The conversion of Saul to St Paul Michelangelo, 1542

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EPAA Annual Conference 2007 Regulatory acceptance
and implementation of 3Rs approaches Criteria
and Drivers for Acceptance
Marcel Leist Doerenkamp-Zbinden Chair For
Alternative in vitro Methods, University
Konstanz, Konstanz Germany
The conversion of Saul to St Paul (Michelangelo,
1542)
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Regulatory acceptance
3R test pipeline
Developers
Feedback processes?
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animals
3R
Major drivers for 3R
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Confidence as key factor for regulatory
acceptance of alternatives
? Validation of old AND new methods Safety
levels, robustness, assay characteristics, ....

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Problems with in vivo assays....
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.
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, ..
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Example
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.
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, ..
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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
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Prejudice in vitro systems do not predict
systemic toxicity
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The 3R
Reduce
Replace
Refine
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Driver for regulatory acceptance of reduction
? Enough is enough - LD50 - Ecotoxicology test
strategies - Two-generation studies
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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,
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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. .
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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. .
14
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. .
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Method developers
Regulators
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Method developers
Regulators
Catalyzers/ Facilitators
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Method developers
Regulators
Catalyzers/ Facilitators (ECVAM)
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The validation dilemma
Are we going to hit?
Real human safety profile
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The human safety profile
Tuning a test
Real human safety profile
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Any model of human safety

• Real world scenarios
• Inexact science
• poor human data

Real human safety profile
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Accuracy and errors
Human data
Animal data
Correlations?
Real human safety profile
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Accuracy and errors
False negative
Accurate
False positive
Correlations?
Real human safety profile
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Animal models of human safety
Animal data
Real human safety profile
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Correlation of models of human safety
Alternative data
Animal data
Real world scenarios!
Real human safety profile
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Correlation of models of human safety
Alternative data
Animal data
Real world scenarios!
Real human safety profile
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Model correlation
Examples from ECVAM/NICEATM study
correlation 0.62
corr. 0.53
correlation 0.56
Comparison to in vitro data
Real human safety profile
Personal communication T. Hartung n 45
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One step further..................
Coverage of complex toxicity by integrated test
batteries (e.g developmental toxicity)
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Integrated test batteries
spermatogenesis
Reproductive toxicity
2-Generation study
Real human safety profile
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Integrated test batteries
Real human safety profile
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Validation procedure and regulatory acceptance

• Early collaboration/contact of
• producer (test developer)
• and customer (regulator)

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Validation procedure and regulatory acceptance
- Buildup of experience how to interpret data
how to deal with data, historic feedback
- Continuous feedback in test pipeline
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University Konstanz
Doerenkamp-Zbinden Foundation
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