Efficacy testing in drug development: the in vitro approach

Substituting in vivo tests with alternative testing has always been a major target in drug development in the pharmaceutical industry, for ethical and practical reasons.' In vitro tests play an important role, especially in the first phase of drug discovery, where much trial-and-error exists in finding new classes of active substances. The introduction of new methodology, such as radioimmunoassays, robot screens, receptor binding, transcription factor testing and biotechnology/genetechnology techniques in general, has contributed to the optimization of prescreening for the efficacy of new molecules. Finally, however, in vivo confirmation of the efficacy of the new therapies is still required. Human atrial tissue, obtained when hearts are connected to a heart-lung machine, can be used as an alternative. However, its availability is limited. The further development of ion channel recording techniques in cells - the patch clamp method - has simplified mechanistic studies in isolated cells, but the screening of hundreds of substances by using this system is not feasible. In addition, as the heart muscle cells differentiate in culture, which is the optimum phase of cell growth for testing and for reflecting the in viva whole organism situation cannot be determined. Furthermore, it must be remembered that only one parameter is being analysed - ion flux leading to muscle cell contraction. New technology, such as the use of dyes as indicators for ion movements in cell systems cultured in a 96-well plate, facilitates the development of automatic large-scale screening systems. Cellular assay systems have been developed that make use of coupling to a luciferase reporter gene and thereby ensure fully automated robotic screens for a large number of test compounds. Similarly as soon as proteins, factors or receptors are structurally identified, the possibility exists of using molecular modelling and the introduction of targeted synthesis of chemical compounds. In summary, efficacy testing in drug development by the in vitro approach has been widely expanded, for ethical and practical reasons, but also by the Virtue of the fact that new technology has become available. It is in the interests of the industry to further develop such approaches.