Joel Lexchin: Bringing Vioxx back to life

In movie lore, zombies are people who have come back to life to reek havoc and kill innocent people. Now there is a proposal to bring Vioxx (rofecoxib) back to life. The question is whether a resurrected Vioxx will behave like a typical zombie or can it actually help people?

As a bit of background, Vioxx was launched in 1999 by Merck as a super aspirin, an anti-inflammatory that would provide pain relief for people with arthritis without causing the gastrointestinal complications that are common from older anti-inflammatories. However, what Merck knew even before Vioxx was approved, was that its properties that helped protect against GI bleeding also made it more prone to cause cardiac complications. When Vioxx was finally pulled worldwide from the market in November 2004, David Graham, Associate Director for Science at the FDA’s Office of Drug Safety, estimated that it had led to 88000–140000 excess cases of serious coronary heart disease in the United States in its 5 years of sales.

The history of drugs being brought back to life is mixed. Perhaps the posterchild for infamous drugs is thalidomide, a product sold in the late 1950s and early 1960s and widely used by pregnant women for morning sickness. Thalidomide was responsible for thousands of babies born with severe malformations and triggered fundamental changes in the way that drugs are regulated all over the world. However, despite this history, thalidomide was reintroduced onto the US market in 2000, initially to treat erythema nodosum leprosum and later other diseases such as multiple myeloma because it offered genuine therapeutic advantages in these situations.

On-the-other hand, the re-emergence of alosetron (Lotronex) for the treatment of irritable bowel syndrome is much more controversial. Alosetron only had “modest” benefits according to the Food and Drug Administration (FDA), but a small minority of patients experienced serious adverse events include severe complications of constipation, ischaemic colitis, hospitalization, surgery, and death and because of this negative benefit to harm ratio was taken off the market. Just over 18 months later, the FDA voted to re-approve alosetron, in part because of lobbying by patient groups, some but not all of which, were receiving funding from GlaxoWellcome, now GlaxoSmithKline, the maker of the drug. Dr. Paul Stolley, who was involved with the initial decision to remove alosetron, charges that its resurrection was the result of industry funding of a substantial portion of the operating costs of the FDA.

Tremeau Pharmaceuticals, the company that wants to start reselling Vioxx, believes that it should be available to treat severe joint pain caused by bleeding in patients with haemophilia. The company claims that it would fill “a huge unmet medical need.” But the published evidence that Vioxx is uniquely effective for this condition is currently weak. There is only a single trial listed on PubMed, a retrospective case series of 28 patients without any control group. If Vioxx is reintroduced to treat this condition, Tremeau would not be able to advertise it for other medical problems but that wouldn’t prohibit doctors in the US from prescribing it for other indications. And that’s a concern.

Accutane (isotretinoin) is highly effective for severe acne but about one in four foetuses exposed to the drug develop severe birth defects. As a result, both the company marketing the product and the EMA (and other regulators such as the FDA) have tried to ensure that physicians and patients are well aware of the risks and that women are using effective contraception. Despite these precautions, in The Netherlands, 45 per 10 000 pregnant women were exposed to isotretinoin during their pregnancy. If this exposure happens despite a long-standing and well publicized program, how sure can we be that a similar program for Vioxx will prevent people at risk of heart disease from getting the drug?

The proposal to revive Vioxx also raises broader issues. Should patients have the right to take risky drugs if they sign a form acknowledging that they are aware of the potential harms? This question crosses over into the area of the “right to try”, which is being championed by various groups. The argument here is that patients who are seriously or terminally ill should have the right to take medications that are still in the experimental stage. Those old enough may remember the controversy in the mid to late 1970s around Laetrile (amygdalin) a purported cancer therapy derived from apricot pits. There was never any evidence that it worked, it was linked to cyanide poisoning and the FDA never approved it. But at one point it was being used by 50,000 to 70,000 Americans, it was legalised by 17 US state legislatures and it was backed by not only a variety of alternative therapy groups, but also by some officials of the National Cancer Center and the Sloan-Kettering Institute. More recently, in the 1990s, there was the use of high-dose chemotherapy with autologous bone marrow transplant for women with breast cancer; a treatment that was fueled by patients’ demands for it and administered to over 41,000 women. Ultimately, a series of randomized trials showed no benefits from this toxic therapy. AIDS groups, that pushed in the 1980s for quick access to medications, later realized that rushing poorly tested drugs to market was bad policy and one activist remarked “We don’t just need drugs, we need information.”

Based on this history, resurrecting Vioxx based on extremely limited evidence is not worth the risk of potentially exposing patients to serious harm. Vioxx is one zombie that should stay dead.

Joel Lexchin is a Professor Emeritus in the School of Health Policy and Management at York University and works as an emergency physician at the University Health Network in Toronto.