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REGULATORY TOXICOLOGY AND PHARMACOLOGY 6,66-72 ( 1986)
A Critical Appraisal of the Duration of Chronic Animal Toxicity Studies
CYNTHIA E. LUMLEY AND STUART R. WALKER
Centrefor Medicines Research, Woodmansterne Road, Carshalton. Surrey, England
Received December 16. 1985
One method of assessing the contribution of studies of longer than 6 months to a safety evaluation program is to compare retrospectively the findings in toxicity tests carried out for 6 months or less with those observed after 6 months. The Centre for Medicines Research has therefore established a databank comprising animal toxicological data obtained from pharmaceutical companies in Europe. Twenty-one companies have provided data for 124 compounds (2 14 studies), including 88 studies of 65 compounds where comparable short-term (~6 months) and long-term (>6 months) data are available. The results from the 88 studies show that, excluding the possibility of identifying carcinogens, tests of longer than 6 months have not added to the overall safety evaluation of these compounds. @ 1986 Academic press Inc.
INTRODUCTION
The pharmaceutical industry conducts extensive toxicity tests in animals during the development of new medicines. The design of these tests must take into account the guidelines suggested by regulatory authorities in the countries where it is hoped to market the drug. These guidelines include recommendations for the minimum duration of animal exposure, which depends upon the proposed duration of human use. However, there is disagreement regarding the amount and nature of animal testing required before a medicine can be used “ethically and safely” in the clinic (Fig. I) (Alder et al., 198 1; Health Protection Branch 198 1; Kesterson, 1982; Koseisho, 1984).
Regulatory authorities are under public pressure to establish guidelines which might increase the safety of medicines to be marketed. As a result, there has been a growing tendancy for more tests to be required, including those of increasing duration (Gross, 1979). However, greater safety cannot be achieved by simply prolonging animal tests (Gross, 1982) and the value of experiments lasting longer than 6 months has not been established. One method of assessing their contribution to a safety evaluation program is to compare retrospectively the results of tests carried out for 6 months or less with results obtained after 6 months. The Centre for Medicines Research has already es- tablished a databank comprising comprehensive animal toxicological data obtained from pharmaceutical companies in the United Kingdom (Lumley and Walker, 1985a,b)
66
0273-2300186 $3.00 Copyright 0 1986 by Academic Press, Inc. All righu of reproduction in any form resewed.
DURATION OF ANIMAL TOXICITY STUDIES 67
Canada
16. Q Q Q
Japan
0' I
1 3 6
Human Exposure Conthsl
FIG. 1. International guidelines for the minimum duration of animal toxicity studies (studies to be carried out in both a rodent and a nonrodent species).
and these data have been used to conduct such a retrospective analysis (Lumley and Walker, 1985~). This databank has now almost doubled in size by including studies from companies in Switzerland and Germany.
COMPOSITION OF THE EUROPEAN DATABANK
Twenty-one pharmaceutical companies with research and development activities in Europe have provided comprehensive repeated-dose toxicology data for compounds tested and evaluated between 1965 and 1982. Those compounds for which data from more than one time period were available and/or those which had been tested in two or more species were submitted. Because of the differences in design, including dose levels and tissues examined, carcinogenicity tests were excluded unless a combined carcinogenicity/toxicity experiment was carried out. These data comprise the European toxicology databank. The methodology of its establishment and data aquisition have been described in detail elsewhere (Lumley and Walker, 1985a,b).
The European databank contains information for 124 compounds studied in one or more species. There are 2 14 case studies, a case study being defined as the full information for one compound tested in one species for one or more time period(s). One hundred case studies on 77 compounds include tests carried out for longer than 6 months. The therapeutic classes of the compounds in the total databank and of those with long-term data are shown in Fig. 2. Also illustrated are the number marketed (a total of 54), the number still in development (2 l), and those for which research has terminated (48). These 48 compounds will not be marketed for commercial reasons (8), clinical findings ( 15) concern about possible carcinogenicity, mutagenicity, or reproductive effects (5), repeated-dose animal toxicity (1 l), or chemical reasons (2). The reason for not marketing 5 compounds was given as “not animal toxicology,” while no reason was specified for 2 compounds and the market status of 1 compound is not known. The species studied are shown in Fig. 3.
