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Introduction

On September 23, 2004, just two months before completion of a three-year 2,600- patient cancer prevention trial of the pain reliever Vioxx (rofecoxib; Merck), the review board for that trial informed the trial’s sponsors, the Merck company, of adverse results for an important pre-defined endpoint. The incidence of adverse cardiovascular events (heart attacks and strokes) had become statistically significantly higher among Vioxx users than in the control group, which was on a placebo (except that about 20 percent of patients in both groups took low-dose aspirin for heart attack prevention). One week later, Merck withdrew Vioxx from all markets worldwide including, of course, the United States. Merck acted alone without consulting the Food and Drug Administration (FDA), which learned about the withdrawal when it was announced to the public. The cardiovascular effects of Vioxx had already been widely discussed in the medical literature (cited below) and occasionally in the popular press (e.g., Wall Street Journal, May 28, 2004). In April 2002, the FDA had added a cardiovascular warning to the Vioxx label (FDA 2002). Nonetheless, Merck’s action was a surprise, indeed a shock, as Merck’s market capitalization dropped 27 percent on the day Vioxx was withdrawn. (As of March 14, 2005, its market cap was 28 percent below what it was the day before the Vioxx withdrawal. As the events described below unfolded, it became apparent that Merck would probably request that the FDA permit Vioxx back onto the market, based partly on the findings of a February 16-18, 2005 advisory committee meeting. The impact on Merck’s market capitalization remains to be seen, of course.)

In the wake of the Vioxx withdrawal, Merck came under widespread criticism, as did the FDA. Some of the criticism focused on advertising. Vioxx had been heavily advertised directly to consumers, as had its chief competitor Celebrex (celecoxib; Pfizer) in the category of Cox-2 inhibitors (often just called “Cox-2s” in the popular press or “coxibs” in the medical literature). The Vioxx withdrawal raised questions about direct-to-consumer (DTC) advertising. In December 2004, Pfizer voluntarily ceased DTC advertising for Celebrex (New York Times, December 20, 2004). Prominent medical academics and others suggested that DTC advertising had made the Vioxx problem much worse, and some newspaper editorial writers (e.g., Boston Globe, January 6, 2005) proposed a permanent ban on DTC advertising for Cox-2s, as did a majority of members of the February 2005 FDA advisory committee.[1]

The Vioxx episode has already begun to exert a substantial impact on Merck (which has another Cox-2, Arcoxia, in advanced clinical trials), other Cox-2 manufacturers (with several Cox-2s approved in Europe or under development),[2] the regulation of drug safety, the FDA as an institution, and the entire drug development and approval process.

The Vioxx episode may also affect DTC advertising and its regulation. At least 3 four questions arise. One is the extent to which advertising increased the uptake of Vioxx. Answering this question, however, is very different from being able to say whether DTC advertising was (as many have claimed) doing more harm than good. A separate question is whether, aside from its impact on usage levels, DTC advertising tended to induce inappropriate usage where its benefits were outweighed by health risks and (perhaps) its financial costs. A third question is whether DTC advertising distorted information about the health benefits and costs of Vioxx. Finally, there is the difficult question of what Merck knew about those costs and benefits, and especially, whether Merck should have learned more by analyzing clinical data or conducting additional clinical trials.

Before addressing these questions, considerable information on the Cox-2 class of drugs is necessary. 

John E. Calfee is a resident scholar and Ximena Pinell is a research assistant at AEI.

Notes

[1] The joint advisory committee meeting transcript reveals at least 18 members favoring an outright ban on Cox-2 DTC advertising, and about 5 opposed to a ban. Okie (2005c) observed, “almost all committee members said that manufacturers should be prohibited from advertising the products directly to consumers.”

[2] Prexige (lumiracoxib, Novartis) was approved in the U.K. in October 2003, but Novartis has not placed the drug on the market pending E.U. approval (Wall Street Journal, February 7, 2005). Other Cox-2s in advanced clinical trials include Arcoxia (etoricoxib, Merck).

[3] Recent summaries of DTC advertising and its effects include Rosenthal, et al., 2002; Calfee 2002 and 2003; and Hoek, Gendall, and Calfee 2004, which addresses the important but neglected case of New Zealand, where regulations are very different from those in the U.S.