The same week that drug manufacturer Merck pulled its highly profitable painkiller, Vioxx, from the market last September, acknowledging that it was linked to heart attacks and strokes, a Las Vegas legend dropped into our local poker game. Ray is one of poker's few long-term success stories. A math wiz, highly praised author of several authoritative books on game theory and high-limit poker, and a practicing Buddhist, Ray was reminiscing about his early days in Las Vegas.
"Cheating was rampant," he said. "Stripped decks, wired hands, coolers, seconds, holdouts and marked cards. You name it, they did it -- the dealers and the players."
Ray had been able to make a great living in poker because he assumed the games might be rigged and acted accordingly. He studied the players and dealers, even watched videos of how card dealers dealt off the bottom of the deck or from the middle. He always expected the worst and was prepared.
"You weren't bothered playing with a bunch of crooks?" I asked.
Ray laughed. "You got to play with someone. We all have cheat in us, given the right circumstances." He smiled slyly. "But even cheats don't cheat all the time. The trick is to know when and how."
With its spectacular medical advances, Big Pharma is the only game in town. We cannot walk away; we must play. But unlike Ray, we are reluctant to assume that drug companies are rigging the outcome. Without this requisite skepticism, we are at their mercy -- in this case, with fatal consequences. The U.S. Food and Drug Administration has linked Vioxx, since it was released in 1999, to more than 27,000 acute heart attacks and sudden cardiac deaths. What the agency didn't report was its own culpability in the debacle.
Even the disclosure of tragic deaths, though, won't stop the same malfeasance from happening again. In order to protect ourselves as patients, we need to know how the game might be fixed. Dissecting the way that Merck developed Vioxx gives us a perfect opportunity.
I was initially reluctant to write another piece on the Vioxx scandal. The mainstream press has more than adequately pointed the finger of blame at Merck for knowing the cardiovascular risks of Vioxx and yet minimizing them to reap huge economic rewards. The medical literature has been equally damning. Two months after Vioxx was recalled, Dr. Richard Horton, editor in chief of the British medical journal Lancet, wrote: "With Vioxx, Merck and the F.D.A. acted out of ruthless, short-sighted, and irresponsible self-interest."
But the medical literature related to Vioxx suggests an even more onerous possibility, which is that Merck intentionally designed its studies to avoid discovering the truth about the potential C.V. risks of Vioxx. I have not been privy to the company's private staff meetings and internal documents. But it has been my experience that undertaking any major research study involves extensive consultation between experts in all pertinent fields, including pharmacologists, epidemiologists, statisticians and business managers. Given the enormous intellectual investment in the design of a drug like Vioxx, it is reasonable to presume that all potential outcomes were seriously entertained. I must presume that Merck would factor in what might happen to Vioxx sales with each study result. And so it's hard to escape the sadly cynical conclusion that the company consciously crafted its tests to avoid exposing the risks of Vioxx to the public.
After all, the stakes of new drug development are enormous. Only a fraction of new drugs submitted to the FDA for approval make it to market; the average cost per approved drug is over $800 million. Any drug that makes it into the marketplace is a potential bonanza to be coddled, cherished and protected. A drug patent lasts 17 years, and then the drug is thrown to the generic manufacturers. The FDA approved Vioxx for sale in May 1999. By 2004, 20 million Americans had taken the painkiller and its annual sales exceeded $2.5 billion. Is it any wonder that Merck sought to present Vioxx to the public in the best possible light?
To understand Merck's approach, we need a crash course in biology. COX (cyclooxygenase) is an enzyme in the body that produces an inflammatory response -- swelling, fever and pain. Drugs that reduce COX activity are called NSAIDs, and traditionally include aspirin and ibuprofen. But COX is present throughout the body and has a host of other effects, some of which are beneficial. For example, it helps protect the lining of the G.I. (gastrointestinal) tract from ulceration and bleeding.
Approximately 1 in 1,200 patients taking traditional NSAIDs for at least two months will die from G.I.-related complications. A conservative estimate: 16,500 NSAID-related deaths occur every year in the United States, approximately equivalent to the number of deaths from AIDS.
The holy grail of anti-inflammatories would be a COX inhibitor without this side effect. This became a real possibility in 1990, when COX was shown to exist as two chemically distinct enzymes -- COX-1 and COX-2. COX-1 protects the G.I. tract, while COX-2 is responsible for the inflammatory response. The obvious answer to the G.I. complications: develop a drug that inhibits COX-2 but not COX-1.
Give Merck credit. It developed Vioxx, a drug with the same degree of anti-inflammatory and anti-pain response as NSAIDs, but with a significant reduction in G.I. complaints and complications.
