10 Years of ICCVAM:
Challenges, Successes
Thomas Hartung
Doerenkamp-Zbinden Professor and Chair for Evidence-based Toxicology, EHS
Director, Center for Alternatives to Animal Testing (CAAT)
Joint appointment: Molecular Microbiology and Immunology
Bloomberg School of Public Health, Johns Hopkins University, Baltimore, US
Professor of pharmacology and toxicology, University of Konstanz, Germany
ICCVAM 10th birthday?
Committee 1994, authorization act 2000
There is only one validation process
• Collaboration with
ECVAM, JaCVAM,
KoCVAM also in
ICATM
• OECD guidance
document 34
… but difference in details, e.g. resources,
active validation, peer-review, acceptance
After Directive 86/609/EEC, now 2010/63/EU
- > $300 million spent by EU and > $300 million by EU member states
for development and validation of alternatives
- 40 methods validated
Impact?
Trends Europe statistics 2008 published in 2010
- Numbers stable compared to 2005 (likely 7.5%
• Only minor
consumers of
increase, error Greece fish use 2005)
- Use for pharma research from 31 to 23% animals
replaced
- Tox uses stably 10%
• Compensated
- 90.000 animals for chemicals (REACH: 9+by
million…)
increased
- Some impact on acute tox, sensitization and
topical
testing
tox visible
- Increase of Botox and pyrogenicity animal numbers
Definition of Validation
Reliability
(reproducibility)
New
TEST METHOD
Relevance:
scientific basis
Relevance:
predictive capacity
REFERENCE
(TEST)
Validation modular approach
“Standardised”
Test definition
Within-lab. variability
Transferability
Reproducibility
Between-lab.variability
“Suitable/Adequate”
Predictive capacity
Relevance
Applicability domain
“Validated”
Performance standards
“Equivalent”
Hartung et al. ATLA 2004, 32:467-472
Open questions modular approach
Test definition
Mechanistic validity, Similarity of tests
Within-lab. variability
Retrospective
Quality?
Scoring?
Metaanalysis
Equivalence of
protocols?
Transferability
Between-lab.variability
Predictive capacity
Reference, PM/DIP
Applicability domain
Define, expand, restrict
Performance
standards
Applicabiliy, Limitations
Equivalence by reference lab?
Hartung ALTEX 2007, 24:73-80
Toward humane
science
Tox-21c
Validation
In vitro
testing
Russell
and
Burch
Toxicology
desperately
needs to
renew its
toolbox
The evolution
of toxicology:
patchwork
•
•
•
•
•
Every scandal gives one patch.
Many patches are 50-80 years old.
No way to remove a patch.
Difficult to integrate new technologies.
Every patch is of its own appearance and
workmanship.
NAS vision report Tox-21c
An atmosphere of departure in
toxicology
Lessons learned from
alternative methods and
their validation
New technologies from
biotech and (bio)informatics revolution
Mapping of pathways of
toxicity (PoT)
Friday 15th Feb 2008: Coalition of EPA, NTP and
NIEHS-CGC to implement NRC vision
[Science 2008, 319:906-7]
• “We propose a shift from primarily in vivo
animal studies to in vitro assays, in vivo assays
with lower organisms, and computational
modeling for toxicity assessments”
• “[toxicity testing] was expensive, timeconsuming, used animals in large numbers and
didn’t always work” Francis Collin, now Director
NIH
• “Animal testing won’t disappear overnight, but
the agencies’ work signals the beginning of an
end.” Elias Zerhouni, at the time Director NIH
quotes: USA TODAY
Hamburg, M.A.
(2011).
Advancing
regulatory
science.
Science 331,
987
“We must bring 21st century approaches to 21st century
products and problems. Toxicology is a prime example. Most
of the toxicology tools used for regulatory assessment rely on
high-dose animal studies and default extrapolation
procedures and have remained relatively unchanged for
decades, despite the scientific revolutions of the past halfcentury. We need better predictive models to identify
concerns earlier in the product development process to
reduce time and costs. We also need to modernize the tools
used to assess emerging concerns about potential risks from
food and other product exposures. … With an advanced field
of regulatory science, new tools, including functional
genomics, proteomics, metabolomics, high-throughput
screening, and systems biology, can replace current
toxicology assays with tests that incorporate the mechanistic
underpinnings of disease and of underlying toxic side effects.
