Establishing risk of human experimentation with drugs: lessons from TGN1412

Drug Experimentation in Healthy Volunteers

“…Moreover, the first dose is calculated by application of a safety factor, which takes into consideration the overall robustness and quality of preclinical data, as well as the potential for adverse effects in the target population (Tibbitts et al, 2010) (Figure 3). In March 2006, TGN 1412, a new monoclonal antibody directed against a human lymphocytic antigen, which was studied in a first-in-man clinical trial at the Northwick Park Hospital of London, caused a catastrophic systemic organ failure in six healthy subjects exposed to the new drug (leading to hospitalization of all six volunteers in intensive care units), despite being administered at a supposed sub-clinical dose of 0.1 mg per kg, which was about 500 times lower than that estimated as safe in animals (Kenter & Cohen, 2006).…”

“…This concept is particularly important for biopharmaceuticals with slow elimination, such as monoclonal antibodies, where the potential for persistent target modulation and alteration of downstream cellular processes requires careful assessment (Tibbitts et al, 2010). However preclinical toxicology, as testified by several toxic reactions observed in early phase trials (Kenter & Cohen, 2006), may not provide suitable information on drug safety to predict which potential adverse effects might occur in humans. For this reason, adverse reactions must be intensively monitored throughout all early phase studies, and first-in-man administration must be conducted in an appropriate pharmacological unit, which can rapidly provide intensive cares.…”

The calm after the cytokine storm: lessons from the TGN1412 trial

“…Shortly after this tragedy, Kenter and Cohen raised a series of issues concerning the analysis of risk for new compounds for clinical development (8). The Medicines and Healthcare Products Regulatory Agency (MHRA) also conducted a thorough evaluation.…”

Why animal studies are often poor predictors of human reactions to exposure

“…22 The few systematic reviews of the animal literature that have been done also pointed to the poor quality of other animal research, and the difficulty of extrapolating from it to humans, 23 a concern which is being increasingly made in other fields of drug development and evaluation. 24,25 Mathews 26 has recently challenged those who have claimed that 'virtually every medical achievement of the last century has depended directly or indirectly on research with animals' to provide evidence justifying their assertion. Some of the key problems have been summarized by Pound and her colleagues 17 :…”