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Slide 1 - Society of Toxicology

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					         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% minor
                                           • Only
increase, error Greece fish use 2005)      consumers of
- Use for pharma research from 31 to 23% animals
                                           replaced
- Tox uses stably 10%
                                           • Compensated
                                            million…)
- 90.000 animals for chemicals (REACH: 9+ by increased
- Some impact on acute tox, sensitization and topical
                                           testing
tox visible
- Increase of Botox and pyrogenicity animal numbers
                    Definition of Validation
Reliability            New                   Relevance:
(reproducibility)      TEST METHOD           scientific basis


                                     Relevance:
                                     predictive capacity


                       REFERENCE
                       (TEST)
            Validation modular approach

Test definition                                    “Standardised”

Within-lab. variability
                          Reprodu-
                          cibility
Transferability

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?
Transferability                                 Scoring?
                                                Metaanalysis
Between-lab.variability                         Equivalence of
                                                protocols?
Predictive capacity       Reference, PM/DIP

Applicability domain      Define, expand, restrict

Performance               Applicabiliy, Limitations
standards                 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, time-
  consuming, 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
                “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 half-
                century. 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
Hamburg, M.A.   of regulatory science, new tools, including functional
(2011).         genomics, proteomics, metabolomics, high-throughput
Advancing       screening, and systems biology, can replace current
regulatory      toxicology assays with tests that incorporate the mechanistic
science.        underpinnings of disease and of underlying toxic side effects.
Science 331,    This should allow the development, validation, and
987             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
                             Regulatory
                               toxicology
In vitro & in silico
      toxicology
                       VAM
                              Evidence-based
                                toxicology
  Mechanistic
   toxicology    academia
                Systems toxicology
               • Costs of $400.000+ per test
Validation
               • Duration of 3+ years validation, 2+ years
- blessing       for peer-review and 2+ years for
                 International acceptance
or curse       • Through-put limited (40 tests in 20 years)
for Tox-21c?
               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
                                              What we lack:
                   EBT                        o Data
                                              o Information
                                                 portal
Method
             Meta-
            analysis
                         Causa-
                         tion of   Clinical
                                              o Meta-analysis
assess-
 ment
               of        health      tox.        & WoE tools
            studies      effects
                                              o Quality scoring
                                                 tools
      EBM, mechanistical toxicology,
                                              o Probabilistic
         biostatistics, validation
                                                 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
                                          ?       Scientific
                       (TEST)
                                                  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)
Melvin Andersen, The Hamner Institute     Michael Holsapple, ILSI/HESI
Richard Becker, Am. Chemical Council      Wendolyn Jones, CropLife America
                                          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
Suzanne Fitzpatrick, US FDA               Raymond Tice, National Toxicology Program
Jack Fowle, US EPA                        Mark Vossenaar, Agilent
                                          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

				
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