Antidepressant Hearings Offer Starting Point For Vioxx Investigation

The congressional interest in pediatric antidepressant safety data will provide a springboard for investigations into the withdrawal of Merck's COX-2 inhibitor Vioxx .

Senate Finance Committee Chairman Charles Grassley (R-Iowa) is already linking the two issues. In a press release issued Oct. 7, Grassley highlighted claims that an Office of Drug Safety reviewer felt that his concerns about the safety profile of Vioxx (rofecoxib) were not appropriately handled by supervisors.

"As my investigative staff continues looking into how FDA handles drug safety issues, particularly with antidepressants and Vioxx, a picture is emerging of an agency that can't see the forest for the trees."

The Energy & Commerce Committee, which has been pursuing its own investigation of pediatric antidepressant use, is also understood to be looking into FDA's handling of Vioxx.

With Congress out of session until after the elections, no hearings on the issue have been scheduled.

Merck announced the withdrawal of Vioxx Sept. 30, after a clinical trial to support a new indication for prevention of colorectal polyps showed an increased rate of cardiovascular adverse events (¹ (Also see "COX-2 Market Growth Could Be Stalled Until Release Of Long-Term Safety Data" - Pink Sheet, 4 Oct, 2004.), p. 3).

The coincidence in timing between the Vioxx withdrawal and the climax of the pediatric antidepressant hearings is likely to pose a significant complication for Merck in managing the communications challenges and potential liability facing the firm (see ² (Also see "Vioxx Withdrawal Fuels Criticism Of DTC; Liability Exposure May Be Test" - Pink Sheet, 11 Oct, 2004.)). Ironically, Merck was one of the few big pharma companies not directly involved in the antidepressant issue.

There could also be much broader ramifications for FDA and the industry as a whole.

The history of FDA is filled with examples of fundamental changes in mission driven by similar coincidences. Most famously, the thalidomide case in the early 1960s coincided with ongoing hearings into the pharmaceutical industry and resulted in the 1962 efficacy amendments.

The Vioxx withdrawal could give ammunition to advocates for fundamental changes in FDA's drug safety regulation; for example, the idea of creating a separate safety agency modeled on the U.K. system could receive renewed attention.

Opponents of direct-to-consumer advertising and critics of drug pricing are also likely to point to Vioxx as a case study to support other changes.

The immediate focus of the Vioxx investigation will be on how FDA handled safety concerns raised by its own reviewers.

Grassley sees a direct parallel between the concerns about FDA's response to safety concerns raised by reviewer Andrew Mosholder regarding antidepressants. In the case of Vioxx, the questions focus on a paper presented by ODS researcher David Graham based on an analysis of Kaiser's HMO claims data (³ (Also see "COX-2 Retrospective Study Prompts Review By FDA, Kaiser On Merck’s Vioxx" - Pink Sheet, 30 Aug, 2004.), p. 6).

After Grassley's staff interviewed Graham Oct. 7, the senator declared that Graham has "been fighting an uphill battle with FDA to let his study see the light of day." According to Grassley, Graham described "veiled threats" and "intimidation" from superiors that led him to tone down his findings.

Grassley is careful to avoid criticizing Merck: "It seems that while Merck was taking a fresh look at its clinical data in search of trouble, FDA was challenging its own researcher," he said. "Merck knew it had trouble on its hands and took action. At the same time, instead of acting as a public watchdog, FDA was busy challenging its own expert and calling his work 'scientific rumor.'"

Although the Vioxx withdrawal is prompting headlines about the limitations of FDA's safety surveillance system, in the long run it could help validate the agency's efforts to develop new tools like HMO claims analyses.

One immediate link between Vioxx and antidepressants is that the need to respond to Vioxx may complicate FDA's attempts to resolve the appropriate language for a new warning for antidepressants. The agency had expected to finalize the warning during the week of Sept. 30, but as of Oct. 8 a decision was still pending.