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Reproducibility in Preclinical Research:Activities and Opportunities
Jonathan KimmelmanBiomedical Ethics / Experimental MedicineMcGill University
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cause effect
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drug response
ANIMAL
drug response
HUMAN
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Photocredit: NIH, Wikimedia
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1: problems
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pl nningplanning
u
ptake
design
reporting
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pl nningplanning
u
ptake
design
reporting
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!
#
$!
$#
%!
%#
&!
'()*+*(,) -.*,)/' 0/1'2.3()*+*(,)' '-.3,-43+-'
ratio
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pl nningplanning
u
ptake
design
reporting
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Source: Kilkenny C et al PLoS One2009; 4: e7824
Random allocation:
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pl nningplanning
u
ptake
design
reporting
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unanalyzable
Source: Henderson V, in preparation
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pl nningplanning
u
ptake
design
reporting
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!"#$%&'$() +, - . / 0 1 2 3 4 5 -6 --
56)/789 %!!:
;,.)
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;3))8 %!$$ ?
;3))8 %!$$ 9
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;6,@ %!$! A
B
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H3*3. %!$$ >I8/-3.J*K7L
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Source: Henderson V, in preparation
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pl nningplanning
u
ptake
design
reporting
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2: activities
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pl nningplanning
u
ptake
design
reporting
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pl nningplanning
u
ptake
design
reporting
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internal validity:
concealedallocation
sample size
justification
standardize
animal handling
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constuct validity:match co-
interventions
characterizationof animals at
baseline
confirmmechanism
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external validity:replicate in
different models
replicate indifferent diseaseseverity
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pl nningplanning
u
ptake
design
reporting
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pl nningplanning
u
ptake
design
reporting
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pl nningplanning
uptake
desig
n
reporting
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programmatic:
research w/inmulticenter
consortium
standardizedesign
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Clinical investigators
Patients Diseaseadvocates
Lab scientists
Industry
Fundingagencies
Regulators
Academicmedical centers
Journals
Referringphysicians
Broader medicalcommunity
Trainees
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Clinical investigators
Patients Diseaseadvocates
Lab scientists
Industry
Funders
Regulators
Academicmedical centers
Journals
Referringphysicians
Broader medicalcommunity
Trainees
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3: opportunities
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1) stakeholders
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Clinical investigators
Patients Diseaseadvocates
Lab scientists
Industry
Fundingagencies
Regulators
Academicmedical centers
Journals
Referringphysicians
Broader medicalcommunity
Trainees
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lack of potential effectiveness
information should not generally be areason for a Phase 1 IND to be placed
on clinical holdFDA Guidance
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Clinical investigators
Patients Diseaseadvocates
Lab scientists
Industry
Fundingagencies
IRBs / IACUCs
Academicmedical centers
Journals
Referringphysicians
Broader medicalcommunity
Trainees
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Clinical investigators
Patients Diseaseadvocates
Lab scientists
Industry
Funding agencies
IRBs / IACUCs
Academicmedical centers
Journals
Referringphysicians
Broader medicalcommunity
Trainees
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2) research domains
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cancer?psychiatric?respiratory?metabolic disease?
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stem cells?gene transfer?immunotherapy?
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3) programmatic
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a) formal process for guidelines
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a) formal process for guidelinesb) structured preclinical testing
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a) formal process for guidelinesb) structured preclinical testingc) incentives
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planningdesignreportinguptake
fundersjournalsregulators ?
?
?