A prescription drug comes with a lot of fine print, including the undesirable side effects it may cause. That information is based on problems the drug, or ones much like it, did cause in clinical trials. Warnings must be included in direct-to-consumer marketing, which is why TV commercials that praise a drug sometimes seem to undermine themselves by tacking on the downsides; and magazine ads that sing a drug's prasies also carry a daunting biography of it—on the reverse side of the page. But the consumer rarely scrutinizes the drug's dangers. Instead, we trust doctors to weigh the benefit/harm tradeoff for us, even though drug companies market to them feverishly.
We got a reminder recently that taking prescription drugs is risky, not just becuase they are potent physiological interlopers, but also because of how they are tested and marketed. And while the FDA has standards and procedures to establish the safety of the drugs, the system isn't perfect. Even if it were, it's not possible to know everything that might happen over the long haul. The case of a group of painkillers known as cox-2 inhibitors—Vioxx, Celebrex and Bextra—is a reminder of that. In the past couple of months they have, in a small percentage of cases, been killing people instead of pain.
In September of last year, Vioxx was withdrawn from the market and from all ongoing studies by its maker, Merck, because of accumulating evidence that it was causing heart attacks and strokes, some of them fatal. In December, Celebrex, from Pfizer, was removed from a clinical trial (and since then, from a few more) because of increased heart attacks, but it is still on the market; Pfizer stopped advertising Celebrex directly to consumers in December as well. The third cox-2 inhibitor, Bextra, also from Pfizer, is also still available but under scrutiny as well.
Celebrex is still being taken by thousands of people in nearly 70 clinical trials, according to the NIH's online database (www.clinicaltrials.gov). Most of the studies are testing it as a cancer preventative among healthy people or an adjunctive treatment for people already being treated for cancer, because the drug reduced precancerous colon polyps in a study conducted late in the 1990s. Though some Celebrex studies have been suspended, patients with end-stage or recalcitrant cancer have little to lose by staying on the drug. (The single listed study using Bextra for treatment of cancer pain has been completed.)
Vioxx, Celebrex, and Bextra are newcomers to a diverse group of pain-relieving drugs called NSAIDs—nonsteroidal anti-inflammatory drugs. They are unique in their ability to specifically inhibit cyclooxygenase-2 (cox-2), an enzyme central to the body's production of prostaglandins, prostacyclins, and thromboxanes. Those chemicals have multiple and complex actions within the body, but notable among them is causing contraction of muscle in many internal organs. For example, prostaglandins cause the contraction of the uterus during labor (and menstruation). They also regulate constriction of muscle within blood vessels, thereby influencing blood flow and blood pressure. Another action of these chemicals is increasing the fluid that accumulates in injured tissue, leading to swelling and pain.
Many common over-the-counter painkillers—aspirin, indomethacin (Indocin), ibuprofen (Motrin), naproxen (Aleve)—are also NSAIDs, and they also inhibit the cox-2 enzyme. But they additionally block cox-1, a related enzyme with both overlapping and unique functions compared to cox-2. About 15 percent of people who take these NSAIDs over a long period, as they would to treat chronic pain, develop bleeding ulcers. Overall, an estimated 10 to 50 percent of people (depending on the study) can't tolerate these drugs because of upset stomach or other gastrointestinal (GI) reactions like diarrhea, bloating, heartburn, or abdominal pain. And even though fewer than five percent of people have life-threatening complications while taking NSAIDs, the less serious side effects are enough of a problem to open a niche for drugs lacking that drawback.
Enter Vioxx, Celebrex, and Bextra. Early studies convinced the FDA they caused fewer GI problems, presumably because at normal dosages they don't tamper with the cox-1 enzyme and its regulation of prostaglandin synthesis in the GI tract. (There, prostaglandins stimulate production of a mucus layer that protects against the stomach's acidity. Without it, ulcers and fatal bleeding can result.) Still, each of the cox-2 inhibitors carries a warning about the possibility of GI irritation, as do the other NSAIDs. In fact, the original claim of being kinder to the GI tract is falling into question as data from ongoing trials is evaluated and old data is reevaluated.
Each of the drugs cleared the FDA's multi-year hurdles, first showing promise in the laboratory with cells and animals, then proving safe for healthy people in clinical trials, and finally showing a power over pain and continued safety in people with medical conditions. When each drug's maker had accrued a sufficient portfolio of studies, involving thousands of people, application was made to the FDA. Celebrex was approved in 1998, Vioxx in 1999, and Bextra in 2001.
Their main use has been easing pain of osteoarthritis (age-related joint damage) and rheumatoid arthritis (an immune-system malfunction that injures joint tissue), and for short-term pain like headache and severe menstrual cramps. Doctors may also prescribe them "off-label," meaning things for which the FDA hadn't originally approved them, like cancer pain or fibromyalgia.
At the time of its withdrawal, Vioxx was being sold in 80 countries and generated $2.5 billion annually, with an estimated 20 million prescriptions filled in the US each year alone—a testament to the need and its blockbuster marketing. Merck's stock immediately plummeted at the news, creating a jump-off-the-cliff visual in its share price graph that rose slowly back to about two-thirds its value by early 2005. (Pfizer's stock value rose slightly as Merck's fell, but it has been on a relentless downward slope since.) The litigation factor is staggering, with Wall Street experts guessing that settlement costs for Merck will be in the tens of billions. TV commercials invite people to qualify for a case; even an online medical dictionary's listing of "Vioxx" opens with four links to trial lawyers looking for clients.
