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Executive Summary

ORTHOCLONE OKT-3 FOUR-YEAR POST-MARKETING SURVEILLANCE by Ortho is being conducted as part of the FDA approval requirements for the first therapeutic monoclonal. The product, approved by FDA on June 19, will be watched in Phase IV studies for the incidence of lymphoproliferative disorders and malignancies. FDA further specified that Ortho must conduct an annual survey of all transplant centers that use Orthoclone OKT-3. According to FDA's summary basis of approval for the monoclonal, a two-year follow-up study of 63 patients was required by the protocol for the pivotal study on the product, an open label controlled randomized multi-center trial of the monoclonal and high dose steroids in the treatment of initial acute renal rejection. A six-month to one-year follow-up was required of 355 additional patients in supporting studies. FDA observed that "two cases of lymphoma or malignancy were observed in Orthoclone OKT-3 treated patients. One additional case occurred in a bone marrow transplant patient." The agency reported in the summary of approval that "the role of Orthoclone OKT-3 in the development of lymphoma in these three patients is not clear. An extended follow-up for the multi-center study (B81-033) was conducted. Follow-up results ranging from three to five months for 44 Orthoclone OKT-3 treated patients showed that no additional lymphomas had developed. One patient had an eyelid skin cancer removed 29 months after the last dose of Orthoclone OKT-3. No additional malignancies were reported." Describing the production process for the monoclonal in the summary basis of approval, FDA noted that it "is a murine antibody which is the product of a hybridoma produced by the technique of Kohler and Milstein." According to the FDA, the production process of Orthoclone OKT-3 begins with the intraperitoneal injection of the hybridoma from seed stock into pathogen-free CAF 3 mice. The ascitic fluid generated by the mouse injections, FDA says, "is harvested, processed by centrifugation, and stored frozen. The material is tested for monoclonal antibody concentration by gel chromatography, and for identity by isoelectric focusing. The crude monoclonal antibody is purified by a combination of ammonium sulfate fractionation and anion exchange chromatography. Quality control testing is performed on the excipient raw materials and ingredients used in the purification process of the crude monoclonal antibody." Final container product testing includes ". . . isoelectric focusing on samples of the final container product to assure its identity as Orthoclone OKT-3 according to the following method and specification: isoelectric focusing -- spectrotype of sample equivalent to spectrotype of OKT-3 standard."

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