adverse events by age. In addition, other studies
should determine whether older people handle
the new drug differently (a 30% decrease in
renal excretion and liver metabolism is normal
in a healthy elderly person). This guideline
also required studies of the pharmacokinetics
(PK) and, where possible, pharmacodynamic
studies of the new drug in the elderly. TheGuide-
linealso urged the study of possible drug interac-
tions with drugs commonly used concurrently in
this age group. Digoxin was given as an example.
Looking even further forward to the future, the
Guidelineencouraged the inclusion of patients
over 75 years.
Medicines in the elderly had become a world
issue and, in 1994, the FDA implemented the ICH
tripartite guidance,Studies in Support of Special
Populations: Geriatrics(Federal Register, August
1994). The agency followed up with specific
requirements on content and format of labeling
for human prescription drugs; addition of a
‘Geriatric Use’ subsection in labeling (Federal
Register, August 1997). This set out priority imple-
mentation lists of drug categories for information
in geriatric population and gave the industry one
year to comply. It also set out the specific content
and format of wording to be used.
15.6 Overview of international
harmonization conference
guidelinesThis guideline was very similar to the 1990 FDA
guideline in intent. It made the following requests:
- Studies should be done in new molecular enti-
ties (NMEs) or new chemical entities (NCEs)
likely to be used in the elderly, either to treat a
disease of ageing or because the disease is also
common in the elderly. - Studies should include patients 65 years and
older, and preferably patients aged 75 or older,
and advised against arbitrary age cutoff
(patients aged 60–65 are not considered
elderly).
3. Meaningful numbers, especially in phase III: a
minimum of 100 patients was suggested for a
non-geriatric-specific disease (e.g. hyperten-
sion).
4. Analysis of the database for age-related differ-
ences of efficacy, adverse events, dose and (gen-
der) relationships. A geriatric database may
contain data from the main phase II and III
studies or from a geriatric-specific study.
5. PK studies, either formal PK studies or on a
population basis, should be carried out. For the
latter, a blood sample is taken from many
patients on up to four occasions. The time of
dosing is recorded, and the time of samples. The
patients must be in ‘steady state’. This way, an
adequate population PK plot can be built.
6. PK studies in renal-impaired patients if the drug
or metabolites are renally excreted. If the NME
is excreted and/or metabolized by the liver, a
hepatic-impaired study should be undertaken.
These studies do not have to be done in elderly
patients (they are usually done on a new NME
anyway).
7. Usually, differences in the therapeutic response
or adverse events are too small to detect at an
equivalent plasma level between ordinary adult
and elderly patients to make this a requirement.
However, separate studies are requested of seda-
tive hypnotic psychoactive drugs or drugs
having a significant CNS effect, and, similarly,
if phase II and III studies are suggestive of an
age-related difference.
8. Drug interaction studies should be done on
digoxin and oral anticoagulants, for these drugs
have a narrow therapeutic range and are com-
monly prescribed in the elderly. These drugs
frequently have their serum levels altered by
other drugs. Where drugs are heavily metabo-
lized by the liver, the effect of drug enzyme
inducers and inhibitors should be explored.
Similarly, drugs which will share the same cyto-
chrome P450 enzyme pathways should be
tested. Ketoconazole, macrolides and quinidine
196 CH15 DRUG RESEARCH IN OLDER PATIENTS