This should allow the development, validation, and
qualification of preclinical and clinical models that accelerate
the evaluation of toxicities during drug development.”
…and a couple of hundred ways to kill a cell
Vision 5: Mapping the (finite number
of) pathways of toxicity
Annotation to:
- Hazard
- Toxin (class)
- Cell type
- Species
The evolution of toxicology
Animal-based
toxicology
In vitro & in silico
toxicology
Mechanistic
toxicology
VAM
Regulatory
toxicology
Evidence-based
toxicology
academia
Systems toxicology
Validation
- blessing
or curse
for Tox-21c?
• Costs of $400.000+ per test
• Duration of 3+ years validation, 2+ years
for peer-review and 2+ years for
International acceptance
• Through-put limited (40 tests in 20 years)
100 PoT = $40 million and 50 years
• No paradigm shift when comparing to
traditional methods
• Rigidity of validity statement versus
dynamic method development
• Lack of points of reference for PoT-based
models
• No agreed concept for ITS validation
My kick-off:
Application of
EBM approaches
to in vitro
to animal studies
to clinical studies
CRC-Press
1 edition
(August 16, 1993)
- Since 1974: „The Oxford Database of Perinatal
Trials“ (3500 trials; 600 reviews)
- First Cochrane Center in 1992: Oxford, UK
- Cochrane Collaboration founded in 1993
- Today: a world-wide network of about 27.000
scientists, physicians, ... About 5.000 reviews
- US Cochrane Center at Johns Hopkins
Evidence-based Toxicology
“Evidence-based medicine goes toxicology!”
Hoffmann and Hartung “Toward an evidence-based toxicology”,
Human Exp. Tox., 2006
EBT
Method
assessment
Metaanalysis
of
studies
Causation of
health
effects
Clinical
tox.
EBM, mechanistical toxicology,
biostatistics, validation
What we lack:
o Data
o Information
portal
o Meta-analysis
& WoE tools
o Quality scoring
tools
o Probabilistic
risk
assessment
Assessment tool for the quality of toxicological data
 Categorizes quality according to Klimisch scores
 Independent, but largely similar tools for in vivo and
in vitro data/studies
 Expert advisory group
 2 rater experiments:
11 rater are applying the draft tool to 11 in vitro and
in vivo studies
 Tool now available on the ECVAM website
 published Schneider et al.
Tox Letters 2009, 189:138-144
 Impact for existing data for REACH
Definition of Validation
Reliability
(reproducibility)
New
TEST METHOD
✔
Relevance:
scientific basis
!!!
✗
Relevance:
predictive capacity
REFERENCE
(TEST)
?
Scientific
Knowledge
:
- PoT
- MoA
The challenge to Tox-21c will be to steer
toward quality control without the creation
of obstacles by formal validation. A balance
between precaution and innovation is
necessary, and this requires informed
decisions by the actors in the regulatory
arena. EBM has shown how the informed
decision process in clinical medicine can be
served. EBT promises to be its translation
for an informed decision process in risk
assessment.
EBT Collaboration
Thursday, March 10, 2011
Washington DC Convention Center
Steering Committee (and their organizations for identification)
Michael Holsapple, ILSI/HESI
Melvin Andersen, The Hamner Institute
Wendolyn Jones, CropLife America
Richard Becker, Am. Chemical Council
Richard Judson, US EPA
Kim Boekelheide, Brown University
Fran Kruszewski, American Cleaning Institute
Robert Chapin, Pfizer
Martin Stephens, Humane Society of the US
Rodger Curren, IIVS
Bill Stokes, National Toxicology Program
Raymond Tice, National Toxicology Program
Suzanne Fitzpatrick, US FDA
Mark Vossenaar, Agilent
Jack Fowle, US EPA
Neil Wilcox, FDA
Alan Goldberg, JHU CAAT
Joanne Zurlo, JHU CAAT
Thomas Hartung, JHU CAAT
We have to
catch him
That’s not
evidence-based
Johns Hopkins is the right environment for
EBTC secretariat