But medicine rarely comes in such neat categories. As far back as 1984, Garret FitzGerald and his colleagues at the University of Pennsylvania, writing in the New England Journal of Medicine, showed that the COX enzyme might prevent arterial blood clot formation. FitzGerald suggested that this side effect might mean little in healthy persons but could be dangerous to patients with severe atherosclerosis. Which sounds reasonable -- a high level of an anti-clotting enzyme wouldn't be necessary in normal vessels, but would be necessary in damaged vessels in which clot formation was more likely.
In 1997, with Vioxx still in clinical trials, FitzGerald himself consulted with Merck. According to Merck's position statement, recently filed in a U.S. District Court in Louisiana, in response to a class-action lawsuit, FitzGerald warned the company that COX-2 had a possible anti-clotting benefit. He expressed concern that suppression of this mechanism by a "coxib" drug such as Vioxx might increase the risk of blocked arteries.
Merck responded to FitzGerald's research by re-analyzing all of its Vioxx clinical data, and included FitzGerald's potentially worrisome lab data in its FDA application. (This data was published in 1999 in the Journal of Pharmacology and Experimental Therapeutics.) Merck also declared that it had adopted the standard procedure for "facilitating rigorous scientific analysis, on an ongoing basis, of all competing hypotheses about potential CV risks or benefits from Vioxx."
Was this a sufficient evaluation of a potentially serious side effect of Vioxx? Or should more have been done? Given that it is standard practice to assess all serious potential risks of new drugs, FitzGerald's concern should have been directly addressed.
But rather than design a study focused on the C.V. risks of Vioxx, Merck created the VIGOR (Vioxx Gastrointestinal Outcomes Research) study in 2000. It compared the incidence of G.I. complications of Vioxx to naproxen, another conventional NSAID, whose most popular brand is Aleve. The goal was to prove that Vioxx was an equally effective but safer drug than an over-the-counter NSAID. Unfortunately, the study, published in the New England Journal of Medicine, revealed a twofold increase in C.V. risk for patients who took Vioxx. Of course, Merck acted surprised. What Merck didn't tell us is that it had stripped the deck of patients at high risk for heart disease.
In the VIGOR study, 80 percent of patients were women with an average age of 58, with Merck being well aware that women, on average, develop C.V. disease 10 years later than men. Only 4 percent of the total subjects had a prior history of C.V. disease and were felt to be at high risk for further C.V. events. It was no surprise, then, that 38 percent of the heart attacks in the group of patients who took Vioxx came from this small 4 percent subgroup.
Ironically, it was Merck's failure to eliminate these few high-risk patients that allowed the C.V. effects of Vioxx to be detected. According to a review of coxibs in the New England Journal of Medicine, published in 2001, if these few high-risk patients had been excluded from the VIGOR study, the difference between Vioxx and naproxen would not have been significant. Therefore Vioxx may have never been taken off the market.
But there's more.
Anyone who's gambled in a casino knows that the key to winning is to get lucky initially and quit before the odds catch up with you. Get in and get out before the odds get a chance to declare themselves.
To understand the risks involved with a coxib, it is necessary to conceptualize risk as a function of time. The risk of electrocution is immediate. You don't grab a hot wire and get electrocuted next year. It's now or never. Similarly, a fatal allergic reaction to a penicillin injection happens within minutes, not in six months. In assessing risk factors with a predictable time of occurrence, it is easy to determine the study period. But other risks can take years or decades to manifest themselves.
It took many years to recognize the detrimental effects of hormone replacement therapy, or the time lag between sun exposure and the subsequent development of a malignant melanoma. Such correlations require following large groups of patients for extended periods of time. A major source of our understanding of cholesterol levels and the development of C.V. disease came from large-population longitudinal studies such as the Framingham Heart Study, which began in 1948 and is still ongoing.
It is self-evident that risk factors can be present for many years before becoming clinically observable. Although elevated levels of cholesterol increase the risk of a heart attack, the rate of heart attacks in teenagers with high cholesterol is far less than that of middle-aged adults with similar cholesterol levels. The cholesterol effect is cumulative; atherosclerosis takes time to become manifest.
If we wanted to minimize or negate the apparent effect of cholesterol on heart disease, we would study the youngest patients we could, and for the shortest period of time. If we ran a nine-month study to compare the incidence of heart attacks in a group of 10-year-olds with high cholesterol vs. normal controls, it is highly unlikely that we would see a difference.
The Framingham study has been ongoing for more than 50 years. Merck's VIGOR study followed its patients for an average of nine months. Even this short period revealed a very disturbing trend.
During the first six weeks of the study, there was no significant difference between the two drugs. As the follow-up period continued, the patients taking naproxen clearly were having fewer heart attacks than those taking Vioxx. But between months 8 and 11, the naproxen rate was relatively constant, while the Vioxx rate appeared to be accelerating. It was at this critical point that Merck concluded its trial.
