Phase I Studies and First-In-Human Trials

Abstract

Clinical trials with new investigational medicinal products have to go through a number of phases, usually beginning with healthy volunteers, to progressively establish their safety and ultimately their efficacy. Disasters occur only rarely during phase I trials, which have a remarkable safety record. In 2006, a contract research organization was conducting the first human testing of TGN1412 an immunomodulatory anti-CD28 monoclonal antibody. All six volunteers receiving TGN1412 became critically ill with potentially life-threatening complications within hours of starting drug infusion. Notably, similar detrimental effects were already known for decades since the first antibody (OKT3) was licensed. A thorough understanding of the pharmacology of a drug often provides a clue to the potential toxicity that one might encounter. Even toxicology studies in higher animals such as monkeys may provide a false sense of security and apparent safety if there is little inter-species cross-reactivity for an antibody or if the response pattern may be highly specific for humans. Clinical pharmacologists with a strong scientific background in the particular field of science should play a key role as investigators. The expertise available in spezialized centers could help to identify early any potential or theoretical risks, improve designs of clinical trial protocols, address other possible shortcomings in the scientific rationale that support the safety of similar agents. The most striking feature of the study with TGN1412 was that six volunteers were exposed simultaneously to a drug with an unknown safety profile in humans. This is irresponsible particularly in a first-in-man dose escalation trial. Exposing only 1 or 2 subjects to start with on a single day, particularly at the start of each dose level, generates significant insights into safety. This chapter discusses considerations in the preclinical development, the clinical trial design, choice of study population, dose finding, necessary clinical environment and finally specificities of first-in-human trials with monoclonal antibodies.