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 the 1

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).