[Federal Register Volume 59, Number 147 (Tuesday, August 2, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-18726]


[[Page Unknown]]

[Federal Register: August 2, 1994]


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Part II





Department of Health and Human Services





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Food and Drug Administration



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International Conference on Harmonisation; Guideline on Studies in 
Support of Special Populations: Geriatrics; Availability; Notice
DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 93D-0138]

 
International Conference on Harmonisation; Guideline on Studies 
in Support of Special Populations: Geriatrics; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a final 
guideline entitled ``Studies in Support of Special Populations: 
Geriatrics.'' The guideline was prepared by the Efficacy Expert Working 
Group of the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
The guideline is intended to reflect sound scientific principles for 
testing drugs in geriatric populations. The guideline provides useful 
information for sponsors submitting applications to both the Center for 
Drug Evaluation and Research (CDER) and the Center for Biologics 
Evaluation and Research (CBER).

DATES: Effective August 2, 1994. Submit written comments at any time.

ADDRESSES:  Submit written comments on the guideline to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23, 
12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: 
    Regarding the guideline: Patrick J. Savino, Center for Drug 
Evaluation and Research (HFD-8), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1012.
    Regarding the ICH: Janet J. Showalter, Office of Health Affairs 
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville, 
MD 20857, 301-443-1382.

SUPPLEMENTARY INFORMATION: In recent years, many important initiatives 
have been undertaken by regulatory authorities and industry 
associations to promote international harmonization of regulatory 
requirements. FDA has participated in many meetings designed to enhance 
harmonization and is committed to seeking scientifically based 
harmonized technical procedures for pharmaceutical development. One of 
the goals of harmonization is to identify and then reduce differences 
in technical requirements for drug development.
    ICH was organized to provide an opportunity for tripartite 
harmonization initiatives to be developed with input from both 
regulatory and industry representatives. FDA also seeks input from 
consumer representatives and others. ICH is concerned with 
harmonization of technical requirements for the registration of 
pharmaceutical products among three regions: The European Union, Japan, 
and the United States. The six ICH sponsors are the European 
Commission, the European Federation of Pharmaceutical Industry 
Associations, the Japanese Ministry of Health and Welfare, the Japanese 
Pharmaceutical Manufacturers Association, FDA, and the U.S. 
Pharmaceutical Manufacturers Association. The ICH Secretariat, which 
coordinates the preparation of documentation, is provided by the 
International Federation of Pharmaceutical Manufacturers Associations 
(IFPMA).
    The ICH Steering Committee includes representatives from each of 
the ICH sponsors and the IFPMA, as well as observers from the World 
Health Organization, the Canadian Health Protection Branch, and the 
European Free Trade Area.
    At a meeting held on September 16, 1992, the ICH Steering Committee 
agreed that the draft tripartite guideline entitled ``Studies in 
Support of Special Populations: Geriatrics'' should be made available 
for comment. Subsequently, the draft guideline which published in the 
Federal Register of April 16, 1993 (58 FR 21082), was made available 
for comment by the European Commission and the Japanese Ministry of 
Health and Welfare, as well as by FDA, in accordance with their 
consultation procedures. At a meeting held on June 24, 1993, the 
comments were analyzed and the guideline was revised as necessary.
    With this notice, FDA is publishing in final form a guideline 
entitled ``Studies in Support of Special Populations: Geriatrics.'' 
This guideline has been endorsed by all ICH sponsors. The guideline 
provides useful information to sponsors submitting applications to both 
CDER and CBER. The guideline addresses harmonization in relation to 
clinical testing programs for drugs intended for use in medicines for 
the geriatric population, which is expected to increase significantly 
in the near future in Europe, Japan, and the United States. The use of 
drugs in the geriatric population requires special consideration due to 
the frequent occurrence of underlying diseases, concomitant drug 
therapy, and the consequent risks of drug interaction. The 
recommendations of this guideline do not materially differ from the 
recommendations of a 1989 CDER guideline entitled ``Guideline for the 
Study of Drugs Likely to be Used in the Elderly.'' Although the ICH 
harmonized guideline provides much useful information for sponsors 
submitting applications to CDER and CBER, the 1989 document contains 
background and additional commentary not present in the harmonized 
guideline. For this reason, FDA intends to provide both the ICH 
harmonized guideline and the 1989 document when information is 
requested on the study of new drugs in a geriatric population.
    Guidelines are generally issued under Sec. 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 Sec. 10.90(b). Therefore, this guideline is not being issued 
under the authority of Sec. 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.
    As with all of FDA's guidelines, the public is encouraged to submit 
written comments with new data or other new information pertinent to 
this guideline. The comments will be periodically reviewed and, where 
appropriate, the guideline will be amended. The public will be notified 
of any such amendments through a notice in the Federal Register.
    Interested persons may, at any time, submit written comments on the 
guideline to the Dockets Management Branch (address above). Two copies 
of any comments are to be submitted, except that individuals may submit 
one copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document. The guideline and received 
comments may be seen in the office above between 9 a.m. and 4 p.m., 
Monday through Friday.
    The text of the final guideline follows:

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 harmonised guidelines based on agreed 
ethical and scientific principles so that the international 
development of valuable innovative drugs is achieved with maximum 
efficiency. Harmonisation 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 labelling. 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).

    Dated: July 27, 1994.
 Michael R. Taylor,
 Deputy Commissioner for Policy.
[FR Doc. 94-18726 Filed 8-1-94; 8:45 am]
BILLING CODE 4160-01-F