Title: The Reduction of Animal Use in the Critical Path to Vaccines
1The 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
2Animals 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).
3Animal 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.)
43Rs 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
5US 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.
6European 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
7European 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
8World 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)
9Status of alternatives in common vaccines
bacterial vaccines
10Status 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
11Critical 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?