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Executive Summary

Monoclonal antibodies for the treatment of certain life- threatening illnesses should be allowed to enter Phase I studies without validating the steps taken to remove murine retroviruses, an expert panel agreed at a Jan. 9-10 workshop sponsored by FDA and the National Institutes of Health on preclinical safety testing of monoclonal antibodies. Recommendations generated at the workshop are expected to be included in FDA's revision of its 1987 "Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use." The panel members, representatives from the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, major U.S. cancer centers and two European research institutes, agreed that murine retroviruses do not pose a sufficiently serious risk to humans that their elimination from monoclonal antibody products should require validation prior to Phase I testing. The steps taken to inactivate and remove viruses, however, must be included in the manufacturing purification scheme, the panel members noted. "I wouldn't be so worried that there might be [murine] retroviruses present, particularly if an inactivation step was built in automatically," remarked David Parkinson, MD, from NCI's Investigational Drug Branch. Parkinson suggested that cancer patients who had failed other therapy "would be willing, I think, to accept a greater risk -- as long as it is not a great risk -- as a tradeoff for more effective therapy developed more quickly." NIAID researchers Malcolm Martin and Jane Hartley agreed that murine ecotropic retroviruses (those endogenous to mouse cells) infect only mouse cells and are not infectious to primates. Xenotropic murine retroviruses (those foreign to mouse cells) have the capacity to infect primate cells but infect and spread very slowly, the NIAID researchers said. Hartley called human infection by xenotropic retroviruses a "very remote concern." Currently, FDA requires viral validation studies prior to Phase I trials to demonstrate that manufacturing inactivation and removal steps adequately have reduced the amount of viruses and retroviruses detected in monoclonal antibody preparations. The removal of viruses is achieved by "spiking" the monoclonal preparation with the virus, running the inactivation procedure, and confirming removal of the virus. FDA estimates that validation studies can cost a company from $20,000 - $30,000. The validation step has been a major sticking point for the industry and may lead to delays in the development of monoclonal antibodies for researchers. Validation testing is "a horrendous impairment to the progress [in monoclonal antibody development], especially when you get into pre-Phase I studies for metastatic cancer patients," NCI's Jeffrey Schlom told the committee. "We are spending an enormous amount of time and effort with these spiking experiments," he said. Panel members agreed that the validation study exemptions could be extended to products for cancer, AIDS and transplant patients. The panel did not address whether products for treatment of sepsis should be exempt from the requirement. Parkinson noted that he would be more "reticent" about risking murine retroviral contamination of monoclonal antibody agents used for diagnostic purposes. FDA Center for Biologics Evaluation and Research Hematologic Products Branch Chief Curtis Scribner, MD, suggested that other required tests, such as mycoplasma, sterility and murine antibody product (MAP), might be eliminated to speed up preclinical monoclonal antibody development. However, committee co-chair Sandra Bridges, MD, from NIAID's Division of AIDS rejected the elimination of mycoplasma and sterility testing, indicating they were necessary to ensure safety of the products. MAP testing would be done anyway, she said.

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