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

10 Years of ICCVAM:Challenges, Successes

ICCVAM 10th birthday?Committee 1994, authorization act 2000

• Collaboration with ECVAM, JaCVAM, KoCVAM also in ICATM

• OECD guidance document 34

There is only one validation process

… 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?

• Only minor consumers of animals replaced• Compensated by increased testing

Trends Europe statistics 2008 published in 2010- Numbers stable compared to 2005 (likely 7.5% increase, error Greece fish use 2005)- Use for pharma research from 31 to 23%- Tox uses stably 10%- 90.000 animals for chemicals (REACH: 9+ million…)- Some impact on acute tox, sensitization and topical tox visible- Increase of Botox and pyrogenicity animal numbers

Definition of Validation

NewTEST METHOD

REFERENCE(TEST)

Reliability (reproducibility)Reliability (reproducibility)

Relevance:

scientific basis

Relevance:

scientific basis

Relevance:predictive capacityRelevance:predictive capacity

Validation modular approach

Test definition

Within-lab. variability

Transferability

Between-lab.variability

Predictive capacity

Applicability domain

Performance standards

Reprodu-cibility

Relevance

“Standardised”

“Suitable/Adequate”

“Validated”

“Equivalent”

Hartung et al. ATLA 2004, 32:467-472

Open questions modular approach

Test definition

Within-lab. variability

Transferability

Between-lab.variability

Predictive capacity

Applicability domain

Performance standards

Mechanistic validity, Similarity of tests

RetrospectiveQuality?Scoring?MetaanalysisEquivalence of protocols?

Reference, PM/DIP

Define, expand, restrict

Applicabiliy, LimitationsEquivalence by reference lab?

Hartung ALTEX 2007, 24:73-80

Toward humane science

Toxicology desperately needs to renew its toolbox

The evolutionof 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.

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)

NAS vision report Tox-21c

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 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.”

Hamburg, M.A. (2011). Advancing regulatory science. Science 331, 987

…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

Regulatory toxicology

The evolution of toxicology

Mechanistic toxicology

In vitro & in silico toxicology

Animal-based toxicology

Evidence-based toxicology

Systems toxicology

VAM

academia

• 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

Validation- blessing or curse for Tox-21c?

CRC-Press1 edition (August 16, 1993)

My kick-off:

Application of EBM approaches

to in vitroto animal studiesto clinical studies

- 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

Method assess-ment

Method assess-ment

Meta-analysis

of studies

Meta-analysis

of studies

EBM, mechanistical toxicology, biostatistics, validation

EBM, mechanistical toxicology, biostatistics, validation

EBTEBT

Causa-tion of health effects

Causa-tion of health effects

Clinical tox.

Clinical tox.

What we lack:o Datao Information portalo Meta-analysis & WoE toolso Quality scoring toolso 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

NewTEST METHOD

REFERENCE(TEST)

Reliability (reproducibility)Reliability (reproducibility)

Relevance:

scientific basis

Relevance:

scientific basis

Relevance:predictive capacityRelevance:predictive capacity

✔!!!

✗?

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 CenterSteering Committee (and their organizations for identification)

Melvin Andersen, The Hamner Institute

Richard Becker, Am. Chemical Council

Kim Boekelheide, Brown University

Robert Chapin, Pfizer

Rodger Curren, IIVS

Suzanne Fitzpatrick, US FDA

Jack Fowle, US EPA

Alan Goldberg, JHU CAAT

Thomas Hartung, JHU CAAT

Michael Holsapple, ILSI/HESIWendolyn Jones, CropLife AmericaRichard Judson, US EPAFran Kruszewski, American Cleaning InstituteMartin Stephens, Humane Society of the USBill Stokes, National Toxicology ProgramRaymond Tice, National Toxicology ProgramMark Vossenaar, AgilentNeil Wilcox, FDAJoanne Zurlo, JHU CAAT

We have to catch him

That’s notevidence-based

Johns Hopkins is the right environment for EBTC secretariat