Anna Olsson

Ethics review of animal-based
research
Working group 4 COST B24
Rony Kalman, Anna Olsson, Claudio Bernardi,
Frank van der Broek, Aurora Bronstad, Isztvan
Guertyan, Aavo Lang, Katerina Marinou,
Jaques Serviere, Walter Zeller
Background
• Action initiated in 2003
• Bringing together laboratory animal
science experts from the COST countries
• COST Manual: recommendations and
guidelines based on evidence-based
information on the most proper execution
of animal experiments
6/7/2009
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Ethics review - background
• Most European countries have some kind
of ethics review system in place
• No reference to ethics review in Directive
86/609/EEC
• Unclear how ethics will be dealt with under
revised Directive
• ?Evidence ?Evidence-based ?Evidence based information?
• Expert opinion + critical discussion
Organization
• Check-list of key issues to be addressed in
a review
– Tool for new committees (and new committee
members) finding their way of working
– Quality tool for crosschecking review work of
existing committees
• Discussion of potential and limitation for
considering aspects
6/7/2009
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Checklist for ethics reviews
• Description and purpose of the study
• Replacement
• Refinement
• Reduction
• Competence
• Other aspects
– Composition of an ethics committee
Ethics committee composition
Minimum expertise
• Scientists with knowledge and expertise in
biological and biomedical research.
• Veterinarian (preferably with qualifications
in laboratory animal medicine)
• A person without affiliation to the
requesting organization
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3

Ethics committee composition
Additional valuable expertise
– Animal technician / caretaker
– Animal protection organizations
– Patient organization
– Statistician
– People with knowledge on alternatives to the
use of animals
– People with knowledge on animal welfare
– Ethicist
The ethics review
Description and purpose of the study
• Is there a description of the background
and scientific reasoning of the general
research and is the hypothesis to be
tested specified?
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4

Replacement
• Is there a precise statement clarifying
why animals cannot be replaced by nonanimal
approaches?
• Is it clear that alternatives have been
evaluated and which literature and
databases have been consulted?
Refinement
• Is the origin of animals intended to be used in the
experiments clear?
– If not standard laboratory animal breeder, (i.e. animals from
the wild), are methods for capture, restraint, identity marking
and transport described and is the acclimatization period
defined?
– Do the animals have special needs (specific congenital
conditions, altered immunological status etc.).
• Is it clear how the animals will be prepared, handled
and acclimatized prior to the experiment?
• Are all experimental stages clear in terms of time scale
and types of procedures involved (acclimatization
phase, experimental phase, termination)?
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Refinement
• Is there a clear protocol for anesthesia and pain
control? Are doses, volumes, administration routes
and frequency, and treatment duration reasonable for
the species and actual procedure performed – and are
they in accordance with relevant literature?
• Are the Humane Endpoint (HEP) Criteria well defined
and are the actions to be taken when reaching these
criteria clear? Is it clearly identified who within the
organization will be finally responsible to make the
decision (attending veterinarian, scientists,
management, other)?
Refinement
• Is there a list of techniques performed during
the experiments? How will these techniques
and the data collection influence the animals?
• Are the follow up inspections with the animals
described, and are they sufficient to identify
potential complications in time?
• Is method and time of euthanasia clearly
defined? If there are any alternatives to
euthanasia available (i.e. sanctuary for
primates, return to herd for farm animals), are
they specified?
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Refinement
• Is there a description of housing and experimental
conditions and enrichment for the animals?
– If special housing conditions (i.e. metabolic cages, single
housing) are requested for the experiment, are they
described?
– If special housing conditions (i.e. moist diet, extra bedding) are
required to guarantee animal welfare, are they described?
– Is the social housing adequate to the animal species and the
research design described?
– Do facilities fulfil all requirements necessary to carry out this
study? (experimental areas, rooms for postoperative care,
special condition for microbiological containment, etc.)
• Has this experiment been evaluated and classified
according to a severity classification system?
Reduction
• Has the committee been assured that only the optimal
number of animals requested is being used in the
study? Was a proper analysis performed on these
aspects by a qualified person?
• Has the potential conflict between the reduction of
number of animals and fairness to the individual
animal been considered in this experiment ?
• Is the re-use of animals an option in this application? If
yes, has the severity of the two experiments (previous
one and the requested one) been taken into
consideration?
• Has the option of performing a limited pilot study been
addressed by the researcher, and if this option was
considered but not taken, was it justified?
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Competences
• Is it clear who the principal researcher in the
project is?
• Are his or her qualifications and competence
clear and sufficient?
• It there a list of the other participants in the
research group? Does the list include details
on education and training of personnel
involved in the procedures?
• Has any experts been consulted during the
study design and the preparation of the
application (statistician, veterinarian, animal
welfare officer, other)?
Organization
• Check-list of key issues to be addressed in
a review
• Discussion of potential and limitation
for considering aspects
6/7/2009
8

