[Federal Register Volume 62, Number 166 (Wednesday, August 27, 1997)]
[Rules and Regulations]
[Pages 45313-45326]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-22701]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 89N-0474]
RIN 0910-AA25


Specific Requirements on Content and Format of Labeling for Human 
Prescription Drugs; Addition of ``Geriatric Use'' Subsection in the 
Labeling

AGENCY:  Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations governing the content and format of labeling for human 
prescription drug products, including biological products, to include 
information pertinent to the appropriate use of drugs in the elderly 
(persons aged 65 years and over) and to facilitate access to this 
information by establishing a ``Geriatric use'' subsection in the 
labeling. The final rule is one of several measures FDA has taken in 
response to the special concerns associated with prescription drug use 
in elderly patients. FDA believes that improving access to information 
that is important to the elderly will facilitate the safe and effective 
use of prescription drugs in older populations.

DATES:  This final rule becomes effective on August 27, 1998. Submit 
written comments on the collection of information provisions by October 
27, 1997. See section IV of this document for the implementation dates 
of this final rule for drug classes and drug products.
ADDRESSES:  Submit written comments on the information collection 
requirements to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT:  Thomas C. Kuchenberg, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-5621.

SUPPLEMENTARY INFORMATION: 

I. Background

    In the Federal Register of November 1, 1990 (55 FR 46134), FDA 
proposed to amend its prescription drug labeling regulations 
(Sec. 201.57) to establish in the ``Precautions'' section a subsection 
on the use of drugs in elderly or geriatric patients (aged 65 years and 
over). The final rule requires, in a new ``Geriatric use'' subsection 
of prescription drug labeling, that sponsors describe available 
information pertinent to the appropriate use of drugs in elderly 
patients. In cases where none of the provisions of the ``Geriatric 
use'' subsection are applicable, FDA may permit omission of the 
subsection or approve an accurate and appropriate alternate statement.
    The final rule recognizes the special concerns associated with the 
geriatric use of prescription drugs and acknowledges the need to 
communicate important information so that drugs can be used safely and 
effectively in older patients. The medical community has become 
increasingly aware that prescription drugs can produce effects in 
elderly patients that are significantly different from those produced 
in younger patients. Although both young and old patients can exhibit a 
range of responses to drug therapy, factors contributing to different 
responses are comparatively more common among the elderly. For example, 
elderly patients are more likely to have impaired mechanisms of drug 
excretion (e.g., decreased kidney function), to be on other medications 
that can interact with a newly prescribed drug, or to have another 
medical condition that can affect drug therapy.
    Geriatric labeling information is of increasing importance because 
of the growing proportion of the population that is over 65 years of 
age, and the significant use of medications by this age group. People 
over age 65 constitute only 12 percent of the U.S. population, but they 
consume over 30 percent of the prescription drug products sold in this 
country. The elderly are expected to constitute 22 percent of the U.S. 
population by the year 2030.
    The final rule is one of several actions taken by FDA to promote 
safe and effective prescription drug use in the elderly. FDA has 
encouraged sponsors to include more elderly subjects, especially those 
over 75 years of age, in clinical studies. In the Federal Register of 
March 5, 1990 (55 FR 7777), FDA announced the availability of a 
guideline entitled ``Guideline for the Study of Drugs Likely to be Used 
in the Elderly.'' The guideline emphasizes FDA's recommendation that 
drugs should be studied in the full range of patients who will receive 
them, including the elderly, and that efforts should be made to 
discover differences in pharmacokinetics related to age, or to 
conditions associated with age (e.g., decreased renal function, 
concomitant drugs, concomitant illness), and that clinical data should 
be analyzed to see whether the drug has different effects, favorable or 
unfavorable, in the old and young. The guideline provides detailed 
advice on how to evaluate new drugs in older patients and is intended 
to encourage routine and thorough evaluation of the effects of drugs in 
elderly populations so that sufficient information can be provided to 
physicians. The guideline did not call for, or anticipate, an increase 
in the number of patients or the number of clinical studies needed to 
evaluate a new therapy. Patients over 65 years of age already 
represented a significant portion of study subjects in most cases, 
based on several FDA surveys. The principal new steps called for were 
to not exclude the very old, to analyze the data already collected, and 
to obtain modest additional pharmacokinetic data. Only in special cases 
(e.g., drugs especially targeted for older patients or where age-
related differences or problems are anticipated) were separate studies 
in the elderly recommended.
     In the Federal Register of August 2, 1994 (59 FR 39398), FDA 
published a guideline regarding the use of drugs in geriatric 
populations entitled ``Studies in Support of Special Populations: 
Geriatrics.'' The guideline was prepared by the Efficacy Expert Working 
Group of the International Conference on Harmonisation (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human 
Use, which is concerned with the harmonization of technical 
requirements among the European Union, Japan, and the United States. 
The guideline reflects sound scientific principles for testing drugs in 
geriatric populations and for submitting

[[Page 45314]]

marketing applications to regulatory authorities worldwide. The 
guideline is consistent with FDA's existing geriatric guideline 
discussed previously.

II. Highlights of the Final Rule

     This final rule furthers FDA efforts to promote safe and effective 
prescription drug use in the elderly by requiring that information on 
the safe and effective use of drugs in the elderly be included in 
labeling, and by specifying a location and format for presenting this 
information.

A. General Provisions

     The final rule establishes, in new Sec. 201.57(f)(10), a 
``Geriatric use'' subsection that provides information on the safe and 
effective use of drugs in patients aged 65 and older. This subsection 
of the ``Precautions'' section of the labeling describes what is known 
about the effects of a drug in the elderly and lists any limitations, 
hazards, or monitoring needs associated with geriatric use.
    Although FDA encourages further study of drug effects in the 
elderly, this labeling change is not intended to require additional 
clinical studies. The ``Geriatric use'' subsection is intended to 
establish a place in prescription drug labeling where practitioners can 
find pertinent information that is already available from clinical 
experience and investigations. FDA believes that providing this 
information in a clear and accessible way should promote the safe and 
effective use of prescription drugs in the elderly.
    Section 201.57(f)(10) also states that specific geriatric 
indications, if any, are to be described in the ``Indications and 
Usage'' section, and specific geriatric dosing instructions are to be 
described in the ``Dosage and Administration'' section. Additional 
details about information summarized in the ``Geriatric use'' 
subsection may be found in other sections of the labeling, as 
appropriate.

B. Sources of Information on Geriatric Use 

    Under Sec. 201.57(f)(10)(ii), the ``Geriatric use'' subsection is 
based on all information available to sponsors that is relevant to the 
use of the drug in elderly patients. The information includes results 
from controlled studies, both those that are part of a marketing 
application and those available to the sponsor but not submitted, 
information gathered from other studies and experience (e.g., adverse 
drug reaction reports), and pertinent information from well-documented 
studies obtained from a literature search.

