The New York Review of Books

Much of what is wrong with the industry is explained in several recent books. They include Merrill Goozner’s The $800 Million Pill, which shows that most innovative research on serious diseases like cancer and HIV/AIDS is done not by drug companies but in government and university labs. Jerry Avorn’s Powerful Medicines discusses the risks and benefits of the drugs themselves, and shows that many of them fall far short of their marketing promises. John Abramson’s Overdosed America presents a clinician’s view of the misinformation that leads doctors to prescribe unnecessary and possibly harmful drugs. Jerome Kassirer’s On the Take explains how the medical profession has allowed itself to be seduced by the billions of dollars lavished on it by the drug companies (for example in subsidizing medical meetings of all types). Sharna Olfman’s No Child Left Different takes a critical look at the promotion and overuse of psychoactive drugs in children. Selling Sickness, by Ray Moynihan and Alan Cassels, explains how the pharmaceutical industry increases sales by convincing essentially normal people that they have chronic conditions (such as erectile dysfunction) that require lifelong drug treatment. Although each of these books emphasizes different parts of the system, they are remarkably consistent when they overlap, and together they make a damning case, not just against the industry but against our entire system for developing, testing, and using prescription drugs.⁴

The Vioxx story exemplifies many of the problems.⁵ It first came to public attention on September 30, 2004, when Merck announced it was pulling Vioxx from the market, citing a clinical trial that showed it doubled the risk of heart attacks and strokes.⁶ Vioxx had been heavily promoted to both doctors and the public. The “direct-to-consumer” ads on television featured 1976 Olympic gold medalist Dorothy Hamill skating effortlessly across an outdoor rink to the Rascals’ “It’s a Beautiful Morning”—presumably free of arthritis pain, thanks to Vioxx. At the time the drug was withdrawn, an estimated 20 million people had taken Vioxx, and it had yearly sales of $2.5 billion. The withdrawal of Vioxx was front-page news and caused great public concern—both among those who felt the drug was uniquely effective in relieving their arthritis symptoms and among those who feared they might have a heart attack or stroke because of the drug. Merck’s stock price fell by more than a quarter on the day of the announcement, and market analysts began to speculate about the company’s uncertain financial future and legal liabilities.

Attention immediately turned to Pfizer’s Celebrex and Bextra.⁷ All were in the same class of drugs, called COX-2 inhibitors, and there were two more in late-stage development, Merck’s Arcoxia and Novartis’s Prexige.⁸ The first of them, Celebrex, which had preceded Vioxx on the market by a few months, was an even bigger success, with sales of $3.3 billion. The others were what are known as “me-too drugs”—additional drugs in the same class. An editorial in The Wall Street Journal, loyal as always to the pharmaceutical industry, found something to celebrate. “The Vioxx withdrawal,” it said, “shows why choice in ‘me-too’ drugs is a good thing.”⁹ I wrote a letter to the editor pointing out that it was premature to conclude that Celebrex and Bextra were in the clear. “Since they are so much like Vioxx,” I said, “I would not bet my ice skates that they are not eventually shown to have similar risks.”¹⁰

It didn’t take very long. Within months, there were reports that Celebrex and Bextra also increased the risk of heart attacks and strokes, at least in some patients at some doses.¹¹ But Pfizer announced that, unlike Merck, it would leave the drugs on the market, although it would stop advertising them to consumers, because, as its CEO explained to a television reporter, whether and how to use the drugs were “complicated” matters that ought to be left to doctors in discussion with each patient. (He did not explain why that very sensible advice should not apply to other prescription drugs promoted directly to the public.)

As confusion grew, the FDA appointed a special advisory panel to hold hearings and advise it about how to handle the situation. There were several possible courses of action for the FDA. For example, all the COX-2 inhibitors could be pulled from the market immediately. Or Celebrex, which seemed safer than the others at usual doses (it acted like a weaker version of Vioxx), could be allowed to remain. (As is often the case with me-too drugs, apparent differences have a lot to do with the dose.) Or they could all be left on the market, including Vioxx, but with some new guidelines restricting their use.

The FDA advisory panel consisted mainly of members of two standing advisory committees—one for arthritis and one for drug safety. During the hearings and deliberations, which were public, there were emotional testimonials from patients who claimed that one or another of the COX-2 inhibitors had produced spectacular results after other types of painkillers had failed. The hearings lasted for three days in mid-February 2005, and the final decision was prominently reported in the press.¹² Although the panel agreed that COX-2 inhibitors as a class did indeed increase the risk of heart attacks and strokes, it concluded that the benefits outweighed the risks (the vote was close in the case of Vioxx and Bextra). It therefore recommended that Celebrex and Bextra remain on the market and that Vioxx be allowed to return, perhaps with strong warnings on the labels for all three, and a moratorium on ads that appealed directly to consumers.

