Unraveling the Cox-2 DebacleA NextGen Perspective 
In 1999, the COX-2 inhibitors were the miracle drugs, promising potent pain relief without the side effects of stomach bleeding. Television ads featuring Dorothy Hamill and the music of Three Dog Night seemed to offer freedom in a pill. By 2005, this picture had soured with mounting concerns about cardiovascular risks, a whistleblower from the FDA, and the eventual withdrawal of two major COX-2 drugs. For many, the COX-2 controversy had come to symbolize the worst of the pharmaceutical industry and government regulation. For Dr. Marcia Angell, the author of The Truth About the Drug Companies: How They Deceive Us and What to Do About It, the situation was nothing short of "a public health disaster." The Next Generation spoke with Dr. Angell for one view of the complicated issues surrounding the controversy. The COX-2 drugs trace their roots to a gene, called COX-1, which contributes to the onset of pain, fever, and notably, inflammation. In the early 1990s, scientists identified a second gene, dubbed COX-2, that operates with COX-1 but with one important difference: while COX-1 was present in all healthy tissues and instrumental in protecting the stomach lining and preventing ulcers, COX-2 appeared to be expressed only in inflamed tissues. This meant that if scientists could suppress the expression of the COX-2 gene, they could relieve inflammation and pain without damaging the stomach. This was especially important because the chief drawback of existing pain relievers, such as ibuprofen or aspirin, was that they elevated a user's risk of gastrointestinal problems. That fact was not lost on medical researchers. Led on by the promise of pain relief without gastrointestinal bleeding, scientists worked to develop a drug that could work as a COX-2 inhibitor. Celebrex, manufactured by Pfizer, was approved by the FDA in December 1998. Vioxx, made by Merck & Co., received FDA approval in May 1999. And Bextra, another COX-2 drug made by Pfizer, was approved in November 2001. [1] With promises of pain killers with fewer gastrointestinal side effects, both Celebrex and Vioxx were reviewed and approved by the FDA in only six months. In a Boston Globe editorial, Dr. Angell describes this rapid review process as a regular practice by which drug companies pay the FDA "user fees" which are "earmarked almost entirely for speeding up drug approvals." [2] Such a practice seems to lead the FDA to act as if its primary job were the speedy evaluation of a drug application, not a careful review of a drug in the public interest. "The public," she writes, "is the primary 'user' of the FDA, not the industry, and funding should reflect that." [3] The reviews of Vioxx and Celebrex are striking for another reason: both drugs were approved without sufficient evidence that they were safer for the stomach than their older, cheaper, over-the-counter cousins, [4] and both were packaged with similar warnings about gastrointestinal side effects as existing painkillers. [5] And while Merck eventually produced studies to convince the FDA to remove the gastrointestinal warning labels from Vioxx, Pfizer never produced evidence that Celebrex was any better for the stomach than the traditional over-the-counter drugs. As one New York Times article put it, "in other words, the world's best-selling COX-2 [inhibitor] has never been proven to the FDA's satisfaction to have the stomach-protecting benefits that originally were supposed to be the point of that category of drugs." [6] Besides the speed of the review or the efficacy of the drugs, there were more serious problems on the horizon for the COX-2 inhibitors. By November 2000, little more than a year after the approval of Vioxx, studies found Vioxx users were more likely to suffer a heart attack than non-users. [7] Despite these findings and despite the possibility that the risk could be associated with the other COX-2's as well, it took until April 2002 for an FDA panel to be sufficiently impressed by the danger for it to recommend adding a cardiovascular warning to the Vioxx label. [8] And it was not until November 2004, a full four years after the initial study showing cardiovascular risks, that Vioxx was withdrawn from the market by Merck & Co. What happened during those four years? Why was so little action taken by the FDA? Dr. David Graham, an employee at the FDA's drug safety office, rose to the national spotlight when he answered that question and claimed that the FDA had been aware of the cardiovascular risks of the COX-2 drugs and had suppressed his attempts to inform the public. Speaking before a Congressional hearing in November 2004, Graham said, "The FDA has let the American people down and, sadly, betrayed a public trust." [9] All drugs carry risks and side effects. Regulators, doctors, and individuals must decide when the benefits of a drug sufficiently outweigh the risks for its use. As Angell writes, "When potential benefits are great, as with many cancer treatments, it is acceptable to run substantial risks. But when there are few benefits over drugs already sold, as in the case of the COX-2 inhibitors, it is not." [10] And by Graham's estimates, strongly disputed by his FDA superiors, the miscalculated risks were in this case exceedingly deadly: he suggested that up to 139,000 Americans who took Vioxx may have suffered heart attack or stroke, and of those, an astounding 26,000 to 55,600 patients might have died. [11] |
