Principles and Practice of Pharmaceutical Medicine

Chronic toxicity studies

As discussed above, the extent of additional
repeated-dose studies are generally outlined in
Tables 6.2 and 6.3. The maximum duration of
chronic studies is generally 6 months, although
the ICH guidelines describe situations where stu-
dies of 9–12-month duration may be necessary in a
non-rodent species.
Protocols for these studies are similar to those
for studies of shorter duration, except that a
minimum of 10–15 rodents per group and 4 non-
rodents per sex per group are required.
Toxicokinetic measurements are still required.
The usual in-life and postmortem observations
are performed.

Reproduction and teratology studies

Thalidomide demonstrated the need to evaluate
new drugs in reproductive toxicology studies.
Some of the earliest guidelines were issued by
the US FDA (the ‘Goldenthal guidelines’). An
ICH guideline now covers the performance of
these studies (Federal Register, 22 September
1994), as amended in 1995 to address possible
effects on male reproduction.
In general, three phases of the reproductive pro-
cess are evaluated. These cover the principal
aspects of reproductive biology, namely concep-
tion and implantation, organ formation and terato-
genesis and finally the development of offspring of
exposed maternal animals allowed to proceed to
term.

Fertility and implantation

The first phase (historically referred to as ‘Segment
I’study, and now under ICH as ‘Stage A’) evaluates
the effect of the new drug on the fertility and the
early implantation stages of embryogenesis. In
these studies, breeding animals of one species
(usually rats or rabbits) of both sexes will be treated
for two or more weeks prior to mating, and then
the females will be further dosed until day 6 of
gestation.

Teratogenesis

The second stage (historically Segment II, now

ICH Stage B) is the teratology study (sometimes

termed ‘the developmental toxicity study’). This is

also done in rats and rabbits. The maternal animal

is exposed to test medication during the period of

organogenesis, and the pregnant animals are typi-

cally sacrificed shortly prior to term for detailed

anatomical study of the fetus.

Developmental studies postpartum

The third stage (Segment III or ICH Stage C)

evaluates treatment during late gestation, parturi-

tion and lactation. Behavioral and neurodevelop-

mental assessments in the offspring are often made

in Segment III studies. In some cases, two of the

studies can be combined and still satisfy the ICH

guideline.

The period in the drug development process at

which results of these studies are required still

varies somewhat from country to country, as is dis-

cussed in the ICH guideline (see Hoyer, 2001, for

the current situation and additional perspective).

Carcinogenicity studies

Carcinogenicity studies involve the treatment of

rodents for long periods approximating to the com-

plete life span (18 months to 2 years) to determine

whether thetest materialpossesses the capabilityto

initiate or promote the development of tumors. The

relevance of these models to the human situation

has been debated for many years. Carcinogenicity

studies have been required for all drugs where

clinical therapy may extend for six months or

longer. Although the scientific debate about the

relevance of these studies continues, they remain

obligatory by regulation.

Several different ICH guidelines have been

issued that address the various aspects of carcino-

genicity testing of drugs, including when studies

are needed (duration of clinical therapy;Federal

Register, 1 March 1996). Other features of the new

drug may mandate carcinogenicity testing, such as

6.7 TOXICOLOGICAL SUPPORT FOR PHASE II AND III STUDIES 71