Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Development of Alternative Carcinogenicity Test Methods in the Pharmaceutical Industry: Evaluation of the Current Validation/Application Status ***

Dr. Frank Förster (Abschlußjahr: 2011)

Language: English

The assessment of the carcinogenic potential of pharmaceuticals for many decades has relied upon the results of chronic, two-year rodent bioassays. According to the standard protocol, the test substance is administered daily in graduated doses to several groups of test animals for the majority of their life span, normally by the oral route. The limitations and disadvantages of this approach are well known and include the large number of animals required, the significant amount of time, money, personal resources and the difficulty in extrapolating for effects not only seen at maximum tolerated doses to lower levels of human exposure.

Over the last 20 years there has been an increasing interest in developing and validating alternative methods based on the concept of the 3Rs: Replacement, Reduction, and Refinement. The possibility of using alternative short-term carcinogenicity testing models employing transgenic mice as a substitute for a second two-year rodent bioassay in pharmaceutical testing was introduced in 1996 with the drafting of a new International Conference on Harmonization (ICH) guidance (S1B) on testing for carcinogenicity of pharmaceuticals.

In the course of this master thesis a literature survey was performed in the most prominent databases for toxicology and on the homepages of international governmental and non-governmental institutions with the aim to identify those tests that were mentioned in the scientific literature and to comment on its validation and/or acceptance status. Those tests that are most promising and/or are under validation by institutions like ECVAM are discussed in detail.

Several knockout mouse models, cell transformations assays, “omics” technology, quantitative structure-activity relationship (QSAR) based methods, neonatal rodent models and models for high throughput screening of various endpoints were mentioned mostly. CPMP, FDA and NIHS came across that genetically modified mouse models for pharmaceutical risk assessment currently under consideration have value in carcinogen identification, that these assays can serve as an alternative to the standard mouse 2-year bioassay in a testing program, but that results of these assays should not be considered on their own, but rather integrated with other available data and considered as part of a weight of evidence approach for risk assessment purposes. Other test systems mentioned above are not considered as substitution of the rodent bioassay for regulatory carcinogenicity testing.

Overall, the regulatory framework for alternative carcinogenicity testing is developing, but needs further discussion. Development of alternative methods and their validation is of high interest, but due to the complexity of cancer genesis, a unique testing strategy is highly improbable and will presumably be done on a case by case basis. Replacement and/or substitution of the standard approach and application of animal free methodology is a long-term goal, but could be speeded up if the validation process could be accelerated.

Pages: 45