E7 Studies in Support of Special Populations: Geriatrics

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guideline for Industry
Studies in Support of
Special Populations:
Geriatrics
ICH-E7
August 1994

TABLE OF CONTENTS
I. STATEMENT OF PURPOSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II. GENERAL PRINCIPLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
III. SCOPE OF GUIDELINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
IV. DEFINITION OF THE POPULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
V. CLINICAL EXPERIENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
VI. PHARMACOKINETIC STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
A. Formal Pharmacokinetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
B. Pharmacokinetic Screening Approach . . . . . . . . . . . . . . . . . . . . . . . . . . 4
VII. PHARMACOKINETICS IN RENALLY OR HEPATICALLY IMPAIRED
PATIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
VIII. PHARMACODYNAMIC/DOSE RESPONSE STUDIES . . . . . . . . . . . . . . . . 5
IX. DRUG-DRUG INTERACTION STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
X. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

This guideline was developed within the Expert Working Group (Efficacy) of the1
International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the
regulatory parties, in accordance with the ICH process. This document has been
endorsed by the ICH Steering Committee at Step 4 of the ICH process, June 24, 1993.
At Step 4 of the process, the final draft is recommended for adoption to the regulatory
bodies of the European Union, Japan and the USA. This guidance was published in
the Federal Register on August 2, 1994 (59 FR 39398) and is applicable to drug and
biological products. In the past, guidelines have generally been issued under §
10.90(b) [21 CFR 10.90(b)], which provides for the use of guidelines to state
procedures or standards of general applicability that are not legal requirements but that
are acceptable to FDA. The agency is now in the process of revising §10.90(b).
Therefore, this guideline is not being issued under the authority of §10.90(b), and it
does not create or confer any rights, privileges or benefits for or on any person, nor
does it operate to bind FDA in any way. For additional copies of this guideline contact
the Executive Secretariat Staff, HFD-8, Center for Drug Evaluation and Research,
7500 Standish Place, Rockville, MD 20855, 301-594-1012. An electronic version of
this guideline is also available via Internet by connecting to the CDER FTP server
(CDVS2.CDER.FDA.GOV) using the FTP protocol.
GUIDELINE FOR INDUSTRY1
STUDIES IN SUPPORT OF SPECIAL POPULATIONS:
GERIATRICS
I. STATEMENT OF PURPOSE
It is important to ensure that clinical testing programs are carried out according
to harmonized guidelines based on agreed ethical and scientific principles so
that the international development of valuable innovative drugs is achieved with
maximum efficiency. Harmonization in relation to medicines for geriatric
populations is an important issue because the total population of the elderly will
increase significantly in the coming years in Europe, Japan and the USA. The
use of drugs in this population requires special consideration due to the frequent
occurrence of underlying diseases, concomitant drug therapy and the
consequent risk of drug interaction.
II. GENERAL PRINCIPLE

Drugs should be studied in all age groups, including the elderly, for which they
will have significant utility. Patients entering clinical trials should be reasonably
representative of the population that will be later treated by the drug.
III. SCOPE OF GUIDELINE
This guideline is directed principally toward new molecular entities that are likely
to have significant use in the elderly, either because the disease intended to be
treated is characteristically a disease of aging (e.g., Alzheimer's disease) or
because the population to be treated is known to include substantial numbers of
geriatric patients (e.g., hypertension). The guideline applies also to new
formulations and new combinations of established medicinal products when
there is specific reason to expect that conditions common in the elderly (e.g.,
renal or hepatic impairment, impaired cardiac function, concomitant illnesses or
concomitant medications) are likely to be encountered and are not already dealt
with in current labeling. It likewise applies when the new formulation or new
combination is likely to alter the geriatric patient's response (with regard to either
safety/tolerability or efficacy) compared with that of the non-geriatric patient in a
way different from previous formulations. The guideline also applies to new
uses that have significant potential applicability to the elderly.
It is recommended that exemptions from the guideline be determined in advance
either by sponsors or, where feasible, by the sponsor and drug registration
authorities, based, e.g., on estimates of the disease prevalence by age or
through examination of the age distribution of usage for other drugs of the same
class or drugs used for the same indication.
IV. DEFINITION OF THE POPULATION
The geriatric population is arbitrarily defined, for the purpose of this guideline, as
comprising patients aged 65 years or older. It is important, however, to seek
patients in the older age range, 75 and above, to the extent possible. Protocols
should not ordinarily include arbitrary upper age cutoffs. It is also important not
to exclude unnecessarily patients with concomitant illnesses; it is only by
observing such patients that drug-disease interactions can be detected. The
older the population likely to use the drug, the more important it is to include the
very old.
V. CLINICAL EXPERIENCE
Geriatric patients should be included in the Phase 3 database (and in Phase 2,
at the sponsor's option) in meaningful numbers. The geriatric subpopulation

