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Executive Summary

Amgen's Neupogen G-CSF should be approved as an adjunct for aggressive chemotherapeutic regimens for all nonmyeloid malignancies to prevent febrile neutropenia, FDA's Biological Response Modifiers Advisory Committee recommended Dec. 14. Amgen filed a PLA for the recombinant DNA granulocyte stimulating factor last December. The recommendation reflects the committee's view that data from a single Phase III clinical trial studying G-CSF in small cell lung cancer treated with a standard dose of CAE (cylcophosphamide, doxorubicin, and etoposide) could be extrapolated to other therapies and other cancers. The committee voted unanimously to recommend approval based on "benefits to the patient's quality of life" rather than on "a proven survival benefit." Oncology unit director at the Ludwig Institute for Cancer Research George Morstyn, MD, presented data from two Phase I and five Phase II studies which, he said, included a "good subset of the sorts of chemotherapy regimens that are in clinical practice in oncology in the U.S." He added that "the tumor types that have been treated [with G-CSF] in these various studies include the major types of cancers that are treated with chemotherapy." Assistant Clinical Professor Jeffrey Crawford, MD, Duke University Hematology/Oncology Division, presented data from Amgen's Phase III placebo-control study conducted at 14 centers. "Response and survival were not primary endpoints," he explained. Instead, the study attempted to show "that G-CSF could serve as an adjunct to chemotherapy and decrease the incidence of infection as manifested by febrile neutropenia," Crawford said. Final analysis of the study showed that G-CSF reduced incidence of fever from 57% in placebo patients to 28% in the treatment, he noted. G-CSF-treated patients also spent approximately one-half as much time hospitalized with fevers and needed antibiotics one-third less often, he added. Neupogen caused only one "consistently seen" side-effect: medullary bone pain occurred in 19% of G-CSF patients, Crawford reported. The pain usually lasted less than 24 hours, he said, and was "handled easily by oral analgesics." FDA reviewer Theresa Gerrard said that "the data presented by Amgen on the efficacy of G-CSF has been reviewed by the licensing committee at FDA. The consensus is that G-CSF is effective in preventing infections defined as febrile neutropenia that are associated with myelosuppressive chemotherapy regimens that are used to treat non-myeloid malignancies." She added that FDA believed "minimal adverse effects could be associated with G-CSF." The committee did not dispute FDA's conclusions. FDA asked the committee to discuss several additional questions about G-CSF. The committee voted five to one "to recommend the use of Amgen's G-CSF for all types of non-myeloid malignancies" based on available data. The lone dissenter, Paula Pitha, PhD, Johns Hopkins Hospital, argued that since G-CSF has affinities for some tumors, like melanomas, more study is needed to prove that it does not encourage tumor growth in such cancers. The committee voted unanimously to permit use of the product in children. The committee did not vote on the FDA's question on whether the Phase III study "validates" the measurement of neutrophils as a surrogate endpoint in Amgen's other studies. None of the committee members supported the proposition as worded, but there was general consensus that the data indicated that G-CSF could be useful with aggressive chemotherapy regimens and/or in cases where severe neutrophil reduction is likely. Committee member Frederick Appelbaum, MD, Fred Hutchinson Cancer Research Center, commented that, in less aggressive chemotherapies, where the affect on neutrophils is "transient, it is going to be a lot harder to demonstrate clear benefit" of G-CSF. Parkash Gill, MD, University of Southern California Norris Hospital, suggested that even in less aggressive chemotherapies, "neutropenia may be of the same severity, [and in that case] the molecule would be useful." The committee recommended that the package insert include a warning that information is not yet available on the effect of G-CSF when used with certain agents, like the nitrosoureas (such as Bristol-Myers Squibb's BiCNU) or mitomycin (Bristol's Mitocin-C), whose myelosuppressive effects are slower than in most treatments. Appelbaum suggested that additional studies with these agents would be useful. Although G-CSF appears headed toward a quick approval, Amgen apparently has not yet received final clearance from FDA for its manufacturing plant. FDA's Gerrard said that "a prelicensing inspection of the Amgen facilities has been completed" and that "manufacturing issues and establishment issues are being reviewed." In addition, Amgen is evaluating the potential cost benefits of the product. G-CSF Product Team Leader Michael Narachi told the committee that Amgen is "in the process of doing a cost effectiveness study at four centers." A company press release indicated that there are 250,000 new chemotherapy patients in the U.S. each year.

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