from that of the region standard), a controlled,
randomized clinical study for efficacy will be
required. This might utilize shorter duration surro-
gate end points, rather than the clinical end points
common to phase III studies.
The ICH issued a further Questions and Answers
Guidance (US Food and Drug Administration,
2004) to provide further explanations of when
bridging studies may be required following six
years of experience.
Bridging safety studies
The new region may also have concerns regarding
the relevance of the safety data of common serious
adverse events and their incidence to their ethnic
population. The guidance recommends that the
clinical efficacy study should be powered to cap-
ture a 1% incidence of an event, namely 300
patients for six months on the new medicine. Addi-
tional patients will be needed for the control group
in a controlled trial, given an expected dropout rate
of 15–30%, dependent on disease and severity of
efficacy depends on the balance of the groups (1:1,
1:2, 1:3). A small safety study might be done
initially to assure the sponsor and the region that
a high incidence of serious events is unlikely to be
seen in the larger study.
Practical implications to sponsors
of new medicines
Most major clinical pharmaceutical manufacturers
recognize that it is not profitable to develop a drug
just for one region. In the past, most drugs were
introduced first in Europe, even by US-based firms
for pricing reasons, often country by country, and in
Japan even later. This has dramatically changed
since the Prescription Drug User Fee Act, which
speeded up US approvals and the introduction
of the ‘centralized procedure’ of Application for
Europe. Frequently, firms will conduct multicentre
studies in both the United States and Europe and
submit them almost simultaneously to the FDA and
EMEA. This was not possible to do for Japan; now
it is! Indeed, Japan now can conduct studies in other
regions on their drugs and combine them with
confidence into their own more extensive clinical
data package for foreign submission. Differences
of Japan’s chemical manufacturing and quality
control section (CMC) still have to be resolved
before full interchangeability (mutual recognition)
of their Common Technical Documents occurs.
Many firms now do PK and PD dose–response
studies on Japanese patients in Japan. In addition,
even if not needed, they conduct a controlled local
comparison clinical study to expand the database
and for sound marketing reasons.
In the United States, because of legislation pre-
viously discussed, data on major ethnic groups are
collected and analyzed and may in general provide
reassurance that the most obvious ethnic differ-
ences are observed. This is of less concern to the
other regions.
For many years, the FDA has encouraged a wide
geographic distribution of phase III multicenter
studies. This can be used to enroll minority and
cultural ethnic groups, because they tend to con-
gregate in regional clusters, for example Hispanics
in Miami and New York. Placement with a physi-
cian investigator of similiar ethnic origin can
enhance the enrollment, for frequently they will
attract patients of that group. It should be noted that
‘hispanic’ analysis has been dropped as a require-
ment unless culturally relevant.
The current regulatory position of the three
regions has been outlined in the notes forThe Gui-
dancefor the Mutual Use ofForeign Data inthe EC,
Japan, and US, Part 1.The ADME concern has
been welldefined andquantified in separate reports.Does it matter? The reality
Despite this huge list of possible factors influen-
cing the drug development and assessment process,
the following realities are emerging.For most drugs the therapeutic range is broad,
and rarely is an optimal dose so critical for
effective treatment. Exceptions, such as cardiac
glycosides, anticonvulsants, anticoagulants and
so on, have a narrow therapeutic window and
must be individualized by titration. Such drugs,244 CH18 RACIAL AND ETHNIC ISSUES IN DRUG REGISTRATION