Pharma company Merck withdrew the popular anti-inflammatory agent Vioxx (rofecoxib) from the marketplace in 2004 for increased risk of death due to adverse cardiovascular events, including death. This followed testimony from that company’s CEO before a committee in the Senate in which he said that there was no difference in cardiovascular risk between this drug and placebo — based upon “combined data from randomized controlled clinical trials”.

Could the CEO have been relaying data based upon selective manipulation or interpretation of trial results? This combined data he was referring to was the result of meta-analyses, or pooled trial results from several smaller studies utilized to obtain more favorable results better than individual trials alone. Increasing the statistical power meant that this statement could have been made, as trials involving rofecoxib up to late 2001 had results based upon outcomes data involving bleeding — but not clotting (the major risk associated with the cardiovascular deaths in the plaintiffs’ cases against Merck).

Trials whose outcomes were based upon the effects of bleeding (but not clotting) allowed the pharma company to compare the drug to other agents which could cause bleeding, improving its safety profile at the time of approval. Investigators yesterday published results (from the Archives of Internal Medicine) based upon their research on trial meta data which showed an increase in adverse cardiovascular effects and death in over 70% of those trials done as of 12/2000.

Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, the comparison reaching a P value of .05 by June 2001, nearly 3

1/2

years before the manufacturer’s voluntary market withdrawal.

In response, Merck stands by its claim that it acted responsibly in removing the drug when it did (after results of the APPROVE trial, the study which demonstrated reofecoxib’s risk of causing clotting), refuting the Archives results yesterday as reaching “incorrect conclusions”.

Lost in all of this could be faults in the drug approval process itself. If Vioxx wasn’t fast-tracked for FDA approval, could there have been greater transparency in the approval process — delaying release of the drug to the marketplace after it was more thoroughly surveilled? Was Merck fully aware of the adverse events in found in 2000 trial data, thereby allowing selective publication of favorable results on a potential blockbuster drug? Most importantly, is this still happening? | LINK

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