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The Reduction of Animal Use in the Critical Path to Vaccines

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Deleted guinea pig test for diphtheria (residual toxin and irreversibility of diphtheria toxoid) ... Vaccination serological test in mice or guinea pigs ... – PowerPoint PPT presentation

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Title: The Reduction of Animal Use in the Critical Path to Vaccines


1
The Reduction of Animal Use in the Critical Path
to Vaccines
VRBPAC Meeting February 17, 2005
Sadhana Dhruvakumar Sr. Scientific Research Speci
alist People for the Ethical Treatment of Animals
(PETA) SadhanaD_at_peta.org (757) 622-PETA ext. 81
10
2
Animals in the Critical Path
  • We must modernize the critical development path
    that leads from scientific discovery to the
    patient - Critical Path report, 3/04
  • Assessing Safety
  • Animal safety testing is laborious,
    time-consuming, requires large quantities of
    product, and may fail to predict the specific
    safety problem that ultimately halts
    development.
  • The traditional tools used to assess product
    safety -- animal toxicology and outcomes from
    human studies -- have changed little over many
    decades and have largely not benefited from
    recent gains in scientific knowledge.
  • Demonstrating Medical Utility (efficacy)
  • Currently available animal models have limited
    predictive value in many disease states
  • Many animal methods of vaccine potency testing
    have low reproducibility, have an ill-defined
    relevance to humans, and utilize
    non-physiological routes of infection (e.g.,
    intracerebral inoculation) and so the results are
    often not an adequate measure of human
    protection
  • Industrialization (manufacturing)
  • With respect to drugs, FDA is emphasizing
    advanced engineering principles and control
    technologies, GMP, and in-process
    characterization procedures and standards over
    the traditional requirement for multiple
    conformance batches to ensure manufacturing
    standards.
  • This mentality should be carried over into
    vaccine manufacturing an emphasis on production
    consistency can lead to reduction in routine
    batch testing on animals (more below).

3
Animal Use in Human and Veterinary Vaccines
  • Used in
  • Vaccine development (research, validation of
    efficacy)
  • Production (sometimes in animals, primary cell
    cultures, eggs)
  • Batch control testing (safety and potency
    testing)
  • Routine batch control testing is responsible for
    80 of animal use in vaccine industry and
    regulation
  • Batch control testing of vaccines accounts for
    10 of all animal use in biomedical research,
    using 10 million animals every year
  • Biologicals testing has the highest proportion
    and number of experiments causing severe pain and
    distress to animals out of various types of
    experiments (basic research, toxicity testing,
    etc.)

4
3Rs impact on vaccine batch control testing
  • Replace
  • Antigen quantification (e.g., with ELISA or
    newer technologies for detection of binding
    interactions such as fluorescence polarization or
    surface plasmon resonance)
  • Deletion of certain tests that are no longer
    needed due to increased production consistency
  • Refine
  • Use of humane non-lethal endpoints
  • Vaccination estimation of immune response
    instead of virulent challenge (usually antibody
    estimation using ELISA or ToBI)
  • Reduce
  • Vaccination estimation of immune response
  • Move testing upstream in production process
    (e.g., final bulk rather than final lot)
  • Single dilution rather than multi-dilution
    vaccination-challenge or vaccination-serology

5
US Department of Agriculture (USDA)
Center for Veterinary Biologics (CVB)
  • Held their first alternatives meeting in April
    2004 Technology and Approaches to Reduce,
    Refine Replace Animal Testing with very active
    participation from over 150 attendees from
    industry and the CVB
  • Has presented to U.S. Interagency Coordinating
    Committee on Validation of Alternative Methods
    (ICCVAM) advisory committee on their development
    of an antigen quantification test (sandwich
    ELISA) for leptospira vaccine
  • Embarking on comprehensive effort to change
    legislation and regulations to encourage use of
    non-animal methods including
  • Umbrella policy holding animal tests to the
    same standards as new in vitro tests
  • Changing language to include novel non-animal
    technologies and encourage movement away from
    animal testing
  • Replace
  • USDA has developed an in vitro potency test
    (antigen quantification) for leptospira vaccine
  • USDA is developing in vitro potency test
    (antigen quantification) for clostridial vaccine
    this involves identifying protective immunogens
    and establishing references
  • We cant expect industry to go out and develop
    the alternatives. Its a static market so the
    demand is there for alternatives but not the
    financial incentive. CVB must be the leader.

