PII-102

T. Leibson, G. Koren; Hospital for Sick Children, Toronto, ON, Canada

BACKGROUND: In 2006, administration of the drug candidate TGN1412 to six healthy volunteers in a clinical trial turned into a catastrophic adverse drug reaction. All six suffered an extreme inflammatory reaction later described as cytokine storm. This systematic review attempts to analyze patterns of medical journal publications following that event and to summarize the major lessons learned from it.
METHODS: A review of Medline and EMBASE from January 2006 to August 2014 was conducted to identify all publications concerning the TGN1412 trial. All publications containing “TGN1412” were explored for relevance.
RESULTS: A total of 150 articles were found. After removal of duplicates and omission of letters to the editor, 131 were included in the qualitative analysis. 48 (37%) were published in high impact journals. Temporal analysis showed that first to appear were editorials, followed by safety reviews and then ethical reviews. Major changes in study design that stemmed from this event included: the introduction of first in human dosage determination by MABEL (Minimal Anticipated Biologic Effect Level), avoidance from simultaneous administration of novel compounds to study subjects and introduction of several kits for detection of in vitro immune reactivity prior to human experimentation.
CONCLUSION: This is the first systematic review of medical journal publications concerning the 2006 TGN1412 trial calamity. A significant number of publications focusing on lessons provide insight into the immense efforts that are undertaken to improve human subject safety in clinical trials. TGN1412 may never become a legitimate medication, but several other CD28 super-antigens are now being developed in an attempt to achieve safe immunomodulation through this pathway.