Establishing risk of human experimentation with drugs: lessons from TGN1412.

Administration of a chemical or biological compound to a human being is never without risk. Although knowledge about risks increases during the development process, risks are still present even when a substance is marketed. Particular care is necessary when a new drug is given to healthy volunteers without previous human testing. General principles for such research have been laid down in guidelines as early as 1983, and these were the basis for many current regulations. Most drugs at that time were small molecules with fairly well characterised, classic, pharmacological mechanisms. Proposed primary objectives for studies in healthy people were therefore to show pharmacological action in man and the dose (or concentration) response curve. This approach was judged safe and was lent support by fi ndings of available surveys. Over time, the main objectives for these trials changed—perhaps owing to the perceived safety of new traditional (small-molecule) medicines—to general tolerance and safety. The advent of increasingly potent and selective compounds for human-receptor systems led to situations in which predictability from animal data was diminishing. The fi rst substances in this category were small molecules with fairly foreseeable pharmacokinetics, and any unexpected adverse events were mostly fully reversible. Biotechnology provided compounds with unique specifi city for human targets, potentially further reducing the predictability of animal work. However, the deaths of two volunteers in clinical studies led to the realisation that they could have been prevented by proper examination of existing data. The serious adverse events that arose during the very fi rst administration of TGN1412, the so-called CD28 superagonistic antibody, have led to immediate reactions from diff erent regulators, ranging from a moratorium on CD28 research to rules about how many individuals should receive a new compound at the same time. A common theme was that special care should be given to ill-defi ned high-risk drugs. In this Viewpoint, we propose a set of factors facilitating rational risk analysis of all new substances to be administered to human beings (fi gure 1). We use TGN1412 as an illustration because it represents a new compound with a complex and novel mechanism.