Exaggerated Benefits of Antipsychotic Drugs Show in Trial Review

Exaggerated Benefits of Antipsychotic Drugs Show in Trial Review

March 21st, 2012 // 12:54 pm @ jmpickett

Source: Pharmalot

Yet another instance of alleged publication bias has emerged. Four years ago, a review of unpublished studies submitted to the FDA by various drugmakers found many antidepressants had little or no effect on patients. How so? Selective reporting nearly doubled the apparent proportion of positive trials, exaggerating the benefits and, presumably, influencing patient treatment .

Now, a review was conducted of antipsychotics and a somewhat similar finding is being reported in PLoS Medicine. A trio of researchers from Oregon Health & Science University examined 24 premarketing trials registered with the FDA for Abilify, Fanapt, Zyprexa, Invega, Seroquel, Risperdal, Consta and Geodon. The results from the FDA documents were then compared with results published in medical journals.

What did they find? The researchers discovered four premarketing trials were submitted to the FDA – two involving Abilify, which is sold by Bristol-Myers Squibb, and another involving Geodon, which is marketed by Pfizer – but these were never published. And three failed to show either study drug had a statistical advantage over placebo.

A fourth trial, which also tested Geodon, showed the drug was superior to placebo, but statistically inferior to the active comparator, Haldol, which also happened to be cheaper. Another finding: four studies of Fanapt, which is sold by Novartis, revealed inferiority to three different comparator drugs, which was not apparent in the published medical journals, but was clear in the FDA review (here is the study).

However, the association between trial outcome and publication status was not statistically significant. And the mean effect size – or the overall difference between drug and placebo – that was derived from the published studies was only slightly higher than what was found in the FDA reviews. Also, the difference between them did not reach statistical significance.

“These findings show that publication bias in the reporting of trials of second-generation antipsychotic drugs enhances the apparent efficacy of these drugs,” wrote the researchers in the latest issue of PLoS Medicine. The lead author, by the way, is Erick Turner, who was also the lead author on the 2008 study of antidepressants that was published in The New England Journal of Medicine.

“Although the magnitude of the publication bias seen here is less than that seen in a similar study of antidepressant drugs, these findings show how selective reporting of clinical trial data undermines the integrity of the evidence base and can deprive clinicians of accurate data on which to base their prescribing decisions.”

However, the researchers also found that when using a meta-analysis to combine trial data and compare all eight drugs to placebo, publication bias had little impact on the overall efficacy of the drugs. By comparison, the earlier paper on antidepressants demonstrated a more substantial impact due to publication bias. They speculated this may have been because the antipsychotics demonstrated superiority to placebo more consistently.

There were also some limitations, such as the small number of trials analyzed and the emphasis on efficacy, not safety. There was also an assumption that the FDA database is complete and unbiased. Nonetheless, Turner believes medical journals can do more to mitigate bias by insisting that study protocols are read by reviewers.

“I think the publication decisions should be made based upon the study protocol,” he tells us. “I used to work at the FDA and when an NDA came in the door, it might be tempting to just look at the results sent you, but if you dig out the old protocol, you can see original intent and methods. so you know what they were planning before the got the data. So have the protocol in mind first.

Only a few journals ask for study protocols and I think they should all be asking for those. And reviewers should not review results of the study first. They shouldn’t make a decision based on the results, which have a biasing effect… If you see, for instance, that methods were changed, there should be a darned good reason for changing methods.”

He also suggests that the FDA make it easier to access study materials submitted by drugmakers. How so? Well, his university hosts a database of FDA drug approval documents, which you can read here. Turner, by the way, was a consultant to or speaker for Bristol-Myers, Eli Lilly, AstraZeneca, GlaxoSmithKline prior to 2006.