reporting framework and regulatory requirements,
but qualitatively, the same serious adverse events
were reported appropriately per capita in all mem-
ber states where the drug was available. It thus
appears, for serious ADRs, that ethnic variation
in Europe does not influence the pattern of adverse
events or its reporting. Other preliminary findings
also showed a similarity of serious ADRs in multi-
national, multicenter European studies, provided
that similar methodology and reporting formats are
used. These observations did not apply to nonser-
ious ADRs, where marked national differences
were seen.
For further discussion, see sections on Evolution
of ICH Topics and Ethnic Factors and Clinical
Responsiveness (Papaluca, Amanti, 1993).
National socioeconomic influences
National reimbursement policies, therapeutic poli-
cies on patients and third-party reimbursement
differences between nations and national or private
insurers can all have an impact on how drugs are
used. Obvious examples are the 1999 refusal of
the United Kingdom government to reimburse the
Glaxo Wellcome antiflu drug Relanza.TMAdvised
National Institute for Clinical Excellence only now
‘at risk’ patients (November 2000), because relief
of one day of illness (out of an average of six days)
did not justify the price. Another example, Ger-
many, France and Italy’s policy on pricing, grants
only ‘improved’ drugs a higher price than the
advertised therapy, even to the denial of some
‘me-too’ drugs. The pricing policy in Japan, with
the compulsory dropping of a company’s drug
price after a few years, irrespective of patent life,
is a further example. Lastly, the lately rescinded
Canadian legislation, basically denying research
costs against developers’ taxes and shortening
patent life nearly crippled research in Canada and
slowed the applications until a price structure had
emerged for drugs in the United States and Europe.
Finally, the US population and US third-party
insurance, both government and private industry,
all pay 30–50% higher prices for the same medi-
cines than Canada, Mexico or Europe. Pressures on
the US manufacturers to reduce US prices will have
a chilling effect on the development of new med-
icines and, hence, on the availability of new med-
icine globally (the United States is the origin of
about 60% of the world’s new chemical entities).Terminology, diagnosis and other
subjective factorsAs previously mentioned, some diseases and syn-
dromes are not universally recognized in the
three regions. Until recently, neither AIDS nor
depression was diagnosed in Japan. Conditions
such as ‘cardiac fatigue’ and ‘postural hypoten-
sion’ in Germany; ‘liver crisis’ in France; ‘heavy
leg syndrome’ (pre-varicose-vein development) in
Switzerland; and ‘anxiety neurosis’ in the United
States are unique to these regions. The end points
for treatment may also be different, for example
that for blood pressure in Japan is 160/95; in
Europe 140/90; and in the United States 130/80.
Indeed, even in the same language, ‘I am in the
pink’ and ‘I feel blue’ have opposite meanings, and
used in self-rating scales but have no or different
meanings for the United States and United
Kingdom, respectively.
The end result of these differences, although
apparent rather than real, may be why the recom-
mended dose of captopril (an ACE Inhibitor,
antihypertensive drug) is 75–450 mg per day in
the United States and 37.5–122.5 mg per day in
Japan (with overall adverse events of 39% and
3.8% respectively). With a nonsteroidal anti-
inflammatory agent, overall adverse events were
45–51% in the United States and 24% in Japan at
the same dosage; however, efficacy was the same
(Dziewanowska, 1992). In general, the British,
Dutch and Scandinavian data are closer to those
observed in the United States, with the German
and Swiss data ‘least reactive’ and French, Italian
and Spanish in between. As mentioned previously,
severe ADRs in clinical studies tend to be the
same; the major difference was in ‘minor’ adverse
events, such as nausea, headache and so on. Thus,
national temperament also may play a part in the
expectation of efficacy and ADR. This finding
was reflected in a study of attitudes of 4000 nurses
from 13 countries to ethnic tolerance of pain240 CH18 RACIAL AND ETHNIC ISSUES IN DRUG REGISTRATION