a pro-drug relying on enzyme conversion subject
to ethnic variation
low bioavailability (ethnic dietary effects)
projected common use in multiple co-
medication
potential for inappropriate use
Properties that reduce a drug’s potential for ethnic
variation (ethnically sensitive) are the converse of
the above, with the addition of low potential for
protein binding and nonsystemic use.
Bridging data package
This consists of information from the complete
clinical data package selected for its relevance to
the new region. PK, PD and early dose-response
date should all be included. If a bridging clinical
study between the foreign data and the new
region’s population is needed, this may be a PK
study, or PD demonstration of efficiency or a full
center running a PK study additionally on volun-
teer patients. A bridging clinical study may not be
needed (a regional regulatory decision). This is
most likely where (a) the medicine is ethnically
in sensitive and medical practice and conduct of
trials are similar, (b) if ethnically sensitive but the
two regions have similar clinical make-up of popu-
lations, and (c) when extrapolation from drugs of a
similar class can be made. If the drug is ethnically
in sensitive and clinical data are derived from dis-
similar ethnic populations, provided that other non-
physiological factors are similar, a simple PD dose–
responsestudymaysuffice.Thiscouldutilizeanend
point predictive of clinical value (surrogate), for
example blood pressure. If PK were also undertaken
in the same study, dynamic effects may be directly
reflected by the blood levels.
If the bridging study shows similarity to the
dose–response study in safety and efficacy, this is
usually sufficient, even if this study shows that a
different dose is indicated. That is especially so if at
that new dose (range) a similar safety and efficacy
profile has been demonstrated.
Where the differences are greater (medical prac-
tice, a new drug class to the region, different con-Table 18.1 Classification of intrinsic and extrinsic ethnic factors (ICH Guidance, 1997)
Intrinsic Extrinsic
Physiological and
Genetic pathological conditions Environmental
Gender Age (children–elderly) Climate
Height Sunlight
Bodyweight Pollution
Race Liver Culture
ADME Kidney Socioeconomic factors
Receptor sensitivity Cardiovascular functions Educational status
Genetic polymorphism Diseases Language
of the drug metabolism
Genetic diseases Medical practice
Disease definition/diagnostic
Therapeutic approach
Drug compliance
Smoking/alcohol
Food habits
Stress
Regulatory practice/GCP
Methodology/end points
18.5 THE EVOLUTION OF ICH TOPIC E5 243