C. Statements on Geriatric Use

    Section 201.57(f)(10)(ii) calls for appropriate labeling statements 
that are based on the information available regarding use of the drug 
in geriatric populations:
    (1) If there have not been sufficient numbers of geriatric subjects 
involved in clinical studies to determine whether those over age 65 
differ from younger subjects in their responses to the drug, and other 
reported clinical experience has not identified such differences, 
Sec. 201.57(f)(10)(ii)(A) requires that the labeling state this fact 
and note that generally the selection of dosage levels for the elderly 
should proceed with caution, usually starting at the low end of the 
dosing range.
    (2) If sufficient numbers of geriatric subjects have been included 
in studies (both those in marketing applications and other relevant 
studies available to the sponsor) to make it likely that a difference 
in safety and effectiveness between older and younger subjects would 
have been detected, but no such differences in safety or effectiveness 
were apparent and no other reported clinical experience identified such 
differences, Sec. 201.57(f)(10)(ii)(B) requires that the labeling state 
this fact. The statement must also indicate the percentage of the total 
number of subjects, or the total number of subjects, in a defined group 
of clinical studies who were 65 and over and 75 and over.
    (3) If evidence from clinical studies and other reported clinical 
experience available to the sponsor indicates that use of the drug in 
elderly patients is associated with differences in safety or 
effectiveness in the geriatric population, or if administration of the 
drug to the elderly requires specific dosage adjustment or monitoring, 
Sec. 201.57(f)(10)(ii)(C) requires that the labeling briefly describe 
these special geriatric conditions and, when appropriate, refer to 
other labeling sections for more detailed discussions.

D. ``Geriatric Use'' and Other Labeling Sections

    Section 201.57(f)(10)(iii)(A) requires that if specific 
pharmacokinetic or pharmacodynamic studies of the drug's action were 
carried out in the elderly, they must be described briefly in the 
``Geriatric use'' subsection and in detail in the ``Clinical 
Pharmacology'' section.
    The potential for problems stemming from the use of drugs in 
patients with certain diseases or from interactions between drugs is 
higher among the elderly because they are more likely to have multiple 
illnesses requiring multiple drug treatments. Section 
201.57(f)(10)(iii)(A) notes that the ``Clinical Pharmacology'' and 
``Drug Interactions'' sections of the labeling ordinarily contain 
information on drug-drug and drug-disease interactions. For example, 
Sec. 201.57(b) requires, in part, that the Clinical Pharmacology 
section of the labeling contain a concise factual summary of the 
clinical pharmacology and actions of the drug in humans.
    Section 201.57(f)(4)(i), the ``Drug Interactions'' subsection of 
the ``Precautions'' section, includes a requirement that the labeling 
shall contain specific practical guidance on preventing clinically 
significant drug/drug and drug/food interactions that may occur in vivo 
in patients taking the drug, including identification of specific drugs 
or classes of drugs with which the drug may interact in vivo in 
patients and a brief description of the mechanism(s) of the 
interaction.
    If the use of a drug in the elderly appears to cause a specific 
hazard, the hazard must be described in the ``Geriatric use'' 
subsection as required under Sec. 201.57(f)(10)(iv), or information 
about the hazard would be placed appropriately under the 
``Contraindications,'' ``Warnings,'' or ``Precautions'' sections of the 
labeling, and the ``Geriatric use'' subsection would refer to those 
sections. Geriatric labeling, under Sec. 201.57(f)(10)(v), may also 
include statements reflecting good clinical practice or experience with 
a particular situation if they would be useful in enhancing the safe 
use of the drug. As an example, the final rule provides a possible 
statement for a sedating drug.

E. Renal Function

    Geriatric patients are more likely than younger patients to have 
impaired renal function. Therefore, when it is known that a drug is 
substantially excreted by the kidney, Sec. 201.57(f)(10)(iii)(B) 
requires a statement to that effect in the ``Geriatric use'' 
subsection, as well as a statement noting that care should be taken in 
dose selection and that it may be useful to monitor renal function. 
Renal function may be monitored by calculating creatinine clearance.

F. Alteration or Omission of Geriatric Statements

    Although the geriatric statements provided in the final rule will 
be appropriate for most drug products, there are certain drugs that are 
not indicated for geriatric use or for which the specified geriatric 
statements are not needed. In this situation, the sponsor, under 
Sec. 201.57(f)(10)(vi), must provide reasons for omitting the specific 
geriatric use information and statements

[[Page 45315]]

in Sec. 201.57 and, if appropriate, may propose alternative geriatric 
language.
    FDA may permit omission of a geriatric use statement and permit the 
use of an alternate statement if FDA determines that the statements 
described in Sec. 201.57(f)(10)(i) through (f)(10)(v) are inappropriate 
or not relevant to the drug's labeling and that the alternate statement 
is accurate and appropriate.

