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FDA INTERIM CYTOKINE STANDARDS WILL BE DEVELOPED

Executive Summary

FDA INTERIM CYTOKINE STANDARDS WILL BE DEVELOPED from manufacturers' submissions to the National Cancer Institute Biological Response Modifiers Program (BRMP). NCI BRMP Cellular and Molecular Immunology Section Chief Craig Reynolds told a Nov. 3 FDA workshop that "the basic scheme for the development of interim cytokine standards . . . begins with a company, corporation, which is interested in having their particular material evaluated for possible use as a standard." FDA is looking to BRMP to develop standards by which recombinant cytokines can be evaluated for licensure. "FDA is required to have U.S. standards for licensed biological products," FDA Cytokine Division Immunologist Theresa Gerard, noted. "It is presumed that FDA would adopt the BRMP standard for each cytokine ]currently in development[." Meanwhile, Gerard said, "the BRMP cytokine standard will be available to everyone: manufacturers, clinicians, and researchers." Noting that clinical efficacy of a product is directly related to its biological activity, Gerard explained that "it has long been the position of the biologics Division of FDA to require potency testing for biological products." Measurement of biological activity is essential, Gerard maintained, because "the bioactivity can decline without significant physical or chemical changes in the product." Furthermore, bioactivity should be monitored periodically due to the effects of degradation and glycosylation on biological activity over time, she said. Outlining the BRMP plan for development of cytokine standards, Reynolds said interested companies should submit approximately 1 mg or 1 mil. units of the final formulation of their product for evaluation. The sample will undergo bioactivity and potency testing at FDA Center of Biologics laboratories, and at BRMP and its contractor Program Resources Inc. Quality control, quality assurance, and stability studies will be conducted by FDA. According to Reynolds, companies should expect a response within 60-90 days after the sample is received by BRMP. Data from the cytokine sample testing will be reviewed by a panel composed of two members each from FDA, the National Institutes for Allergy and Infectious Diseases and BRMP. The panel will evaluate the sample data based on biological activity, purity, stability, formulation, and such practical considerations as whether the sample is in lyophilized or liquid form. "It would be more practical to have the standard lyophilized," Gerard maintained. Once a standard is chosen for a particular cytokine, the company will be notified and will be requested to submit 3-5 mg or approximately 10 mil. units of the product in final formulation for distribution. BRMP will then send out 5,000 vials at 1,000-2,000 units per vial of each cytokine standard to fill demands by investigators. Noting that the amount of sample to be sent out would eliminate possible use in clinical studies, Reynolds added, "we are proposing that the vial ]will include[ a label that clearly states the material is for standardization purposes only, not to be used for research." Hazelton Laboratories has been tentatively appointed as a contract repository where samples will be aliquotted, put into vials and stored for distribution. BRMP plans to mount an advertising campaign through major journals announcing the availability of the new cytokine standards. "Present plans are that we will undergo at least three cycles of advertising each year in a variety of different journals to try to make ]the standards[ as widely available as possible," Reynolds remarked. Part of the workshop discussion focused on the World Health Organization's standards for interleukin-2 (IL-2) and interim cytokine standards for IL-1, recombinant tumor necrosis factor (TNF), and recombinant granuocyte colony stimulating factor (G-CSF). WHO is also developing standards for IL-3, GM-CSF, IL-4, M-CSF and IL-5 that will not appear for two or three years. Neither Gerard or Reynolds ruled out the possibility of using some of the World Health Organization standards, but emphasized the immediacy of the need for a standard. "We recognize there is an immediate need for the establishment of internal standards, because of the expanding use of these cytokines in clinical trials," Gerard stated.
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