May 4, 2012

The case of the missing drug trial...

Publication bias. On one simple level it is about cherry-picking data, putting your best foot forward and presenting work in a positive light. On a much more real level it can result in a drug being licensed that doesn’t do exactly what it says on the box.

The story all began when lead author, Erick Turner, noticed that a database, initially set up by PhRMA (Pharmaceutical Research and Manufacturers of America) to “serve the valuable function of making clinical trial results for many marketed pharmaceuticals more transparent….” had mysteriously disappeared from the internet. This database was one Erick Turner and his collaborators had used and included in their recent PLoS Medicine paper. While the paper was in press they discovered it had disappeared. The PLoS paper describes the publication bias that exists in antipsychotic drug trials.

In the paper the researchers compare the data found in the literature against the data in the US Food and Drug Administration (FDA) database. Therefore being able to determine whether publication bias is present and go further to quantify it to assess the extent to which it inflates apparent drug efficacy. The benefits of a study like this are clear for all to see. If only positive results are published and seen in the literature, with negative results left in the bottom drawer, your drug -- one that acts only slightly better than a placebo will suddenly become the wonder drug. And it seems every “Big Pharma” company markets their latest drug as the new wonder drug.

But the question has to be asked; how much of the data have we actually seen? Such a reality can obviously affect clinical decision-making and patient outcomes. We are yet to see the dire consequences of these actions but the sleeping giant is there. The missing database, once found at, was originally set up to prevent this sort of thing happening. It was supposed to act as a source to access the results of Phase III and IV studies, whether negative or positive. And in a bizarre twist of fate, the website exists no more. With no explanation as to why it was taken down or as to what becomes of the data that already existed on the site.

Erick Turner’s paper provides good reading, and helpful insight into the drug trial process. “In the US, all new drugs have to be approved by the FDA before they can be marketed. During this approval process, the FDA collects and keeps complete information about premarketing trials, including descriptions of their design and prespecified outcome measures and all the data collected during the trials. Thus, a comparison of the results included in the FDA reviews for a group of trials and the results that appear in the literature for the same trials can provide direct evidence about publication bias.”

It turns out that for this particular case, antipsychotics, the publication bias was not on a level previously seen as with antidepressants. Perhaps this could relate to the comparative market sizes for both types of drugs. The antidepressant drug market reached sales of almost $9.6 billion in 2008, and even doubling between 1996 and 2005. Antipsychotics, remaining the standard care for the treatment of mental disorders such as schizophrenia and bipolar disorder and generated $1.4 billion of revenue in 2010 in the top seven countries including the US.

The authors also note another possible reason; simply possibly because antipsychotics demonstrate superiority to placebo more consistently. Without increased access to regulatory agency data, publication bias will continue to blur distinctions between effective and ineffective drugs.

Written by Dr. Charles Ebikeme for The All Results Journals. 

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