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Executive Summary

Triton Biosciences Fludara I.V. received a unanimous recommendation for approval from FDA's Oncologic Drugs Advisory Committee at its Sept. 11 meeting. The drug was recommended for use in the "palliative treatment of patients with B-cell chronic lymphocytic leukemia who are refractory to at least one prior alkylating agent-containing regimen." Fludara I.V., an orphan drug rated "1A" (new chemical entity representing an important therapeutic gain) by FDA, has been available to patients with refractory chronic lymphocytic leukemia since November 1989 through a Group C/Treatment IND. Approximately 1,000 patients have been treated with the drug to date. CLL is diagnosed in about 9,600 U.S. patients each year. Triton filed an NDA on Nov. 22, 1989 for Fludara. The product was licensed from NCI in 1984. The studies supporting the NDA were conducted by the National Cancer Institute in conjunction with the South West Oncology Group (SWOG) and the University of Texas M.D. Anderson Cancer Center. Data were presented by Michael Keating, MD, from the M.D. Anderson Cancer Center. In the SWOG Phase I/II study, patients received 15-25 mg/m bolus infusions of fludarabine over 30 minutes for five days every four weeks. In the M.D. Anderson Phase I/II trial, patients were given 22-40 mg/m bolus infusions over 30 minutes for five days every three to four weeks. Refractory CLL patients normally have an expected response rate of 5% to 10% and a median survival of six to 12 months, Keating said. Among the 32 patients participating in the SWOG study, there were four (13%) complete responses and six (19%) partial responses. In the M.D. Anderson study, with an enrollment of 101 patients, six (13%) evaluable patients had complete responses, and 17 (35%) had a partial response to treatment with fludarabine. The median duration of response was 65 weeks in the SWOG study and 91 weeks in the M.D. Anderson study, with median survival ranging from 82 to 137 weeks. * The committee based its recommendation for approval primarily on patient response rates rather than survival data, given the lack of appropriate historical controls for comparison. Committee reviewer Albert Bernath, MD, Geisinger Medical Center, Danville, Pennsylvania, called the response rates "impressive." He characterized the complete response rates as "possibly the most impressive...ever seen in a group of heavily pretreated patients where CRs [complete responses] are almost unheard of." While the committee agreed with Bernath's assessment that "there are no unusual safety concerns with this class of drug in the dosages that are proposed," Phase IV studies were suggested for patients with impaired renal function, particularly those with a creatinine clearance less than 50 ml/min. Early Phase I studies with fludarabine suggested that the drug's toxicity may be greater in patients with renal insufficiency. In the early studies, there were 14 cases of fatal neurotoxicity at fludarabine doses exceeding 96 mg/m. * Fludarabine is the first drug to be evaluated according to NCI guidelines, published in November 1988, which outline clinical criteria for eligibility, complete and partial responses, and toxicity, NCI Investigator Bruce Cheson, MD, told the committee. In the past, FDA and NCI have been at odds over what criteria constitute clinical efficacy and whether or not to require survival data. Committee reviewer Bernath suggested that approval of fludarabine based on response rate might be a first and could lead to companies seeking approval for other similar drugs based on response rate rather than survival data. "Are we going to be setting a precedent by even considering a drug solely based on response rates?" Bernath asked. FDA Office of Drug Evaluation I Director Temple, MD, commented that he did not think the evaluation of fludarabine is "all that precedent setting." While FDA has balked at response rates in the past, Temple said that "some of the elements of response here are at least clinical measures, which is a little different from just seeing decreasing tumor diameters." He added that "there has never been (and we didn't need the Lasagna committee to tell us either)...the provision that you have to include survival." In the future, however, Temple said that FDA would like to see more "quality of life analysis" in such studies. Triton Biosciences, based in Alameda, California, is a subsidiary of Shell Oil. The petrochemical giant has been seeking a buyer for the biotech firm since April ("The Pink Sheet" April 23, T&G-8). Established in 1983 through a development partnership with Cetus for interferons, Triton has received over $100 mil. in funding for R&D from Shell. Pilot studies are underway with an oral form of fludarabine.

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