The National Institutes of Health (NIH) announced today that it has suspended the use of COX-2 inhibitor celecoxib (Celebrex? Pfizer, Inc.) for all participants in a large colorectal cancer prevention clinical trial conducted by the National Cancer Institute (NCI).The study, called the Adenoma Prevention with Celecoxib (APC) trial, was stopped because analysis by an independent Data Safety and Monitoring Board (DSMB) showed a 2.5-fold increased risk of major fatal and non-fatal cardiovascular events for participants taking the drug compared to those on a placebo.
Additional cardiovascular expertise was added to the safety monitoring committees at the request of the Steering Committees 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 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 three years. The trial began in early 2000 and is scheduled to have been completed by Spring 2005.
Investigators at the 100 sites in the APC trial located primarily in the United States, with a few additional sites in the United Kingdom, Australia, and Canada, have been instructed to immediately suspend study drug use for all participants on the trial, although the participants will remain under observation for the planned remainder of the study.
"Data from the report on rofecoxib (Vioxx?) informed us of the need to focus on specific cardiovascular issues, and our Institutes brought in the experts to do so, said Elias A. Zerhouni, M.D., NIH Director. "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 Andrew C. von Eschenbach, M.D. "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."
However, another ongoing study looking at whether Celebrex can prevent colon cancer has not found any increased risk of heart attacks in patients taking the drug. This trial, the PreSAP trial, used the same heart measures and the same safety monitoring board as the APC trial.
"Pfizer is taking immediate steps to fully understand the [APC study] results and rapidly communicate new information to regulators, physicians, and patients around the world," Pfizer CEO Hank McKinnell says in a news release.
Because the two studies came up with opposite findings -- and because earlier studies showed no obvious sign of heart problems linked to Celebrex -- the FDA has not yet decided whether to ban Celebrex, to add additional warnings to the drug's label, or to wait for more information. But Acting FDA Commissioner Lester Crawford, MD, says the agency won't drag its feet.
"We will evaluate this information and may make statements very soon with regard to Cox-2 drugs in general and this product in specific," Crawford said today in a joint FDA/National Institutes of Health news conference.
NIH sponsors over 40 studies using celecoxib for the prevention and treatment of cancer, dementia and other diseases. In light of these new findings, NIH Director Zerhouni requested:
- a full review of all NIH-supported studies involving this class of drug.
- NIH Institutes to inform the principal investigators for all of these studies and will ask them to communicate directly with their study participants and explain the risks and benefits
- NIH to ask each investigator to inform us of the their plan to analyze their data in light of the information
- the Institutional Review Boards (IRBs) for all related trials to assess the new information and to conduct a safety review as well