Principles and Practice of Pharmaceutical Medicine

population. Professor Naito concluded that, if the
metabolism of a new drug was influenced by
genetic polymorphism, then additional regional
PK and dose-ranging studies might be required.
Dr S. Walker of CMR approached European and
UScompanies for information on 21 drugs available
in the three regions. Within thisnarrow sample, only
one drug had genetic polymorphism, but even this
did not translate to ethnic variations. Three other
drugs showed regional variability in PK, but these
were attributable to different formulations, different
sample times and reduction of the initial dose. The
CMR survey confirmed that the reported levels of
adverseeventswerelowerinJapanesepatients,even
when adjusted for dose – a cultural variation.
The US report on findings in the literature were
given by the first author of this chapter and Dr. R.
Williams of the FDA. Much of the earlier part of
this chapter was drawn from these reports.
Deciding what to do about this complex issue
took another four years! Two more conferences
were needed to resolve the issue, but finally in
July 1997, Step 3 was concluded, Europe and
Japan referred it to their governmental bodies and
the United States published the draft guidelines in
theFederal Register.Phase IV acceptance by the
ICH Steering Committee occurred in February
1998, and the final guidance document was imple-
mented in the United States in June 1998 (Step 5)
(Federal Register, 1998).

Outline of the ‘Guidance’ – E5

Overall, it will not be necessary to repeat the entire
clinical drug program in each of the other two
regions. Eachregional authority will judgewhether
the clinical data fulfill their regulatory regional
requirements (i.e. are a complete package). If so,
can they be extrapolated to their population? If the
authority is concerned that a drug could be subject
to ethnic factors impacting on efficacy or safety,
then limited clinical data gathered in people of that
region may be required to ‘bridge’ the clinical data
between thedata generated in oneregionto those of
the area in which the data were generated. If new
data are required by the new region anyway (inade-
quate for regional requirements), the study could

What is a complete package?

Studies should be adequately well-controlled end

points and medical and diagnostic definitions

appropriate to the region. The specific needs are

mostly covered in other ICH guidances GCPs

[(E6), dose response (E4), adequacy of safety

data (E1 and E2), studies in elderly (E7), reports

(E3), clinical trials (E8) and statistics (E9)]. Occa-

sionally, a region may feel that other studies are

needed in areas that other regions are less con-

cerned with; a different ‘golden’ standard as com-

parator, or at a dosage as approved in that region, as

well as patients with renal or hepatic insufficiency,

are given as examples.

Ethnic factors and population

extrapolation of a drug

Some properties of a drug or its class may make it

insensitive to ethnic factors. This will make it easier

for extrapolation to different regions and reduce the

need for ‘bridging’ clinical data. Properties that

make it susceptible to ethnic influences see Table

18.1 willrequirebridgingstudies,sometimesofPK/

dynamics studies or safety and efficacy either or

both.

Assessing the potential sensitivity

of a drug to ethnic factors

If a drug is of a known class, the sensitivity may

already be determined, but by the end of phase I

most of the PK and PD of a drug will be known. The

properties of the compound that may indicate

potential ethnic variation (ethnically sensitive) are

nonlinear PK

a steep efficacy and safety PK dose curve

narrow therapeutic dose range

highlymetabolized,especially if through just one

pathway (potential for drug–drug interaction)

metabolism by enzymes known to show genetic

242 CH18 RACIAL AND ETHNIC ISSUES IN DRUG REGISTRATION