should be represented sufficiently to permit the comparison of drug response in
them to that of younger patients. For drugs used in diseases not unique to, but
present in, the elderly, a minimum of 100 patients would usually allow detection
of clinically important differences. For drugs to treat relatively uncommon
diseases, smaller numbers of the elderly would be expected. Where the
disease to be treated is characteristically associated with aging (e.g.,
Alzheimer's disease) it is expected that geriatric patients will constitute the major
portion of the clinical database.
The overall database of the dossier should be examined for the presence of
age-related differences, e.g., in adverse event rates, in effectiveness, and in
dose-response. If these relatively crude overview analyses show important
differences, further evaluation may be needed.
The geriatric data used in the overview can come either from the inclusion of
elderly patients in all or most of the main Phase 3 or Phase 2/3 studies or from
studies conducted exclusively in geriatric patients, at the sponsor's option.
Inclusion of both groups in the same studies has the advantage of allowing
direct comparisons of younger and older patients using data collected in similar
ways. Such comparisons are more difficult when separate studies of young and
old patients are used. Certain assessments, however, e.g., studies of cognitive
function, require special planning and can be best accomplished in separate
studies.
VI. PHARMACOKINETIC STUDIES
Most of the recognized important differences between younger and older
patients have been pharmacokinetic differences, often related to impairment of
excretory (renal or hepatic) function or to drug-drug interactions. It is important
to determine whether or not the pharmacokinetic behavior of the drug in elderly
subjects or patients is different from that in younger adults and to characterize
the effects of influences, such as abnormal renal or hepatic function, that are
more common in the elderly even though they can occur in any age group.
Information regarding age-related differences in the pharmacokinetics of the
drug can come, at the sponsor's option, either from a Pharmacokinetic Screen
(as described subsequently) or from formal pharmacokinetic studies, in the
elderly and in patients with excretory functional impairment.
It is recognized that for certain drugs and applications (e.g., some
topically-applied agents, some proteins) technical limitations such as low
systemic drug levels may preclude or limit exploration of age-related
pharmacokinetic differences.
A. Formal Pharmacokinetic Studies

Formal PK studies can be done either in healthy geriatric subjects or in
patient volunteers with the disease to be treated by the drug.
The initial PK study can be a pilot trial of limited size conducted under
steady-state conditions to look for sizable differences between older and
younger subjects or patients. A larger, single-dose PK study of sufficient
size to permit statistical comparisons between geriatric and younger
subjects' or patients' pharmacokinetic profiles is also acceptable.
In either case, if large (i.e., potentially medically important) age-related
differences are found, the initial PK study may need to be followed by a
multiple-dose PK study of sufficient size to permit statistical comparisons
(geriatric vs. younger) at steady-state.
B. Pharmacokinetic Screening Approach
Sponsors may opt, instead of conducting a separate PK evaluation of the
elderly, to utilize a pharmacokinetic screen in conjunction with the main
Phase 3 (and Phase 2, if the sponsor wishes) clinical trials program. This
screening procedure involves obtaining, under steady-state conditions, a
small number (one or two) of drug blood level determinations at "trough"
(i.e., just prior to the next dose) or other defined times from sufficient
numbers of Phase 2/3 clinical trials patients, geriatric and younger, to
detect age-associated differences in pharmacokinetic behavior, if they
are present. It is important to record time of dosing prior to blood
concentration measurements, and relation of dosing to meals, and to
examine the influence of demographic and disease factors, such as
gender renal function, presence of liver disease, gastrointestinal disease
or heart disease, body size and composition, and concomitant illnesses.
Small differences are unlikely to be of medical importance. Where the
screen detects large differences, formal pharmacokinetic studies may be
indicated unless the screen's results are sufficiently informative.
The advantage of a pharmacokinetic screen is that it can assess the
effects, not only of age itself, but also of other factors associated with age
(altered body composition, other drugs, concomitant illness) and their
interactions.
VII. PHARMACOKINETICS IN RENALLY OR HEPATICALLY IMPAIRED
PATIENTS
Renal impairment is an aging-associated finding that can also occur in younger
patients. Therefore, it is a general principle, not specific to these guidelines, that

