Alternative approaches and animal use in pharmaceutical industry

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Alternative approaches and animal use in
pharmaceutical industry
Wolfgang Hartwig Executive Vice President
Global Head of RD Bayer
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Use of animals in pharmaceutical RD
As long as there are unmet medical needs
Pharmaceutical industrys role is to develop and
provide patients with innovative, safe and
efficient medicines. For ethical, scientific and
regulatory reasons and despite significant
technological progress, currently this mission is
dependent upon studies in animals. Whenever
performing studies in animals pharmaceutical
industry fully applies the 3Rs principle
refinement, reduction, replacement.
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Laws and Ethics

• Pharmaceutical RD is highly regulated
• Pharmaceutical legislation and guidelines impose
  use of animals
• World Medical Association Ethical principles for
  medical research involving human subject
• The ethical use of animals in research is also
  highly regulated
• EU Directive on Protection of Vertebrates used
  for Scientific and other Experimental Purposes
  (86/609/EEC)
• Council of Europe Convention ETS123, Appendix A
• Specific guidelines at EU and national level

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Alternatives are good business

• Using animals is expensive, resource intensive
  and time consuming
• Alternatives, where accepted, offer many
  advantages
• Low Costs
• Low amounts of testing material needed
• High throughput testing possible
• Easy to perform studies

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Alternatives are good business, however

• They do not mimick the complexity of an intact
  organism, e.g. the functional network of more
  than 200 differentiated cell types
• They are poor predictors for chronic effects.

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Three Rs
Russell and Burch

• Replacement
• Reduction
• Refinement

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Evolution in technologies led to paradigm shift
in RD
In vivo Tests Pharmacology
gt 30 years ago
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Dramatic increase in screening compounds
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Only a limited number of compounds is tested in
animals
gt 1000000 Screening Assay
Isolated Target
10000 in vitro testing
Cellular Systems
100 in vitro testing
In vitro ADME and TOX
5 in vivo testing
Animal testing
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Specific examples for reducing the number of
animal tests
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Many alternatives have been developed already and
are used by Pharmaceutical Industry

• - In vitro models for
• in depth profiling of activity, kinetics and
  metabolism
• general cytotoxicity
• hepatotoxicity
• nephrotoxicity
• neurotoxicity
• bone marrow toxicity
• endocrine toxicity
• - Embryonal stem cell test (EST) for
  teratogenicity
• - Phototoxicity (3T3 NRU)
• - Photogenotoxicity (Photo MNT, Photo Comet)
• - Cardiac toxicity (HERG)

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Modern in vitro toxicological testing strategy
Are there structural alerts? Can potential
toxicities be predicted based on mode of action?
in silico
First Safety Assessment
Genes
Genotoxicity Ames, Cytogene-tics in
vitro, Cardiotoxicity hERG Assay in
vitro, General toxicity cytotoxicity in
vitro, others (e.g. omics) if appropriate
Cells
Tox Profiling in vitro
tissues
Second Safety Assessment
Only compounds which have passed these hurdles
are tested in animals
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Some replacement methods have also been accepted
by regulators

• All accepted methods target only acute effects
• - 3T3 NRU Phototoxicity test
• - Skin corrosivity test
• - HERG Assay
• Together with all stakeholders the goal of
  pharmaceutical industry is to broaden the number
  of validated and accepted alternative methods
• In particular, support of regulatory authorities
  is needed here

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Three Rs

• Replacement
• Reduction
• Refinement

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Reduction of animal numbers in research

• Better designed studies
• More data from one animal study
• Defined animal strains and transgenic animals are
  used
• Refined in-life analysis empowered by genomics
  (DNA-Chips), proteomics and metabonomics
  (Biomarker)
• Enhanced data interpretation by bioinformatics
  and cheminformatics
• Standardisation of animal care and hygiene

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Reduction of animal numbers in toxicological
studies

• International harmonisation of testing
  requirements
• no duplication of studies due to geographical
  differences in testing requirements
• some obsolete tests, e.g. LD50, replaced by more
  sophisticated endpoints
• Optimisation of study design
• combination of different endpoints in one study
  (e.g. inclusion of safety pharmacology parameters
  in toxicological studies)
• Tailored toxicological programs

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Examples for reduction of animal tests

• Improved study design
• Up to 75 reduction in specific areas like
  osteoporosis and cancer pain models
• Flexible and focussed testing strategies
• Tailored toxicological program to support a
  limited number of clinical doses in man
  (exploratory IND) saves 30 animals as
  compared to the conventional approach

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Three Rs

• Replacement
• Reduction
• Refinement

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Refinementsanimal models

• Animal Care
• Excellent control of the macro environment
• Health surveillance programmes
• Extensive staff training
• Social and complex housing
• Animal models
• Using telemetry techniques
• Non invasive imaging
• Non invasive blood pressure
• Improvement in anaestesia protocols and post op
  care
• Specialist staff

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Conclusion

• Evolution of technologies in drug discovery and
  development contributes to a continuous
  replacement, reduction and refinement of the
  number of animal tests.
• Improved study design and focussed testing
  strategies help to reduce the animal numbers.
• Despite all efforts, studies in animals still
  play a significant role in Pharmas mission to
  provide innovative and safe medicines for complex
  diseases.
• Pharmaceutical industry recognizes the importance
  of highest possible ethical standards in animal
  welfare where animal testing is still necessary.
  Moreover, it strives together will all
  stakeholders to continuously reduce the number of
  animal tests.