When asked why it concluded its VIGOR study at this key juncture, a Merck spokesperson replied with a terse e-mail: "VIGOR was an endpoint-driven study and it ended when it was designed to end."
Merck repeatedly contended that it was actively investigating possible reasons for the adverse findings in the short VIGOR study. One of them was that the difference between Vioxx and naproxen could be best explained as a cardio-protective benefit of naproxen as opposed to an untoward side effect of Vioxx. Most researchers disagree. To date, no large-scale study has demonstrated more than a possibly small protective effect of naproxen, and certainly not of the magnitude that would explain the VIGOR difference. In fact, a recent study of naproxen and prevention of Alzheimer's disease was halted because of an apparent increase in C.V. events.
Listen to Peter S. Kim, president of Merck Research Laboratories, explain why Vioxx had a higher C.V. complication rate than naproxen. "Because the VIGOR study compared two drugs -- Vioxx and naproxen -- and did not contain a placebo arm, it was not possible to conclude, based on this study alone, whether naproxen was having a beneficial CV effect or whether Vioxx was having a detrimental CV effect."
When I asked Merck why it didn't include a placebo group in the study, which would have underscored the C.V. effects of Vioxx, it referred me again to its court statement: "For ethical reasons, Merck could not conduct a placebo-controlled study in a population that required pain medicine (because patients in the placebo arm would receive no pain relief)."
Yet placebo control studies are commonly used to study anti-pain medications. Indeed, many peer-reviewed osteoarthritis and rheumatoid arthritis studies of NSAIDs and coxibs, including Vioxx, have included a placebo group for comparison. (Unfortunately, these studies were of too short a duration -- 6-12 weeks -- to assess any long-term C.V. effect. Merck, nevertheless, cites the data to show no evidence of C.V. effect of Vioxx.)
In an August 2001 article in the Journal of the American Medical Association, Drs. Mukherjee, Topol and Nissen from the Cleveland Clinic compared rates of heart attacks in trials performed with selective COX-2 inhibitors, including Vioxx, to heart attack rates compiled from a large number of studies on aspirin for heart disease prevention. Their review included 48,000 patients; the Merck VIGOR trial had 8,000.
The authors concluded: "The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors." Even more compelling, they stated: "We believe that it is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents. Until then, we urge caution in prescribing these agents to patients at risk for cardiovascular morbidity."
Merck did make a motion in that direction. According to an article in the New York Times earlier this year, the company planned to initiate a major C.V. risk study called VALOR in 2002. But just days before company researchers were to submit the study's protocol to the FDA, the project was abruptly halted. Merck did not explain why. It issued a general statement, saying that as it was designing the study, "we continued to ask ourselves and our consultants whether this was the right way to definitely answer" the question of whether Vioxx posed C.V. risks. "We ultimately decided not to conduct that particular study."
In 2002, with Vioxx selling extremely well, Merck was no doubt convinced that the odds of keeping the painkiller on the market remained in its favor. After all, when the VIGOR study revealed that patients who took Vioxx showed a twofold increase in heart attacks, Merck must have figured that it could face potential lawsuits. Just as all Big Pharma companies do, Merck must have calculated that profits from sales would outweigh losses from lawsuits.
In fact, as a study in the Archives of Internal Medicine would later show, Merck, through heavy promotion, sought to create as wide a market as possible for Vioxx. (The study revealed that 73 percent of people who took Vioxx did not need a coxib, that a standard NSAID like aspirin would have been sufficient.) Apparently, selling Vioxx as a niche drug for people who really did suffer G.I. problems from NSAIDs, and who were at low risk for heart disease, did not meet Merck's profit-and-loss forecast.
Merck initiated several more studies of Vioxx, all primarily intended to uncover further potential markets for the drug. In each case, it avoided delving specifically into possible C.V. complications. Most notable was the APPROVe study, which looked toward the prevention of colon polyps, as well as other studies for possible treatments for colorectal and prostate cancer.
In September 2004, when the APPROVe trial revealed the same twofold increase in C.V. complications as the VIGOR study, Merck recalled Vioxx. Even then, Dr. Alise Reicin, vice president of clinical research at Merck, reiterated that this was a puzzling finding. She said that Merck has so far been unable to identify a mechanism behind the increased risk. The fact is that Merck avoided initiating studies to find one.
To further distance Merck from any responsibility for those who had recently begun taking Vioxx, Kim added, "While the cause of these results is uncertain at this time, they suggest an increased risk of confirmed CV events beginning after 18 months of continuous therapy."
