22
Exploratory IND: a study proposal from Novartis Rossella Belleli ECD BIOS Novartis 17 Nov 2005
Expl
orat
ory
IND:
a s
tudy
pr
opos
al fr
om N
ovar
tisRo
ssel
la B
elle
liEC
D BI
OS
Nov
artis
17 N
ov 2
005
Belle
li R.
exp
IND
Pres
enta
tion
outli
ne
•W
hat i
s an
exp
lora
tory
(exp
)IND
com
pare
d to
a „
trad
ition
al“
IND
−In
trod
uctio
n to
„tr
aditi
onal
“ IN
D−
FDA
guid
ance
on
expI
ND
•Ex
ampl
eof
an
expI
ND
from
Nov
artis
−De
sign
−Po
ssib
le s
cena
rios/
outc
omes
−So
me
cons
ider
atio
ns•
Conc
lusi
ons
Belle
li R.
exp
IND
Intr
oduc
tion:
„Tr
aditi
onal
“ IN
D, 2
1CRF
312
/1
•W
hat i
s a
trad
ition
al IN
D (In
vest
igat
iona
l New
Dru
g ap
plic
atio
n)ht
tp:/
/ww
w.a
cces
sdat
a.fd
a.go
v/sc
ripts
/cdr
h/cf
docs
/cfc
fr/CF
RSea
rch.
cfm
?CFR
Part
=312
&sho
wFR
=1−
Docu
men
tatio
n*su
bmitt
ed to
FDA
to p
erfo
rm c
linic
al
inve
stig
atio
nus
ing
an in
vest
igat
iona
l new
dru
g−
The
amou
nt a
nd ty
peof
info
rmat
ion
depe
nds
on th
e sc
ope
of th
e cl
inic
al in
vest
igat
ion
plan
ned
−„S
tand
ard“
toxi
colo
gy p
rogr
am−
„Sta
ndar
d“ d
osin
g st
rate
gy(fr
om ~
1/10
HED
cal
cula
ted
from
N
OAE
L to
MTD
)
* In
vest
igat
or‘s
bro
chur
e, p
lann
ed p
roto
cols
, che
mis
try,
man
ufac
tory
an
d co
ntro
l inf
orm
atio
n, P
harm
acol
ogy
and
toxi
colo
gy
info
rmat
ion,
Pre
viou
s hu
man
exp
erie
nce
Belle
li R.
exp
IND
„New
“ ex
plor
ator
y (e
) IN
D: F
DA d
raft
guid
ance
/1
http
://w
ww
.fda.
gov/
cder
/gui
danc
e/63
84df
t.pdf
•M
otiv
atio
n/ra
tiona
le−
Ther
e is
flex
ibili
tyin
the
type
and
am
ount
of d
ata
to b
e su
bmitt
ed
with
a „
trad
ition
al“
IND
depe
ndin
g on
the:
•go
alof
the
inve
stig
atio
n•
spec
ific
hum
an te
stin
gpr
opos
ed•
expe
cted
risk
s−
But:
spon
sors
hav
e no
t tak
en fu
ll ad
vant
age
of th
is fl
exib
ility
and
pr
ovid
e m
ore
info
rmat
ion
than
requ
ired!
Few
er th
an 1
0% o
f IN
Ds fo
r new
mol
ecul
ar e
ntiti
es (N
ME)
pro
gres
sbe
yond
the
inve
stig
atio
nal s
tage
(was
te o
f res
ourc
es, t
ime)
•O
bjec
tive:
cla
rify
wha
t clin
ical
and
pre
-clin
ical
app
roch
essh
ould
be
cons
ider
ed w
hen
plan
ning
exp
lora
tory
IND
stud
ies
Belle
li R.