6
European Center for the Validation of Alternative
Methods (ECVAM)
  • Since 1993, Biologicals is one of 11 key areas
    set up with a permanent Biologicals Working Group
    and a Pyrogenicity Task Force ECVAM also works
    with Advisory Group on Alternatives to Animal
    Testing in Immunobiologicals (AGAATI) on these
    issues
  • Workshops and other communication efforts
  • Has organized 9 workshops on alternatives in
    biologicals production and quality control
    (Including Three Rs Approaches in the Quality
    Control of Inactivated Rabies Vaccines)
  • Has organized 5 VACTRAINING sessions to
    provide hands-on lab training in alternatives
  • Financially contributes to other relevant
    conferences, expert reports, manuals, training
  • Has published many workshop reports and
    scientific papers and reports
  • Replace
  • Validated commercially available ELISA kits for
    rabies potency testing (1999)
  • Validated human-blood-based pyrogenicity test
    (just completed)
  • Prevalidation of Vero cell test for specific
    toxicity testing of diphtheria toxoid
  • Prevalidation of ELISA, ToBI and rocket
    immunoelectrophoresis assay for batch potency
  • testing of tetanus antisera and immunoglobin
    validation of ToBI recommended (2000)
  • Refine
  • Sponsored development of humane endpoints for
    rabies, pertussis, and erysipelas challenge tests
    (1999)
  • Validated ELISA and ToBI test for batch potency
    testing of human tetanus vaccine (2000)
  • Validated ELISA test for swine erysipelas
    vaccine

7
European Directorate for Quality Medicine(EDQM)/
European Pharmacopeia (Ph. Eur.)
  • Has organized various international conferences

  • Replacement, reduction and refinement of the
    use of animals in the quality control of
    vaccines in November 2002
  • Serological Potency Tests for Diphteria and
    other Vaccines in October 2004
  • Replace
  • Accepts antigen quantification test for rabies
    (1998)
  • Deleted Abnormal Toxicity Test (in favor of
    production consistency approach)
  • Deleted guinea pig test for diphtheria (residual
    toxin and irreversibility of diphtheria toxoid)
  • Deleted in vivo test for polio (for some
    manufacturers)
  • Deleted residual pertussis toxin test for
    acellular pertussis (for some manufacturers)
  • Refine
  • Accepts vaccination-serology tests for tetanus,
    diphtheria, and cholera vaccines (in lieu of
    vaccination-challenge)
  • Recommends use of humane endpoints in
    vaccination-challenge procedures
  • Reduce
  • Accepts single dilution assays for diphtheria,
    tetanus, and acellular pertussis vaccines (in
    lieu of multiple dilution assays)
  • Accepts vaccination-serology tests for tetanus,
    diphtheria, and cholera vaccines (in lieu of
    vaccination-challenge)
  • A licensing authority can waive tests in
    monographs if it is assured of production
    consistency

8
World Health Organization (WHO)
  • Replace
  • Accepts antigen quantification for batch release
    of Hep B vaccines (1999)
  • Studying deletion of Abnormal Toxicity Test
  • Refine
  • Replaced live poliomyelitis vaccine
    neurovirulence monkey test with a transgenic
    mouse test and MAPREC (mutant analysis by
    polymerase chain reaction and restriction enzyme
    cleavage) (2000)
  • Accepts ToBI test for tetanus toxoid and Vero
    cell test for diphtheria toxoid (1995)
  • Reduce
  • Accepts single dilution assays for tetanus and
    diphtheria toxoids
  • Accepts TOBI test for tetanus toxoid and Vero
    cell test for diphtheria toxoid (1995)

9
Status of alternatives in common vaccines
bacterial vaccines
10
Status of alternatives in common vaccines viral
vaccines
Already not tested in animals Influenza (tested
in eggs), Meningococcal and Pneumococcal (only
need pyrogen test which can be done in vitro),
Oral typhoid, Varicella, Measles, Mumps, Rubella
Currently no alternatives available BCG (2 safe
ty tests on 6 guinea pigs each)
Not covered here Yellow Fever, Smallpox, Japane
se Encephalitis, Anthrax
11
Critical Path opportunities for promoting
progress and change
  • Devote more FDA research to better defining
    pathogens, vaccines, human-based tissue
    engineered models of infection, and adjuvants
    with a goal of developing of modern non-animal
    technologies such as antigen quantification and
    enabling rational vaccine design
  • Validate and accept newer non-animal technologies
    (fast-tracking technologies already validated by
    other regulatory bodies)
  • Promote switching licensed products over to
    modern non-animal technologies for ongoing batch
    testing (e.g., fee waivers, incentives, research
    assistance)
  • Better familiarize FDA reviewers/researchers with
    new technologies
  • Publish guidances and organize workshops on
    animal testing alternatives
  • In 50-100 years, we will be far beyond using
    animals as surrogates for humans in vaccine
    testing how do we get there from here?
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