drugs excreted (parent drug or active metabolites) significantly through renal
mechanisms should be studied to define the effects of altered renal function on
their pharmacokinetics. Such information is needed for drugs that are the
subject of this guideline but it can be obtained in younger subjects with renal
impairment.
Similarly, drugs subject to significant hepatic metabolism and/or excretion, or
that have active metabolites, may pose special problems in the elderly.
Pharmacokinetic studies should be carried out in hepatically-impaired young or
elderly patient volunteers.
If a Pharmacokinetic Screen approach is chosen by the sponsor (Section VI,
see above), and if patients with documented renal impairment or hepatic
impairment (depending on the drug's elimination pattern) are included and the
results indicate no medically important pharmacokinetic difference, that
information may be sufficient to meet this Geriatric Guideline's purpose.
VIII. PHARMACODYNAMIC/DOSE RESPONSE STUDIES
The number of age-related pharmacodynamic differences (i.e., increased or
decreased therapeutic response, or side effects, at a given plasma
concentration of drug) discovered to date is too small to necessitate dose
response or other pharmacodynamic studies in geriatric patients as a routine
requirement. Separate studies are, however, recommended in the following
situations:
Sedative/hypnotic agents and other psychoactive drugs or drugs with
important CNS effects, such as sedating antihistamines;
Where subgroup comparisons (geriatric versus younger) in the Phase 2/3
clinical trials database indicate potentially medically significant
age-associated differences in the drug's effectiveness or adverse
reaction profile, not explainable by PK differences.
IX. DRUG-DRUG INTERACTION STUDIES
Such interactions are of particular importance to geriatric patients, who are more
likely to be using concomitant medications than younger patients, but of course
are not limited to this age group. Therefore it is a general principle, not specific
to these guidelines, that in cases where the therapeutic range (i.e., range of
toxic to therapeutic doses) of the drug or likely concomitant drugs is narrow, and
the likelihood of the concomitant therapy is great, that specific drug-drug
interaction studies be considered. The studies needed must be determined
case-by-case, but the following are ordinarily recommended:

Digoxin and oral anticoagulant interaction studies, because so many
drugs alter serum concentrations of these drugs, they are widely
prescribed in the elderly, and they have narrow therapeutic ranges;
For drugs that undergo extensive hepatic metabolism, determination of
the effects of hepatic-enzyme inducers (e.g., phenobarbital) and inhibitors
(e.g., cimetidine);
For drugs metabolized by cytochrome P-450 enzymes, it is critical to
examine the effects of known inhibitors, such as quinidine (for
cytochrome P-450 2D6) or ketoconazole and macrolide antibiotics (for
drugs metabolized by cytochrome P-450 3A4). There is a rapidly growing
list of drugs that can interfere with other drugs that metabolize, and
sponsors should remain aware of it;
Interaction studies with other drugs that are likely to be used with the test
drug (unless important interactions have been ruled out by a
pharmacokinetic screen).
X. REFERENCES
A. Federal Register. Vol.59, No. 102, Tuesday, August 2, 1994, pages
39398-39400.
B. "Guideline for the Study of Drugs Likely to be Used in the Elderly" (1989).