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Figuring the Benefits and Risks of Drug Therapy
Lessons from the Vioxx Withdrawal

Michael Weber, M.D.
November 5, 2004

A large number of people have arthritis and other serious aches and pains and so there is a strong interest in developing more effective ways of treating these conditions. The most widely used types of pain killers have been aspirin-like drugs called non-steroidal anti-inflammatory agents that are available under a variety of brand names at drug stores and supermarkets. But these treatments can have a serious drawback: in susceptible people they cause irritation and even more severe damage to the linings of the stomach and small bowel, leading to problems like ulcers and bleeding that can sometimes require major surgery and on occasion even prove fatal.

For this reason, five years ago physicians and their patients were excited when a new class of drugs called selective COX 2 inhibitors came to the market. These newer drugs, usually referred to as the coxibs, effectively reduced pain and inflammation without affecting the COX 1 system that is responsible for protecting the lining of the gastrointestinal system. In clinical trials they were shown to have pain benefits similar to those of the older drugs but to have the advantage of being significantly less likely to cause ulcers or other serious complications.

This would have been a great tale of medical progress if it hadn't been for the chance finding that Vioxx, one of the two coxibs initially released, was linked to a higher rate of myocardial infarctions (the technical term for heart attacks) when compared with one of the older aspirin-like drugs called naproxen during a large study that had been designed primarily to confirm the safety of these drugs in the gastrointestinal system.

This surprising discovery lead to some obvious questions. Since a similar study involving Vioxx's competitor, Celebrex, did not show evidence for an increase in heart attacks, could the Vioxx discovery simply be a matter of chance? And, even if it were true, how could it be explained? The manufacturer of Vioxx, Merck & Company, not unreasonably argued that Vioxx was not responsible for increasing the probability of heart attacks, but rather that the comparison drug naproxen - somewhat akin to the well-known actions of aspirin - might have important protective effects against heart attacks and strokes.

At the time of that controversy, I recall that I served as an occasional advisor to Pharmacia, then the manufacturer of Celebrex, who saw a possible competitive advantage in the allegations regarding Vioxx's safety. At that time, I felt that Merck's argument might be plausible and I recommended that Pharmacia be cautious in pursuing this marketing approach. But in the end, despite some later evidence that naproxen may in fact be superior to other drugs of its type in preventing heart attacks, the evidence regarding the potential dangers with Vioxx - when used in relatively high doses - continued to slowly accumulate.

Observations of outcomes in large numbers of patients being treated by one of the large health maintenance organizations or who were being covered by one of the Medicaid plans also seemed to indicate increased heart attacks and strokes with Vioxx. And though such retrospective findings can be biased and misleading - as Merck, again not unreasonably, pointed out - the questions continued to grow. The Food and Drug Administration also expressed concern, making it clear that they did not buy into Merck's defense of Vioxx and even pointing out hypothetical reasons for why an agent like Vioxx could increase the likelihood of the blood clots that are associated with heart attacks. Indeed, in 2002 the official labeling for Vioxx was changed to include a warning about the dangers of increased cardiovascular events.

The final blow came very recently in a study designed to test whether Vioxx might have the ability to prevent a certain type of bowel polyp. What made this experience more definitive was that Vioxx was compared with a placebo, so that it was no longer possible to claim that differences in heart attack rates - as was the case in the earlier comparison with naproxen - could be explained by heart-protective properties of the other drug. Now, Vioxx was found to double the incidence of myocardial infarctions; and even though the actual number of events was relatively small, and there was no evidence for an increase in death rates, the results could no longer be denied. Merck rapidly withdrew their product from the market.

This experience with Vioxx highlights a dilemma that not infrequently confronts clinicians. How can we know whether the benefits of a drug clearly outweigh its risks? The first issue is one of quantifying. In the case of Vioxx, we can probably make reasonable estimates of how many lives could be saved and how many major surgeries or hospitalizations avoided by the gastrointestinal benefits of this drug. And, at the same time, we might be able to make an estimate, from the risk point of view, of how many excess heart attacks or strokes might be inadvertently produced. But even if we could come up with reasonable calculations, how could we equate major gastrointestinal events against major cardiovascular events and decide, overall, whether this treatment is beneficial or harmful? Ironically, just a matter of days before the precipitous withdrawal of Vioxx, a commentary in Lancet by Dr. Eric Topol, prompted by the publication of data on a new coxib, continued to question the wide use of this drug class despite uncertainty regarding its relative benefits and risks.