exp
IND
„New
“ ex
plor
ator
y (e
) IN
D: F
DA d
raft
guid
ance
/2
•De
finiti
onof
exp
IND
stud
y/ie
s: e
arly
pha
se I
stud
y/ie
s w
ith v
ery
limite
d hu
man
exp
osur
ean
d no
ther
apeu
tic in
tent
(no
asse
ssm
ent
of m
axim
um to
lera
ted
dose
).•
Poss
ible
goa
ls:
−U
nder
stan
ding
the
rela
tions
hip
betw
een
the
mec
hani
sm o
f act
ion
of a
dru
g an
d th
e tr
eatm
ent o
f a d
isea
se−
Prov
ide
phar
mac
okin
etic
info
rmat
ion
−Se
lect
the
mos
t pro
mis
ing
lead
prod
uct f
rom
a g
roup
of
cand
idat
es−
Expl
ore
a pr
oduc
t‘s b
iodi
strib
utio
n ch
arac
teris
tics
usin
g va
rious
im
agin
g te
chni
ques
•O
bjec
tive:
iden
tify
early
in th
e pr
oces
s pr
omis
ing
cand
idat
esfo
r fu
rthe
r dev
elop
men
t and
elim
inat
e th
ose
lack
ing
prom
ises
, sav
ing
reso
urce
s
Belle
li R.
exp
IND
„New
“ ex
plor
ator
y (e
) IN
D: F
DA d
raft
guid
ance
/3
Safe
ty P
rogr
am D
esig
ns –
Exam
ples
1.Cl
inic
al s
tudi
es fo
r PK/
imag
ing
(mic
rodo
ses,
no
phar
mac
olog
ical
effe
ct )
2.Cl
inic
al s
tudi
es to
stu
dy p
harm
acol
ogic
al e
ffect
−M
ultip
le d
oses
up
to 7
day
s(2
-wee
k to
x in
a s
ensi
tive
spec
ies
+ to
xico
kine
tics;
non
-rod
ent 1
-wee
k to
x)−
Star
ting
dose
no
grea
ter t
han
1/50
NO
AEL
(No-
obse
rved
-ad
vers
e-ef
fect
-leve
l)−
Max
dos
e=
low
est o
f (1)
1/4
NO
AEL,
or (
2) ½
AU
C in
rat
or A
UC
in d
og o
r (3)
dos
e w
ith p
harm
acol
ogic
al e
ffect
−Fu
rthe
r esc
alat
ion
afte
r con
sulti
ng F
DA3.
Clin
ical
stu
dies
to e
valu
ate
the
mec
hani
sm o
f act
ion
rela
ted
to
effic
acy
Belle
li R.
exp
IND
„New
“ ex
plor
ator
y (e
) IN
D vs
trad
ition
al IN
D
Exp
IND
•ex
plor
ator
y ob
ject
ive
•m
ultip
le c
ompo
unds
•lim
ited
expo
sure
/dos
e ra
nge
(1/5
0-1/
4NO
AEL)
•lim
ited
dura
tion
(up
to 7
day
s)•
smal
ler t
ox p
rogr
am (l
ess
stud
ies,
le
ss a
nim
als)
•le
ss d
rug
subs
tanc
e•
earli
er in
to m
an•
term
inat
es e
arlie
r uns
ucce
ssfu
l pr
ogra
ms
•do
es n
ot re
plac
e a
trad
ition
al IN
D
Trad
ition
al IN
D•
broa
der o
bjec
tive
•on
ly 1
com
poun
d•
dose
rang
e fro
m ~
1/10
HED
fro
m N
OAE
L up
to M
TD•
unlim
ited
dura
tion
•fu
ll to
x pr
ogra
m
•m
ore
drug
sub
stan
ce•
if su
cces
sful
, ear
lier i
nto
phas
e II
•ne
eded
for f
urth
er d
evel
opm
ent
Belle
li R.
exp
IND
Nov
artis
exa
mpl
e: ra
tiona
le fo
r an
expI
ND
•3
com
poun
ds (A
,B,C
)hav
e be
en s
elec
ted
as s
uita
ble
for t
he ta
rget
or
gan
•Al
l hav
e po
tent
ials
give
n th
e pr
e-cl
inic
al P
K/PD
pro
file
•PK
pro
pert
ies
are
high
ly s
peci
es d
epen
dent
⇒un
cert
ain
whi
ch is
pr
edic
tive
for h
uman
s•
One
com
poun
d (C
) has
the
high
est p
oten
cy, b
ut c
anno
t be
furt
her
deve
lope
d ⇒
Sele
ct o
ne o
ut o
f tw
o co
mpo
unds
base
d on
hum
an P
K/PD
dat
a⇒
C=„t
ool c
ompo
und“
to p
rovi
de a
Pro
of o
f Mec
hani
smif
the
othe
r tw
o fa
ilH
uman
PK/
PD d
ata
avai
labl
eea
rlier
for d
ecis
ion
mak
ing
com
pare
d to
sta
ndar
d IN
DIf
all c
ompo
unds
hav
e no
PD
effe
ctw
ith e
noug
h dr
ug e
xpos
ure ⇒
term
inat
e th
e pr
ojec
t ear
lier ⇒
save
reso
urce
s/tim
e
Belle
li R.
