Principles of Scientific Validation The Amden Validation Workshops

Regulators will only accept alternatives to animal tests in toxicology, if the new tests will allow them to classify and label chemicals in the same way as the current animal tests. The OECD has therefore decided that in-vitro toxicity tests can be accepted for regulatory purposes only after a successful experimental validation study. In order to approach this problem scientifically, European and American scientists agreed in 1990 in Amden, Switzerland, on a definition of experimental validation and the essential steps in this process. At this workshop, validation was defined as "... the process by which reproducibility and relevance of a toxicity testing procedure are established for a particular purpose ..." [6], regardless of whether the method is an in-vitro or in-vivo test.

The four essential steps of the experimental validation process were defined in the following manner:

1. Test development in a single laboratory.

2. Experimental validation under blind conditions in several laboratories.

3. Independent assessment of the results of the validation trial.

4. Regulatory acceptance.

Steps 2 and 3 serve as the essential parts of a formal validation study conducted for regulatory purposes. The report of the First Amden workshop on validation [6] encouraged scientists to initiate several international validation studies. Since the Draize eye test has been the most widely criticized toxicity test, a worldwide validation study on nine alternatives to this procedure was coordinated by the EU and the British Home Office. However, this and other extensive international validation attempts failed [7].

Therefore, the leading scientists involved met for the Second Amden validation workshop in 1994, to improve the concept of the validation procedure. The workshop recommended the inclusion ofnew elements into the validation process [8], which had not been sufficiently identified in the First Amden validation workshop. The following three essential elements were recommended:

• The definition of a biostatistically based prediction model.

• The inclusion of a prevalidation stage between test development and formal validation under blind conditions.

• A well-defined management structure.

With regard to in-vitro tests, a prediction model should allow the prediction of in-vivo endpoints in animals or humans from the endpoints determined. The prediction model must be defined mathematically in the standard operation procedure of the test that will undergo experimental validation under blind conditions with coded chemicals [8]. In order to assess the limitations of a new test before it is evaluated in a validation study, the test should be standardized in a prevalidation study with a few test chemicals in a several laboratories [9]. This will ensure that the in-vitro test method, including the prediction model, is robust and that the formal validation study with coded chemicals is likely to be successful. Finally, the goal of a validation study has to be clearly defined, and the management structure must ensure that, within the study, the scientists who are responsible for essential tasks can conduct their duties independently of the sponsors and the managers of the study, for example, biostatistical analysis, and the selection, coding and shipment of the test chemicals.

The improved concept of experimental validation for regulatory purposes defined in the Second Amden workshop was accepted by ECVAM in 1995, and in 1996 by US regulatory agencies [10] and also by the OECD [11]. Since this agreement was made at the international level, scientists have tried to follow the ECVAM/

US/OECD principles for new validation trials. The improved validation concept was immediately introduced into ongoing validation studies, for example, the ECVAM/COLIPA validation study on in-vitro phototoxicity tests and the ECVAM validation study of in-vitro skin corrosivity tests. When these validation studies had been finished successfully, the two new methods were accepted as the first in-vitro toxicity tests at the international level for regulatory purposes by the EU Commission in 2000 [12, 13] and by the OECD in 2004 [14, 15].

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