III. Comments on the Proposed Rule

    The agency received approximately 60 comments on the proposed rule. 
The comments came from Congress, prescription drug manufacturers, 
physicians, professional societies, organizations with special 
interests in the elderly, the lay public, and others. Most comments 
agreed with the proposed labeling change, calling it ``long overdue,'' 
``timely and important,'' and a ``major step'' in promoting the safe 
and effective use of prescription drugs in the elderly.
    Many comments expressed the belief that a ``Geriatric use'' 
statement in the labeling would result in increased awareness among 
practitioners and patients and thus enhance the physician's ability to 
provide quality health care to older patients.
    1. While expressing support, some comments reflected confusion 
about the practical effect of the regulation, recommending such steps 
as the use of large print, bright ink, and ``simple language'' to make 
the labeling more easily read and understood by older patients.
    The agency believes these comments misinterpret the intent of this 
rulemaking. The regulation does not describe information that would be 
distributed directly to the patient. Rather, the rule amends the 
``professional'' labeling requirements for prescription drugs, commonly 
referred to as the physician package insert, to require that a 
``Geriatric use'' subsection appear in the ``Precautions'' section of 
the package insert. Professional labeling is designed for and directed 
to physicians and other health care professionals and is required to 
provide information ``under which practitioners licensed by law to 
administer the drug can use the drug safely and for the purposes for 
which it is intended * * *'' (Sec. 201.100(c)(1) (21 CFR 
201.100(c)(1)).
    Although this final rule does not require that written information 
on geriatric use be distributed directly to elderly patients or 
establish any print size requirements, the agency expects that it will 
result in more and better information reaching these patients. The 
final rule amends the labeling requirements to give physicians and 
other health care professionals easier access to more information about 
geriatric use. A health care community so informed will be better able 
to deliver superior care and to provide more information on the safe 
and effective use of prescription drugs to elderly patients.
    Because some confusion exists regarding the purpose of this 
regulation, and as a result of the changes made in response to comments 
received, FDA has reformatted and redesignated some provisions in 
proposed Sec. 201.57(f)(10) for this final rule. These changes were 
made to clarify obligations and options provided in the regulation. 
Except where specific substantive changes or additions are indicated 
and were made in response to comments, these changes do not involve 
changes in the obligations imposed on sponsors by the regulation. FDA 
has also replaced the word patient with the more appropriate 
``subject'' when referring to individuals participating in clinical 
studies.
    2. Some comments opposed establishing a ``Geriatric use'' 
subsection in prescription drug labeling. The comments stated that in 
communicating drug information to patients, the role of pharmacists and 
other health care practitioners should be adequate to reduce problems 
in the elderly, making this labeling change unnecessary.
    The agency disagrees. FDA recognizes that pharmacists and other 
health care practitioners play important roles in communicating 
information about prescription drug use to elderly patients. However, 
surveys show that a substantial number of elderly patients fail, in 
some way, to comply with their prescription drug regimen; and the 
elderly population is greatly in need of medication counseling and 
information. Pharmacists and others cannot transmit information they do 
not have, and information on how younger and older patients respond 
differently to a drug is difficult to find.
    The final rule does not diminish the role that health care 
professionals play in communicating information to the elderly about 
their prescription drugs. Rather, it facilitates that role by providing 
health care professionals with more information about how drugs affect 
older patients.
    3. One comment claimed that the proposed ``Geriatric use'' 
subsection is redundant because existing FDA guidelines and labeling 
regulations already provide that important information should be 
included in the labeling.
    FDA acknowledges that some prescription drug labeling consistent 
with existing FDA guidelines and regulations contains information on 
use in the elderly. This reflects growing recognition of the need to 
provide patient information on individualizing drug therapy and, 
specifically, of the need to provide information on use in the elderly.
    The final rule is intended to make geriatric labeling format and 
content more consistent by requiring that there be a ``Geriatric use'' 
statement in prescription drug labeling, that the statement reflect all 
information available to the sponsor that is relevant to the 
appropriate use of the drug in elderly patients, that the information, 
or direct reference to it, be found in a particular location in the 
labeling, and that the statement follow a standard format. The 
``Geriatric use'' statement will give practitioners and others easier 
access to more information about prescription drug use in elderly 
patients.
    4. Other comments objected to a ``Geriatric use'' subsection on 
economic grounds, saying that the costs of producing and compiling the 
information necessary to comply with this labeling change will be 
significant, adding to the already high cost of drug development. The 
comments were concerned that these costs would be passed along to the 
elderly consumer, who may not be able to afford them.
    The agency's review of the cost issues posed by the comments is 
contained in section VI of this document. The agency agrees that 
manufacturers will incur some costs as a result of this final rule. The 
agency believes, however, that the costs associated with the final rule 
will not be significant, especially in light of the potential benefits 
of the labeling change. This rule does not require any new clinical 
studies, but the preparation of the ``Geriatric use'' subsection should 
include analyses of previously collected data and available literature.
    The cost of preparing the ``Geriatric use'' subsection may be 
offset by lower health care costs resulting from fewer adverse 
reactions to prescription drugs. Because older people take about three 
times as many prescription drugs as younger individuals and because 
taking several drugs together substantially increases the risk of drug 
interactions, unwanted effects, and adverse reactions (Ref. 1), 
labeling addressing this information should result in fewer adverse 
reactions. A number of studies have indicated that adverse drug 
reactions and patient noncompliance contribute to costly emergency room 
and hospital visits (Ref. 2). If the information required by the rule 
prevents only a modest fraction of these

[[Page 45316]]

adverse reactions, the health care savings will be sizeable.
     Costs will also be lessened by the manner in which the rule is to 
be implemented. The extended period allotted for implementation is 
designed to reduce burdens for both industry and the agency. 
Implementation will take place over 6 years (in accordance with the 
plan described in section IV of this document). The implementation 
schedule divides drug products subject to this regulation into four 
multiyear groups based on the date of approval of the products' new 
molecular entities (NME's). FDA recognizes that it will be more 
difficult to develop geriatric labeling for older NME's, due to the 
probable need to manually examine data and the likelihood that a more 
extensive literature search will be needed. In contrast, the 
information available for recently approved drugs is more likely to be 
readily available to sponsors and more likely to be computer 
accessible. As a result, implementation will proceed in reverse 
chronological order.
    In addition, the agency will not require prior approval of labeling 
changes for drug products under Sec. 201.57(f)(10)(ii)(A) (i.e., where 
insufficient data exist to determine whether the responses of geriatric 
patients to a drug are different from responses of younger patients).
    5. Some comments found the proposed regulation ``confusing'' and 
suggested that FDA provide ``model labeling'' for each drug or drug 
class.
    The regulation does provide specific ``model'' language for several 
possible labeling statements. The agency has revised proposed 
Sec. 201.57(f)(10) to make the ``Geriatric use'' labeling requirements 
clearer and to make several organizational and other general changes. 
The agency does not agree, however, that it should draft model 
geriatric labeling for each drug or drug class. The agency does not 
believe that a small number of ``models'' could be developed that would 
be helpful in formulating the labeling of all drug products, nor does 
the agency have the resources necessary to draft such labeling.
    6. Several comments objected to the agency's designation of 65 
years and older as the age range to which this rule would apply. Some 
comments called the choice ``arbitrary,'' noting that, while 65 years 
old has become widely used as a sociological marker of the beginning of 
senior citizen status, there is no physiological basis for identifying 
65 years old as the age at which differences in drug effects begin to 
occur.
    One comment suggested that the age be lowered to include persons in 
their fifties; others suggested that the appropriate age should be 60 
years old; another thought 80 years and older would be the most 
meaningful age category with regard to differences in drug response. 
Several comments complained that the proposed rule treated all persons 
over 65 years old as a homogeneous group, and suggested that it be 
changed to categorize 65 to 74, 75 to 84, and 85 years and older as 
three distinct age categories for purposes of assessing drug response.
    Other comments suggested that age not be used at all to define the 
geriatric population, but that other factors, such as changes in body 
composition or organ function, be used as criteria for categorizing 
appropriate labeling statements.
    The agency recognizes that attempts to define populations to which 
clinical or regulatory requirements apply are subject to certain 
limitations and are difficult to achieve. This is evidenced by the 
number and variety of suggestions for alternative age designations 
posed by the comments. Nonetheless, for ease of implementation, it is 
necessary to specifically and simply define the population to which 
this final rule applies.
    Defining the geriatric population based on age (persons 65 years of 
age and older) lends an important element of uniformity in the 
development of the ``Geriatric use'' subsection and establishes 
boundaries for the application of the final rule. These boundaries are 
necessary to enable manufacturers to determine how to gather, evaluate, 
and communicate geriatric use information. Defining the scope of the 
final rule in this way also will aid practitioners who consult the 
``Geriatric use'' subsection, allowing them to presume that, unless 
otherwise stated, the population being addressed is 65 years of age and 
older and that this standard remains constant in all prescription drug 
labeling. The agency notes that age 65 is a widely used marker for the 
beginning of elderly status and believes that 65 years of age is a 
reasonable starting place for a discussion of differences in drug 
response that are related to advancing age. However, the agency does 
not consider 65 years of age to be an absolute boundary for this 
rulemaking. For some drugs, it may be more appropriate for the labeling 
to reflect evaluation of another elderly age group, or, where there are 
important differences in response, to address specific subgroups within 
the geriatric population. In some cases, changes might be expressed as 
a continuous function of age. FDA would expect the manufacturer to 
advise the agency of these cases, and to submit, as appropriate, 
``Geriatric use'' labeling that reflects and communicates these special 
concerns.
    FDA agrees with the comments that note that the interaction of drug 
responses and the aging process can vary widely among individuals. As 
with labeling for any age group, ``Geriatric use'' labeling is no 
substitute for the sound medical judgment of the prescriber, who must 
keep in mind individual responses to drug therapy.
    7. Several comments questioned the scope of the review a 
manufacturer would have to undertake to obtain all ``available 
information,'' as described in the preamble to the proposed rule. The 
comments claimed that the required review would be too broad in scope, 
impossible to complete, and would yield irrelevant or useless 
information. In particular, the comments objected to the use of 
information obtained from FDA's Spontaneous Reporting System (now the 
Medical Products Reporting Program or MedWatch) for adverse drug events 
as the basis of labeling statements, and suggested excluding it from 
the scope of review. Specifically, these comments requested that the 
evaluation reflect information from the following: (1) All controlled, 
clinical trials contained in the new drug application; (2) other 
controlled, clinical trials in the applicant's possession that are 
reasonably relevant to the use of the drug in older patients; (3) 
postmarketing studies or published literature that specifically concern 
the use of the drug in older patients; and (4) pharmacokinetic and 
pharmacodynamic studies that have been conducted in the elderly.
    The agency has considered the scope of ``available information'' in 
light of the recommendations made in these comments. Aside from the 
suggestion that MedWatch information not be required, the comments 
support the same review of information as set forth in the proposal. In 
order for ``Geriatric use'' labeling to be a meaningful prescribing 
tool, it must reflect a comprehensive review of a broad range of 
information sources. The agency believes that the scope of the review 
appropriately includes information both in the applicant's possession 
and available through a search of professional literature or published 
studies that are relevant to an evaluation of the geriatric use of the 
drug.
    Concerning the inclusion of MedWatch information, FDA regards a

