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Revisiting Vioxx: Monitoring Future Drugs Post Approval

SYNTHESIS of: Press Release, Penn Medicine News. “NSAIDs and Cardiovascular Risk Explained, According to Studies from the Perelman School of Medicine,” May 2, 2012; and “FDA Must Be Proactive About Postapproval Drug Safety: IOM,” May 3, 2012, Medscape


Nearly 10 years after Merck withdrew the COX-2 inhibitor Vioxx® (rofecoxib) from the market in 2004 because it increased the risk of heart problems when used for over one year, eight randomized trials conducted by researchers at the University of Pennsylvania Perelman School of Medicine confirmed the possible adverse side effects of COX-2 inhibitors like Vioxx®.
Initially, COX-2 inhibitors were viewed as a better alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs) like Advil because they are less likely to cause gastrointestinal bleeding.
Vioxx® selectively blocks COX-2, which produces prostaglandins (specifically prostocyclin) that cause pain and inflammation. However, prostocyclin also acts as an anticoagulant and relaxes blood vessels. In mice populations, removing COX-2 resulted in high blood pressure and blood clotting. An investigative team led by Penn’s Garret FitzGerald, MD, chair of the department of Pharmacology and Director for Translational Medicine and Therapeutics, had already noted that both Celebrex® (celecoxib) and Vioxx® inhibit prostocyclin in humans.
            Other COX-2 inhibitors such as Bextra® (valdecoxib), Arcoxia® (etoricoxib), and Celebrex® have either been removed from the market, failed to attain Federal Drug Administration (FDA) approval, or are accompanied by a warning label.
It is important to note that the risk of having a cardiac event after 18 months of taking Vioxx compared to subjects taking a placebo is 1.9%, or double the risk, still small by FDA standards. Merck identified the increased risk in its own post-market study but was not permitted to publicize them due to FDA labeling restrictions.
Penn’s recent research does include new findings that may have implications for patients without preexisting heart disease. In mice, inhibition of COX-2 led to hardening of the arteries. Based on this, researchers predict that the use of COX inhibitors in healthy subjects can raise the risk of events such as heart attack or stroke to that of diabetics or smokers. Patients with preexisting heart disease are still most at risk.
The Institute of Medicine (IOM), an independent, nonprofit organization, believes it knows how the FDA can take a proactive stance on potential adverse effects that may emerge during the post-approval stage. Most exploratory research is done before a product hits the market, not after. In an effort to resolve this dilemma, the IOM, in a report entitled “Ethical and Scientific Issues in Studying the Safety of Approved Drugs” (May 1, 2012), recommended that the FDA develop a system to track the safety of drugs after they have been approved. The guidelines come in the wake of several drugs that encountered problems after they had been approved for use, such as Vioxx®.
In 2007, the passage of the FDA Amendments Act (FDAAA) strengthened the FDA’s ability to track post-market drug safety. Before the Act was passed, the agency could only withdraw the product from the market or instruct the manufacturer to alter the label or add warnings. Now, a monitoring system designed to beef up the FDAAA has been created. Known as BRAMP (benefit and risk assessment and management plan), it will monitor benefits and risks during the entire “life cycle” of a drug.
The IOM highlights a key question: should research be conducted on subjects after the drug is already on the market in order to test the effects of the drug in specific sub-populations that may have different benefit-risk profiles than those in the initial clinical trials? The IOM advocates the same strict adherence to ethical guidelines that applies to post-market testing.
The million-dollar question left unanswered by the IOM is who will foot the bill for the additional monitoring and research: will it be Uncle Sam or the pharmaceutical industry?

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