Comparable short-term (~6 months) and long-term (~6 months) data are available
68 LUMLEY AND WALKER
FIG. 2. Therapeutic class of pharmaceutical compounds in the toxicology databank. GI, gastrointestinal: CVS, cardiovascular system: CNS, central nervous system; A-lnf, anti-infectives; Resp, respiratory system; Endo, endocrine; A-All, anti-allergics; Mist, miscellaneous. Total databank: q , marketed; RI, under devel-
research terminated. Long-term studies: 8, marketed, R!, under development; minated.
in 88 case studies (65 compounds). In 48 of these, the short-term data include pathology examination at, or before, 3 months, while in 40 studies 6 month data are available. The data have been analyzed to determine whether any new information became apparent after 6 months.
RESULTS
Analysis shows that in 70 of 88 cases there were no novel, significant toxicological findings after 3 or 6 months (Table 1). In 14 of the remaining 18 studies there were new findings after 3 months but, as there was no pathology examination at 6 months,
Prinate
FIG. 3. Species used in studies of pharmace 2 14 case studies; long-term: 100 case studies).
compounds in the toxicology databank (total databank: ong-term studies; %, short-term studies.
DURATION OF ANIMAL TOXICITY STUDIES 69
TABLE I
RESULTS OF THE EUROPEAN STUDY
No. of case studies
Conclusion Pathology,
1 or 3 months Pathology, 6 months Total
All toxicologically significant effects seen in short-term study
New findings were seen in an alternate species within 6 months
The new findings did not influence the progression of the compound to market or termination of research
Total
34 36 70
3 0 3
11 4 15
48 40 88
no conclusion can be drawn as to whether all effects would have been apparent by then. In neither of the two studies in dogs where 18 month data are available were new findings observed after 12 months.
The 40 case studies with pathology examinations at 6 months are summarized in Table 2 by therapeutic class and species. In 4 of these there were new significant findings after 6 months. Details of these are shown in Table 3. It is apparent that experimental design is an important factor, as in all of these cases the dose levels used in the long-term test were the same or higher than those used in the short-term test. In one case (No. 26) the number of animals examined in the short-term test may have been too small to reveal the organ weight changes observed in the long-term test, when a larger number was included. With more appropriate choice of dose levels and number of animals studied, some of the effects first seen after 6 months may well have become apparent earlier. In no case study did the findings after 6 months influence the progression of the compound to market or termination of research.
CONCLUSIONS
The toxicology databank established on the basis of U. K. case studies has doubled in size by the inclusion of data from pharmaceutical companies in Switzerland and Germany. The number of studies with comparable short- and long-term data has increased from 45 (United Kingdom alone) to 88 (European databank). The results presented here reinforce the conclusion from the U. K. analysis (Lumley and Walker, 1985c), namely, that, excluding those to investigate carcinogenicity, tests of longer than 6 months have not added to the overall safety evaluation of these compounds.
