Worldwide Withdrawal of Vioxx Prompts FDA to Strengthen Drug Safety

After the drug Vioxx, an anti-inflammatory and pain reliever, was voluntarily pulled from the world market in late September 2004, the U.S. Food and Drug Administration (FDA) has been scrutinized for its handling of the drug. Critics argue that the FDA was too lax in monitoring Vioxx despite mounting evidence linking the drug to cardiovascular problems such as blood clotting, strokes and heart attacks.

In November of 2004, the U.S. Senate Finance Committee conducted a hearing to consider allegations of mismanagement by the FDA and Vioxx manufacturer, Merck Co., Inc. (Merck) regarding the safety of Vioxx.

Vioxx Voluntarily Pulled from Worldwide Drug Market

Vioxx, a non-steroidal anti-inflammatory drug (NSAID) showed promise as an improved method of treating arthritis and acute pain without the gastrointestinal side effects associated with traditional NSAIDs such as ibuprofen or naproxen. However, on September 30, 2004, Merck announced that it was withdrawing its multibillion dollar drug from the world drug market. Vioxx had several times been linked to an increased risk of heart attacks, stroke or other cardiovascular (CV) events since being approved by the FDA and entering the U.S. drug market in 1999.

General Overview of FDA Approval of a Drug

In general, the FDA approves a drug to enter the U.S. market after the drug's sponsor sufficiently demonstrates that the drug is safe and effective through mandatory clinical trials. Since all modern drugs may contain potential risks in addition to their significant health benefits, the FDA maintains a policy of approving only those drugs whose demonstrated benefits outweigh any known risks.

However, it is clearly impossible to identify every potential risk during those trials, and occasionally, adverse effects are identified only after FDA approval. For that reason, the FDA has a post-market drug safety program that is designed to assess adverse events which are reported after the drug has been placed on the market. The FDA acknowledges that Vioxx is the most recent illustration of the importance of post-market drug safety.

FDA Under Scrutiny for its Handling of Vioxx

A history of clinical studies show that Vioxx had been linked to an increase in the risk of blood clots, heart attacks and strokes for almost three years before it was pulled from the market. The American Medical Association, National Stroke Association and Arthritis Foundation had asked Merck to test Vioxx specifically for such CV effects, but Merck declined. Although Merck has taken the majority of the blame for the current scandal, the FDA was also privy to the potential CV risks of Vioxx. Thus, the FDA is being scrutinized for its failure to react promptly to concerns regarding Vioxx.

Data from and Early Merck Study Indicated a Problem

Shortly after the FDA approved Vioxx in 1999, Merck conducted a study entitled "Vioxx Gastrointestinal Outcome Research" (VIGOR). VIGOR was designed to explore the clinically meaningful gastrointestinal (GI) effects of Vioxx versus naproxen. The results of VIGOR were submitted to the FDA in June 2000, and indicated that Vioxx was associated with fewer GI effects than naproxen.

However, VIGOR data showed an additional finding. There was a higher rate of CV events in patients taking Vioxx versus those taking naproxen. The FDA Arthritis Advisory Committee met to discuss the safety information in February 2001. However, the FDA did not affirmatively act until over one year later.

FDA Label Changes & Added Uses for Vioxx

In April 2002, the FDA changed Vioxx labeling to advise doctors to use caution when prescribing the drug for patients with heart disease. The FDA also changed the new label to note that Vioxx 50mg is not recommended for chronic use. At the same time, however, the FDA added rheumatoid arthritis to its list of approved uses of Vioxx.

Further Studies Continue to Link Vioxx to Heart Problems

Over the next two years, two studies, one conducted by a Vanderbilt University doctor and another conducted by Harvard Medical School, linked Vioxx to CV events. The Vanderbilt study showed more CV events occurring in Medicaid patients taking high doses of Vioxx (more than 25mg) than those who did not. The Harvard study found that Vioxx raised the risk of heart attack and hypertension relative to Celebrex, another NSAID drug and the second-best selling rival of Vioxx.

In addition, the FDA partially funded a study analyzing the records of Kaiser Permanente patients who had taken Vioxx. The conclusions of that study were labeled as those of the author and deemed not necessarily reflective of FDA policy. The author, Dr. David Graham, agreed to revise his conclusions, which showed heightened CV risk for Vioxx, and to submit a draft report for FDA review by September 30, 2004, the day Merck announced worldwide withdrawal.

Post-Withdrawal of Vioxx: FDA Announces a New Drug Policy

On September 30, 2004, the FDA issued a public health advisory on the drug. Then, on November 5, 2004, the FDA announced a five-step plan to strengthen its drug safety program. The Center for the Drug Evaluation and Research (CDER) of the FDA will:

1. Sponsor an Institute of Medicine study of FDA's drug safety system;
2. Implement a program for addressing differences of professional opinion;
3. Fill the currently vacant position of Director of the Office of Drug Safety;
4. Conduct workshops and Advisory Committee meetings to discuss drug safety/risk management issues; and
5. Publish final versions of three Risk Management Guidances to help pharmaceutical firms manage risks involving drugs and biological products.

On November 18, 2004, the U.S. Senate Finance Committee conducted a hearing to consider allegations of mismanagement by the FDA and Merck regarding the safety of Vioxx.

On April 7, 2005, Bextra, another NSAID drug, was pulled off the market at the request of the FDA and European regulators, due to the risk of serious and potentially fatal skin reactions to the drug, and the FDA announced that Celebrex and all other prescription NSAIDS must carry a black-box warning on the label that users face an increased risk of CV side effects. The FDA also asked manufacturers of non-prescription NSAIDS to revise their labels to clarify information about potential side effects, including CV effects, serious skin reactions and gastrointestinal bleeding.