by Jill Margo
A new Australian-led study is set to send shivers down the spine of the international pharmaceutical industry and those who prescribe and use its products.
At first glance, it is simply a re-analysis of data from a study first published 14 years ago.
But significantly, it is the first of a new initiative which encourages misreported studies to be formally corrected and abandoned studies to be published.
An initiative of The British Medical Journal, it is based on the premise that science does not always self-correct, particularly when there are commercial factors at work. Called Restoring Invisible and Abandoned Trials, or RIAT, it aims to ensure doctors and patients have complete and accurate information to make treatment decisions.
The upshot is expected to be a steady stream of clinical trials from around the world being reanalysed and, as a result, a major shift in the way drug companies approach how they conduct and interpret trials and data.
ORIGINAL STUDY FOUND DRUG WAS SAFE
The new study is a reanalysis of an older study that found the drug paroxetine was safe and effective for adolescents with major depression.
What is revealed was that the drug was actually neither safe nor effective for such adolescents.
“It is not just about anti-depressants and children, ” says lead author, Jon Jureidini, professor of child psychiatry at Adelaide University.
“It’s a paradigm of industry finance, of clinical trials reporting tainted results. It’s a rallying point for how difficult it’s been to get the truth about questionable drugs.”
“We’ve used this trial to demonstrate the need to have access to the full complement of raw data.”
Through this exercise his team uncovered significant flaws inherent in the system for reporting adverse events.
INCREASED SUICIDAL THINKING
Jureidini said paroxetine was a heartbreaking example because it showed adolescents already struggling with major depression were being given medication that could worsen their condition. It increased suicidal thinking and behavior.
He identified the original paroxetine study as an example of a misreported trial in need of restoration because of its important implications for research and practice.
“It was once the highest selling anti-depressant in Australia. The main reason it lost that position was that newer drugs came along and were subject to pharmaceutical promotion. It had very little to do with the fact that it is a bad drug.”
“Sadly, there is no reason to believe this case is a one-off. We know there are several other examples,” says Juredini of the Critical and Ethical Mental Health research group at the Robinson Research Institute.
Jureidini says the main lesson from the study is that anyone looking after a person on antidepressants needs to be vigilant about potential harmful effects because the literature is not going to provide a safe guide to what the dangers of the drugs are.
“We are not saying people shouldn’t be given prescribed medication but that any prescription has to be based on a judgement by doctors.” he says. “Without good information doctors can’t make good decisions.
“The way the pharmaceutical industry is set up is that it does the research and it writes up the results. Our study demonstrated the importance of access to a study’s protocol and its data. It is a call to arms that we need to take the harms of drugs more seriously.”
The RIAT team’s findings were published in the BMJ this week.
Around the turn of the century, SmithKline Beecham, now GlaxoSmithKline (GSK), funded a study to compare the effectiveness and safety of the antidepressant drugs paroxetine and imipramine with placebo for adolescents suffering major depression.
The conclusion that paroxetine was safe and effective was published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2001.
The following year, despite criticism of the study by the Food and Drug Administration, more than two million scripts were written for children and adolescents in the United States.
In 2012 GSK was fined a record $US3bn for the fraudulent promotion of a range of drugs including paroxetine.
The RIAT team used previously confidential trial documents to reanalyse the original data on paroxetine. It also obtained further information from GSK.
It found neither paroxetine nor high dose imipramine was more effective than placebo in the treatment of major depression in adolescents.
The team considered the increase in harms with both drugs to be clinically significant and concluded “paroxetine was ineffective and unsafe in this study”.
Peter Doshi, associate editor of the BMJ noted the original manuscript was written by an outside medical writer hired by the drug company rather than any of the 22 named authors. He says the lead author had been the focus of a press investigation in 1999 which documented his under-reporting of financial ties to drug companies.
Doshi also detailed the refusal of the American Academy of Child and Adolescent Psychiatry to intervene and retract the paper. He noted that for those who had been calling for a retraction of the original paper for many years, the system had failed.
DRUG REGULATION FAILING
This reanalysis shows the extent to which drug regulation is failing, according to Fiona Godlee, editor-in-chief of the BMJ.
She calls for independent clinical trials rather than trials funded and managed by industry.
She also wants legislation to ensure trial results and patient data are fully available for independent third party scrutiny.
In an editorial in the same journal, David Henry, a former member of Australia’s Pharmaceutical Benefits Advisory Committee, says liberating the data from clinical trials has the potential to benefit patients, prevent harm, and correct misleading research.
Now a professor of public health at the University of Toronto, he says data sharing is not without its risks.
“But the pay-off from a systematic effort to reactivate important clinical trials will be high and will further justify the original huge investments of time and money.”
Henry told the Financial Review it is reasonable to expect most trials are accurately reported, but as a significant number make simple mistakes and some deliberately misrepresent results, the data should be available for an independent check.
He was one of the reviewers of this latest paper. While the review process was long and hard, he said the work involved in the actual paper itself was massive.
“They had to read through tens of thousands of pages of material to check the facts and the company made that difficult for them.”
“It is very important that the results of the trials that determine the treatments in common use and affect the lives of so many should not remain proprietary.”
“These drugs are usually being subsidised by the public system and the results should be in the public domain and open to reanalysis and reinterpretation.”
A spokeswoman for GSK in Australia says in 2012, it divested Aropax to the company Aspen.
She said the findings in the new paper “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 Aropax.”
“This is widely known and clear warnings have been in place on the product label for more than a decade.”
She said the original trial from the 1990s had been reviewed many years ago by regulators and by GSK which identified the increased risk.
“GSK was able to help this team to 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 [a project advocating clinical research adopt principles of open research].”
“We have also led the way in giving external researchers access to the very detailed patient-level data behind our studies, granting access to more than 50 research teams around the world so they can independently use our data in their research.”
Asked to comment on GSK’s good citizenship, Jureidini said “some of it resulted from it meeting its obligations arising out of litigation”.
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