Limited benefit as a reason to
deny a license
• Ethics review is often described (and
possibly perceived by the public) as
balancing animal harm against benefit to
humans (and other animals)
• Committees usually focus on the animal
harm side
• To fulfil their responsibility towards the
public, committees should possibly
address both
Limited benefit as a reason to
deny a license
• Law rules out some uses: tobacco product
development (UK), cosmetics (EU)
• On the other hand, law also “rules in”
uses: safety testing of products however
futile these are perceived
• Do committees really have remit to decide
here?
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Replacement alternatives
• Standard question - under present
directive, llegal to use animals if nonanimal
method exist
• Replacement alternatives exist mainly for
some standard procedures (toxicity) +
teaching
• Replacement in science generally means
a change of approach – attitudes of
scientists rather than ethics committee
decisions
Responsibility and authority:
humane endpoints
• HEP means that data collection from an
animal stops when it has reached predefined
clinical status
• Potential conflict of interest between many
involved:
– Animal caretakers / technicians inspecting
animal
– Scientist running study
– Veterinarian responsible for animal welfare in
the facility
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Responsibility and authority:
humane endpoints
• Not applying HEPs when they should be
applied means more suffering than
necessary
• Veterinary decision carries most weight
(ETS123, 86/609/EEC)
• Involving all personnel in planning to
prevent conflicts
• Ethics committee to handle conflicts adhoc
Severity banding
• Speed up procedure
• Transparency
• Severity: number or an equivalent term
(e.g. “moderate”), with various and quite
often obscure underlying algorithms of
calculation
• Making this procedure too automatic risks
the quality
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Study design: the need for
qualified personnel
• Optimal number of animals – again a
standard question
• Power analysis or equivalent to estimate
animal numbers
• However dependent on specialized
knowledge only a scientist from the field
knows: variation, size of biologically
relevant effect etc
Study design: the need for
qualified personnel
• More efficient to educate the scientists and
to require them to consult with statisticians
than to try to cover this aspect in detail in
the committee
• It may still be useful for the committee to
have a statistician linked to them to
discuss protocols that seem weak or
otherwise complicated
6/7/2009
12

Reduction and standardization
• Standardizing to reduce number of
animals
• Narrowing down the range of conditions
(sex, age, genotype) reduces the potential
for extrapolation
• Consider possible culling of animals if only
one sex used
Reduction and standardization
• Narrowing down the range of conditions
reduces the potential for extrapolation
• Systematic variation rather than increased
variation (e g several inbred strains rather
than one outbred, several housing
conditions)
• Animal studies in general use too few
animals – n for animal studies much
smaller than the reduction in variation
(compared to human clinical trials) justifies
6/7/2009
13

Reduction vs Refinement
• Repetitive use of animals when not part of
the same protocol
• The benefit of Reduction compared with
the additional cost in Refinement
• The level of the total burden (including
possible non-recovery from first
intervention)
• Total duration plus recovery interval
Review of previous projects –
harm evaluation
• Information about animal welfare / animal
harm in previous projects potentially very
useful in hte evaluation of future projects
using similar approaches
• Information not found in existing literature
• Committees with retrospective review
process can do this internally
• Central database for information transfer
across committees
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Ensuring scientific validity
• Scientific validity critical for ethical
acceptability
• Most committees do not address
• Assumed ensured through funding
• But not all work funded through peerreviewed
applications
• Funding application often not detailed
enough
Ensuring scientific validity
• Concurrent scientific application
(assuming ethics is evaluated by
somebody else) and ethics application
(assuming science is evaluated by
somebody else) means harm is not
weighed against benefits
• Evaluation for funding should include
overall ethics assessment
• Ethics committee should evaluate details
6/7/2009
15

Communicating with the public
• Transparency versus need to protect
information (innovation and personal
integrity concerns)
• Freedom-of-information acts will enable
access also to this information
• Proactive – online publication of lay
summaries
Appropriate level of review
• Project, experiment, procedure?
• Different levels mean different focus and
review possibilities
• Project: replacement
• Experiment: reduction
• Procedure: refinement
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Appropriate level of review
• The proposed checklist aims to include
everything
– Mission impossible?
– Adminstrative burden for ethics committees – and
scientists
• Alternative: general review (on project level) +
trust that institutions have mechanisms in place
to ensure use of refined techniques, competent
personnel etc
The social role of the ethics review
committee
• ‘Culture of care’ – responsible use of
animals
• “Trust is good – control is better” – or?
• Education
• Discussion of ethical issues – internally
and with the public
6/7/2009
17

• To the COST office
for supporting this
action and Timo
Nevalainen for
initiating it
• To working group
members
Thanks
• For your attention
• olsson@ibmc.up.pt
6/7/2009
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