No, the risk didn't begin after 18 months. This would be analogous to saying that daily sunbathing for 18 months poses no risk for melanoma if no melanomas are detected during that time, and that the risk doesn't begin until the melanomas are first discovered. The risk is present from the beginning but only evident at 18 months.
Finally, Merck is asking us to believe that it didn't suspect from the outset that Vioxx might increase the risk of heart attacks and strokes. It's telling us that its studies were adequately designed to detect both the incidence and possible underlying mechanisms of cardiovascular risks. It wants us to accept that a nine-month study, abruptly concluded, was insufficient evidence for the withdrawal of Vioxx because it was reasonable to presume that naproxen had a cardio-protective effect.
For me, the sad but inescapable conclusion is that Merck made an informed decision to avoid knowing the full extent of Vioxx's potential risks for heart attacks and strokes.
And the FDA was either extraordinarily lax or frankly complicit. In April 2002, the federal agency did state that Merck must affix a new label to Vioxx, advising doctors to use caution when prescribing it to patients with heart disease. But it didn't rule that the drug be withdrawn from the shelves.
Based upon their review of available data about Vioxx, a team of medical scientists from the University of Berne, Switzerland, published this summary in a December 2004 issue of Lancet: "Our findings indicate that Vioxx should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarize the accumulating evidence need to be clarified."
This situation is not likely to change. On at least three occasions, Congress has voted to approve partial FDA funding by pharmaceutical companies. Beginning in 1992 with the passage of PDUFA -- the Prescription Drug User Fee Act -- pharmaceutical companies have been paying up to $500,000 for each new drug application. Currently, greater than 50 percent of drug reviewers at the FDA are funded by the pharmaceutical industry.
According to the Center for Science in the Public Interest, 10 of the 32 FDA advisory board members who, in 2005, recommended the continued sale of coxibs, had previously consulted for Merck, Pfizer or Novartis. (Pfizer and Novartis have not withdrawn their coxibs, Celebrex and Prexige, respectively, from the market.) To be fair, this isn't entirely damning, as many top researchers have ties with pharmaceutical companies yet maintain unbiased positions. Dr. FitzGerald, one of Merck's harshest critics, has received research funding from Merck.
When Merck withdrew Vioxx, the FDA responded: "The risk that an individual patient taking Vioxx will suffer a heart attack or stroke related to the drug is very small." This is both true and profoundly misleading.
A truly independent agency for the evaluation of new drugs is essential. But the unfortunate truth for the foreseeable future is that we are dependent upon the pharmaceutical industry and its hired security guards -- the FDA -- to police itself.
We are not helpless. We do have one ace in the hole -- the simplest and most difficult of questions. Do I need this medication? Or, as Ray would say, is this the only game in town and do I need to play?
If you have rheumatoid arthritis and can barely dress and feed yourself, a doubled chance of a heart attack on Vioxx might be an acceptable trade-off for increased mobility. A disabling stroke, no matter how unlikely, doesn't seem like a reasonable risk for a twinge of tennis elbow.
The decision to take any medication is highly personal, a reflection of everything from genetic predispositions to cultural values to the loftiest of metaphysics. It cannot depend exclusively upon statistics. An honest and thorough medical system can provide the information, but the old saw, know thyself, is essential to such choices.
So is know thy playing partner.
And the key to making the right personal decision is that we need transparency of data. We need to get our hands on the deck and look for ourselves. There are plenty of smart and independent folks who could sift through the information and give us an informed opinion. We must demand that study data be made publicly available to those without a vested interest.
The best place to start is with your own family doctor. If you and your physician had adopted Ray's approach to medication, you would have known in August 2001 that leading cardiologists such as Dr. Topol had major concerns about possible Vioxx C.V. effects. And you would have carefully discussed the labeling change ordered by the FDA in 2002. Unless you are an Internet health letter, medical journal junkie, only your doctor would have received this news in a timely fashion.
However, the problem of post-approval drug side effects will not go away. After 30 years on the market, it is still unclear as to the C.V. effects of the allegedly "safe" NSAIDs such as Aleve. We have to anticipate the unknown, accept certain knowledge limitations, and trust someone to be our advocate in an ever more confusing medical landscape. And we need to balance a well-deserved skepticism with an equal appreciation of what modern medicine has accomplished.
In the big picture, Merck has had an outstanding reputation. It offers a variety of formidable drugs that both improve and save lives. As a niche drug, prescribed to those unresponsive to the older NSAIDs, or to those with unacceptable G.I. complaints or at high risk for ulcers or bleeding, Vioxx would have been a good alternative. If the properly designed studies had been carried out, and we had been given full and prompt access to the data, we could have made our own smart choices. It's a tragedy that Vioxx led to fatal heart attacks and strokes. And it's a sad irony that those who were clearly benefiting from the drug no longer find it available to them.