Your Dangerous Drugstore

###1.

On April 5, 2006, a New Jersey jury found that Merck’s arthritis drug Vioxx caused John McDarby, a seventy-seven-year-old retired insurance agent, to suffer the heart attack that left him debilitated in 2004. (The drug was not blamed for the heart attack of a second plaintiff in the same case.) The jury also found Merck guilty of consumer fraud for not warning doctors and the public of the drug’s cardiovascular risks. McDarby and his wife were awarded $4.5 million, plus another $9 million in punitive damages because the company was found to have misled the US Food and Drug Administration (FDA). Merck now faces about ten thousand similar lawsuits, and has vowed to fight every one of them. So far, there have been verdicts in four cases—two for Merck and two against (the McDarby case and an earlier one in Texas, in which the plaintiff was awarded $253.5 million, which under Texas law must be cut to $26.1 million).¹ If there are more losses, and the chances are there will be, Merck, despite its defiant talk, may ultimately have to try to reach a settlement instead of fighting each case.²

The defeat was not just a loss for Merck, but for the industry as a whole, which has seen its reputation plummet in the past few years. Polls show that among American businesses, the pharmaceutical industry now ranks near the bottom in public approval—above tobacco and oil companies, but well below airlines and banks and even insurance companies. This situation contrasts sharply with the generally high regard in which the industry was held just a few years ago.³

There are three main reasons for the drop in public esteem. First, people are growing increasingly skeptical about the industry’s justifications for its high and rapidly escalating prices. To many, it looks more like simple profiteering than what the industry claims it is—a necessity to cover high research and development costs. People are beginning to realize that even after the pharmaceutical industry’s much-vaunted R&D expenditures, it still has enough left over to make it consistently one of the most profitable industries in the US. Second, as more people began to purchase drugs from Canada in recent years, it became generally well known that prices in the US are much higher than in other countries. While the industry claims that other countries are “free riders,” it seems to many Americans that it is the drug companies who are free riders. Finally, many older people have become all too aware of the fact that the new Medicare drug benefit, as a result of pressure from the powerful pharmaceutical lobby, specifically prohibits Medicare from using its huge purchasing power to bargain with drug companies for lower prices (even though it is allowed to regulate doctors’ fees and hospital payments). This prohibition adds to the disillusionment with a bill that is not only weirdly byzantine but provides far less help than it might, and it increases resentment toward the pharmaceutical industry.

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.

In my book I discussed the power of the big pharmaceutical companies to sell just about anything. What Merck should have done after it got the results of the VIGOR trial was immediately launch a large enough clinical trial to investigate the cardiovascular risks as quickly as possible. Instead, a few months later, it signed Dorothy Hamill to skate its problems away. The company reportedly spent $160 million on direct-to-consumer ads for Vioxx in 2000, and continued to spend approximately $100 million a year during the next four years.¹⁹ The costs of even a very large clinical trial would almost certainly have been less than what the company spent on ads. But as expensive as they are, the costs of direct-to-consumer ads are small compared with what drug companies spend promoting their products to doctors. In a variety of expensive ways doctors became convinced—just as the public did more cheaply—that Vioxx was some sort of a breakthrough. The fact that it was no more effective than naproxen, or presumably other over-the-counter remedies, was a fact soon forgotten.

That the advisory panel recommended halting direct-to-consumer ads highlighted the hollowness of the pharmaceutical industry’s contention that such ads are “educational”—designed to encourage patients to discuss medical problems with their doctors. It should be obvious that there is nothing educational about watching Dorothy Hamill pitch a drug or about the other prescription drug ads we see on television. They are meant to persuade patients (and doctors) to use the drug. And they work—as they did spectacularly well in the case of the COX-2 inhibitors. That is why every other advanced country except New Zealand does not permit such ads. But despite the fact that senior officials of the FDA, including the last two commissioners, have repeatedly endorsed the fiction that direct-to-consumer ads are educational, the advisory panel clearly knew better. If ads were truly educational, panel members would not have recommended a moratorium on broadcasting them. ²⁰