[[Page 45317]]

review of information from this system or from the Vaccine Adverse 
Events Reporting System (VAERS) for vaccines as potentially important 
in developing comprehensive labeling for the safe and effective use of 
the drug in the elderly. The agency fully appreciates the limitations 
associated with MedWatch and VAERS data, but believes that this 
information when placed in its proper context can in some cases yield 
data on the age-relatedness of adverse effects that are interpretable 
and valuable. In submitting ``Geriatric use'' information, a 
manufacturer should evaluate the merit of particular MedWatch reports 
and utilize them appropriately.
    8. Several comments argued that the proposed ``Geriatric use'' 
labeling subsection does not adequately address problems that are 
frequently associated with prescription drug use in the elderly. The 
comments contended that the labeling statements should discuss the 
issue of polypharmacy in the elderly and include specific information 
on drug-drug interactions. Another comment asserted that the rule 
overlooks the development of ``drug allergies'' and the ``psychological 
effects'' of prescription drugs in older patients.
    The agency believes that the final rule adequately addresses the 
problems most commonly associated with prescription drug use in the 
elderly, including those areas cited in the comments. Section 
201.57(f)(10)(ii)(C) directs that differences in safety or 
effectiveness of a drug in the elderly, or specific monitoring or 
dosage adjustment requirements, shall be described briefly in the 
``Geriatric use'' subsection and, as appropriate, be discussed in more 
detail in the appropriate section of the labeling. In addition, as 
stated in Sec. 201.57(f)(10)(iii)(A), data about drug-disease and drug-
drug interactions are ordinarily included in the ``Clinical 
Pharmacology'' section (Sec. 201.57(b)) and ``Drug interactions'' 
subsection of the ``Precautions'' section (Sec. 201.57(f)(4)(i)), and 
this information is often particularly relevant to the elderly.
    9. Other comments expressed concern that the overall approach of 
the prescribed ``Geriatric use'' statements is too general and overly 
cautious. In particular, these comments objected to language in 
proposed Sec. 201.57(f)(10)(ii)(A), advising that `` * * * [i]n 
general, dose selection for an elderly patient should be cautious, 
usually starting at the low end of the dosing range * * * '' and to the 
caveat in proposed Sec. 201.57(f)(10)(ii)(B) that, although no 
differences between older and younger patient responses had been 
observed, `` * * * greater sensitivity of some older individuals cannot 
be ruled out.'' The comments found these generalizations to be less 
than helpful and were concerned that they might cause undue caution by 
health professionals, possibly resulting in suboptimal or even 
subtherapeutic dosing of elderly patients.
    The final rule is intended to provide information to health 
professionals about a subgroup of the population that may have a 
different response to certain drug products than the population as a 
whole. Section 201.57(f)(10)(ii)(A) and (f)(10)(ii)(B) include some 
words of caution but are phrased carefully to avoid any implication of 
universal application. FDA does not intend that ``Geriatric use'' 
statements substitute for medical judgment, but FDA intends that 
geriatric labeling information be used, along with professional 
judgment, as a tool for achieving optimum prescribing practices. The 
information on prescription drug use in elderly patients required by 
this final rule will assist health professionals in tailoring drug 
therapy to the individual needs of patients.
    The cautionary tone of Sec. 201.57(f)(10)(ii)(A) and (f)(10)(ii)(B) 
reflects the agency's opinion that, in general, the greater likelihood 
of impaired excretory function or impaired homeostatic mechanisms in 
the elderly does suggest a cautious approach. That caution should not 
result in a failure to attain therapeutic goals, even if a period of 
adjustment is necessary to determine the optimum dose for individual 
patients. If a sponsor believes that particular statements presented in 
this provision are not appropriate or relevant, the sponsor, under 
Sec. 201.57(f)(10)(vi), may seek permission to omit these statements or 
propose an alternative statement.
    10. Several comments questioned other specific aspects of the 
proposed labeling statements and requirements. The comments questioned 
the terms ``sufficient numbers of patients'' and ``enough elderly 
patients'' as used in proposed Sec. 201.57(f)(10)(ii)(A) and 
(f)(10)(ii)(B), respectively. The comments asked how many patients 
would be ``sufficient'' or ``enough'' to determine if a particular 
labeling statement applied. One comment asked if ``enough elderly 
patients'' meant enough to reveal differences that are clinically 
significant or statistically significant.
    The question of a sufficient number of subjects arises when 
analysis shows no difference between younger and older subjects but the 
small number of subjects available for analysis precludes any real 
conclusions about the population as a whole. In such cases, as stated 
in Sec. 201.57(f)(10)(ii)(A), a labeling statement would, in part, 
state that clinical studies did not include sufficient numbers of 
subjects aged 65 and over to determine whether they respond differently 
from younger subjects. Adequacy of subject numbers depends on the 
specific comparisons being made and the number of ``events'' 
(therapeutic effects, adverse events) observed, and there is no number 
that will always constitute ``adequate.'' Thus, smaller numbers could 
be informative about high-rate events when no difference is found, and 
a positive finding (a difference) could arise in any size population 
(and be described under Sec. 201.57(f)(10)(ii)(C)).
    FDA advises that, with regard to the phrases ``sufficient numbers 
of subjects aged 65 and over'' in Sec. 201.57(f)(10)(ii)(A) and 
``enough elderly subjects'' in Sec. 201.57(f)(10)(ii)(B), participation 
of at least 100 subjects age 65 and older in clinical studies would 
allow detection of clinically important differences. This is the number 
of elderly subjects recommended in the ICH guideline entitled ``Studies 
in Support of Special Populations: Geriatrics.'' Results in elderly 
subjects would be compared with those in the (usually) larger number of 
younger subjects. The information gathered from available sources, as 
described in Sec. 201.57(f)(10)(ii), would ordinarily be descriptive 
and not necessarily subject to intense statistical analysis. The 
primary purpose of examining the information is to detect substantial 
and consistent (across studies) differences in drug response in the 
elderly as compared to the overall population. There are problems in 
interpretation wherever subsets of the overall trial population are 
examined, but these difficulties do not mean the effort should not be 
made. Within the limitations of these analyses, however, a finding of 
``no difference'' in a population with less than 100 elderly usually 
would lead to the statement described in Sec. 201.57(f)(10)(ii)(A), 
while a finding of no difference in a larger population could lead to 
the statement in Sec. 201.57(f)(10)(ii)(B). A finding of difference, 
whatever the population, would lead to labeling as in 
Sec. 201.57(f)(10)(ii)(C).
    FDA's ``Guideline for the Format and Content of the Clinical and 
Statistical Sections of New Drug Applications,`` which refers to subset 
analyses, discusses the analysis and presentation of data regarding 
drug response in different subsets of the population, and the agency's 
``Guideline for the Study of