Many regulatory authorities still suggest that tests of longer than 6 months be com- pleted before applying for marketing authorization (Fig. I), presumably in the belief that this might guarantee the increased clinical safety of new medicines. In particular, the Canadian guidelines suggest l&month repeated-dose toxicity studies in both a rodent and a nonrodent species for oral or parenteral drugs to be administered clinically for 1 month or longer (Health Protection Branch, 198 1). At a workshop held in October 1984 (Walker and Dayan, in press), a short list of effects that had apparently taken
70 LUMLEY AND WALKER
TABLE 2
TOXICITY DATA FOR PHARMACEUTICAL COMPOUNDS
Time (months)
No. Species Therapeutic class 1-6 12 18 24
1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Rat 7 Rat 8 Rat 9 Rat
10 Dog II Dog 12 Primate 13 Primate 14 Primate 15 Primate 16 Primate 17 Primate
18 Rat 19 Rat 20 Rat 21 Rat 22 Rat 23 Rat 24 Dog 25 Dog 26 Primate 27 Primate 28 Primate 29 Primate
30 Rat 31 Rat 32 Rat 33 Rat 34 Rat 35 Dog 36 Dog 37 Dog 38 Dog 39 Dog 40 Dog
Drugs acting on the central nervous system
NSAI xxx X NSAI xxx X NSAI xxx X NSAI xxx X Tranquillizer xxx X Anticonvulsant xxx X Psychotropic xxx X Analgesic xxx X Antidepressant xxx X Tranquillizer xxx X NSAI xxx X NSAI xxx xxxa NSAI xxx X NSAI xxx X NSAI xxx X NSAI xxx X NSAI xxx X
Drugs acting on the cardiovascular system
Beta-blocker xxx X Antihypertensive xxx XXX” Antihypertensive xxx XXX” Antihypertensive xxx X Hypolipidemic xxx X Not specified xxx X Beta-blocker xxx X Calcium antagonist xxx X Antihypertensive xxx XXX” Hypolipidemic xxx X Hypohpidemic xxx X Hypolipidemic xxx X
Miscellaneous drugs
Endocrine xxx X Cytotoxic xxx X GI agent xxx X GI agent xxx X GI agent xxx X Endocrine xxx X Endocrine xxx X Endocrine xxx X GI agent xxx X GI agent xxx X Respiratory xxx X
X X X X X X X X X X X X X X
X
X
XXX” X X X X X
X
X X X X
Nofe. 0, no toxicity; X, toxic findings already noted seen again; XXX, new significant toxic findings; NSAI, nonsteroidal anti-inflammatory.
0 Did not influence the progression of the compound.
Num
ber
Tim
e (m
onth
s)”
Ther
apeu
tic
clas
s M
ax
dose
s (m
g/kg
) sp
ecie
s Nu
mbe
r of
ani
mal
s
TABL
E 3
CASE
ST
UDIE
S W
ITH
NEW
SI
GNIF
ICAN
T FI
NDIN
GS
AFTE
R 6
MON
THS
Find
ings
wi
thin
Ne
w fin
ding
s af
ter
6 m
onth
s 6
mon
ths
-
12
3 6
12
NSA
I 32
0 32
0 45
0 Pr
imat
e 4
12
14
19
1 6
12
Antih
yper
tens
ive
2000
16
00
1600
R
at
20
24
36
20
3 6
9 18
An
tihyp
erte
nsiv
e 65
2 10
0 10
0 10
0 R
at
30
30
20
36
26
Antih
yper
tens
ive
Prim
ate
6 12
80
0 80
0 6
14
Com
men
ts
Dea
th;
body
wei
ght
and
food
inta
ke
decr
ease
d: e
dem
a; d
eter
iora
tion
in c
ondi
tion;
re
d ce
ll pa
ram
eter
s,
prot
ein,
al
bum
in
and
seru
m
enzy
mes
dec
reas
ed; b
rown
ur
ine,
os
mol
ality
de
crea
sed;
ga
stro
inte
stin
al
hem
orrh
age/
er
osio
n/ed
ema
Body
wei
ght
gain
and
foo
d in
take
in
crea
sed;
ser
um e
nzym
e ch
ange
s: c
olor
atio
n of
som
e tis
sues
Dea
th;
food
inta
ke d
ecre
ased
; re
spira
tory
dep
ress
ion;
he
mat
olog
ical
and
clini
cal
chem
istry
cha
nges
; liv
er w
eigh
t in
crea
sed;
gas
tric
ulce
rs; t
hym
us
smal
l: ad
rena
l we
ight
in
crea
sed
Atax
ia;
beha
viora
l ch
ange
s; h
eart
rate
dec
reas
ed; v
omiti
ng;
colo
ratio
n of
som
e tis
sues
; liv
er
weig
ht i
ncre
ased
Kidn
ey:
inte
rstit
ial
neph
ritis
(3/7
hi
gh
dose
ani
mal
s; f
irst n
oted
35
week
s)
Hea
rt: w
eigh
t in
crea
sed
(hig
h an
d in
term
edia
te
dose
s)
Hea
rt: r
elat
ive
weig
ht
incr
ease
d;
scle
rotic
int
erst
itial
m
yoca
rdia
l st
reak
s (9
mon
ths)
Se
min
ifero
us
tubu
les:
deg
ener
ative
ch
ange
s ( 1
8 m
onth
s)
Adre
nals
and
pitu
itary
: he
mat
ic
suffu
sion
s (1
8 m
onth
s)
Hea
rt: w
eigh
t de
crea
sed
(all
dose
s)
