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BRISTOL-MYERS SQUIBB’s TAXOL APPROVED DEC. 29 FOR REFRACTORY OVARIAN CANCER AT LOWEST STUDIED DOSE; FDA CREDITS PRE-NDA WORK FOR FIVE-MONTH REVIEW

Executive Summary

Bristol-Myers Squibb's chemotherapy agent Taxol (paclitaxel) is approved for use by refractory ovarian cancer patients at the lowest dose used in clinical trials: 135 mg/m. The appropriate dosing level for Taxol was one of the few specific points that FDA asked its Oncologic Drugs Advisory Committee to resolve at the Nov. 16 review of the Taxol NDA ("The Pink Sheet" Nov. 23, p. 5). Bristol-Myers Squibb had supported a dose of 170 mg/m infused over a 24-hour period; the committee voted 10-1 in favor of the lowest studied dosage level of 135 mg/m. At the meeting, both FDA and the committee said that while adverse events of Taxol treatment were proportional to dosage level, efficacy was not. Approved Taxol labeling states: "Adequate trials of dose- response have not been completed" and "larger doses...have so far produced responses similar to 135 mg/m." The initial approved indication is for second-line treatment of metastic ovarian cancer after failure of previous treatments. Taxol will be available for use by physicians and hospitals "within two weeks." The company submitted the NDA (20-262) for the Pacific yew bark-derived anti-tumor agent on July 22 ("The Pink Sheet" Aug. 10, In Brief). Questions about chemistry, purity and manufacturing represented the final hurdles for approval after the November advisory committee meeting. FDA said Dec. 29 that those issues "have been resolved sufficiently to market the product." Although paclitaxel is a very complex molecule derived from a variable natural source, FDA said, there "are adequate controls" in place to assure product purity and quality. Indicating that the agency did not allow final chemistry details to delay Taxol's approval, the approval letter signed by Division of Oncology & Pulmonary Drug Products Director Gregory Burke, MD, acknowledges "commitments" made by the company in the areas of chemistry, manufacturing and controls and microbiological sections of the NDA. A Phase IV trial "for information requested by our Division of Biopharmaceutics" is also expected, the letter says. In addition, FDA has not yet completed its validation of the analytical methods for Taxol. The approval letter states that FDA expects Bristol- Myers Squibb's "full cooperation in resolving any problems that may arise" in this area. The agency attributed its rapid five-month review of the Taxol NDA to cooperation with the National Cancer Institute, Bristol- Myers Squibb and Canada's Health Protection Branch, which also approved the product Dec. 29. FDA said that "people had been working on the [Taxol] data for a few years" prior to submission of the actual application, thus reducing review time. FDA is trying to expand the amount of work done on applications for products for life-threatening diseases prior to the actual filing of the NDA. An agency official said that pre-NDA work is "a standard we are trying to evolve into for products for life-threatening diseases." The review period for Taxol is the shortest in memory for a cancer drug from submission of NDA to approval, FDA said. The review represents one of FDA's fastest product reviews in any category -- shorter than that for Bristol- Myers Squibb's AIDS drug Videx (ddI), but longer than that for Retrovir (AZT) (approximately four months). An FDA press release said that Taxol may be "particularly useful" for patients who have failed treatment with platinum-based chemotherapy agents. At the advisory committee meeting, Bristol- Myers Squibb said 25% of patients refractory to platinum-based therapies responded to Taxol. Overall objective response rates (reduction of tumor size by at least one half) in clinical studies ranged from 22% to 30%, with a median survival of 11.1 months, compared to an expected survival of six months. Taxol is contraindicated in patients who have a history of hypersensitivity reactions to Taxol or to other drugs formulated in Cremophor (polyoxyethylated castor oil). At a symposium on cancer chemotherapy held at MD Anderson Cancer Center in October, the center's Timothy Madden, MD, suggested that better solubilizing agents will have to be found for Taxol to prevent hypersensitivity reactions ("The Pink Sheet" Oct. 19, p. 10). Taxol's label says patients should be pretreated with corticosteroids, diphenhydramine and H[2] antagonists before receiving Taxol "in order to prevent severe hypersensitivity reactions." Labeling states that 41% of treated patients had hypersensitivity reactions of some kind (flushing, rash, dyspnea, mild hypotension), while 2% suffered major reactions (hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema or generalized urticaria). Another precaution states that in vitro data suggest there is a possibility of an inhibition of Taxol metabolism in patients receiving ketaconazole (Janssen's Nizoral).
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