[[Page 45318]]

Drugs Likely to be Used in the Elderly'' specifically relates this 
discussion to the geriatric population. The ICH guideline ``Studies in 
Support of Special Populations: Geriatrics'' reflects sound scientific 
principles for testing drugs in geriatric populations. FDA recommends 
consulting these documents for guidance and encourages individuals to 
contact the agency if questions arise on the sufficiency of data to 
support ``Geriatric use'' statements not addressed by the guidelines.
    11. One comment said that the use of numbers and percentages 
required in proposed Sec. 201.57(f)(10)(ii)(B) would be impractical, 
stating that a burdensome amount of updating and revision would be 
necessary as new information becomes available. The comment suggested 
that the statements should address whether ``certain thresholds have 
been reached,'' with the agency verifying that the manufacturer has the 
numbers to support the statements.
    The agency disagrees with the comment. The expression of 
percentages or actual numbers of older subjects involved in clinical 
studies is an essential part of Sec. 201.57(f)(10)(ii)(B). The 
percentage or total number of geriatric subjects precedes the statement 
that ``No overall differences in safety or effectiveness were observed 
between these subjects and younger subjects, * * * but greater 
sensitivity of some older individuals cannot be ruled out.'' This 
statement applies where sufficient numbers of elderly subjects have 
taken part in studies to reveal a different response between age 
groups, but where no differences were detected. The statement suggests 
that adjusting dosage recommendations for geriatric patients generally 
will not be necessary. To permit such an implication, it is important 
to provide practitioners with numbers so that they can weigh the 
evidence in relation to the needs of an individual patient.
    FDA also does not believe that Sec. 201.57(f)(10)(ii)(B) will be 
overly burdensome or require constant updating. This provision provides 
for alternative labeling formats using either percentages or the total 
number of subjects, age 65 and over and age 75 and over, included in 
clinical studies. The comment may have misunderstood this provision 
because the percentages refer to the number of subjects included in 
clinical studies and, unless additional studies are performed, there is 
no need to update or revise the percentages.
    The revised implementation plan should permit ample time for 
collection and evaluation of data. Manufacturers are urged to contact 
the agency if they have questions as to the significance of geriatric 
data related to this requirement.
    12. Several comments addressed proposed Sec. 201.57(f)(10)(iii)(B), 
which requires a statement in the ``Geriatric use'' subsection of the 
labeling for drugs that are substantially excreted by the kidney. The 
comments asked for more guidance to determine when a drug is 
``substantially excreted'' by the kidney. Another comment suggested 
that the proposed statement not apply to drugs that are substantially 
excreted by the kidney but pose no greater risk to patients with renal 
impairment.
    Some drugs, such as phenobarbital, are primarily metabolized and 
excreted by the liver, while a number of other drugs, such as 
diuretics, are primarily excreted by the kidneys. The prescriber's 
knowledge and experience with the individual patient will determine the 
course of treatment, and FDA does not feel it would be useful at this 
time to further quantify this phrase. This provision is intended to 
alert practitioners to the fact that adequate kidney function is 
important to the optimum safety and effectiveness of the drug product.
    If a sponsor believes that none of the requirements described in 
paragraphs Sec. 201.57(f)(10)(i) through (f)(10)(v) are appropriate or 
relevant, the sponsor must provide reasons for the omission of a 
labeling statement and may propose alternative statements as provided 
under Sec. 201.57(f)(10)(vi).
    13. Another comment recommended that, for drugs that are 
substantially excreted by the kidney, FDA require pharmacokinetic and 
pharmacodynamic studies in elderly persons.
    As stated earlier in this preamble, although the agency encourages 
further study of drug effects in the elderly, the rule is not intended 
to require additional clinical studies. The ``Geriatric use'' 
subsection is intended to provide a place in prescription drug labeling 
where practitioners can find pertinent information that is already 
available from clinical experience and investigations. For example, in 
the ``Guideline for the Study of Drugs Likely to be Used in the 
Elderly,'' FDA has encouraged assessment of the pharmacokinetic effects 
of age and of decreased excretory function.
    This final rule does not add new requirements for conducting 
geriatric studies. As stated in the preamble to the regulation on 
pediatric labeling, various provisions of the Federal Food, Drug, and 
Cosmetic Act (the act) and the Public Health Service Act (the PHS act), 
and existing regulations authorize FDA to require such studies under 
certain circumstances (see section III.C of the document published in 
the Federal Register of December 13, 1994 (59 FR 64240 at 64242)).
    14. A few comments objected to the use of the formula provided in 
the proposed labeling section for calculating creatinine clearance from 
a serum creatinine measurement. One comment criticized the specific 
formula, Cockroft-Gault (Nephron 16:31-41, 1976), pointing out its 
limitations when applied to older patients, and suggested that another 
formula, Jelliffe (Lancet 1:975-976, 1971), might be more accurate and 
appropriate for a ``Geriatric use'' dosage adjustment. Another comment 
suggested that any formula can become obsolete, and proposed that the 
regulation not include a formula. The comment said that the agency 
should instead provide more general guidance for dosing in the presence 
of kidney impairment that would allow for the use of state-of-the-art 
assessment tools.
    While a survey of available literature indicates that the Cockroft-
Gault formula provides a reasonably good estimate of renal function in 
the elderly, the agency agrees with concerns that a specific formula 
might be superseded either by a more precise formula or by a new method 
for estimating creatinine clearance. Because codification of a specific 
formula could result in less flexibility and to accommodate possible 
changes in methods of estimating renal function, FDA has deleted the 
actual formula from the final rule. The agency, however, wishes to 
stress the importance of monitoring renal function by calculating 
creatinine clearance. Creatinine clearance can be measured (often 
difficult outside the metabolic unit) or can be estimated from a 
creatinine clearance measurement using a formula.

