A clinical evaluation of genetic stability

Mutation in a genetically engineered cell line has not been shown to have been responsible for adverse clinical reactions in a currently licensed biotechnology product. There exists, however, the theoretical possibility that mutations in the production cell line could ultimately lead to patient exposure to aberrant proteins which could result in unanticipated or deleterious effects. The clinical trials of recombinant antihaemophilic factor, a large complex glycoprotein, which is administered chronically, offered a unique opportunity to explore this theoretical concern. In this retrospective analysis of patient data, evidence for unanticipated or adverse events which could possibly be attributed to mutations in the genetically engineered cell line was sought. Extensive analysis of a variety of patient data such as the efficacy, alterations in pharmacokinetic parameters, and inhibitor formation, gave no support for concern over host cell mutation. While this retrospective analysis cannot absolutely exclude the possibility of mutational events, those clinical data in combination with the product characterization information indicate that for this recombinant product, mutation is a highly improbable event.