Searle/Pfizer Celebrex lower incidence of GI complications than NSAIDs should be reflected in labeling; committee recommends "modified" NSAID class warning for COX-2 inhibitor.
December 2, 1998
Health News Daily via NewsEdge Corporation : CELEBREX LABELING SHOULD INCLUDE DATA SHOWING FEWER GI COMPLICATIONS and endoscopically determined lesions versus non-steroidal anti-inflammatory drugs, FDA's Arthritis Advisory Committee recommended Dec. 1. While FDA cited inconsistent results and lack of validity of the endoscopic surrogate endpoint, the committee agreed that the data presented by the company conclusively showed that Searle/Pfizer's cyclooxygenase-2 inhibitor celecoxib is associated with fewer serious gastrointestinal adverse events, a limiting factor in NSAID therapy. The product will be co-promoted by Pfizer.
The committee recommended including upper GI ulcer complication rates of .2% for Celebrex versus 1.68% for NSAIDs. These results were obtained in 14 controlled trials with 11,008 patients, representing 1,763 patient years. No ulcer complications, which include bleeding, perforation and gastric outlet obstruction, were seen with placebo.
Using endoscopic ulcers as surrogates for upper gastrointestinal tract ulcer complications, Searle found approximately a 5%-9% incidence of gastroduodenal ulcers with Celebrex vs. 24% for naproxen in two 12-week arthritis studies. The company reported an 8% cumulative incidence of ulcers at 12 weeks for Celebrex vs. 38% for naproxen in a serial endoscopy study.
FDA indicated that three of these studies "reveal a significantly lower ulcer incidence in the celecoxib group at twelve weeks in both rheumatoid arthritis and osteoarthritis patients," and also pointed to a study including ibuprofen 800 mg t.i.d. which showed similar significant results (8% cumulative incidence of ulcers at 12 weeks with Celebrex vs. 28% with ibuprofen). However, the agency expressed concern regarding "inconsistent results" seen in ulcer incidence rates across celecoxib studies. The agency maintained that in one study no statistically significant differences were seen in ulcer incidence rates at four, eight and twelve weeks between celecoxib and diclofenac, the comparator agent.
Claiming that "these studies were not designed for a statistical comparison of clinically significant upper GI events," FDA recommended a "Phase IV trial with appropriate clinically relevant endpoints" in order to test the "hypothesis that celecoxib produces a lower incidence of clinically significant UGI events compared to NSAIDs." The committee was reluctant to mandate the Phase IV trial.
"The studies in this NDA suggest that celecoxib may produce fewer clinically significant UGI events than currently marketed NSAIDs," FDA Division of Gastrointestinal and Coagulation Drug Products Medical Officer Lawrence Goldkind, MD, acknowledged, emphasizing, however, "there is no substitute for a trial to test such an important claim."
Goldkind presented Celebrex ulcer incidence of 4% as compared to placebo (2%) as determined by endoscopy, but pointed out that the studies from which the data were obtained were designed to evaluate both efficacy and GI safety of Celebrex as compared to an active comparator. Noting that "no statistical comparison to placebo was stipulated in the protocol," Goldkind concluded that "the difference between placebo and celecoxib associated ulcer rates has not been fully addressed in the clinical safety development program so far. "
The committee voted in favor of a modified NSAID class warning for Celebrex. However, after further discussions, members indicated that it should be labeled as a "highly selective" NSAID. FDA reviewers presented data on the incidence of renal toxicity and on preclinical safety findings, concluding that the results were similar to those seen with NSAIDs.
One issue for FDA to resolve following the committee meeting will be whether Celebrex should carry an indication for acute pain in addition to treatment of signs and symptoms of osteoarthritis and rheumatoid arthritis. Searle showed efficacy for Celebrex in an acute dental pain model, but post-surgical pain studies failed to show efficacy, FDA said.
"Osteoarthritis studies show some positive results and may be regarded as supportive, but still inconclusive, evidence of efficacy in the treatment of acute pain," FDA Division of Anti-inflammatory, Analgesic and Ophthalmic Drugs Medical Officer Mordechai Averbuch, MD, maintained. "For these reasons we believe that celecoxib, at this time, has not yet met the requirements to gain the treatment of acute pain indication," he concluded.
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