title: Safety of phase I clinical trials with monoclonal antibodies in Germany--the regulatory requirements viewed in the aftermath of the TGN1412 disaster.
abstract: This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.
authors.affiliation: Paul-Ehrlich Institute, Federal Agency for Sera and Vaccines, Langen, Germany. liebe@pei.de
authors.forename: B
authors.initials: B
authors.lastname: Liedert
authors.forename: S
authors.initials: S
authors.lastname: Bassus
authors.forename: C K
authors.initials: CK
authors.lastname: Schneider
authors.forename: U
authors.initials: U
authors.lastname: Kalinke
authors.forename: J
authors.initials: J
authors.lastname: Löwer
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000633:toxicity; D017321:Clinical Trials, Phase I as Topic / Q000941:ethics / Q000331:legislation & jurisprudence* / Q000379:methods; D017277:Drug Approval / Q000331:legislation & jurisprudence*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D026724:Ethical Review; D005858:Germany; D017408:Guidelines as Topic; D006805:Human Experimentation / Q000941:ethics / Q000331:legislation & jurisprudence*; D006801:Humans; D007880:Legislation, Drug; D019055:No-Observed-Adverse-Effect Level; D012016:Reference Values; D012107:Research Design; D018570:Risk Assessment; D018675:Toxicity Tests
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C509303:TGN-1412