), published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP)[1]
, has come under scrutiny before with previous allegations that the paper had been “ghostwritten” by an outside medical writer hired by the pharmaceutical company.
The latest analysis published in The BMJ — which includes data made available after legal challenges in the United States and negotiations between the researchers and GSK — “sets the record straight” and “shows the extent to which drug regulation is failing us”, says BMJ editor in chief Fiona Godlee.
Godlee claims that the revelations show that the public and clinicians cannot be certain that the information they need to make informed decisions is unbiased.
Examination of the analysis was undertaken by researchers, working for the Restoring Invisible and Abandoned Trials (RIAT) initiative, who trawled through clinical study reports and case report forms not made available at the time.
Their analysis found that neither paroxetine nor high-dose imipramine was more effective than placebo in adolescents with major depression — a result explained by the original study looking at different outcome measures than set out in the initial protocol.
They also found a far higher level of serious side effects, including suicidal thoughts, than had been reported in 2001 with apparent discrepancies in the recording of adverse events, prompting them to conclude that “paroxetine was ineffective and unsafe in this study”.
Out of 275 trial participants aged 12–18 years, the analysis found that 11 adolescents taking the drug and one in the placebo group developed suicidal or self-harming behaviour. In the original JAACAP paper, this had been reported as five participants on the drug and one participant on placebo.
Study author David Healy, professor of psychiatry at Bangor University in Wales, says the original study was representative of “the industry approach towards trials in general”.
He adds that getting hold of all the necessary information as well as convincing The BMJ
[2]
to publish had been a lengthy process and a “huge amount of work”.
Healy and the RIAT team believe that “ghost writing, conflicts of interest, and junk research are all serious problems enabled by the lack of complete access to all trial data”.
And that these results highlight the clear need for ”AllData” not just AllTrials — the initiative set up to encourage the registration of all trials and reporting of full methods and summary results.
David Taylor, director of pharmacy and pathology at the Maudsley Hospital in South London and Royal Pharmaceutical Society spokesperson on mental health, says that the latter examination exposes practices of more than 20 years ago – adjusting research methods post hoc to produce favourable outcomes.
“It is clear that had this trial been presented and published as it was originally intended, then it would have been very unlikely that paroxetine would have been used at all in this patient group,” says Taylor.
“No one can doubt the necessity for all trials to be registered before starting and publicly reported on completion, with anonymised original patient data available for reanalysis.”
A GSK spokesperson says: “The findings from this team’s analysis appear to be in line with the longstanding view that there is an increased risk of suicidality in paediatric and adolescent patients given antidepressants like paroxetine.
“This is widely known and clear warnings have been in place on the product label for more than a decade. As such we don’t believe this reanalysis affects patient safety.”
The company added that it helped the team carry out their reanalysis by providing access to the detailed data from the original trial.
“This reflects our commitment to data transparency — we publish the results of all our studies regardless of whether they are positive or negative and we are the only pharmaceutical company to be part of the AllTrials campaign,” the spokesperson adds.
References
[1] Keller MB, Ryan ND, Strober M et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 2001;40:762–772.
[2] Le Noury J, Nardo JM, Healy D et al. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015;351:h4320
