Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Developments in Regulatory Pharmaceutical Toxicology:

Dr. Daniel Gommel (Abschlußjahr: 2004)

Today pre-clinical risk assessment of a medicinal product relies mostly on in vivo and less on in vitro experiments. Whereas in vivo methods represent the foundation of toxicity risk assessment, for ethical as well as scientific reasons, the use of in vitro methods is promoted.

The CPMP issued a position on the replacement of animal studies by in vitro models which set the framework for later developments in reduction, refinement and replacement of in vivo methods. Institutions, such as the European Centre of Validation of Alternative Methods (ECVAM) and the U.S. Interagency Coordination Committee on the Validation of Alternative Methods (ICCVAM) were founded in particular for validation purposes of newly developed methods. Yet, only few in vitro methods were successfully established, e.g. in cardiotoxicity, phototoxicity, genotoxicity and local tolerance testing.

A major focus has been turned to the new toxicology-subdiscipline Toxicogenomics, defined as the study of the relationship between the structure and activity of the genome and the adverse biological effects of exogenous agents. Methods being employed in Toxicogenomics are the so-called "-OMICS" technologies (e.g. Genomics, Proteomics and Metabonomics) relying on the huge increase in knowledge about gene structure and function, and being able to analyse comprehensive sets of biomolecules (e.g. DNA, RNA, proteins and metabolites). The potential of the methods is currently being evaluated by institutions such as the ILSI/HESI (Health and Environmental Science Institute) and NCT (National Center of Toxicogenomics). As one of the result a first draft guidance for industry about pharmacogenomic data submission was issued by the FDA in Nov. 2003. The guidance encourages companies to submit data obtained by the use of "-OMICS" technology on a voluntary basis in order to provide the grounds for a validation. Today several companies have specialised in using "-OMICS" technology for risk evaluation and partly cooperate with the FDA in order to establish validated biomarkers.

In general it is understood that well established in vivo methods will remain the basis of preclinical risk assessment whereas in vitro methods including "-OMICS" technologies today mostly supplement, however, have the potential to substitute for some animal testing in the future. An important feature of the new technology is the potential to obtain valuable (and inexpensive) information in early drug development that will potentially provide the means to reduce medical and financial risk in drug development and therefore help to increase efficiency in providing efficacious and safe drugs to the patient.

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