The National Institutes of Health (NIH) announced 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."
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
Pfizer Inc said it received new information about the cardiovascular safety of its COX-2 inhibitor Celebrex (celecoxib) based on an analysis of two long-term cancer trials.
As reported to Pfizer by the Data Safety and Monitoring Board, one of the studies (the APC cancer trial) demonstrated an increased cardiovascular risk over placebo, while the other trial (the PreSAP cancer trial) revealed no greater cardiovascular risk than placebo.
"These clinical trial results are new. The cardiovascular findings in one of the studies (APC) are unexpected and not consistent with the reported findings in the second study (PreSAP). Pfizer is taking immediate steps to fully understand the results and rapidly communicate new information to regulators, physicians and patients around the world," said Hank McKinnell, Pfizer chairman and chief executive officer.
Celebrex is approved for use in the United States for the treatment of arthritis and pain, at recommended doses of 100mg to 200mg daily for osteoarthritis and 200mg to 400mg a day for rheumatoid arthritis. It is also approved for a rare condition called familial adenomatous polyposis in doses up to 800mg per day. The APC cancer trial was studied Celebrex at doses of 400mg to 800mg per day. In the PreSAP cancer trial the dose was 400mg per day.
"In placing this new information in context, it is important to understand that the APC trial results differ from both the PreSAP cardiovascular results as well as the large body of data that we and others have accumulated over time, in which an increased risk of serious cardiovascular events in arthritis patients, even at higher-than-recommended doses, had not been seen," said Dr. Joseph Feczko, president of worldwide development for Pfizer.
"Celebrex is an important medicine that provides necessary pain relief to many patient. Patients being treated with Celebrex should discuss appropriate treatment options with their healthcare professionals. Physicians should factor this new information, as well as ulcer risks and gastrointestinal bleeding seen with traditional NSAIDs, into their prescribing decision."
In the Adenoma Prevention with Celecoxib (APC) trial, patients taking 400mg and 800mg of Celebrex daily had an approximately 2.5 fold increase in their risk of experiencing a major fatal or non-fatal cardiovascular event compared to those patients taking placebo, according to the National Cancer Institute (NCI). Based on these statistically significant findings, the sponsor of the trial, the NCI, has suspended the dosing of Celebrex in the study.
In a separate long-term study, the Prevention of Spontaneous Adenomatopus Polyps (PreSAP) trial, there has been no increased risk for Celebrex patients taking 400mg daily compared with those taking placebo. These findings are based on an identical analysis used to assess cardiovascular risk in the APC trial and conducted by the same independent safety review board. The information from this Pfizer sponsored trial was also received by Pfizer last night and, as with the APC information, was immediately shared by the company with the U.S. Food and Drug Administration.
The two studies, which are following patients over a five-year period, have enrolled a total of about 3,600 patients, some of whom have participated for more than four years. Pfizer estimates that about 2,400 patients evaluated in the cardiovascular analysis have completed two years of treatment.
A third long-term study involving Celebrex in patients at high-risk for Alzheimer's disease is also under way with about 2,000 patients enrolled, about 750 of whom are on 400mg per day of Celebrex. As with the cancer studies, this study is monitored by independent safety experts who meet regularly to assess adverse events. A review by this board as recent as December 10 did not result in any recommendations to change the conduct of this study.
In September and October, the Data Safety and Monitoring Boards of the APC and PreSAP cancer trials conducted a preliminary review of all the then- available data and determined to proceed with the studies. With the cooperation of Pfizer, the safety review boards convened a panel of cardiovascular experts to conduct additional reviews and analyses of the data from these two trials. Last evening, Pfizer received preliminary information resulting from the reviews. The company has not yet received the full analyses of these studies.
As previously announced, Pfizer will continue to work with FDA on the company's plans to sponsor a major clinical study to further assess Celebrex in osteoarthritis patients at high-risk for cardiovascular disease.
Consumer attorney Guerry R. Thornton, Jr., an Atlanta lawyer who handles Vioxx cases, favors new regulatory reforms in the wake of news about heart attack risks with Celebrex, Pfizer's blockbuster drug.
"The pace of drug safety issues raises more concern about the effectiveness of the FDA," he says. "When drugs show health risks after they are approved, consumers are correct to ask: Are we being used as guinea pigs to serve the profit motive of the pharmaceutical industry?"
Thornton will be lobbying Washington for new drug approval laws. He thinks the system places to much emphasis on perceived benefits and not enough on the risks. "Like Vioxx, maybe the Celebrex review should have found that heart risks outweighed its benefits. The FDA relies on drug company data, and this needs to change," says Thornton.
The risk of heart attacks has long been a concern related to Cox-2 inhibitors like Celebrex and Vioxx. "The trial bar acted quickly in the Vioxx controversy and should use its influence to help bring about reform," says Thornton. "Certain senators favor protection for FDA approved drugs. Such laws should not provide a safe haven for negligent drug companies."
Pfizer announced findings that indicate a 2.5% increased risk of heart attacks in Celebrex users. In 2004, 19.8 million prescriptions were filled for Celebrex. Pfizer's sales have reached over $2 billion per year.