IV. Implementation

    15. Several comments addressed the proposed implementation plan for 
the ``Geriatric use'' labeling requirement. Under the proposal, 
manufacturers would have had 1 year from the date of publication of a 
final rule to comply with the ``Geriatric use'' labeling requirements 
for all products. FDA acknowledged that it may be unable to review all 
supplements by this effective date, and stated that it would exercise 
its enforcement discretion not to take action against any product that 
lacks revised labeling, provided that the applicant has submitted its 
proposed labeling changes in a timely manner and otherwise acted in 
good faith to comply with the requirements of the final regulation.

[[Page 45319]]

    The comments asserted that it would be impossible for companies to 
comply with the proposed implementation scheme, and that the agency 
would not have the resources to meet approval dates, thus creating new 
backlogs in an already over-burdened system. Some comments suggested 
other timeframes, such as a 2-year, 3-year, or 4-year effective date. 
Other comments recommended that the agency employ a ``staggered 
implementation scheme,'' similar to the one used for the implementation 
of FDA's physician labeling regulations under 21 CFR 201.59.
    FDA agrees that the proposed implementation could pose difficulties 
and has revised the plan to reduce the burdens of compliance on both 
manufacturers and the agency, while allowing for efficient 
implementation of the ``Geriatric use'' labeling requirements. The 
agency has considered the comments and has adopted a plan that will 
stagger implementation dates. Because some drug classes and drug 
products are more likely than others to have a significant impact on 
geriatric patients, based on existing labeling, research, and reports 
from health care professionals, FDA has provided for staggered 
implementation of geriatric labeling requirements to expedite labeling 
for certain drug products and drug classes. The implementation plan is 
discussed in greater detail in sections IV.A and B of this document.
    Certain changes to an approved application require prior FDA 
approval of a supplemental application in accordance with 
Sec. 314.70(b) (21 CFR 314.70(b)) or Sec. 601.12(b). For those products 
not regulated under section 351 of the PHS act (42 U.S.C. 262), changes 
to add or strengthen contraindications, warnings, precautions, or 
adverse reactions or to add or strengthen dosage and administration 
instructions to increase a product's safety (for products other than 
biological products) may be put into effect at the time a supplement 
covering the change is submitted to FDA in accordance with 
Sec. 314.70(c). Labeling changes should be implemented immediately 
under Sec. 314.70(c)(2)(i) where additional data or clinical trials 
indicate a need to add or strengthen a contraindication, warning, 
precaution, or adverse reaction.
    Applicants may make some minor labeling changes to products, other 
than biological products, without submitting a supplement in accordance 
with Sec. 314.70(d). The applicant is to describe such changes in the 
annual report.
    Applicants need not obtain prior FDA approval of many supplements. 
For instance, the statement in the ``Geriatric use'' subsection can 
refer to a particular data base. Where the completion of additional 
clinical trials and accumulation of data simply strengthen conclusions 
reflected in existing statements in the geriatric labeling, revision of 
labeling to incorporate these additional numbers may be regarded as 
changes to strengthen instructions about dosage and administration. 
Under Sec. 314.70(c)(2)(iii), these labeling changes may be implemented 
at the time a supplement is submitted to FDA.
    For those products regulated under section 351 of the PHS act, 
labeling changes must be made in accordance with Sec. 601.12. In the 
Federal Register of July 24, 1997 (62 FR 39890), FDA revised the 
requirements in Sec. 601.12 for the reporting of changes, including the 
reporting of changes in labeling, to an approved license application. 
With the revision of Sec. 601.12, manufacturers will be required to 
implement and report changes in labeling by the same procedures as 
described above for other drugs.
    As noted above, persons who have questions regarding such changes 
for biological products should contact the appropriate division.
    16. One comment argued that manufacturer and agency implementation 
burdens would be lessened if the geriatric labeling change applied only 
to those drugs approved in the last 3 to 5 years. The comment claimed 
that drugs on the market for a longer time (older drugs) have been used 
to a sufficient extent that practitioners can determine any unique 
problems encountered by the elderly patient, making a ``Geriatric use'' 
subsection unnecessary.
    FDA recognizes that while professional experience with older drugs 
may decrease the need for geriatric labeling, there may be less 
understanding of the pharmacokinetics of older drugs. Moreover, 
previously unrecognized problems may be revealed through new research 
or the circumstances under which drug products are used may change. 
Such a situation could, for example, result from the discovery of an 
adverse interaction in geriatric patients between an older drug product 
and one that has recently been approved.
    FDA further recognizes that ease of compliance with this final rule 
may vary depending on the amount of, and the ability to access, 
available information. The implementation plan for this final rule 
takes these and other factors into account to minimize burdens for 
manufacturers. For instance, the agency expects that the need for a 
``Geriatric use'' subsection often may be greatest for recently 
approved drugs where there is little collective professional experience 
with the drug in older patients. In addition, this information is most 
likely to be readily available to manufacturers from a current data 
base. Likewise, the agency expects geriatric use information for drugs 
that have been marketed for a longer period of time will be more 
extensive and more diffuse, and thus more difficult to retrieve and 
summarize. Printed reports and clinical data for these drugs may be 
scattered and less likely to have been processed and stored in a 
computer data base than would be the case for more recently approved 
drugs. In these cases, a manual search to gather available information 
may be necessary. The implementation plan for this final rule 
recognizes that the necessity for such a search is likely to be 
directly related to the date of an NME approval or biological product 
license approval. Therefore, under the implementation scheme for the 
final rule, sponsors will be required to submit geriatric labeling 
supplements at an earlier date for more recently approved products than 
for products that have been marketed for a longer time. The agency 
believes that this implementation plan will allow manufacturers to work 
within a reasonable timetable to craft meaningful and usable 
``Geriatric use'' labeling.
    As discussed in section IV, comment 15 of this document, the 
implementation plan has been revised to reduce the burdens of 
compliance for both the agency and manufacturers. In revising the 
implementation plan, the agency specifically considered and addressed 
the concerns associated with drugs that have been marketed for a number 
of years. The revised plan gives manufacturers of these drugs longer 
periods of time to submit geriatric labeling. At the same time, the 
agency has determined that priority should be given to implementation 
for certain categories of drugs that either alone or in combination 
with other drug products may be more likely to cause problems in 
geriatric patients.
    Implementation of the ``Geriatric use'' subsection of prescription 
drug labeling is as follows:

A. Priority Implementation

     Geriatric patients are more likely to have more problems with 
certain classes of drugs than with others because of the following: 
Age-induced physiological changes in the patient, the narrow 
therapeutic range of some drug

[[Page 45320]]

products, and the potential for drug-drug and drug-disease 
interactions, as well as other factors. The revised labeling for drugs 
subject to priority implementation must be submitted to FDA by August 
27, 1998. FDA has therefore selected the following drug classes or drug 
products for priority implementation:
1. Psychotropic Drugs:
    a. Antidepressants,
    b. Anxiolytics,
    c. Hypnotics, and
    d. Antipsychotics;
2. Nonsteroidal Anti-inflammatory Drugs (NSAID's);
3. Digoxin, Antiarrhythmics, and Calcium Channel Blockers;
4. Oral Hypoglycemics;
5. Anticoagulants; and
6. Quinolones.

B. Implementation Based on the NME or Biological Product License 
Approval Date

    All drug products not subject to priority implementation, must 
comply with this regulation on the basis of the year in which the drug 
product's NME (active moiety) or biological product license was first 
approved. For combination products, application holders must determine 
the approval date of the earliest NME or biological product license. 
That earlier date will be the controlling date for implementation 
purposes. The date of issuance of a biological product license should 
be used for a combination biological product.
    FDA is aware that, for a variety of reasons, drug products subject 
to approved drug applications are not always marketed. An approved 
product may, for example, be withheld from the marketplace for economic 
reasons. Later, when conditions change, the drug may be manufactured 
and actively marketed. To further lessen the burden of implementing 
this rule, FDA will not require geriatric labeling for approved 
products that are not currently marketed, including products selected 
for priority implementation. If, however, an unmarketed approved drug 
product is subsequently marketed, the product must include appropriate 
geriatric labeling at the time it is marketed.
    The implementation schedule is based on the NME or biological 
product license approval date as follows:
    1989 to present: Revised labeling due August 27, 1999,
    1982 through 1988: Revised labeling due August 28, 2000,
    1975 through 1981: Revised labeling due August 27, 2001,
    1963 through 1974: Revised labeling due August 27, 2002, and
    Prior to 1963: Revised labeling due August 27, 2003.
    FDA will notify all holders of approved abbreviated applications of 
the changes in the listed product's geriatric labeling and provide 
directions on how to incorporate the new text in the labeling. All 
holders of approved abbreviated applications for which there is no 
reference listed new drug application (NDA) drug product in the 
prescription drug product list section of the publication entitled 
Approved Drug Products with Therapeutic Equivalence Evaluations are 
expected to comply with the implementation plan described in sections 
IV.A and B of this document by submitting geriatric labeling.
    The agency encourages sponsors to voluntarily implement these 
provisions prior to the scheduled implementation date, where feasible.
    All supplements submitted under this rule should be noted as 
``Geriatric Labeling Supplement'' in the ``Reason for Submission'' 
block.

V. Legal Authority

    This final rule to revise prescription drug labeling regulations to 
require a ``Geriatric use'' subsection is authorized by the act and by 
the PHS act. Section 502(a) of the act (21 U.S.C. 352(a)) prohibits 
false or misleading labeling of drugs, including, under section 201(n) 
of the act, failure to reveal material facts relating to potential 
consequences under customary conditions of use. Section 502(f) of the 
act identifies as misbranded any drug whose labeling does not bear 
adequate directions for use, as well as such adequate warnings against 
unsafe dosage or methods or duration of administration as are necessary 
to protect users. In addition, section 502(j) defines as misbranded 
those drugs that are dangerous to health when used in the manner 
prescribed, recommended, or suggested in their labeling.
    In addition to the misbranding provisions, the premarketing 
approval provisions of the act authorize FDA to require that 
prescription drug labeling provide the practitioner with adequate 
information to permit the safe and effective use of the drug product. 
Under section 505 of the act (21 U.S.C. 355), FDA will approve an NDA 
only if the drug is shown to be both safe and effective for its 
intended use under the conditions set forth in the drug's labeling. 
Section 701(a) (21 U.S.C. 371(a)) authorizes FDA to issue regulations 
for the efficient enforcement of the act.
    Under Sec. 201.100(d) of FDA's labeling regulations, prescription 
drug products must bear labeling that contains adequate information 
under which licensed practitioners can use the drug safely for its 
intended purposes. Section 201.57 describes specific categories of 
information, including information for drug use in selected subgroups 
of the general population, which must be present to meet the 
requirements of Sec. 201.100. In addition, under Sec. 314.125 (21 CFR 
314.125), FDA will not approve an NDA unless, among other things, there 
is adequate safety and effectiveness information for the labeled 
indications.
    Section 351 of the PHS act provides legal authority for the agency 
to regulate biological products, including labeling. Licenses for 
biological products are to be issued only upon a showing that they meet 
standards ``designed to insure the continued safety, purity, and 
potency of such products'' prescribed in regulations (42 U.S.C. 
262(d)). The ``potency'' of a biological product includes its 
effectiveness (21 CFR 600.3(s)). Section 351(b) of the PHS act 
prohibits falsely labeling a biological product. FDA's regulations at 
21 CFR part 201 apply to all prescription drug products, including 
biological products.
    A drug product not in compliance with Sec. 201.57(f)(10) of this 
final rule would be considered to be misbranded and an unapproved new 
drug under the act. A noncomplying product that is a biological product 
would, in addition, be considered falsely labeled and an unlicensed 
biological under the PHS act.

