New Cox-2 pain relievers are marketing marvel, not miracle drugs.

Pharmacia Corp. (recently acquired by Pfizer, Inc.) makes what was the 10th most frequently prescribed drug in the United States last year. It touts Celebrex as "a major advance in the treatment of the debilitating diseases osteoarthritis and rheumatoid arthritis, because of its efficacy and excellent gastrointestinal safety profile."

When Celebrex (celecoxib) and Vioxx (rofecoxib)--a new kind of pain medication known as Cox-2 inhibitors--were introduced in 1999, manufacturers and medicos alike hailed them as a kind of "super-aspirin" that lacked the stomach-shredding side effects of the older nonsteroidal anti-inflammatory drugs (NSAIDs). But many champions are leaving the arena as questions arise about the efficacy and safety of Cox-2 drugs.

Vioxx, manufactured by Merck & Co., "has a demonstrated risk that is underappreciated by its sponsor and benefits that are oversold to the public and physicians through an aggressive marketing campaign, while risks are purposefully hidden," said David Miceli of Montgomery, Alabama, who cochairs ATLA's Cox-2 Litigation Group. Merck "has profited tremendously from its bad acts."

Attorneys across the country are screening Vioxx and Celebrex cases--some seeking damages for plaintiffs' injuries or potential injuries, others hoping to hold the manufacturers accountable for overpromoting drugs that are far more expensive than older versions, but no better at relieving pain.

The drugs, approved to treat arthritis, menstrual pain, and "acute" pain in adults, have been heavily marketed to both doctors and consumers: Vioxx, which runs ads featuring former Olympic figure skater Dorothy Hamill, spent over $160 million on consumer advertising in 2000; Celebrex spent almost $80 million, according to AdWatch, the health policy arm of the Henry Kaiser Family Foundation. The campaigns are working: In 2001, Celebrex racked up $3.1 billion in sales worldwide, and Vioxx, the 13th most-prescribed drug in the United States, had worldwide sales of $2.6 billion.

Older NSAIDs--such as ibuprofen, naproxen, and diclofenac--work by inhibiting the two types of cyclooxygenase enzyme, one of which causes inflammation and thus pain. The Cox-1 enzyme, however, helps maintain the muscle surface of the gastrointestinal (GI) tract, so suppressing the enzyme can increase perforations, ulcers, and bleeding. Vioxx, Celebrex, and Bextra (valdecoxib, introduced by G.D. Searle & Co. in 2001) suppress only the second enzyme, leaving the first alone to protect the GI tract.

While Vioxx and Celebrex have been marketed as safer than traditional NSAIDs because of their stomach-protecting propensity, reports of serious side effects have begun to emerge. In June 2002, a research team led by A. Whelton noted in a presentation to the European United League Against Rheumatism an increase in hypertension and heart attacks among those taking Vioxx. The medical journal the Lancet published a study associating Vioxx with kidney failure, and other studies have associated both Vioxx and Celebrex with heart problems, kidney damage, aseptic meningitis, and slow healing of bone fractures.

Drug company studies

A metastudy by the Cleveland Clinic published in the Journal of the American Medical Association analyzed data from two major studies funded by the drug companies and two smaller ones--all for cardiovascular risks. (Debabrata Mukherjee et al., Risk of Cardiovascular Events Associated with Selective Cox-2 Inhibitors, 286 JAMA 954 (2001).) It found that neither Pharmacia/Pfizer nor Merck had identified and studied cardiovascular risks for their products. The annualized heart attack rates for patients taking Vioxx or Celebrex, the researchers found, were "significantly higher" than those in a group taking placebos. "The available data raise a cautionary flag about the risk of cardiovascular events with Cox-2 inhibitors," they concluded.

The Pharmacia-sponsored Celebrex Long-Acting Safety Study (CLASS), involving about 8,000 arthritis sufferers, compared that drug to the older NSAIDs ibuprofen and diclofenac to determine whether it was less harmful to the stomach. In a JAMA article in 2000, the researchers published data accumulated over six months and concluded that Celebrex caused fewer ulcers than the older drugs. (Fred E. Silverstein et al., Gastrointestinal Toxicity with Celecoxib vs. Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: The CLASS Study: A Randomized Controlled Trial, 284 JAMA 1247 (2000).) However, researchers at that point had 12 months of data that, when analyzed as a whole, showed no significant difference.

The FDA said the CLASS study "did not show a safety advantage in upper gastrointestinal events for Celebrex compared to either ibuprofen or diclofenac." Because some of the study participants were also taking aspirin, which does affect the stomach, some analysts say the results may have been skewed. The company maintained that among those not taking aspirin, the rate of ulcers was lower in Celebrex takers.

Pharmacia squawked, believing that "the conclusions drawn by the analysis in the JAMA article were flawed and unsound. It contains no new clinical information, and is based on an inappropriate re-analysis of several older clinical studies containing data that were not suitable for combination and comparison."

In a June 2002 editorial, the British Medical Journal said the Celebrex study misled consumers with "overoptimistic" data. It said the study was "seriously biased" because the complete results "clearly contradict[ed] the published conclusions" and showed a similar number of stomach complications in all patients, whether they took Celebrex or the older pain relievers.

