CPI releases new concerns about Pfizer’s Celebrex study

(Drug Topics)The Center for Public Integrity (CPI) has called into question the ethics and necessity of the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen study (PRECISION), sponsored by Pfizer and run by Steven Nissen, MD, with the Cleveland Clinic. CPI asserts that the study puts patients at risk unnecessarily and that the FDA is partially responsible for the study even being able to commence, because the agency did not follow the recommendation of its own advisory panel in 2005. In 2005, the FDA called a three-day hearing to review the risks of three COX-2 inhibitors — celecoxib (Celebrex), rofecoxib (Vioxx), and valdexocib (Bextra). The previous September, pharmaceutical firm Merck had withdrawn rofecoxib voluntarily, shortly before evidence surfaced to suggest that the drug caused an estimated 39,000 and 60,000 deaths from heart attacks and strokes, respectively. The 2005 committee considered whether the other two COX-2s might also increase the risk of cardiovascular problems, including death, and whether any of the three COX-2s should be allowed on the market. The panel determined all three drugs increase the risk of cardiovascular problems. While the FDA’s committee agreed the COX-2s were potentially dangerous, the experts recommended the COX-2s be allowed to stay on the market if they carried a black box warning. The committee, while unanimously voting that celecoxib caused risk, voted 31 to 1 in favor of keeping the drug on the market for specially selected patients. But the FDA then issued a decision that CPI said appeared to ignore the conclusion of the panel. Just months later, after urging in a letter from Pfizer, FDA ordered black box warnings on all non-selective NSAIDs and the remaining COX-2s. “The effect was to make the non-selective NSAIDs seem as risky as the COX-2s,” the Center said, adding, “The FDA’s ruling sowed confusion among both doctors and patients about which painkillers are the safest.” Did this forge PRECISION? Nissen insists PRECISION is crucial to determining which of a trio of painkillers is safest. But some public health experts argue the trial is unethical, in part because human test subjects were not accurately informed of the risks, and in part because the trial is being used to get answers that they say already exist. Experts and the Center also argue the dangers of celecoxib would already be clear if the Food and Drug Administration (FDA) had not “muddied the waters with its 2005 ruling.” PRECISION is a $100 million, multinational study of celecoxib, ibuprofen and naproxen. Although Nissen declined Drug Topics’ request for comment through a Cleveland Clinic spokeswoman, he has responded to questions about this trial in the past to Nature Publishing Group in 2006. In the Nature interview, when asked how he responds to the ethical concerns about the study, he said, “If you don't know which of the three drugs is safest then there's not an ethical question, there is equipoise, which is what is required for a clinical trial. I feel very strongly that any of the three drugs we're studying could prove to be superior for safety, and if that's the case then the trial is entirely ethical.” He further defended the study saying, “This trial has a unique governance model — the design is not Pfizer's, it's ours. It's an academically directed trial designed to answer a scientific question, not a marketing-driven study by Pfizer. It also doesn't buy anybody any time, because all three of these drugs are already being prescribed in the dark by people who don't know their relative safety.”