the conversion of saul to st paul (michelangelo, 1542) marcel leist doerenkamp-zbinden chair for...
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The conversion of Saul to St Paul (Michelangelo, 1542)
Marcel LeistDoerenkamp-Zbinden ChairFor Alternative in vitro Methods,University Konstanz, KonstanzGermany
EPAA Annual Conference 2007
Regulatory acceptance and implementation of 3Rs approaches
Criteria and Drivers for Acceptance
Regulatory acceptance
Aca
dem
ia
Feedback processes?Developers
3R test pipeline
Major drivers for 3R
3Ranimals
confidence
Validation
Experience
Communication
Optimised strategies
(De)validation
Confidence as key factor for regulatory acceptance of alternatives
Validation of old AND new methods
Safety levels, robustness, assay characteristics, ....
…also heterogeneity in the design of the available in vivo studies underlies much of the scatter, and this puts a limit on validating in vitro data as predictors of in vivo data. Further analysis of the in vitro-in vivo correlation would therefore require high quality in vivo data, …..
Quantitative extrapolation of in vitro whole embryo culture embryotoxicity data to developmental toxicity in vivo using the Benchmark Dose approach.
A.H. Piersma et al, (2007) Toxicol. Sci.
Problems with in vivo assays....:
…also heterogeneity in the design of the available in vivo studies underlies much of the scatter, and this puts a limit on validating in vitro data as predictors of in vivo data. Further analysis of the in vitro-in vivo correlation would therefore require high quality in vivo data, …..
Quantitative extrapolation of in vitro whole embryo culture embryotoxicity data to developmental toxicity in vivo using the Benchmark Dose approach.
A.H. Piersma et al, (2007) Toxicol. Sci.
Example:
Avoidance of prejudice: „....in vitro systems do not predict systemic toxicity......, in vivo systems are better“
Example: TeGenero TGN1412
The Journal of Immunology (2007), 179, 3325
Prejudice: in vitro systems do not predict systemic toxicity
The 3R
Reduce Replace
Refine
Driver for regulatory acceptanceof „reduction“
„Enough is enough“
- LD50- Ecotoxicology test strategies- Two-generation studies
…study retrospectively evaluates 176 multi-generation studies to assess potential differences between the first and the second generation, both in terms of the types of effects observed and in terms of the effective doses. All substances classified as reproductive toxicants by the Directive 92/32/EEC or considered as toxic to fertility by the California EPA for which we found a multi-generation study were included …..
…The second generation ….. affected neither the overall NOAEL nor the critical effect. Therefore, it had no impact on the ensuing risk assessment, nor on classification and labeling. ….
A retrospective analysis of the two-generation study: What is the added value of the second generation? G. Janers et al, (2007) Reproductive Toxicol. 24, 97
…study retrospectively evaluates 176 multi-generation studies to assess potential differences between the first and the second generation, both in terms of the types of effects observed and in terms of the effective doses. All substances classified as reproductive toxicants by the Directive 92/32/EEC or considered as toxic to fertility by the California EPA for which we found a multi-generation study were included …..
…The second generation ….. affected neither the overall NOAEL nor the critical effect. Therefore, it had no impact on the ensuing risk assessment, nor on classification and labeling. ….
A retrospective analysis of the two-generation study: What is the added value of the second generation? G. Janers et al, (2007) Reproductive Toxicol. 24, 97
…study retrospectively evaluates 176 multi-generation studies to assess potential differences between the first and the second generation, both in terms of the types of effects observed and in terms of the effective doses. All substances classified as reproductive toxicants by the Directive 92/32/EEC or considered as toxic to fertility by the California EPA for which we found a multi-generation study were included …..
…The second generation ….. affected neither the overall NOAEL nor the critical effect. Therefore, it had no impact on the ensuing risk assessment, nor on classification and labeling. ….
A retrospective analysis of the two-generation study: What is the added value of the second generation? G. Janers et al, (2007) Reproductive Toxicol. 24, 97
Methoddevelopers
Regulators
Methoddevelopers
Regulators
Catalyzers/Facilitators
Methoddevelopers
Regulators
Catalyzers/Facilitators(ECVAM)
The validation dilemma:
Are we going to hit?
Real human safety profile
The human safety profile
Tuning a test
Real human safety profile
Any model of human safety
Real human safety profile
Real world scenarios:- Inexact science- poor human data
Accuracy and errors
Animal data
Human data
Real human safety profile
Correlations?
Accuracy and errors
Real human safety profile
Correlations? False positive
False negative
Accurate
Animal models of human safety
Animal data
Real human safety profile
Real world scenarios!
Correlation of models of human safety
Animal data
Real human safety profile
Alternative data
Real world scenarios!
Correlation of models of human safety
Animal data
Real human safety profile
Alternative data
Comparison to in vitro data
Model correlation
Real human safety profile
Examples from ECVAM/NICEATM study
corr. = 0.53
correlation = 0.56
correlation = 0.62
Personal communication T. Hartung; n = 45
One step further..................
Coverage of complex toxicity by integrated test batteries (e.g developmental toxicity)
Integrated test batteries
Real human safety profile
Reproductivetoxicity
spermatogenesis
2-Generation study
Integrated test batteries
Real human safety profile
Validation procedure and regulatory acceptance
Early collaboration/contact of producer (test developer) and customer (regulator)
Agreement on relevant reference points
- Gold standard
- Reference data base
- Reference compound base
- State of the art of method and competitors
- Situation in other sectors and countries
- Buildup of experience how to interpret data; how to deal with data, historic feedback
Biological systemExposure situationModel endpointPrediction model
Test Validated Test
AppliedTest
Regulator input: tuning
Regulator input: fine-tuning/post-validation
- Continuous feedback in test pipeline
Validation procedure and regulatory acceptance
University Konstanz
Doerenkamp-ZbindenFoundation