Merck's Vioxx Gastrointestinal Outcomes Research Study (VIGOR) also involved about 8,000 participants and assessed only the drug's effects on the stomach; the company ordered no end-point analyses for effects on the cardiovascular system.

The study concluded that Vioxx takers had a lower rate of GI distress than those taking naproxen. The researchers noted, "the incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group," but found "the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups." They drew conclusions only about clinical upper gastrointestinal events, bleeding, and ulcers.

After the VIGOR results were released, the FDA said Merck had minimized the fourfold to fivefold increase in heart attacks among study participants taking Vioxx compared with those taking naproxen. It found the company's explanation--that Vioxx did not increase the risk of heart attacks, but instead, naproxen protected those taking it from heart attacks because the drug can thin the blood, like aspirin--unacceptable. In a September 2001 warning letter to Merck, the FDA wrote, "You fail to disclose that your explanation is hypothetical, has not been demonstrated by substantial evidence, and that there is another reasonable explanation: that Vioxx may have prothrombotic properties."

FDA actions

The FDA, which lists Vioxx and Celebrex information on the "Hot Topics" section of its Web site, required both drugs to carry the same stomach-upset and bleeding warnings ibuprofen and naproxen had when the agency approved them in 1999.

After the CLASS results, the FDA found that Celebrex is just as likely to cause ulcers as older NSAIDs and is no better at reducing pain or inflammation than ibuprofen. In June 2002, it mandated a new label for the drug, one without any claim that it is safer for the stomach than other NSAIDs.

The agency did allow Merck to change its Vioxx label to claim it has a lower risk than older NSAIDs of causing ulcers, gastrointestinal bleeding, and other digestive-tract complications.

As early as November 1999, an FDA memo stated that the board monitoring the VIGOR study was concerned about "excess deaths and cardiovascular events experienced in Group A [Vioxx group] compared to Group B [naproxen]." In March 2002, the FDA reported that five people taking Vioxx had aseptic meningitis, an inflammation of membranes on the brain and spine. In April 2002, after the agency warned Merck that it had misrepresented the drug's safety and minimized potentially serious cardiovascular complications found in VIGOR, it required the company to include a warning of cardiovascular risks on the Vioxx label.

Litigation

The companies continue their full-court-press marketing, but burgeoning litigation may put the brakes on. Almost two years ago, consumers began filing suits, and the number of potential actions is now in the thousands, said Shelly Sanford, a Houston attorney who cochairs ATLA's Cox-2 Litigation Group with Miceli.

Potential litigation includes personal injury suits in Texas and Louisiana, consumer class actions in Illinois and New York (alleging consumer fraud, RICO violations, negligence, and breach of warranty), a third-party payer class action in New Jersey, and a payer class action against Merck in New Jersey (involving breach of warranty, unjust enrichment, and violations of the state Consumer Fraud Act). Cases are also on file in California, Mississippi, and other states.

"The pressure put on doctors by the marketing was huge for Celebrex, which is not proven to be better for pain and not proven to be better for gastrointestinal risks compared to other NSAIDs," said Sanford. In addition, Vioxx "may increase the risk for cardiovascular events, and both Vioxx and Celebrex increase hypertension and edema."

Third parties and consumers paid significantly more for Vioxx and Celebrex than they would have for older NSAIDs, when the Cox-2 drugs were meant to be prescribed in limited cases involving patients with serious gastrointestinal risks. The drugs were prescribed for millions of people and cost at least seven times more than the older NSAIDs but were of no greater value for pain relief and caused cardiovascular risks, Sanford said.

John Xydakis, a plaintiff attorney in Clarendon Hills, Illinois, has filed a class action in Cook County, alleging Merck misrepresented claims on its Vioxx labeling and covered up adverse results of the VIGOR research. The plaintiff, who has not sustained any actual physical injuries, is suing for the "increased risk" of serious problems that may be caused by Vioxx. This theory is based on juries' assessment of increased risk in other types of cases.

While this may not be an acceptable cause of action in every state, Xydakis is convinced that Vioxx cases will result in federal multidistrict litigation because so many cases are pending in the district courts. Merck is currently trying to remove his class action to federal court, arguing that the plaintiff's recovery for the costs of medical monitoring is sure to exceed the jurisdiction's damages limit of $75,000. The company has stated in other court pleadings and documents that plaintiffs under these circumstances cannot claim nearly that amount in damages.

Managed care companies, pharmacy benefits managers, some doctors, and consumer groups support the plaintiffs' views.

"A seemingly magic bullet appears to have self-destructed," said Sidney Wolfe, director of the Public Citizen Health Research Group, in testimony before the FDA Arthritis Drugs Advisory Committee. He noted that the benefit of reducing GI distress "appear[s] to have been grossly exaggerated and oversold" and recommended keeping gastrointestinal warnings on both Vioxx and Celebrex. He said evidence that is "rapidly accumulating about the heart damage caused by these drugs" warrants a separate, boxed warning on labels.

Express Scripts, Inc., which manages pharmacy benefits for about 50 million insured Americans, has said that Vioxx, Celebrex, and Bextra are overpriced and overprescribed. It wants managed care entities to recommend that doctors prescribe traditional, cheaper NSAIDs first.