On December 17, the National Institutes of Health (NIH) announced that it suspended the use of the COX-2 inhibitor celecoxib (Celebrex) for all participants in a large colorectal cancer prevention clinical trial conducted by the National Cancer Institute (NCI). The study - the Adenoma Prevention with Celecoxib (APC) trial - was stopped because analysis by an independent Data Safety and Monitoring Board showed a 2.5-fold increased risk of major fatal and nonfatal cardiovascular events for participants taking the drug compared with those on a placebo.

Additional cardiovascular expertise was added to the safety monitoring committee at the request of the steering committee for this trial after a September 2004 report that the COX-2 inhibitor rofecoxib (Vioxx) caused a two-fold increased risk of cardiovascular toxicities in a trial to prevent adenomas. The APC trial is a study of more than 2,000 people who have had a precancerous growth (adenomatous polyp) removed. They were randomized to take either 200 mg of celecoxib twice a day, 400 mg of celecoxib twice a day, or a placebo for 3 years. The trial began in early 2000 and is scheduled to be completed by spring 2005.

Investigators at the 100 sites in the APC trial located primarily in the United States, with a few sites in the United Kingdom, Australia, and Canada, have been instructed to immediately suspend study drug use for all participants in the trial, although the participants will remain under observation for the planned remainder of the study.

"Data from the report on rofecoxib informed us of the need to focus on specific cardiovascular issues, and our institutes brought in the experts to do so," said NIH Director Dr. Elias A. Zerhouni. "Our overwhelming commitment is to advance the health and to protect the safety of participants in clinical trials. We are examining the use of these agents in all NIH-sponsored clinical studies. In addition, we are working closely with our colleagues at FDA to ensure that the public has the information they need to make informed decisions about the use of this class of drug."

"The rigor of our clinical trials system has allowed us to find this problem," said NCI Director Dr. Andrew C. von Eschenbach. "We have a strong system that provides us with the opportunity to both find ways to effectively treat and prevent disease and to do so in a way that protects the lives and safety of the participants."

NIH sponsors more than 40 studies using celecoxib for the prevention and treatment of cancer, dementia, and other diseases. In light of these new findings, Dr. Zerhouni requested:

• A full review of all NIH-supported studies involving this class of drug
• That all NIH institutes inform the principal investigators for all of these studies, asking the PIs, in turn, to communicate directly with their study participants and explain the risks and benefits
• That NIH asks each investigator to inform NIH of their plan to analyze their data in light of the information
• That the Institutional Review Boards for all related trials assess the new information and conduct a safety review

Questions and answers about the APC trial are available at: http://www.nih.gov/news/pr/dec2004/od-17Q&A.htm. More information about regulation of COX-2 inhibitors is available from the FDA at http://www.fda.gov/cder/drug/default.htm.

By Jo-Ann Kriebel