On April 7, 2005, however, following revelations that many panel members had financial ties to Merck or Pfizer, the FDA, which usually takes its advisory committees’ advice, decided differently. As expected, it announced that Celebrex could remain on the market, with a strong warning on its label. But the agency asked Pfizer to take Bextra off the market, and indicated that if Merck wanted to bring Vioxx back, it would have a difficult battle.

The story of the approval and marketing of the COX-2 inhibitors illustrates nearly every major criticism of the pharmaceutical industry made in my book The Truth About the Drug Companies: How They Deceive Us and What to Do About It. Among other things I criticize the lax standards for approval of drugs, the conflicts of interest that pervade the system and influence decisions, the slowness of both industry and the FDA to respond to danger signals, the power of the industry’s huge marketing campaigns, and the baseless justifications for me-too drugs.

In late 1998 and early 1999, Celebrex and then Vioxx were approved by the FDA. They were given rapid “priority” reviews—which means the FDA believed them likely to be improvements over drugs already sold to treat arthritis pain. Was that warranted? Neither drug was ever shown to be any better for pain relief than over-the-counter remedies such as aspirin or ibuprofen (Advil) or naproxen (Aleve). But theory predicted that COX-2 inhibitors would be easier on the stomach, and that was the reason for the enthusiasm. As it turned out, though, only Vioxx was shown to reduce the rate of serious stomach problems, like bleeding ulcers, and then, mainly in people already prone to these problems, a small fraction of users. In other words, the theory just didn’t work out as anticipated.

Furthermore, people vulnerable to stomach ulcers could probably get the same protection and pain relief by taking a proton-pump inhibitor (like Prilosec) along with an over-the-counter pain reliever.¹³ So the COX-2 inhibitors did not really fill an unmet need, despite the one seemingly attractive claim made in favor of them. Nevertheless, the FDA acted as if they did, by giving these drugs expedited review and approval.

In my book I discussed the conflicts of interest pervading the FDA, including the fact that many members of FDA advisory committees are paid consultants for drug companies. Although they are supposed to recuse themselves from decisions when they have a financial connection with the company that makes the drug in question, that rule is regularly waived. With that in mind, I checked the minutes of the 1999 advisory committee meeting that led to the approval of Vioxx. Sure enough, four of the six members, including the chairman, were granted waivers because they had a “potential for a conflict of interest.”¹⁴

Worse yet, of the thirty-two members of the 2005 panel that was charged with deciding whether the COX-2 inhibitors were safe enough to stay on the market, ten had financial connections with one of the manufacturers, according to a front-page story in The New York Times that appeared a week after the panel’s decision.¹⁵ As is often the case, these ten members with conflicts of interest were not disqualified. And as it turned out, they voted 9–1 in favor of Vioxx and Bextra. Without their votes, the panel would have recommended that these two COX-2 inhibitors be removed from the market (there would still have been enough votes to keep Celebrex). This does not prove that these nine advisers were biased, but it certainly raises the question, especially since Vioxx and Bextra were rejected by the majority of panel members with no known ties to the manufacturers. That is why FDA advisory committees should not include people with conflicts of interest, no matter how expert they may be.

The clinical trial that caused Merck to withdraw Vioxx was designed to see whether the drug could prevent the recurrence of colorectal polyps; the finding that the drug increased the risk of heart attacks and stroke was an accidental result of the trial. The company professed to be surprised. Then the CEO, Raymond Gilmartin, who claimed his wife took Vioxx right up until the drug was withdrawn, said the results were “unexpected.”¹⁶

But in fact, it could hardly have been a complete surprise. There had been signs of trouble for years.¹⁷ In 2000, a company-sponsored trial was published in The New England Journal of Medicine comparing Vioxx with over-the-counter naproxen in patients with rheumatoid arthritis.¹⁸ This was called the Vioxx Gastrointestinal Outcomes Research, or VIGOR, trial (medical researchers and their sponsors love catchy acronyms), and it was intended to show that Vioxx was easier on the stomach than naproxen (Aleve). In relieving pain, the drugs proved to be the same, but those taking Vioxx had only half the risk of serious stomach problems. Unfortunately, the study also showed at least a fourfold increase in the risk of heart attacks. The details of the cardiovascular effects were not described in the published paper, but an FDA analysis indicated that the drug was more likely to cause heart attacks or strokes than to prevent stomach ulcers. Merck tried to explain the alarming finding away by saying the difference probably showed that naproxen protects the heart, not that Vioxx harms it. But, of course, without testing that hypothesis, it was simply self-serving speculation. Moreover, within a year, other evidence came to light that Vioxx increased cardiovascular risks, and that Celebrex may do so as well.