exp
IND
Nov
artis
exa
mpl
e: o
bjec
tives
Prim
ary
1.De
fine
PK p
rofil
eof
2/3
com
poun
ds in
hum
ans
2.As
sure
and
ass
ess
safe
tyun
der p
ropo
sed
cond
ition
s
Seco
ndar
y1.
Dete
rmin
e de
rived
PD
prof
iles
2.De
term
ine
phar
mac
olog
ical
dos
e3.
Com
pare
obt
aine
d PK
pro
files
and
, if p
ossi
ble,
als
o PD
pro
file
with
m
arke
ted
drug
Belle
li R.
exp
IND
Nov
artis
exa
mpl
e: o
vera
ll st
udy
desi
gnIn
term
edia
te e
valu
atio
n
SAD
A, B
SAD
C (t
ool c
pd)
CO A, B
MD
best
cpd
If:bo
th c
ompo
unds
hav
e si
mila
rly p
os P
K/po
s PD
Or:
pos
PK
but n
o PD
If:bo
th c
ompo
unds
no
PK
If:on
ly 1
cpd
pos
PK/
pos
PDor
cle
arly
sup
erio
r
Scen
ario
s:
MD
best
com
poun
d
SAD:
sing
le a
scen
ding
dos
es
(one
wee
k be
twee
n do
ses)
CO:s
ingl
e do
se c
ross
-ove
r (o
ne w
eek
betw
een
dose
s)M
D:7
day
mul
tiple
-dos
ing
Part
A1
Part
BPa
rt C
Star
tEn
d (~
6 m
onth
s)
I III
Best
cas
e: I
IPa
rt A
2
Part
C
??
Belle
li R.
exp
IND
Nov
artis
exa
mpl
e: s
tudy
des
ign
part
A1
mar
kete
d re
fere
nce
mar
kete
d re
fere
nce
mar
kete
d re
fere
nce
mar
kete
d re
fere
nce
mar
kete
d re
fere
nce
mar
kete
d re
fere
nce
mar
kete
d re
fere
nce
mar
kete
d re
fere
nce
mar
kete
d re
fere
nce
mar
kete
d re
fere
nce
Wee
k6 d
ay
1
B 1
/2
B 1
/2
B 1
/2
B 1
/2
B 1
/2
A 1/
2
A 1/
2
A 1/
2
A 1/
2
A 1/
2
Wee
k x
day1
*
B 1
/4
B 1
/4
B 1
/4
B 1
/4
Plac
ebo
A 1/
4
A 1/
4
A 1/
4
A 1/
4
Plac
ebo
Wee
k5 d
ay
1
B 1
/8B
1/1
6B
1/5
0Pl
aceb
o2
j
B 1
/8B
1/1
6Pl
aceb
oB
1/5
02
i
B 1
/8Pl
aceb
oB
1/1
6B
1/5
02
h
Plac
ebo
B 1
/8B
1/1
6B
1/5
02
g
B 1
/4B
1/8
B 1
/16
B 1
/50
2f
2
A 1/
8A
1/16
A 1/
50Pl
aceb
o2
e
A 1/
8A
1/16
Plac
ebo
A 1/
502
d
A 1/
8Pl
aceb
oA
1/16
A 1/
502
c
Plac
ebo
A 1/
8A
1/16
A 1/
502
bN
=20
A 1/
4A
1/8
A 1/
16A
1/50
2a
1A1
Wee
k4 d
ay
1W
eek3
day
1W
eek2
day
1
Wee
k1 d
ay
1N
Sequ
enc
eCo
hort
Part * Af
ter F
DA c
onsu
ltatio
n, if
the
¼ d
ose
is s
afe
and
show
s po
sitiv
e PK
, but
no
or
not e
noug
h PD
resp
onse
Belle
li R.