In a sense, Merck was doing what big drug companies often do. It was touting the benefits of its drug (such as they were), downplaying or explaining away the risks, and marketing it as though it were a medical miracle. Less explicable is the dereliction of the FDA. If Merck didn’t want to launch a study of the cardiovascular effects of Vioxx (and it had nothing to gain commercially by doing so), why didn’t the FDA insist on it? After all, the FDA’s responsibility is to ensure that prescription drugs are safe and effective, and there was clearly something that needed looking into here. The FDA should also have taken a close look at the ads, since one of its jobs is to ensure that they are accurate and balanced—which they obviously were not.

But the FDA did nothing. Later, it protested that it doesn’t have the authority to mandate additional studies once a drug is marketed, but that is sophistry. The FDA has the authority to pull drugs off the market, and that threat would have been enough to get Merck to organize a trial. Finally, in 2002, after a year of wrangling, it got Merck to add a tepid warning to the drug’s labeling information—the material in small print that comes with prescription drugs (and that few actually read). That hardly met the agency’s responsibility. The part of the FDA that approves new drugs now receives half of its funding from “user fees” paid by drug companies for each drug evaluated. These were first authorized by Congress in 1992, and in return the FDA was required to speed up its review of drugs. I warned in my book about the baleful effects of the user fees, which put the FDA on the payroll of the industry it regulates. This story brings that warning home.

2.

The Vioxx case underlines the importance of clinical trials in deciding whether drugs work or not. Without them, doctors and patients would have to decide on the basis of personal accounts indicating whether or not a given patient seems to improve. That is an unreliable (not to mention dangerous) method. As I wrote:

The assumption that a drug works if a patient gets better does not allow for natural variations in the illness, for the placebo effect (the tendency of both doctors and patients to imagine a drug is working), for all the other times when the drug might fail, or for the possibility that another drug might have worked better.

That is why clinical trials were such an important medical advance when they were first introduced in the middle of the twentieth century, and why the FDA requires clinical trials rather than a collection of testimonials to decide whether drugs are safe and effective.

I mention this because the public hearings held by the FDA advisory panel permitted testimonials from people who said they wanted the COX-2 inhibitors left on the market because nothing else relieved their pain. The panel was reportedly much influenced by these testimonials (could that have explained the pro-Celebrex vote by panel members not on Pfizer’s payroll?), and it ultimately concluded that, although the drugs should be used far less widely than they were, they might be uniquely effective for some people. But while that is possible, there was no evidence on which to base that conjecture.

Not only are testimonials an unreliable way to judge a drug’s effectiveness, they are particularly useless when those giving the testimony are selectively chosen. According to the transcript, at least one of the patients who spoke at the hearings was brought there by Pfizer, the maker of Celebrex and Bextra. I have not seen any evidence that patients who had suffered heart attacks or strokes while on these drugs were brought to Washington to testify; nor, so far as I know, were those who had tried a COX-2 inhibitor but preferred Advil or Aleve.

The notion that testimonials are useful in evaluating drugs reflects the biases of some doctors (mainly those in clinical practice) and much of the public. Many patients like to think they are uniquely different from others, not only as persons, but biologically. However, biological variations among patients are probably far less significant than is widely believed, and would need verification, in any case. Clinicians, for their part, want as many choices of drugs as possible, even if they have little basis for choosing among them. When a drug doesn’t seem to work, they want to be able to say, “Here, try this and see if that’s better.” So it should not be surprising that testimonials played such a big part in these hearings. They were open hearings, and it would have taken a brave panel member to point out publicly that testimonials are not a good basis for making a decision about the benefits of drugs.

Drug companies are quick to exploit the view that there is great biological variability among patients; it is one of their justifications for turning out so many me-too drugs. They like to present me-too drugs as backups for one another. But there is little evidence to support the notion that if a particular drug doesn’t work for a patient, another one in the same class will. Drug companies don’t test their me-too drugs on patients who have found a similar drug ineffective, so there is no way to know for sure. But much of what may look like differences among me-too drugs probably has mainly to do with the size of doses. It may be, for example, that a double dose of Celebrex would act just like Vioxx for virtually everyone.