That such a stellar product could meet this fate couldn't be foreseen by doctors, whom we seek out as experts about drugs. Certainly Merck didn't know it would get this bad. There were signals along the way, but at what point do signals merit withdrawal?
The clinical data Merck submitted to the FDA to get the drug approved had used low doses for over a year or the highest dose (50 mg) for six months without any hint of cardiovascular problems. The FDA's drug approval team scrutinized it, knowing that early laboratory studies of Vioxx showed an enhancement of blood clotting. After the drug was approved, the first real warning signs came from a clinical trial called "Vioxx Gastrointestinal Outcomes Research" (VIGOR), which treated 8,000 patients with rheumatoid arthritis with either Vioxx or naproxen (Aleve). In 2002 the study investigators reported increased rates of myocardial infarction (heart attack) among patients on a high dose (50 mg) of Vioxx—an incidence of 0.5 percent compared to 0.1 percent among patients given naproxen. That incidence rate sounds tiny, but when multiplied by millions of people in the general population, could mean thousands of heart attacks.
The FDA slapped a precaution on Vioxx's labeling because of that, explained Dr. Sandra Kweder, Deputy Director of the Office of New Drugs at the FDA, in a statement before the US Senate's Committee on Finance in November of 2004. "FDA approved extensive labeling changes to reflect the findings from the VIGOR study. The new label provided additional information...to reflect all that was known at the time about the potential risk of cardiovascular effects with Vioxx. The new labeling change also noted that Vioxx 50 mg was not recommended for chronic use."
That is how the process is meant to work—new warnings added as new information accrues. The FDA also had Dr. David Graham, Associate Director for Science in its Office of Drug Safety, lead a team, in collaboration with healthcare provider Kaiser Permanente in California, to thoroughly review data from all existing cox-2 inhibitor studies, specifically looking for cardiovascular side effects.
Meanwhile, a nail in Vioxx's coffin appeared in the form of a multi-year clinical trial begun in 2001 called "Adematous Polyp Prevention on Vioxx" (APPROVe), which sought to affirm the manufacturer's hope of discovering a cancer prevention application for the drug. But 36 months into the study, a significant increase in heart attack and stroke was discovered by the study's independent safety board (a review strategy built into all clinical trials). On September 30 Merck announced its removal of the drug from all studies and from pharmacy shelves. In retrospect, data had given a hint of cardiovascular problems at 18 months, but not clearly enough to warrant shutting down the study.
"This was the first demonstration of a difference in comparison to a placebo group and supported the previous signal seen in the VIGOR trial and some of the epidemiological studies," Dr. Kweder explained in her November statement. The drug had never before been compared to a placebo (an inactive stand-in for the actual drug) in a large study because until then studies had been testing its ability to relieve serious pain, and giving a placebo to some participants would have been unethical. In other trials before APPROVe, comparison of Vioxx with Celebrex or another NSAID may have masked the magnitude (small though it is) of Vioxx's risks in particular.
The same day as Merck's withdrawal of Vioxx, Dr. Graham presented his team's findings in an internal FDA report: there was an unquestionable risk of heart attack or stroke with Vioxx. The report threw in some other wrenches. Celebrex was safer, and by the report's calculations, close to 28,000 heart attacks, some of them fatal, could likely have been avoided between 1999 and 2003 if people had been taking Celebrex instead of Vioxx. Further, Vioxx was as harsh on the GI tract as anything to which it had been compared, especially at high dose. And, no data was found to support Merck's suggestion that Vioxx's higher heart attack rate in the VIGOR study, compared to naproxen, was not necessarily their drug's fault. Instead, they claimed, naproxen could actually be protecting people's hearts, making Vioxx look bad. (A study was halted in December because of 50 percent more heart attacks or strokes among recipients of naproxen compared to Celebrex or a placebo.)
Dr. Graham had earlier presented these findings at two conferences, but acquiesced to a request by his superiors at FDA to omit the strong warning in the report's concluding statements about Vioxx (rofecoxib): "High-dose use of the drug should be ended and lower-dose rofecoxib should not be used by physicians or patients. If lower-dose rofecoxib remained on the market, physicians and patients needed to understand that risk of AMI [acute myocardial infarction, heart attack] and SCD [sudden cardiac death] were substantially increased and that there were safer alternatives." The FDA has agreed to let Graham publish the report's full findings in the British medical journal, Lancet, later this year.
As for Celebrex, the Adenoma Prevention with Celebrex (APC) trial, terminated in December for excess fatal and nonfatal cardiovascular events, succumbed because of more careful data analysis by the study's independent review board. NIH Director Elias Aerhouni said in a press release that "data from the report on rofcoxib (Vioxx) informed us of the need to focus on specific cardiovascular issues, and our Institutes brought in the experts to do so."
Contrary to the insistence of an action movie that people can be smashed and slammed and shot and hardly notice, in the real world even small injuries can send us to the medicine cabinet for pain relief, and chronic pain is several orders of magnitude more daunting. Unmitigated pain not only lengthens healing time of serious injuries or surgery, but can lead to depression, poor sleep and appetite, and social withdrawal.
The cox-2 inhibitors were a nice addition to the painkiller palette. Their fate is not certain, but the FDA and NIH are telling patients to "consult a doctor" about whether to take the ones still on the market. Yet most doctors are in the dark about the nitty-gritty of drug trial data as much as we are. And while the FDA has created a new Safety Initiative to improve its and the medical community's awareness of drug study data, the cox-2 story is a reminder: pharmaceuticals can be a godsend, but no one can promise they will do no harm.