exp
IND
Nov
artis
exa
mpl
e: d
esig
n pa
rt B
mar
kete
d re
fere
nce
A do
se x
B do
se y
2*f
B do
se y
mar
kete
d re
fere
nce
A do
se x
2*e
A do
se x
B do
se y
mar
kete
d re
fere
nce
2*d
mar
kete
d re
fere
nce
B do
se y
A do
se x
2*c
A do
se x
mar
kete
d re
fere
nce
B do
se y
2*b
B do
se y
A do
se x
mar
kete
d re
fere
nce
2*a
3B
wee
k9
day1
wee
k8
day1
wee
k7
day1
NSe
quen
ceCo
hort
Part Cros
s-ov
er s
tudy
if b
oth
com
poun
ds h
ave
posi
tive
PK a
nd P
D si
gnal
afte
r par
t A1
x, y
= s
ugge
sted
PD
effe
ctiv
e do
ses
dete
rmin
ed fr
om p
revi
ous
SAD
phas
eN
on-p
aram
etric
met
hods
to c
hoos
e th
e „b
est“
com
poun
d,
base
d on
qua
litat
ive
and
quan
titat
ive
crite
ria•
* Sa
mpl
e si
ze m
ay b
e m
odifi
ed b
ased
on
part
A1
Belle
li R.
exp
IND
Nov
artis
exa
mpl
e: d
esig
n pa
rt C
mar
kete
d re
fere
nce
Fron
trunn
er d
ose
u10
-12*
5C
Wee
k 9
or 1
2; D
ay
8W
eek
8 or
11;
Day
1-7
NCo
hort
Part
Lim
ited
mul
tiple
dos
ing
with
com
poun
d th
at s
how
ed b
est P
K/PD
pr
ofile
to c
olle
ct b
iom
arke
r dat
aW
ill n
ot b
e pe
rform
ed w
ith c
ompo
und
Cu
= su
gges
ted
PD e
ffect
ive
dose
det
erm
ined
from
pre
viou
s SA
D (a
nd C
O) p
hase
* Sa
mpl
e si
ze m
ay b
e m
odifi
ed b
ased
on
prev
ious
par
t/s
and/
or o
nan
ad
ditio
nal b
iom
arke
rs s
tudy
with
the
mar
kete
d re
fere
nce
Belle
li R.
exp
IND
Nov
artis
exa
mpl
e: s
ome
cons
ider
atio
ns /
1
•Su
itabl
e ci
rcum
stan
ces
for e
xpIN
D
•Ex
plor
ator
yna
ture
of t
he s
tudy
: not
eno
ugh
info
rmat
ion
avai
labl
e to
se
lect
one
of t
he 3
com
poun
ds fo
r a tr
aditi
onal
IND
⇒ne
ed to
gen
erat
e da
tafo
r dec
isio
n m
akin
g an
d le
arni
ng p
urpo
ses
•H
iera
rchi
cals
et o
f obj
ectiv
es (P
K, P
D, a
dditi
onal
bio
mar
kers
)
•Ad
aptiv
e st
rate
gy: i
nfor
mat
ion
colle
cted
dur
ing
the
stud
y ar
e us
ed
for d
ecid
ing
diffe
rent
stu
dy d
esig
n op
tions
(par
t B b
ased
on
part
A1
...) a
nd m
odify
ing
sam
ple
size
Belle
li R.
exp
IND
Nov
artis
exa
mpl
e: s
ome
cons
ider
atio
ns /
2
•Q
ualit
ativ
e as
sess
men
t of P
K/PD
pro
files
+ sa
fety
driv
es th
e do
se
esca
latio
nfo
r eac
h co
mpo
und
(no
MTD
to b
e es
tabl
ishe
d)
•Q
ualit
ativ
e as
sess
men
t of P
K/PD
pro
files
driv
es th
e co
mpo
und
com
paris
on⇒
use
of n
on-p
aram
etric
met
hods
to c
hoos
e be
twee
n th
e tw
o co
mpo
unds
•O
pen
issu
es: w
ithin
the
dose
-esc
alat
ion
cons
trai
nts
of th
e ex
pIN
D,
the
PD e
ffect
may
not
be
deta
ctab
le
⇒ch
alle
nge
FDA
with
inte
rim re
sults
to fu
rthe
r esc
alat
e
⇒a
full
IND
may
be
open
ed w
ith o
ne o
r a b
acku
p co
mpo
und
Belle
li R.
