Historically, the regulatory control of clinical research has been different in Europe, the United States and Japan.
NON-CLINICAL TESTING
REQUIREMENTS
Historically,
the regulatory control of clinical research has been different in Europe, the
United States and Japan. In Europe, the Clinical Trial Directive (Direc-tive
2001/20/EC) came into force on 01 May 2004. Although the Directive has set the
same regulatory framework for the control of clinical trials across Europe,
there are differences between Member States in their transpositions of the Directive,
resulting in some diversity in the regulatory mechanisms and requirements.
Similarly, there has been no harmonisa-tion on the precise extent of
pre-clinical testing (toxi-cology and pharmacology) required before conducting
the first study of a new drug in man. Various offi-cial (FDA, 1968) and
unofficial (PMA, 1977; ABPI, 1985) guidelines have provided details of the
basic studies that should be conducted in advance of a Phase I study. A partial
consensus was reached on the non-clinical testing required with the publishing
of the ICH M3 guideline, which came into operation in March 1998 (EMEA, 1998).
However, even the latest revi-sion of this guideline (November 2000a) shows
areas of non-agreement in the data expectations of the EU, United States and Japan
during the various phases of clinical development (e.g. duration of toxicology
test-ing and timing of reproduction toxicology studies).
Although
certain classes of therapeutic agents and drugs for the treatment of certain
types of life-threatening or serious disease may warrant a more flexible
approach, the general guidance is that, before initiating studies in humans of
a pharmaceutical agent, the following studies should be undertaken:
·
Acute toxicity studies in two mammalian species.
·
Repeat-dose toxicity studies in two mammalian species (one
non-rodent), the duration of which should equal or exceed the duration of the
proposed human clinical study (see details below).
·
Safety pharmacology studies to include the assess-ment of
effects on the cardiovascular, central nervous and respiratory systems.
·
In vitro evaluation of
genotoxicity to include eval-uation of mutations and chromosomal damage before
Phase I with additional tests required before Phase II.
·
Studies to evaluate the absorption, distribution, metabolism
and excretion (ADME) of drugs in animals. Results of these studies should be
avail-able by the completion of the Phase I studies and before beginning
patient studies.
·
When appropriate, local tolerance studies in animals using
the proposed route of administra-tion for human studies. Such evaluations may
be included as part of other toxicity studies.
·
Reproduction toxicity studies appropriate for the population
to be studied. For example, in the EU, embryofoetal development studies are
required before the inclusion of females of childbearing potential in Phase I
studies. If a male-only popu-lation is to be studied at Phase I, it is usually
sufficient to include appropriate examination of the reproductive organs in the
repeated dose toxicol-ogy studies. Studies of fertility, early embryonic
development, pre- and post-natal development and development will be required
before extending the participant population and the duration of admin-istration
in the clinical studies.
·
Carcinogenicity studies are not normally required in advance
of the conduct of clinical trials but on occasions may be warranted, for
example if genotoxicity studies identify a potential risk.
In
addition to describing the type of non-clinical studies that should be
performed before administration to humans, the ICH M3 guideline addresses the
dura-tion of repeated-dose toxicology studies required to support human
administration. Study duration should be based on the intended clinical use and
dosage regi-men. The non-clinical data required to support early human studies
are of limited duration; in the US, single-dose toxicology studies with
extended exami-nations can support single-dose human trials, but in Europe 2
weeks repeated dosing in two species, one rodent and one non-rodent, is required
for adminis-tration of a single dose. This will also support up to 14 days
repeated administration of a standard new chemical entity. For longer-term
human administra-tion, the required duration of non-clinical testing varies
somewhat across the ICH regions, as noted in the ICH M3 guideline. For a simple
daily-repeated dosing regime, however, 6-month rodent data and 9-month
non-rodent data are widely acceptable to support Phase III clinical trials
longer than 3 months.
Thus,
although a relatively limited package of data on a product may be sufficient to
allow the adminis-tration of single doses, a more extensive package of studies
will be required subsequently, in order to facil-itate assessment of the safety
of longer-term studies in more mixed populations. Progress through the vari-ous
stages of drug development will require continued assessment of human safety
data with the possibility of further non-clinical studies being required,
depend-ing on the information generated.
The
basic battery of non-clinical safety studies is intended to be adequate for the
identification and char-acterisation of potential toxic effects, which may be
relevant during the early phase of clinical develop-ment. For some types of
product, however, a ‘stan-dard’ non-clinical programme may not be appropriate;
abbreviated or extended testing programmes may be required and must be
justified on a case-by-case basis. For example, it is generally not appropriate
to perform genotoxicity assays for proteins and peptides unless there are
concerns over impurities in the product. It may also be appropriate to reduce
the repeated dose toxiciology testing of such products, performing studies only
in a single relevant species, rather than using a second animal species that is
unresponsive to the test material. Conversely, extension of non-clinical
programmes may be appropriate where there are special concerns over issues such
as immunotox-icity, when special monitoring of immune responses should be
included in the toxicology studies. In any case, the non-clinical programme
should be designed and, if necessary, adjusted to provide data that will
fulfill the aims of non-clinical testing and allow a reasoned assessment of
product safety before admin-istration to humans.
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