Development and Implementation of

Performance Standards

Guy B. Mulder, DVM, MS, DACLAM

Exec. Director, Veterinary and Professional Services
Research Models and Services

Todays talk
Performance standards
The Guide
General approach
Goal

Key steps
Key stakeholders
Our philosophy and approach
Standardized process
Proposal, review and analysis, post-approval monitoring

Illustrate with several examples

Performance standards
The Guide endorses a performance-based
approach to meeting Guide recommendations
Performance approach requires(Guide, p 6)

Professional input
Sound judgment
Team approach
Clearly defined outcomes and goals
Regular monitoring of performance measures

Oversight, review and approval by the IACUC

Goal
A performance approach allows use of alternative
methods to those outlined in the Guide to provide
equivalent or improved conditions for animals
Conditions that do not meet minimal Guide
recommendations should result in deleterious
changes in animal welfare that are measurable

Key steps in using performance standards

1. Gap analysis
Identify exceptions to the Guide
Can you comply with Guide recommendations?

2. Define desired outcomes/goals

3. Identify performance measures

Requires review of current literature and industry practices

4. Plan and perform an evaluation

Compare alternative vs. Guide recommendation

IACUC review and approval

5. Review of results
IACUC: approve, disapprove, or require modifications to the
exception

6. Regular monitoring

Post-approval monitoring, annual review, etc.

Key stakeholders
The IACUC
Attending veterinarian
Researchers
Animal users
Specialists (as needed)
Unique expertise in areas of study design, equipment,
interpretation of results, etc.

Vivarium management
Including husbandry personnel

Standardized approach is beneficial

Documents review by
IACUC
Transparency
Key decisions and ongoing
requirements are documented
and readily accessible
Historical record

Standardized form
Consistency and
documentation purposes

Standardized process (IACUC form)

Describe specific procedure/practice for exception
Species affected
Guide recommendation on the subject
May include regulatory guidance as well

Proposed exception
Rationale for the exception
Proposed performance measures
Proposed methods to investigate the exception
Research proposal with hypothesis
Including statistical analysis when applicable

Results reviewed
Variance approved/modified/denied by IACUC

Post-approval monitoring parameters developed

Identify exceptions
Examples
Cage density of mice and rats
Cage change frequency
Multiple rodent species in the
same housing room
Water bottle sanitation
frequency

Example exception (variance)

Cage density guidelines
New = Female + litter

Species:
Mice and rats

Breeding cages
1 male + 2 females &
litter(s)
Strict interpretation of
space recommendations
problematic

Guide, p 57

Application of variance
Applied only to production
facilities housing mice and
rats
Variance specifies
not apply to animals that are
experimentally manipulated
Guide, p 56

Guide recommendation
Space allocation
Table 3.2 (prior slide)

Also allows for adjustment

to space allocation
guidelines
Based on performance
indices

Space allocation
performance indices

Health
Reproduction
Growth
Behavior
Activity
Space utilization
Special needs
e.g. obesity

Experimental use
Guide p 56

Proposed variance
Continued use of .cage density standards
developed by Charles River based upon many
years of experience with producing rodents at
these densities
Densities modified over the years in response to internal
evaluations and professional judgment

Rational for variance

The Guide acknowledges that space allocation
recommendations are based on professional
judgment and experience
Production (commercial breeding) and sale is
different from research use of animals
No experimental manipulations

Lack of published peer-reviewed literature

establishing specific space allocations for rodents in
breeding (or experimental) settings
Internal data indicating animal welfare is not
compromised at current CRL cage densities

Rationale for variance

Existing space allocations meet definition of
adequate space
(Guide, p 56)
- Adequate space to express natural postures and
postural adjustments without touching walls of
enclosure
- Able to turn around
- Access food and water
- Rest away from soiled areas

- Sufficient space for mothers and litters to allow

pups to develop to weaning without detrimental
effects for mother or litter
(Guide, p 57)

Selecting performance measures

Objective measures that are clinically relevant and
clearly quantifiable
Multiple measures from each of the following
categories:
Production indices
Behavioral indices
Clinical measures

Collected in standard production settings

Production barrier rooms, isolators
Supplemented with laboratory measurements as needed

Post-approval monitoring
Utilizing key performance indicators

Practical sampling considerations

Not overly reliant on extensive instrumentation or
practices that may induce confounding variables
or limit sample size
Telemetry for heart and respiratory rate, serum and
urine constituents, complex behavioral assessments,
etc.

Restrict to representative number of stocks and

strains - Not all
Limited number of sampling locations (facilities)
Providing environments are similar

How to select specific performance measures?

What are likely to be the measurable adverse
events that could arise from selecting the
alternative?
Based on that, select the most likely measures to be
affected.

