Sleight-of Hand: Merck Tried to Reformulate Vioxx in 2000 While Denying Risk

Merck aimed to re-formulate the arthritis drug Vioxx five years ago in order to reduce the potential for heart attacks, adding to previous evidence that the company was fully aware of the dangers of the drug well before it withdrew it from the market last year.

The revelation came as Merck and plaintiffs’ attorneys were gearing up for a trial in Texas, the first case over the liability of the drug to go to court.

Merck withdrew Vioxx from the market in September of last year after a clinical trial examining its potential effects in cancer patients showed that the drug significantly increased the risk of heart attacks and other heart-related problems.

But that clinical trial was hardly the first to show a link between Vioxx and cardiovascular problems. Clinical studies and company documents dating back to 2000 reveal the potential heart risks and company officials’ concern over them. Vioxx was approved for sale by the U.S. Food and Drug Administration in May 1999.

Now a document obtained by plaintiffs’ lawyers for Vioxx patients shows that Merck was, in fact, so worried about the potential for heart-related adverse effects that it sought to develop a safer formulation of the drug at about the same time it was reassuring doctors and physicians that Vioxx was indeed safe, in the wake of the large clinical study in 2000 revealing the heart-attack risk.

The document names former Merck research chief Edward Skolnick, saying he suggested combining Vioxx, which is theorized to lead to blood clotting that causes heart attacks, with another drug that could potentially prevent  blood clotting.

Vioxx is known as a COX-2 selective inhibitor because it blocks an enzyme in the body that causes pain but does not as completely     block an enzyme known as COX-1, as several older anti-inflammatory painkillers do. COX-1 protects the lining of the stomach, and the theory behind the development of Merck’s of Vioxx and Pfizer’s Celebrex was that the newer drugs would be easier on the stomach and cause fewer ulcers than older painkillers such as aspirin because they blocked less of the COX-1 enzyme.

But the intended stomach benefits barely came to fruition for Vioxx, which has only a moderately better effect on the stomach, and could not be proved at all for Celebrex or Bextra. Meanwhile, a much more serious problem, heart attacks, became suspected with Vioxx, and was confirmed by both Merck’s ‘VIGOR’ trial reported in 2000 and by independent analysis from researchers elsewhere. The VIGOR trial suggested a five-fold increase in the risk of a heart attack for patients on Vioxx compared with patients on an older painkiller, naproxen.

But Merck continued to maintain the drug was safe and, in fact, armed its sales force with a handy card to show to doctors. The “Cardiovascular Card” suggested that Vioxx might be eight times safer than other painkillers, according to Rep. Henry Waxman (D-Calif.), who helped conduct government hearings on the issue this spring. Meanwhile, the company ordered its sales reps never to discuss negative results related to Vioxx and heart attacks, Waxman writes in the New England Journal of Medicine.

In addition, the thousands of lawsuits filed against Merck after the drug was pulled from the market have brought to light a series of unflattering internal email exchanges, particularly involving Skolnick, that essentially admit to the company’s grave, but only private concern over the Vioxx heart attack problem.

Publicly, Skolnick and other officials maintained that Vioxx was safe, that the clinical trial results thus far had been inconclusive, and they suggested that naproxen—the drug against which Vioxx was compared in the Vigor study--may protect the heart, which would explain why fewer naproxen patients had heart attacks than Vioxx patients. Critics argued Merck was dragging its feet to conduct a clinical trial that definitively examined Vioxx’s heart-related issues and that the naproxen ‘cardioprotective effect’, for which there was no evidence, was a ruse to shift the blame away from Vioxx.

When it withdrew the drug last year, Merck asserted that as soon as it had received the results of the most recent study that showed an increase heart attack risk once-and-for-all, it made the decision to suspend sales of Vioxx. But the evidence had been mounting for years.

Now, the revelation of the much earlier possible plan to reformulate Vioxx shows that Merck may not have believed its own public statements and marketing messages. Indeed, if the company was giving serious consideration to the proposed mixture of Vioxx and a heart attack protecting   anti-inflammatory drug, such as aspirin, it clearly believed the Vioxx blood clotting effects were real and significant.

Merck said that as of March 31, it had been served with, or is aware of being named as a defendant in, about 2,300 lawsuits, which include about 4,600 plaintiff groups alleging personal injuries resulting from the use of Vioxx, and in about 225 putative class actions alleging personal injuries and/or economic loss.

Analysts have pegged Merck’s potential liability in the Vioxx matter at up to $20 billion, which would rank it with one of the worst product-liability disasters in drug history: the fen-phen diet drug recall that has plagued Wyeth (formerly American Home Products) to this day. However, Merck’s payout may be much lower, depending on the outcome of upcoming trials and the amounts of the company’s first group of settlements, analysts have said.

An advisory committee to the U.S. Food and Drug Administration in February narrowly voted to allow Vioxx back onto the U.S. market, with restrictions. The FDA usually takes the advice of is panels, but the Vioxx debacle has been so widely publicized, and the risks now seem so clear, that the decision to allow it to return to drugstores is certainly in doubt. The same panel also said Celebrex and Pfizer’s follow-on drug, Bextra, could remain on the market despite links to cardiovascular safety problems. However, in April the FDA asked Pfizer to remove Bextra from the market.