European Partnership on Alternatives Approaches to Animal Testing: Working Group 4 Industries perspe

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European Partnership on Alternatives Approaches
to Animal Testing Working Group 4Industries
perspective Vaccines for Human Use

• EFPIA, Brussels, 12 October 2006
• European Vaccine Manufacturers
• Cecile Ponsar, GSK Biologicals EVM

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Industries perspective Vaccines for Human Use

• Status on vaccines
• Purpose of animal use
• Some figures
• Vaccine specificities
• Types of testing
• Industries point of view
• Target
• Reducing animal testing/use
• Proposal
• From alternative method to alternative approach
• Option in the field of commercial release

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Vaccines and Pharmaceuticals Animal Use

• Animal use All stages of vaccine development
  and commercialization
• Basic research on disease processes
• Use of models of diseases to test candidate
• Preclinical safety, efficacy, stability testings
• Production and control development (process and
  testing validation, detoxification,
  inactivation,)
• Quality control for commercial release

Pharmaceuticals
Biopharmaceuticals (Vaccines)

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Vaccines versus Pharmaceuticals Some Figures
Comparison of relative percentages of animal used
for regulatory purposes
Regulatory activities
Regulatory activities
Toxico
RD
RD
Batch release
20
Process change
Control change
80
Stability
Toxico
Vaccines
Pharmaceuticals
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Vaccines versus Pharmaceuticals Some Figures
Comparison of relative percentages of animal used
for commercial purposes
Commercial activities
Non commercial
Batch release
100 RD
0 Commercial
Vaccines
Pharmaceuticals
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Vaccines and Regulatory Requirements

• Specificities of vaccines compared to
  pharmaceuticals
• Each lot of medicines for human use is tested for
  quality by the manufacturer (Art 51 Codified
  Directive 2001/83/EC as amended by 2004/27/EC)
• Each lot of vaccine must be released by and may
  be tested by control authorities (Art 113 114
  Codified Directive 2001/83/EC as amended by
  2004/27/EC) before release onto the EU market

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Vaccines and Regulatory Requirements

• Specificities of vaccines compared to
  pharmaceuticals
• Biological nature versus a well characterized
  chemical product
• Complex mixture of active ingredient(s),
  immunostimulant(s) and adjuvant(s) versus active
  ingredient(s) and excipient(s)
• Vaccines action way on disease indirect through
  immune system versus direct drugs action on
  disease
• Inherent variability of biological systems

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Vaccines and Regulatory Requirements

• Specificities of vaccines compared to
  pharmaceuticals (Contd)
• Prophylactic application versus therapeutic
  application
• Vaccination policy defined by governments
  responsability
• Regulations aimed/politics focused at minimizing
  health risk
• In practice, each vaccine lot is tested and
  released by
• local authority
• Double batch release Double testing
• Double animal number

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Vaccines Type of Testing

• Two families of in vivo quality control tests
• Innocuity tests Low number of animals
• 20 of regulatory activities
• Efficacy tests High number of animals
• 80 of regulatory activities

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Vaccines Industries Point of view

• In vivo test first bottleneck in
• release lead-time
• Variability and repeats
• Genetic backgrounds
• Animals availablity (supplier qualification)
• Animal health status
• Animal house capacity

Time/cost consuming
10 of control activites but 100 of total
release time 10 of control activities but 50
of total control cost
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Vaccines Industries Point of view

• What has been achieved so far?
• On the OMCLs side
• Mutual recognition of batch release within the EU
  avoiding repetitive testing (time, workload,
  cost)
• EU Union free circulation within the EU
• Harmonisation of specifications, methods, data
  interpretations
• Collaborative studies
• EDQM OMCL network trust building between
  partners
• Reducing animal testing
• Test only new ag bulk entering into final lots
  (in vivo)
• EDQM OMCL internal procedure for in vivo tests
  waiving

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Vaccines Industries Point of view

• What has been achieved so far (Contd)?
• On the manufacturers side
• Increase the lot size but not infinite
• In vivo tests from final container to final bulk
  stage
• On both sides
• Implement in vitro alternatives to in vivo tests
  wherever and whenever possible

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Vaccines Industries Point of view

• What could be considered?
• Enhance development of alternatives methods but
• Limitations to alternative methods
• Some alternatives more animals, longer, more
  onerous
• Variation to the marketing authorization required
• Within EU Room left for legislation
  interpretation Divergence
• Outside the EU No global harmonized regulatory
  framework
• Cultural, political and social (public opinion)
  differences
• Current scientific knowledge making some
  alternatives unrealistic
• A lenghty, non harmonized and onerous process

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Vaccines Industries Point of view
More than 85 of vaccines are developed and
produced in Europe
EVM survey, 2006
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Vaccines and Animal Use Target

• Recent developments have boosted various actors
  in science, industry and policy making to
  consider ways of replacing experiments on animals
  by
• Alternatives methods
• Target Reducing the number of animals used for
  testing purposes by proposing
• Alternative approaches
•  3 Rs Refine, Reduce, Replace 

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Vaccines and Animal Use Target

