have local clinical data developed, it did not appear
that actual regulations precluded the use of
‘foreign’ (usually US) data in most European coun-
tries (Safety Workshop ICH 1, 1992), although
some nations (France, Italy and Germany) required
some clinical experience in their countries prior
to approval.
In Japan, there has been harmonization with the
other regions in the area of toxicology (animal
studies); the Japanese Ministry of Health, Labor
and Welfare (MHLW) accepts appropriate foreign
animal data and animal safety studies performed
according to ICH guidelines. Indeed, Japan has
played a major role, and its then current fertility
and reproductive animal studies requirements have
been adopted by the other two regions.
However, the acceptance of ‘foreign’ clinical
data has been a major issue for all the health
authorities for a long time. Previously, all phase
II and III clinical studies needed to be performed.
Mandatory clinical studies were required in
many European countries and in Japan on Japanese
people. Phase I studies could be done outside
Japan,but onlyif the drug was in wide use in that
country (which had to be a developed country)
and if the drug’s performance was unaffected by
racial differences in physiology. The Japanese
position has been that diet, and perhaps genetics,
can play a significant role in PD, and that a drug’s
safety or efficacy may be different in the Japanese
than in other races (MHW Notification 660 and
Notification, June 1987) because of subsequent
metabolic differences. Clearly, there are a few
drugs where this rationale is justified, but
there are many others where metabolism may be
largely irrelevant (e.g. ophthalmologicals, topi-
cals). However, these differences appear to consti-
tute a major reason why (without exception) phase
II and III trials had to be carried out on Japanese
patients (Uchida, 1988; Fairburn, 1989; Homma,
1991; for further discussion, see Apple and
Weintraub, 1993).
18.3 Objective differences
Now to first examine those differences which can
be quantified more readily.
Population demographics between
tripartite areasThe United States is a nation of many racial,
ethnic and national origins and is the most hetero-
geneous population of the three areas. Given the
successive waves of European, African and Asian
immigrants, themselves imposed upon even ear-
lier waves of Bering Straits immigrants (Native
North and South American Indians, and Eskimo),
makes the US population the most diverse in the
world. Although inter-marriage has occurred,
many major racial groups remain regionally or
locally clustered and still adhere to cultural
aspects of their area of origin. However, many of
the smaller distinct racial and ethnic groups may
not be represented in the US pharmaceutical data-
bases, either due to the realities of setting up
clinical studies or because only small numbers
are present in that population. In general, only
Caucasians, Blacks, Asians and Hispanics may
have measurable populations in a database
(Edwards, 1992). As of 1990, American Indians
comprise 0.8% of the population, with the other
minorities comprising larger or smaller percen-
tage of the population: Hispanic (any race)
9.8%; Pacific Asian 2.9%; Black 12.1% (US
Bureau of the Census, 1991). Europe has a
Caucasian ‘heterogeneous’ population made up
of Anglo-Saxon/Celtic, Germanic, Gaelic, mid-
European and ‘Latin’ races. There are sizeable
populations of migrant foreign workers, as much
as 10% in Germany, and many resident Asian and
African citizens of Britain and in France (5%). In
contrast, Japan is populated almost entirely by
ethnic Japanese, truly homogeneous, although a
sizable non-national immigrant population of
other guest Asian workers exists.
The definitions of racial groups are not totally
satisfactory (e.g. what is ‘Black’?), and ethnicity
and geography can wreak havoc on the meaning of
‘representative’ for example Pacific Islanders and
Asians make up 9.8% of the Pacific states popula-
tion and 61.8% of the US state of Hawaii (US
Bureau of the Census, 1991). What is Hispanic,
other than a language group that contains a combi-
nation of genetic groups from Europe, Africa
and Native America? Diseases such as stroke are18.3 OBJECTIVE DIFFERENCES 233