193
Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
dossier, but many individual country requirements
exist for non-CTD format, stability studies across
temperature zones, labeling and packaging. In
addition, specific product type guidelines devel-
oped by many jurisdictions may require additional
or different product specifications.
Marketing and reimbursement teams also
may have country- or region-specific require-
ments that must be accommodated to support
commercial success, e.g., a pack size equivalent
to one month’s supply is the maximum quantity
permitted to be dispensed or reimbursed on
each occasion.
Nonclinical
As the nonclinical plan is developed, it must
be integrated with both the clinical and CMC
programs. Clinical studies must be supported
by appropriate nonclinical studies. For example,
nonclinical toxicology studies should use the
route of administration proposed in the clinical
study, of the same or longer duration. Results of
nonclinical studies conducted prior to the first
Phase 1 study should provide information to
guide clinical study starting dose selection. Simi-
larly, reproduction study timing generally will be
determined by the timing of including women of
child-bearing potential in clinical studies.
In countries that have adopted ICH
guidelines, the nonclinical program required to
support clinical studies generally is harmonized.
However, even in ICH countries, differences
exist in long-term toxicity study duration to sup-
port Phase 3 trials and marketing applications.
For example, ICH M3(R2) on the duration of
repeat-dose toxicity studies provides different
recommendations for the EU and US. In the EU,
a six-month repeat-dose study in two species
(rodent and nonrodent) is required. However, the
US requires a nine-month nonrodent study.
Therefore, the nonclinical plan must meet
local regulatory requirements to initiate clinical
studies and meet global nonclinical requirements
needed to support the market application.
Clinical Development
Increasingly, the clinical development pro-
gram’s goal should not only be global but,
essentially, simultaneous.
Simultaneous global clinical develop-
ment can bring many benefits to the global
regulatory strategy:
• broader regulatory oversight—
simultaneous submission and regulatory
agency review allow the authorities’
views and experiences to be included in
the clinical development program
• reduced drug availability lag—successful
simultaneous clinical development
should result in earlier innovative drug
therapy availability to populations in
new markets and, ultimately, a reduction
in drug lag from core countries’
marketing time
• ethnic factors—broader clinical
development enables a science-based
approach to define intrinsic and
extrinsic factors and identify meaningful
ethnic differences (In addition,
registration dossiers will include higher
ethnic diversity.)
Global clinical development data should satisfy
not only US and EU requirements, but also
address ethnic differences and satisfy the local
data requirements for marketing applications
in countries such as Japan, China, South Korea,
Taiwan, Mexico and India.
Global programs have contributed to the
geographic shift in selecting countries for clinical
trials. Drivers for this shift also include access
to wider, often treatment-naive populations and
a reduction in development costs. Increasingly,
countries outside the traditional drug develop-
ment core countries are offering quality sites and
good investigators.
Organizations may set out to design a global
clinical development program, but whether this
can be truly simultaneous depends on many
Global Pharmaceutical and Biologics Regulatory Strategy, Second Edition
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
dossier, but many individual country requirements
exist for non-CTD format, stability studies across
temperature zones, labeling and packaging. In
addition, specific product type guidelines devel-
oped by many jurisdictions may require additional
or different product specifications.
Marketing and reimbursement teams also
may have country- or region-specific require-
ments that must be accommodated to support
commercial success, e.g., a pack size equivalent
to one month’s supply is the maximum quantity
permitted to be dispensed or reimbursed on
each occasion.
Nonclinical
As the nonclinical plan is developed, it must
be integrated with both the clinical and CMC
programs. Clinical studies must be supported
by appropriate nonclinical studies. For example,
nonclinical toxicology studies should use the
route of administration proposed in the clinical
study, of the same or longer duration. Results of
nonclinical studies conducted prior to the first
Phase 1 study should provide information to
guide clinical study starting dose selection. Simi-
larly, reproduction study timing generally will be
determined by the timing of including women of
child-bearing potential in clinical studies.
In countries that have adopted ICH
guidelines, the nonclinical program required to
support clinical studies generally is harmonized.
However, even in ICH countries, differences
exist in long-term toxicity study duration to sup-
port Phase 3 trials and marketing applications.
For example, ICH M3(R2) on the duration of
repeat-dose toxicity studies provides different
recommendations for the EU and US. In the EU,
a six-month repeat-dose study in two species
(rodent and nonrodent) is required. However, the
US requires a nine-month nonrodent study.
Therefore, the nonclinical plan must meet
local regulatory requirements to initiate clinical
studies and meet global nonclinical requirements
needed to support the market application.
Clinical Development
Increasingly, the clinical development pro-
gram’s goal should not only be global but,
essentially, simultaneous.
Simultaneous global clinical develop-
ment can bring many benefits to the global
regulatory strategy:
• broader regulatory oversight—
simultaneous submission and regulatory
agency review allow the authorities’
views and experiences to be included in
the clinical development program
• reduced drug availability lag—successful
simultaneous clinical development
should result in earlier innovative drug
therapy availability to populations in
new markets and, ultimately, a reduction
in drug lag from core countries’
marketing time
• ethnic factors—broader clinical
development enables a science-based
approach to define intrinsic and
extrinsic factors and identify meaningful
ethnic differences (In addition,
registration dossiers will include higher
ethnic diversity.)
Global clinical development data should satisfy
not only US and EU requirements, but also
address ethnic differences and satisfy the local
data requirements for marketing applications
in countries such as Japan, China, South Korea,
Taiwan, Mexico and India.
Global programs have contributed to the
geographic shift in selecting countries for clinical
trials. Drivers for this shift also include access
to wider, often treatment-naive populations and
a reduction in development costs. Increasingly,
countries outside the traditional drug develop-
ment core countries are offering quality sites and
good investigators.
Organizations may set out to design a global
clinical development program, but whether this
can be truly simultaneous depends on many