Even if we grant the possibility that some people may respond very differently to these drugs, does that justify accepting a greatly increased risk of heart attacks and strokes? Since those who most need pain relievers for arthritis are precisely older people who are most vulnerable to cardiovascular disease, the drugs have been estimated to have caused tens of thousands of heart attacks among the millions of people who have taken them regularly.²¹ That is a tremendous cost to balance against the dubious proposition that the drugs offer something unique for pain relief. It is the FDA’s job to see that the benefits of prescription drugs outweigh the risks. It seems clear to me that the agency failed to do so in this case.

The courtroom is not a good place to resolve questions like whether Vioxx caused someone’s heart attack. For one thing, when there are other possible causes of a medical condition, it’s usually impossible to know which one was responsible in any specific case. The best we can do is deal with statistical probabilities. For example, if we look at large numbers of people and find that heart attacks are more than twice as common in those who took Vioxx (as some studies have found²² ), then we can say that the drug outweighs all other risks in the average person like those in the trials. But our legal system requires juries to determine causation in particular individuals, with particular sets of risks, something that is rarely possible. It is an illusion of our tort system to think that we can, and it is one reason these kinds of cases yield such inconsistent verdicts. The best we can do is assume each person is typical of those studied in clinical trials.

John McDarby had a number of other conditions that could have affected his heart, such as diabetes and clogged arteries, and Merck made the case that his heart attack should be attributed to them, not Vioxx. This strategy had been successful in earlier cases. But McDarby’s lawyers stood the argument on its head. They made the case that precisely because of these other heart risks, he was especially vulnerable to the dangerous effects of Vioxx—in their words, “the last person who should have been on Vioxx.” That is certainly a commonsensical view, and clearly the jury saw it that way. Essentially, they were persuaded that a push is more dangerous if you’re standing on the edge of a cliff.

The punitive damages in the McDarby case were based largely on the jury’s finding that Merck had misled the FDA by not supplying it with an internal analysis the company had done of Vioxx’s risks. Merck argued that it withheld the analysis because it was flawed, but had supplied all the underlying data. Whatever the truth about McDarby’s claims, the FDA certainly had enough information to take stronger action years ago.

We have an FDA precisely because we know that drug companies, given their inherent conflict of interest, should not be left to decide on their own whether their products are safe. Caveat emptor may be a reasonable approach for many consumer products, but not for prescription drugs. But the Vioxx story underscores the extent to which the FDA has come to see itself as representing the drug companies, not the public.

Two reforms are necessary. First, the conflicts of interest that pervade the agency should be eliminated. The Prescription Drug User Fee Act (PDUFA) that authorized drug companies to pay user fees in return for quick approval of their drugs comes up for renewal in 2007. Congress should let it die, and instead appropriate adequate support from public funds for this vitally important agency. The FDA should also prohibit experts who consult for drug companies from sitting on its advisory panels. No one’s expertise is indispensable, contrary to the current practice of granting virtually automatic waivers on those grounds.

Second, the FDA should be made much more transparent. Drug companies are required to inform the agency about all the clinical trials they sponsor on drugs for which they are seeking FDA approval. But the agency does not make the studies public without permission of the sponsor, and drug companies naturally publish only the most favorable results. By allowing less favorable results to remain buried, the agency puts proprietary interests ahead of the public interest, and doctors and the public come to believe prescription drugs are better than they are. That should stop. All studies involving human subjects should be registered at inception in a publicly available, central database, and the salient results added at completion.

These reforms will require congressional legislation—an uphill battle, in view of the power of the pharmaceutical lobby in Washington. That power will need to be offset by concentrated pressure from citizen and advocacy groups with an interest in regulating prescription drugs, something that has so far been lacking. But the spotlight does belong squarely on the FDA. That, after all, is where the public’s protection should lie, not with juries after the damage is done.