From alternatives methods to alternative
approaches In vaccine arena Room for
opportunities
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Vaccines and Animal Use Target

• While in vivo tests play an important role in
  RD and in quality control of vaccines for human
  use, creative ways for reducing the number of
  animals should be considered for
• commercial batch release
• 30 of all the animals used by the vaccine
  industry
• To be multiplied for release by control
  authorities

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Vaccines and Animal Use Target

• Prerequisites
• To maintain the following priorities
• SAFETY
• EFFICACY
• STABILITY
• Industry remains responsible

Global Quality
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Vaccines and Animal Use Proposal

• Premises
• Consistency
• Nature of the product
• Development of analytical tools
• Testing history

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Vaccines and Animal Use Proposal

• A bit of history
• First regulatory requirements for quality control
  introduced after vaccine-related accidents (1900
  to 1955)
• Independent testing by the Medicines Control
  Laboratory introduced on a national basis
  (1970-1980)
• Development of specific Directives in 1989
  recognizing the value of batch release
  (2001/83/EC OCABR as a  may  clause)
• Quality control introduced due to large
  differences in quality between batches of the
  same vaccine Variability
• Double testing would offer a better ensurance of
  quality

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Vaccines and Animal Use Proposal

• Since then, times have changed.Consistency
• From process and product variability to
  consistency of production each batch of a
  product is of the same quality and is within the
  same specifications as the clinical trial lots
  shown to be safe and efficacious
• Quality control should monitor critical steps
  during production rather than rely on control of
  the final batch

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Vaccines and Animal Use Proposal

• Since then, times have changed.
• Nature of the product
• New and well-characterized products (purified
  proteins, polysacharrides, recombinant antigen,)
• Analytical tools development
• Physichochemical, immunochemical or biomolecular
  methods better able to monitor consistency than
  in vivo testing
• Testing history Huge positive restrospective
  experience

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Vaccines and Animal Use Proposal

• Proposals characteristics
• Important impact on the number of animals
• Short- to mid-time frame
• Joint effort shared by industry and authorities
• Authorities resistance to change
• Stepwise approach

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Vaccines and Animal Use Proposal

• Option 1 In vivo tests waiving by the control
  authority based on retrospective analysis
• FDA/BGTD/WHO approach
• No sample testing by OMCL
• Only administrative release of each lot by OMCL
• Test waiving following file submission by the
  manufacturer to a reference OMCL and approval by
  the OMCL

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Vaccines and Animal Use Proposal

• Option 1 In vivo tests waiving by the control
  authority under defined circumstances
• Production and testing history (retrospective
  analysis)
• GMP Inspection history
• Post-marketing surveillance
• Test waiving maintained through
• Periodic Quality Review (in force since January
  2006)
• Protocol review by the OMCL
• Periodic testing by the OMCL

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Vaccines and Animal Use Proposal

• Option 2 In vivo tests waiving by the control
  authority and by the manufacturer i.e. no animal
  testing for well known products under defined
  circumstances
•  Build quality in rather than quality out 
• With punctual check for control and for retaining
  expertise

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Vaccines and Animal Use Proposal

• In any option
• In vivo test only used by the manufacturer and
  the control authority for the purpose of
  characterizing new vaccines (new antigens, new
  combinations) or major changes to the
  manufacturing process

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Vaccines and Animal Use Proposal

• Summary Percentage of animal saving for
  commercial control activities by the
  manufacturer and the control authority

30 of all the animals used by the manufacturer
x for release by authority
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Vaccines and Animal Use Conclusion

• Animals have and will continue to have a key role
  in research, development and quality control of
  vaccines
• Development of biotechnologies, increased GMPs
  and better control of production processes gives
  room for reducing the number of animals used in
  release activities
• While development of alternatives methods remain
  the ultimate goal, a new way of thinking batch
  release could lead to a drastic reduction in
  animal testing in the short-to mid-term

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Vaccines and Animal Use Conclusion

• Strong incentive for Manufacturers to maintain
  and continuously improve their quality level
• All this requires communication and close
  collaboration between legislator, control
  authorities and manufacturers
• Thank you!

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Vaccines and Animal use

• Back-up

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Regulatory Requirements for A.T. Status
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Regulatory Requirements for A.T. Status
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Regulatory Requirements for A.T. Status
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Vaccine Type of Testing
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OMCLs release capacity Proposal

•   More emphasis is now being placed on
  consistency of production than on testing
  parameters that may be linked with quality at
  each stage of the process Laboratory testing for
  lot release is only a small part of the overall
  regulatory process of the NRA. This does not mean
  that the laboratory testing for lot release has a
  lesser role. It is important that the laboratory
  staff, as technical experts, are involved at all
  stages of the regulatory process, providing input
  into review of the dossiers, facility
  inspections, clinical evaluation and most
  especially in the lot-release-process. Moreover,
  the need for testing will not disappear. Apart
  from the need for lot release testing as defined
  in the MAA, the NCA will be involved in
  regulatory research, to characterize products
  better physically and chemically, in test
  validation and in the preparation of Intl
  standards and references 
• J. Milstein, WHO 2002