exp
IND
Conc
lusi
ons
/1
ExpI
ND:
opp
ortu
nity
to te
st d
rugs
in h
uman
s ea
rlier
com
pare
d to
a
trad
ition
al IN
DAd
vant
ages
+M
ultip
le c
ompo
unds
can
be te
sted
sim
ulta
neou
sly
+M
ore
desi
gn fl
exib
ility
beca
use
of re
duce
d ris
kSe
vera
l seq
uent
ial s
tudi
esca
n be
pla
nned
Sing
le a
nd m
ultip
le d
oses
Cros
sove
r
+To
xico
logy
pro
gram
abb
revi
ated
+Sm
alle
r qua
ntity
of d
rug
(from
3-1
0kg
to <
500g
)+
Shor
ter t
imel
ines
(fro
m 1
8 m
onth
s to
8 m
onth
s to
FIM
)+
Effe
ctiv
e to
elim
inat
e no
n pr
omis
ing
cand
idat
es e
arly
on
Belle
li R.
exp
IND
Conc
lusi
ons
/2
Rest
rictio
ns/D
isad
vant
ages
−„O
bjec
tives
mus
t be
expl
orat
ory“
−Sa
fety
risk
ssh
ould
be
min
imiz
ed−
Dose
rang
e(s
tart
-sto
p do
se) l
imite
d,in
par
ticul
ar w
ithlo
w
NO
AEL
−Do
sing
dur
atio
n lim
ited
(up
to 7
day
s)−
Toxi
colo
gy p
acka
gere
duce
d, b
ut m
ay h
ave
to b
e st
agge
red
if m
ultip
le c
ompo
unds
are
test
ed, d
ue to
cap
acity
lim
its−
Onc
e th
e ex
pIN
D ob
ject
ives
are
ach
ieve
d, it
sho
uld
be c
lose
d an
d a
trad
ition
al IN
Dm
ight
be
open
ed in
stea
d−
Star
t of p
hase
II d
elay
ed
Belle
li R.
exp
IND
Than
ks to
:
Mic
hael
Loo
by, M
arku
s Jo
hn, G
erar
dus
Brui
n, B
ill R
obin
son
(Nov
artis
)
Belle
li R.
exp
IND
The
expI
ND
will
acc
eler
ate
disc
over
y an
d de
velo
pmen
t of n
ew p
harm
aceu
tical
age
nts
•Pot
entia
l del
ayed
pro
gres
sion
to
Pha
se 2
•MTD
not
est
ablis
hed
•Lar
ger q
uant
ity o
f AP
I
•Slo
wer
dec
isio
ns
•Lat
e an
d co
stly
attr
ition
Dis
adva
ntag
es
•Pre
dict
able
AP
I req
uire
men
t
•Fas
ter p
rogr
essi
on to
clin
ical
tria
ls
•Cap
abilit
y to
eva
luat
e ca
ndid
ates
ba
sed
on h
uman
dat
a
•Bet
ter d
evel
opm
ent d
ecis
ions
m
ade
mor
e qu
ickl
y
•Ear
ly a
nd le
ss c
ostly
attr
ition
•Ful
l tox
icol
ogy
prof
ile
•Esc
alat
ion
to M
TD in
clin
ical
tria
ls
•Pro
gres
sion
dire
ctly
to P
h 2
Ben
efits
•5 –
6 st
udie
s
•170
rode
nt a
nd 6
NR
•3 –
6 m
onth
s
•9 –
12 s
tudi
es
•220
rode
nt a
nd 3
8 N
R
•9 –
18 m
onth
s
Prec
linic
al R
esou
rces
10 -
300
g1
–3
Kg
Act
ive
Phar
mac
eutic
al
Ingr
edie
nt (A
PI)
expI
ND
Con
vent
iona
l IN
D
Belle
li R.
