Limitations Of FDA's Adverse Event Reporting System Highlighted By Vioxx

Merck's withdrawal of Vioxx illustrates the shortcomings of adverse event reporting systems for detecting common events.

"I wouldn't say that this is a structural problem, but I would say this is a feature of any adverse event reporting system when you have a very, very common adverse event," FDA Center for Drug Evaluation & Research Acting Director Steven Galson, MD, said during a media call Sept. 30.

Separating an "adverse event such as heart disease which occurs millions of time each year" from "those events that are due to a drug…is almost impossible," he said.

"So it's a feature of any adverse event system that it's very difficult when there is an event that occurs commonly to associate it with a product."

FDA held the call to discuss Merck's voluntary withdrawal of Vioxx (rofecoxib) from the market after data from the APPROVe trial showed increased cardiovascular risk after 18 months of treatment.

The agency plans to require long-term data for all COX-2 inhibitors (see ¹ (Also see "FDA Will Require Additional Long-Term Data For COX-2 Inhibitors" - Pink Sheet, 30 Sep, 2004.)).

The Vioxx withdrawal could support a push for enhancements to FDA's Adverse Event Reporting System and longer-term studies of marketed products.

"When you have data that is collected after a drug is approved, there are lots of things that can confound the results, can mix up the conclusions," Galson said.

"When we had this very high quality data from a clinical trial, it was easy to come to these conclusions with a high degree of certainty. You just don't have that high degree certainty with post-marketing data," he said.

FDA added cardiovascular risk information to Vioxx' label in April 2002 based on data from the Vioxx Gastrointestinal Outcomes Research study, which was a controlled trial.

"We have been concerned and aware of the potential for cardiovascular effects with this drug for quite a few years," Galson said.

However, FDA said its original safety database of 5,000 patients on Vioxx did not show an increased risk of heart attack or stroke.

During a call with analysts to discuss the withdrawal, Merck Research Labs President Peter Kim, PhD, explained that "the adverse events for all of our drugs are collected on a world-wide basis using" FDA's AERS safety database.

"That adverse event worldwide reporting system has not turned up anything that was of concern to us or to the regulatory agencies," he added.

FDA is working on approaches to obtain funding for a planned upgrade to AERS. The agency has delayed plans to issue a request-for-proposals for a contractor to upgrade the current system (² (Also see "FDA Adverse Event Reporting System Redesign Proposal Coming Soon" - Pink Sheet, 18 Feb, 2004.)).

- Tericke Blanchard