title: Safety of biologics, lessons learnt from TGN1412.
abstract: In 2006, a first-in-man phase-I clinical trial of an immunomodulatory mAb, TGN1412, ended in disaster when six healthy recipients suffered a life-threatening systemic inflammatory response, termed a 'Cytokine Storm'. A subsequent investigation concluded that these serious adverse events, not predicted by pre-clinical safety testing, were unforeseen biological effects in man. However, the adverse events had been exacerbated by administration of a near-maximum immuno-stimulatory dose to volunteers, because the calculation of a safe starting dose in man had been based upon results from pre-clinical safety testing in a non-responsive species. In hindsight, many lessons have been learnt from this experience and these have prompted a revision of the European guidelines for first-in-man phase-I clinical trials of biologics. Perhaps the most important lesson is that greater caution needs to be exercised when evaluating new biologics.
authors.affiliation: Biotherapeutics Group, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire EN6 3QG, UK. Richard.Stebbings@nibsc.hpa.org.uk
authors.forename: Richard
authors.initials: R
authors.lastname: Stebbings
authors.forename: Stephen
authors.initials: S
authors.lastname: Poole
authors.forename: Robin
authors.initials: R
authors.lastname: Thorpe
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D017321:Clinical Trials, Phase I as Topic; D016207:Cytokines / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D012107:Research Design; D012449:Safety
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C509303:TGN-1412