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FDA CELL LINE "POINTS TO CONSIDER" REVISION

Executive Summary

FDA CELL LINE "POINTS TO CONSIDER" REVISION may abbreviate murine monoclonal antibody retrovirus testing procedures, Center for Biologics Evaluation and Research Immunoconjugate Lab Director Robert Kozak, PhD, said Jan. 26 at the BioEast '93 biotech conference in Washington, D.C. Since cell lines that produce MAbs "are going to contain retroviruses," he said, "you will not have to test for them up front" under the PTC document as it is currently envisioned. However, manufacturers "probably will still be asked to quantify how much virus will be there and then to show in a viral validation study that that amount will be cleared," Kozak added. CBER is revising both its cell line and monoclonal antibodies PTC documents. The documents, designed to explain current regulatory thinking on manufacturing issues, were last revised in 1987. A first draft of the MAb PTC is targeted to be ready for an internal review at the end of February; the cell lines PTC is awaiting review by upper management. The issue of murine retroviral contamination was addressed by an FDA/National Institutes of Health workshop on preclinical safety testing of MAbs a year ago ("The Pink Sheet" Jan. 20, 1992, p. 13). The MAb points to consider document, Kozak said, may be expanded in areas including: the development and characterization of purified MAbs; preclinical toxicology; MAbs made in ascites; characterization of immunoconjugates; and clinical issues. One "big change in...emphasis" in the cell lines PTC will be in the general viral validation section of the document, Kozak predicted. "I think the approach in the future will be to validate for known or suspected virus, as opposed to looking at a panel of viruses," he said. In its current form, the cell lines points to consider document emphasizes that MAbs be tested for virus contamination both by in vitro and in vivo methods. The revised document will also recommend an amplification step in retrovirus testing in most cases, he predicted. One area in which "there is still a lot of discussion" is "the acceptability of generic virus inactivation data for limited [or] early Phase I studies" of MAbs, Kozak noted. "My guess would be that's it's still going to be on a case-by-case basis," he said. However, "certainly the generic would be discussed and possibly acceptable." National Cancer Institute Investigational Drugs Branch Chief David Parkinson, MD, explained that for "people with life- threatening diseases,...there may be a greater good in the relaxation of certain of the stringent steps in the interest of one or two clinical trials to find whether agents are worth the resources of taking them forward for more serious and more formal product development." Parkinson made a similar point during the January 1992 FDA/NIH workshop. Parkinson noted that "the nature of [monoclonal antibodies] to a large extent has limited our ability to judge the particular drug characteristics of an agent in preclinical models." He added that his "own perspective is that the expensive safety testing is one of the reasons why so few agents have gone into the clinic," given the tenuous data on agents gained from preclinical trials. An "indirectly related" problem in the development of MAbs is that "there have been increasingly few commercial sources for GMP antibody production," Parkinson said.
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