With respect to cage space and a mother with

litter, reproductive indices, growth, general health,
aggression, and stereotypic behaviors appear to
be reasonable measures for consideration

Performance measures
Categories:
Production indices
Behavioral indices
Clinical measures

Multiple measures
from each

Space allocation
performance indices

Health
Reproduction
Growth
Behavior
Activity
Space utilization

Reproductive performance
Example indices
Production Index (PI)
Pups weaned per female breeder per week

Litter size at birth

Survival to weaning
Sex ratio
Weaning weight
Inter-litter interval
Time to first plug
Time to female pups vaginal opening

Behavioral assessment
Example Indices
Aggression/Fighting
Maternal aggression
towards pups
Aggression between
weanlings and adults

Hair loss (barbering)

Stereotypic behavior
Space utilization within
cage

Scoring systems
For each parameter
Most data collected in
production rooms by
trained husbandry
technicians
Space utilization
required 24-7
videography, difficult to
achieve in a functioning
barrier room.

Behavioral assessment scoring

Behavioral measure scoring

Behavioral measures
Space utilization
Performed in a behavioral
lab
24-7 video
Light and dark cycle
recording
Spanned the breeding life
(multiple litters) of breeding
groups

Clinical measures
Examples
Mortality
By sex, breeding colony
segment, etc.

Animals euthanized for cause

Body conditioning scoring
Growth curve comparisons
Weaning through 10 weeks of
age

LAS, 49(3), pg. 319-23, 1999

Stocks, strains and genotypes to be

evaluated
Evaluating all possible stocks, strains and
genotypes is not practical (or affordable)
Concentrated on common lines
e.g., C57BL/6, CD-1, CD, BN
Inbred and outbred mice and rats
Selected stocks and strains reflect the majority of
mice and rats being produced and utilized for
research

Research proposal
Team approach

Veterinarians
Behavioral scientist w/ significant rodent experience
IACUC members
Production management
Husbandry staff

IACUC
Reviewed and approved research protocol

Interpretation of results
Differences will be identified between groups
Must Question: Are they physiologically, metabolically or
behaviorally relevant?
A statically significant difference at some P value (e.g., p
< 0.05) does not mean that there is a problem - may just
reflect adaption.
Adaption can occur without harm to welfare
Failure to adapt or being forced to try to adapt to extremes
without adequate time or resources results in clinical harm.
e.g. Housing room temperatures for rodents are generally
below the thermoneutral zone; social housing, nesting
material, bedding allow adaptation

Interpretation of results
It is unlikely that all findings will be in agreement
between Guide recommendations and
alternatives.
IACUC must consider:
Is there a definable and consistent mechanism that is
clearly linked to detrimental animal welfare?
If so, further evaluation may be warranted
Or, the IACUC can require modifications, restrictions,
or deny the exception.

CRL experimental design

Latin square factorial design:
Cage x breeding condition x strain

Animals:
Inbred: C57BL/6, BN
Outbred: CD-1, CD
Breeding conditions:
Mice: female alone,
pair, trio
Rats: female alone, pair

Cage sizes:
Small*
CRL standard
2011 Guide
Huge*
*Unrealistic. Added to
attempt to force a change.

30

Cage sizes
Mice

226 cm2
305 cm2*
432 cm2
800 cm2

Rats

580 cm2
758 cm2*
903 cm2
1355 cm2

*CR standard caging

31

Smallest and largest mouse cages

32

Smallest and largest rat cages

33

Behavioral measures
1/0 sampling (yes/no) for
Play behavior or popcorning
2 minutes every 30 minutes over a
24 hour period

Scan sampling of adult behavior

every
30 minutes over a 24 hour period

Two 24 hour periods observed

One during 0-8d of pups
One during 14-21d of pups

48 mouse cages, 32 rat cages

Additional measures
Reproductive measures
Litter size at birth
Litter size at weaning
Weaning weight
Production Index (PI)
Wean/female/week

Other
Hair loss (pups/adults)
Fighting/wounding
Stereotypies

Settings
Behavioral lab
48 mouse cages
32 rat cages

Barrier room
480 mouse cages
320 rat cages

35

RESULTS (PARTIAL)
Full results to be published soon
By Kate Pritchett-Corning & Brianna Gaskell

36

Preliminary results
Cages can be too small
Excessive soiling in smallest
cages
CD rats breeding in pairs in
the smallest showed a
decrease in reproductive
performance
Reproductive performance
did not decrease with mice
in smallest cage

37

Significant behavior change?

Corner inactivity
Only seen in adults
Only seen at specific pup ages
Seen in all cages, more frequent in smaller cages
With a smaller cage, females may benefit from
vertical space that allows them to escape older
pups.

38

Corner inactivity

Review by IACUC
Full results of the
evaluation were presented
to the IACUC
The IACUC approved the
use of CRL cage densities
for breeding mice and rats

Post-approval monitoring
IACUC review of performance indicators
Annual review of the variance for 2 consecutive years
Key performance indicators

De novo review at end of year 3

Literature review
Determine if new/additional studies are warranted

Regular ongoing review

Production management review production indices
routinely (weekly to monthly)
Veterinarians involved as needed when problems arise
Communicate with IACUC as necessary

Thank you
&
Questions