Program

PL-4

Why TGN1412 was safe and BIA 10-2474 dangerous. The case for mechanism based drug development

[Speaker] Adam F. Cohen:1,2
1:Centre for Human Drug Research Leiden, the Netherlands, 2:Leiden University Medical Centre, the Netherlands

First administration of a new substance to humans is extremely safe and the rate of serious complications low. These experiments are often performed in healthy subjects who do not otherwise benefit and perhaps because of that any serious mishap gets wide attention. Two famous cases need further examination to see what can be learned from them to improve safe and informative drug development. A number of aspects of early drug reesearch will be covered in this lecture.
The first one of the method paradox. Current development delivers extremely sophisticated interventions that affect human biology fundamentally. Yet, in the more standard drug development plans the methodology of the evaluation of effects is in many cases less sophisticated or is not used in the decision making about further steps. Such methods or biomarkers have to be developed and validated beforehand which impacts the planning of Phase I experiments.
Secondly there is often a mismatch between the methodology and the pharmacological mechanisms of the intervention. To obtain such a match, it is necessary to define a detailed set of questions that can be answered in early research. Just describing these generically in terms of tolerability and safety is insufficient.
When a medicine is developed preclinically, a very large amount of information is generated. Currently this is often done by a multitude of external suppliers, in contrast to the all in-house activities that were common in the 1980's. This has led to a fragmentation of knowledge that is visible in the Investigator's brochure with a collected but unconnected set of data. The investigator administering a drug for the first time to a human being has the task of bringing this collection of animal models, manufacturing information, toxicology and pharmacokinetics in biological systems ranging from cell culture to several animal species, together in a starting dose. This is also true for regulators. The IB-Derisk (www.IB-derisk.org) tool will be demonstrated for this purpose.
The safety of subjects in trials has to be balanced against the importance of developing new drugs and this can only be assured by integration of knowledge by adequately educated specialists.
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