Agencies “failed miserably” over COX-2 inhibitor

North America's regulatory agencies have “failed miserably” in an important aspect of their public mandate, and new national agencies are needed to monitor drug safety, according to the Canadian Medical Association.

If the US Food and Drug Administration and Canada's regulatory agency, Health Canada, had used an active surveillance system that targeted serious adverse events, then the alarm over the cyclo-oxygenase-2 inhibitor rofecoxib (Vioxx) would have been sounded much earlier, says the association.

Both regulatory agencies put their emphasis and resources into assessing drug benefits, not harmful effects, states an editorial in the CMAJ (2005;172:5, 4 Jan). “The bar for approval is low, requiring only that the agent be more effective than placebo. Pre-marketing approval trials are too small to flush out all of the risks of a drug,” it says.

“The built-in bias toward approving drugs without adequate assurance of their safety, and with only a fragmentary and under-funded mechanism for post-approval surveillance based on physician reporting of isolated adverse events, is a fundamental and (often literally) fatal flaw,” stresses the editorial.

The FDA and Health Canada have shown their structural inability to do ongoing safety monitoring of new drugs and devices, and industry is far too conflicted to be able to do this important task, the association argues. New national agencies are needed to monitor drug safety independently from the approval process, it says, arguing that only then can doctors and patients be assured an unbiased safety assessment of the drugs they are prescribing and taking.

On 30 September 2004, Merck withdrew rofecoxib from the market, acknowledging that the drug carried “serious cardiovascular risks” (BMJ 2004;329:816, 9 Oct).

Rofecoxib was originally approved by the FDA and Health Canada in 1999. This was despite evidence in the original clinical trials of a non-statistically significant increase in risk of cardiovascular events and despite the known potential for cardiovascular events associated with any drug that interferes with cyclo-oxygenase-2 enzyme regulators of prostacyclin, points out the editorial.

Even a simple cumulative meta-analysis of post-approval ongoing trials of rofecoxib would have shown, by December 2000 (four years before the drug was withdrawn), a statistically significant excess risk of cardiovascular events associated with rofecoxib, proposes the journal.

According to the editorial, the public expects that the FDA and Health Canada will protect it by restricting approvals to drugs that have been thoroughly tested and are likely to be free of serious risks. These agencies' current emphasis on partnerships with industry and rapid approval of drugs is in conflict with this public expectation, the association argues.

Health Canada defended its process for approving drugs against the association's criticisms. “We vigorously assess the safety, efficacy, and quality of all medications before approving them for use in Canada,” Dr Karen Dodds, an acting associate assistant deputy minister at Health Canada, told Canadian press.

On 22 December 2004, Health Canada issued a safety warning regarding the selective cyclo-oxygenase-2 inhibitor selective non-steroidal anti-inflammatory drugs (rofecoxib, celecoxib, valdecoxib, and meloxicam).