Insight into how pharma manipulates research evidence: a case study

SKB knew eight adolescents self-harmed or reported emergent suicidal ideas compared to only one in the placebo group but hid this. Michael Valli

TRANSPARENCY AND MEDICINE – A series examining issues from ethics to the evidence in evidence-based medicine, the influence of medical journals to the role of Big Pharma in our present and future health.

Here Jon Jureidini explains what he encountered while examining internal documents as an expert witness in a case against a pharmaceutical company.

It’s well known that academic literature on medication in psychiatry is distorted by selective publication – failing to publish studies with negative results or selectively publishing only positive results from studies with mixed outcomes.

I had the unusual opportunity to see inside the process of how the marketing department of a pharmaceutical company controls and distorts information in the medical literature. This chance arose when I was provided with access to a huge number of internal documents because I acted as an expert witness for a US law firm.

Between 1993 and 1998, SmithKline Beecham (SKB, subsequently GlaxoSmithKline) provided $5 million to various academic institutions to fund research into paroxetine (also known as Aropax, Paxil (GSK) or Seroxat), led by Martin Keller. Keller was from Brown University and received $800,000 for participation in the project.

The results were published in 2001 by Keller et al. in the journal article, “Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial”, in the Journal of the American Academy of Child & Adolescent Psychiatry (JAACAP). The article concluded that “paroxetine is generally well tolerated and effective for major depression in adolescents”.

This was a serious misrepresentation of both the effectiveness and safety of the drug. In fact, when SKB set out their methodology for their proposed study protocol, they had specified two primary and six secondary outcome measures. All eight proved negative, that is, on none of those measures did children on paroxetine do better than those on placebo.

HmanJp/ Wikimedia Commons

The published article misrepresented one of the primary outcomes so that it appeared positive, and deleted all six pre-specified secondary outcomes, replacing them with more favourable measures.

SKB papers also revealed that at least eight adolescents in the paroxetine group had self-harmed or reported emergent suicidal ideas compared to only one in the placebo group. But these adverse events were not properly reported in the published paper. Instead, some were described as “emotional liability” while others were left out altogether.

Although published in Keller’s name, the article was ghostwritten by agents of SKB, and the company maintained tight control of the article’s content throughout its development.

GlaxoSmithKline’s internal documents, disclosed in litigation, show that company staff were aware that the study didn’t support the claim of efficacy but decided it would be “unacceptable commercially” to reveal that.

According to a company position paper, the data were selectively reported in Keller et al.‘s article, in order to “effectively manage the dissemination of these data in order to minimise any potential negative commercial impact”.

Ano Lobb/Flickr

As it turns out, the Keller et al. article was used by GlaxoSmithKline to ward off potential damage to the profile of paroxetine and to promote off-label prescribing to children and adolescents.

While problems with the study and the Keller et al paper have been thoroughly exposed in legal actions, the bioethical and medical literature, a book, and a BBC Panorama documentary, the paper continues to be cited uncritically as evidence of the efficacy of paroxetine for treatment of adolescent depression.

Repeated attempts to get JAACAP to retract the offending paper have been unsuccessful.

For paroxetine, the concern is that adolescents are being harmed because well-intentioned physicians have been misled about its safety and effectiveness.

But more broadly, the case raises questions about how widespread such dubious practice is in the academic community, and in the editorial practices of “scientific” journals.

This is the ninth part of Transparency and Medicine. You can read the previous instalment by clicking the link below:

Part One: Power and duty: is the social contract in medicine still relevant?

Part Two: Big debts in small packages – the dangers of pens and post-it notes

Part Three: Show and tell: conflicts of interest undeclared for clinical guidelines

Part Four: Eminence or evidence? The ethics of using untested treatments

Part Five: Don’t show me the money: the dangers of non-financial conflicts

Part Six: Ghosts in the machine: better definition of author may stem bias

Part Seven: Clearing the air: why more retractions are good for science

Part Eight: Pharma’s influence over published clinical evidence

Part Ten: Why data from published trials should be made public

Part Eleven: Open disclosure: why doctors should be honest about errors

Part Twelve: Reaching full and open disclosure for universities, medical schools and doctors

Part Thirteen: Ethics of accepting suppliers’ gifts in the business v medical world

Part Fourteen: Conflicts of interest in guideline development: the NHMRC responds

Part Fifteen: Consumer input in Medicines Australia’s code of conduct review