Meeting report: Validation of toxicogenomics-based test systems: ECVAM-ICCVAM/NICEATM considerations for regulatory use

Abstract

This is the report of the first workshop "Validation of Toxicogenomics-Based Test Systems" held 11-12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities.

Figure 1

Scheme of the different steps in a toxicogenomics-based test. Three distinct levels were identified where validation is necessary: one-off validation (left), which should be performed once and is mainly related with the quality of the microarray and the instrumentation (blue); routine validation and QC (top), representing the ongoing requirements that are the responsibilities of the experimental toxicologist and the manufacturer (red); and the extent of validation necessary whenever a technical or methodologic change is introduced in the test (right): a method should meet the preestablished performance standards in order to be considered reliable and relevant as the original test method (green). Q-PCR, quantitative PCR.

Figure 2

Process flow showing different independent prediction levels considered important in assessing validity of a toxicogenomics-based test method.