Reproducibility in Preclinical Research

:
Activities and Opportunities 
Jonathan Kimmelman 
Biomedical Ethics / Experimental Medicine 
McGill University 
cause  effect 
drug response
ANIMAL 
drug response
HUMAN 
Photocredit: NIH, Wikimedia
1: problems 
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
!
#
$!
$#
%!
%#
&!
&#
'()*+*(,) -.*,)/' 0/1'2.3()*+*(,)' '-.3,-43+-'
r
a
t
i
o
 
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
Source: Kilkenny C et al PLoS One 2009; 4: e7824 
Random allocation: 
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
unanalyzable 
Source: Henderson V, in preparation 
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
!"#$%&'$() +, - . / 0 1 2 3 4 5 -6 --
56)/789 %!!:
;,.)<3+9, %!$!
;3))8 %!$$ (
;3))8 %!$$ = >
;3))8 %!$$ 3
;3))8 %!$$ ?
;3))8 %!$$ 9
;6,@ %!$! ,
;6,@ %!$! A
B<*9+,+ %!$$ ,
B<*9+,+ %!$$ A
C.3D %!$! ,
C.3D %!$! A
E,/2,.*,+ %!$$ > >
F,443./ %!$! ,
F,443./ %!$! A
F<,+9 %!$! ,
F<,+9 %!$! A
F<,+9 %!$! (
F<,+9 %!$! =
G8 %!$! ,
H,6,)*+9,4
%!$$ ,
>
H,6,)*+9,4
%!$$ A
>
H,*-, %!$% > >
H3*3. %!$$ >
I8/-3.J*K7L
M,77, %!$$

>*+ %!!:
Source: Henderson V, in preparation 
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
2: activities 
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
internal validity: 
concealed 
allocation 
sample size
justification 
standardize
animal handling 
constuct validity: 
match co-
interventions 
characterization 
of animals at
baseline 
confirm 
mechanism 
external validity: 
replicate in
different models 
replicate in
different disease 
severity 
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
planning
planning
u
p
t
a
k
e

d
e
s
i
g
n

reporting
programmatic: 
research w/in 
multicenter 
consortium 
standardize
design 
Clinical investigators 
Patients
Disease
advocates
Lab scientists 
Industry
Funding agencies
Regulators
Academic 
medical centers 
Journals
Referring physicians
Broader medical 
community
Trainees
Clinical investigators 
Patients
Disease
advocates
Lab scientists 
Industry
Funders
Regulators
Academic 
medical centers 
Journals
Referring physicians
Broader medical 
community
Trainees
3: opportunities 
1) stakeholders 
Clinical investigators 
Patients
Disease
advocates
Lab scientists 
Industry
Funding agencies
Regulators
Academic 
medical centers 
Journals
Referring physicians
Broader medical 
community
Trainees
“lack of… potential effectiveness
information should not generally be a
reason for a Phase 1 IND to be placed
on clinical hold”

FDA Guidance
Clinical investigators 
Patients
Disease
advocates
Lab scientists 
Industry
Funding agencies
IRBs / IACUCs
Academic 
medical centers 
Journals
Referring physicians
Broader medical 
community
Trainees
Clinical investigators 
Patients
Disease
advocates
Lab scientists 
Industry
Funding agencies
IRBs / IACUCs
Academic 
medical centers 
Journals
Referring physicians
Broader medical 
community
Trainees
2) research domains 
cancer? 
psychiatric? 
respiratory? 
metabolic disease? 
stem cells? 
gene transfer? 
immunotherapy? 
3) programmatic  
a) formal process for guidelines 
a)  formal process for guidelines 
b)  structured preclinical testing 
a)  formal process for guidelines 
b)  structured preclinical testing 
 
c)  incentives 
planning 
 
design 
 
reporting 
 
uptake 
 
 
funders 
 
journals 
 
regulators 
 
?
?
?

Sign up to vote on this title
UsefulNot useful