Subm
itted
to
mar
ket;
dose
s in
12-m
onth
st
udy
were
hig
her
than
tho
se in
3- a
nd
6-m
onth
st
udie
s; n
ew f
indi
ng
seen
in
high
-dos
e gr
oup
only
Not
mar
kete
d be
caus
e of
find
ings
in
a sp
ecia
l rat
stu
dy; d
oses
at 6
and
12
mon
ths
were
the
sam
e
Not
mar
kete
d bu
t st
ill un
der
deve
lopm
ent;
all
findi
ngs
afte
r 6
mon
ths
were
see
n in
bot
h tre
ated
and
co
ntro
l gr
oups
and
wer
e no
t dos
e re
late
d; h
owev
er,
beca
use
they
wer
e m
ild
in c
ontro
ls
and
occa
sion
ally
m
oder
ate
and
mor
e fre
quen
t in
tre
ated
th
e po
ssib
ility
that
the
y we
re
treat
men
t-rel
ated
ca
nnot
be
tota
lly
exclu
ded
Not
mar
kete
d be
caus
e of
the
resu
lts o
f a
spec
ial r
at s
tudy
; the
sam
e do
ses w
ere
used
in b
oth
stud
ies;
the
num
ber
of
anim
als
exam
ined
at
6 m
onth
s m
ay
have
bee
n to
o sm
all
to d
etec
t wei
ght
chan
ge s
een
at 1
2 m
onth
s.
a Ti
me
of p
atho
logi
cal
exam
inat
ion.
72 LUMLEY AND WALKER
longer than 12 months to develop in 15 separate rat studies was presented by the Health Protection Branch and discussed. However, the relevant experimental details were not provided and there were no data from tests longer than 12 months in a nonrodent species on which to base the requirement for 18-month studies in the dog. The conclusion of the group attending the meeting (with one exception) was that, on the basis of the data currently available, there was no justification for conducting 18-month tests in two species.
To date there is no published evidence to support 18-month tests. The results of the present investigation suggest that erroneous conclusions may be drawn regarding the value of long-term tests if careful attention is not given to experimental design. Rather than prolonging investigations to identify toxicity in animals, the emphasis should be on postmarketing surveillance to determine safety in the target species-man.
ACKNOWLEDGMENTS
We are grateful to the following companies for supporting this study and particularly for providing data: Bayer AG, Beecham Pharmaceuticals; Boehringer Mannheim GmbH; The Boots Company PLC; Ciba- Geigy AG and Ciba-Geigy Pharmaceuticals; Fisons Pharmaceuticals; Glaxo Group Research Ltd.; Hoechst AG; Knoll AG, May & Baker Ltd.; Pfizer; Reckitt & Colman; Roche Products Ltd. and F. Hoffman- LaRoche & Co.; Sandoz Ltd; Schering AG; Smith Kline & French Research Ltd.; Sterling-Winthrop Group Ltd.: Thiemann Arzneimittel GmbH; Thomae GmbH; The Wellcome Research Laboratories: Wyeth Research (U. K.).
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GROSS, F. H. (1979). Constraints of drug regulation on the development of new drugs. Arch. Toxicol. 43, 9-17.
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Health Protection Branch (198 I). Pre-clinical Toxicologic Guidelines. Bureau of Human Prescription Drugs, Health Protection Branch, Health and Welfare, Canada.
KESTERSON, J. W. (1982). Drug safety evaluation: Animal toxicology studies and their interpretations. Drug Info. J., January/June, 22-34.
KOSEISHO (1984). Toxicity Test Guidelines 1984. Yakugyo Jiho Co. Ltd, Japan. LUMLEY, C. E., AND WALKER, S. R. (1985a). The establishment of a computer-based toxicology databank.
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compounds: A retrospective analysis. Fundam. Appl. Toxicol. 5, 1007- 1024. WALKER, S. R., AND DAYAN, A. D. (in press). Long-Term Animal Studies-Their Predictive Valuefor Man:
Proceedings, Centre for Medicines Research Workshop, held at the Ciba Foundation, London, October 2, 1984. MTP Press Ltd, Lancaster.