exp
IND
Drug
sub
stan
ce re
quire
d to
sup
port
FIH
stu
dies
(Rod
ent a
nd n
onro
dent
equa
lly s
ensi
tive)
7478
1To
tal
55 5 12 2CPD
(g)
CPD
(g)
Stud
ySt
udy
55 700
12 5 5 2 2
DR
F +
2-w
k ro
dent
*
7-da
y G
LP n
onro
dent
CV
Safe
ty P
harm
Mut
agen
icity
DR
F +
2-w
k G
LP ro
dent
DR
F +
2-w
k G
LP n
onro
dent
CV
Safe
ty P
harm
CN
S Sa
fety
Pha
rmPu
lmSa
fety
Pha
rmM
utag
enic
ityC
last
ogen
icity
Prop
osed
Exp
lora
tory
IND
R
equi
rem
ents
Full
IND
Req
uire
men
ts
•Ass
ume
500
mg/
kg M
TD a
nd 5
0 m
g/kg
NO
AEL
in ro
dent
s
* Inc
lude
s in
viv
o m
icro
nucl
eus,
CN
S an
d pu
lmon
ary
asse
ssm
ent o
nst
udy
anim
als
DR
F =
dose
rang
e-fin
ding
Belle
li R.
exp
IND
How
wou
ld a
sim
ulat
ion
of th
e ex
pIN
Dco
ncep
t app
ear i
n a
situ
atio
n w
here
bot
h do
se a
nd A
UC
crit
eria
wer
e m
et
Exp
erim
enta
l D
ata
Com
poun
d #8
from
the
data
set
2 w
eek
rode
nt to
xici
ty s
tudy
NO
AE
L do
se 3
0 m
g/kg
≡17
7 m
g/m
2N
OA
EL
AU
C =
197
0 ug
.h/m
LN
onro
dent
qual
ifica
tion
177
mg/
m2
No
findi
ngs
NR
NO
AE
L D
ose
= 36
0 m
g/m
2A
UC
= 3
450
ug.h
/mL
CN
S, C
V, r
espi
rato
ry,
geno
toxi
city
No
findi
ngs
FIH
Par
amet
ers
Sta
rting
Dos
e (1
/50
rode
nt N
OA
EL
dose
) = 3
.5 m
g/m
2 (to
tal d
ose
for a
60k
g pe
rson
: 5.7
mg)
Sto
p D
ose
(1/4
rode
nt N
OA
EL
dose
) =44
mg/
m2
(tota
l do
se fo
r a 6
0kg
pers
on: 7
1mg)
Sto
p E
xpos
ure
(1/2
rode
nt N
OA
EL
AU
C) =
985
ug.h
/mL
Sta
rt do
se =
31
mg/
m2
Sto
p do
se =
555
mg/
m2
Sto
p ex
posu
re =
466
0 ug
.h/m
L
Belle
li R.
exp
IND
How
wou
ld a
sim
ulat
ion
of th
e ex
pIN
Dco
ncep
t app
ear i
n a
situ
atio
n w
here
bio
avai
labi
lity
in th
e no
nrod
ents
peci
es w
as lo
w
Exa
mpl
e #4
9 fro
m th
e da
tase
tE
xper
imen
tal
Dat
a2
wee
k ro
dent
toxi
city
stu
dyN
OA
EL
dose
49
mg/
kg ≡
236
mg/
m2
NO
AE
L A
UC
= 2
.75
ug.h
/mL
Non
rode
ntqu
alifi
catio
n23
6 m
g/m
2Lo
w e
xpos
ure
rela
tive
to ro
dent
NR
NO
AE
L D
ose
= 20
0 m
g/m
2A
UC
= 0
.3 u
g.h/
mL
CN
S, C
V, r
espi
rato
ry,
geno
toxi
city
No
findi
ngs
FIH
Par
amet
ers
Sta
rting
Dos
e (1
/50
rode
nt N
OA
EL
dose
) = 4
.7 m
g/m
2(to
tal d
ose
for a
60k
g pe
rson
: 7.6
mg)
Sto
p D
ose
(1/4
rode
nt N
OA
EL
dose
) =59
mg/
m2
(tota
l dos
e fo
r a 6
0kg
pers
on: 9
6mg)
Sto
p E
xpos
ure
(NR
AU
C) =
0.3
ug.h
/mL
Sta
rt do
se =
6.2
mg/
m2
Sto
p do
se =
27.
8 m
g/m
2 S
top
expo
sure
= 0
.62
ug.h
/mL
Out
com
eE
xpos
ure
in th
e N
R is
low
er th
an in
the
rode
nt a
t the
NO
AE
L eq
uiva
lent
dos
e. T
he N
R e
xpos
ure
beco
mes
the
AU
C ta
rget
for
capp
ing
dosi
ng a
nd th
e tri
al is
sto
pped
at a
saf
e do
se.