Another good example of this problem, again pertaining to a product withdrawn from the market by its manufacturer, was with the diabetes drug, troglitazone. This drug was effective in treating type 2 diabetes, a very common condition in the United States that increases risks, among other things, of heart disease, strokes and kidney failure. But troglitazone, despite its clear value in treating diabetes, at times had toxic effects on the liver, which in some cases were fatal. But clinical experts, seeing the value of troglitazone in treating diabetes, argued that this drug - provided, of course, that physicians carefully monitored liver tests in their patients - should continue to be available. Again, there was the difficult issue of comparing one set of estimated benefits with a totally different set of estimated adverse outcomes.

Trying to put numbers on benefits and risks is an imprecise and difficult art that depends partly on known facts, but also to a large extent on assumptions and speculations. Even so, it is an exercise worth undertaking. Certainly data on a drug's benefit risk ratio would help clinicians make decisions - on a patient by patient basis - about whether the supposed benefits of a drug outweigh its dangers. It might be very valuable for the Food and Drug Administration, when evaluating new products, to require that experts make their best efforts to provide quantitative benefit and risk estimates - however approximate they might be - that could be useful in describing drugs and guiding their use.

The experiences with Vioxx and troglitazone help underscore another issue, in particular the advantages of having more than one drug in a class. In fact, in withdrawing Vioxx, Merck made the point that since other drugs of its type were now on the market they could remove their own product without depriving patients of an acceptable alternative. Likewise, it became feasible to withdraw troglitazone from the market once newer competitors, which were less likely to have liver problems, became available. There are other strong clinical and scientific reasons for encouraging the availability of choices within drug classes, but certainly those people who argue against so-called me-too drugs because of what they regard as the high costs of developing new products should be aware of just how important it can be to have apparently similar, but at the same time clearly different, agents available.

The safety of drugs is a legitimate concern not just for physicians and patients, but also for the pharmaceutical industry and obviously the Food and Drug Administration. One of the reasons commonly given for the relative slow process of drug approval is that the Food and Drug Administration is so meticulous in studying safety issues and ensuring that clinical trial experience provides reasonable confidence that a newly available drug can be considered acceptably safe. Obviously, the Vioxx story reminds us that the process of safety evaluation doesn't end with a drug's approval for marketing, but might have to be continued for as long as the drug is used.

Even so, what is troublesome about the Vioxx story is that over 20 million patients were exposed to this drug, generating literally millions of years of patient exposure. Despite this extraordinarily large experience, in the end it was the unexpected findings of a relatively small trial - not even based on the types of patients who typically take Vioxx - that finally drew attention to the specific safety issue. In a commentary in the New England Journal of Medicine, Dr. Garret FitzGerald argued that even small scale studies of underlying mechanisms of drug action could have anticipated the clinical problems and brought the issue of Vioxx's safety to a head far sooner. As an expert in the field, Dr. Fitzgerald makes a fair point, but drugs can cause problems in such unexpected areas that it is often difficult to know where to start looking.

Solutions to this difficult problem of drug safety have included the creation of registries where all, or at least a substantial number, of patients exposed to a product are followed systematically by clinicians for a prolonged period of time (after the drug has been marketed) to ensure that any untoward effects - even those that might not have been anticipated based on previous knowledge of the drug - can potentially be identified.

Another useful approach might be practice-based studies in which large numbers of prescribing physicians enroll patients into relatively simple clinical trial protocols. This type of approach not only helps to familiarize relevant members of the physician community with a drug that they are likely to be using, but also provides information on what actually might be happening in the practice setting rather than in the somewhat atypical academic environment in which most clinical trials traditionally have been carried out. Certainly, getting a large number of interested and experienced doctors - with the knowledge and input of the patients they are treating - to systematically build a large base of experience creates a practical and powerful way of expanding our knowledge of both the benefits and risks of treatments.

This whole issue surrounding Vioxx, however, will help solidify the FDA's agenda for the foreseeable future. High on the list of ideas to be considered are methods for better measuring the benefits and risks of therapies - albeit an imprecise science - so that physicians and patients can make more informed therapeutic choices. Secondly, the FDA must maintain its willingness to actively consider newer or later generation drugs in the same classes as drugs already approved: Vioxx may be an important example of how competitive products can be essential in providing alternative treatment choices. And more thought must be given to post-marketing surveillance of drug safety. It now seems appropriate that some form of active monitoring, rather than the passive spontaneous reporting on which we have traditionally depended, should be required throughout the life of new drugs.

Michael Weber, MD, is professor of medicine and Associate Dean for Research, at the State University of New York, Downstate College of Medicine. He has published numerous research articles in the medical literature and has authored and edited ten books. Together with Dr. Suzanne Oparil, he is responsible for the widely used reference volume Hypertension. He was one of the founders of the American Society of Hypertension and has also served as its president. He is currently chair of the Society's Hypertension Specialists Program. He is also a Fellow of the American College of Physicians, the American College of Cardiology, and the American Heart Association.

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