VI. Analysis of Impacts

A.  Introduction

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). If a rule has a 
significant impact on a substantial number of small entities, the 
Regulatory Flexibility Act requires agencies to analyze regulatory 
options that would minimize the impact of that rule on small entities. 
The agency believes that this final rule is consistent with the 
regulatory philosophy and principles

[[Page 45321]]

identified in Executive Order 12866 and the Regulatory Flexibility Act.
    The Unfunded Mandates Reform Act (Pub. L. 104-4) requires that 
agencies prepare an assessment of anticipated costs and benefits before 
proposing any rule that may result in an annual expenditure by State, 
local, and tribal governments, in the aggregate, or by the private 
sector, of $100,000,000 or more (adjusted annually for inflation). The 
rule does not impose any mandates on State, local, or tribal 
governments, or the private sector that will result in an annual 
expenditure of $100,000,000 or more.
    The following discussion presents FDA's assessment of the direct 
costs that the rule will impose on the prescription drug industry. 
(Further background data are provided in the agency report entitled 
``Threshold Assessment of Requirements for Geriatric Labeling'' on file 
at the Dockets Management Branch (Ref 3.).)
    Comments to the agency by an innovator trade group and one large 
innovator firm ( a pharmaceutical firm that develops new drugs) 
indicated that the proposed requirements would impose a severe economic 
burden. However, these comments provided no written estimates of either 
the expected costs or the extent of the research effort that would be 
needed to comply with the new provisions. FDA's cost estimates, 
therefore, are based on extrapolations from various agency data bases 
and plausible assumptions of unit costs. The estimates took into 
account the number of labels affected, the estimated availability of 
data on the elderly, the estimated availability of computerized data 
files, and the amount of existing geriatric labeling. Costs that are 
not considered include possible industry efforts to conduct new 
clinical trials to generate data on problems unique to the elderly, 
possible market shifts among competing products due to changes in 
labeling, possible displacement of industry workers due to the costs of 
the regulatory requirements, or any other costs beyond direct effects. 
Because part of this analysis was prepared in 1993, in support of this 
final rule as then drafted, much of the underlying data are several 
years old. As explained below, the use of more recent data would 
probably project significantly lower costs.

B. Methodology

    Estimating the costs to industry required several steps. Data on 
numbers of marketed drugs, use by the elderly, the frequency of 
labeling supplement approvals, and the existence of geriatric labeling 
were available from FDA data files or from previously conducted 
studies. Information on the effort required to determine appropriate 
label changes and physically change labels was developed from industry 
sources and drug reviewing officials within FDA.
1. Number and Age of Products Affected
    Two separate analyses were conducted to estimate the number of 
products affected by the rule. One analysis estimated the number of 
innovator products, and the other, the number of generic products that 
would be subject to the rule. An analysis of 1993 IMS America data on 
marketed products (data derived from a proprietary data base in the 
National Disease and Therapeutic Index maintained by IMS America; 
Plymouth Meeting, PA) determined that about 1,578 innovator labels 
would be subject to the rule. The actual number of innovator product 
labels subject to the rule is probably slightly larger than this number 
because the IMS data collection methodology most likely missed very 
small volume products. However, because there is no easy way to 
estimate the number of omitted products and the degree of error is 
thought to be of little practical significance, the counted number of 
products was used.
    Conversations with industry representatives indicated that the 
process of complying with the regulation would be much more difficult 
for drugs that have been marketed for a longer time. Products approved 
before 1975, and in some cases before 1980, lack computer readable 
clinical trial data. Therefore, subgroup analysis of these early data 
would require some data entry directly from data recording sheets or 
individual patient records. Most clinical trial data used for products 
approved since 1985 are already in an easily analyzable form. However, 
some data for products approved between 1975 and 1985, although 
computerized, would not be in a compatible format. This data would 
require additional manipulation before subgroup analysis could be 
performed.
    Table 1 shows the distribution of the 1,578 innovator products by 
year of FDA approval. Based on the trend of automation described 
previously, geriatric labeling compliance will become progressively 
less expensive with the more recent the date of drug product approval. 
Compliance activities for products approved after 1985 will cost less 
than for products approved between 1975 and 1984. Products approved 
before 1975 will require the greatest expenditure.

      Table 1--Number of Innovator Products by Year of FDA Approval     
------------------------------------------------------------------------
      Year                              Approvals                       
------------------------------------------------------------------------
Pre-1975                                                 1,191          
1975 to 1984                                               199          
1985 to 1991                                               188          
Total                                                    1,578          
------------------------------------------------------------------------

    An analysis of abbreviated new drug application (ANDA) approvals 
conducted in July 1996, found 2,417 generic products (excluding 
different strengths and package sizes) approved for marketing at that 
time. The estimated costs for labeling changes in section VI.C of this 
document are based on all 2,417 generic products. Although not 
insignificant, these costs will be considerably less than the costs for 
innovator products.
2. Current Incidence of Geriatric Use
    Ideally, the agency would like to have had access to data on 
geriatric subjects included in clinical trials for all approved drugs 
currently marketed. Such information would have helped determine the 
cost and effort required to analyze the data and the likelihood that 
the data would prove useful for labeling revisions. Although the 
elderly are the largest consumers of certain drug products (e.g., for 
the treatment of cancer and cardiovascular disease), in the past 
elderly individuals were not commonly included in controlled clinical 
trials. Therefore, clinical data on elderly patients for drugs that 
have been marketed for many years will be sparse--even for drugs 
commonly used by the elderly. Recently, elderly individuals have been 
included and identified as a subgroup in clinical trials. Consequently, 
more data will be

[[Page 45322]]

available for recently approved products.
    Because comprehensive summary data on geriatric subjects in 
clinical trials do not currently exist, insight on the incidence of 
geriatric use was gained for this analysis from IMS America data on the 
number of times a product was mentioned during a doctor/patient visit 
or phone conversation. Specifically, annual statistics were generated 
(as of the year ending September 30, 1991) on the number of product 
mentions for all patients and for patients age 65 and older for all 
prescription products. The term ``mention'' means that a specific drug 
was recommended, prescribed, or handed to the patient by the physician. 
Although the actual number of instances where the patient used the 
product may be different than the number of mentions, this analysis 
used only the ratio of elderly use to total use, which tended to cancel 
out any significant bias.
    The raw data on product mentions were summarized into 
therapeutically equivalent product groups to account for the 1,578 
innovator products marketed in 1991. Geriatric use ranged from nearly 
zero to almost 100 percent depending on the product. The analysis 
showed that fully half of the innovator products are infrequently used 
by the elderly--that is, geriatric patients constitute less than 25 
percent of the market share for 789 of the 1,578 products. By contrast, 
the elderly constitute more than 50 percent of the market share for a 
quarter of the innovator products. This information does not indicate 
the percentage of elderly subjects participating in clinical trials. In 
recent years, however, geriatric participation in clinical trials for 
drug products frequently used by the elderly has increased, and it is 
likely that less frequent use of a drug product by geriatric patients 
is consistent with low participation by the elderly in clinical trials 
for that product.
3. Current Incidence of Geriatric Labeling
    In 1989, FDA's Division of Drug Advertising and Labeling conducted 
a survey of geriatric labeling covering the top 25 drug products used 
by the elderly and all products in the top 12 classes of drugs used by 
the elderly. This survey included 425 products including 370 innovator 
products and 55 generic products. Because the labeling survey did not 
provide geriatric labeling information for all products, and the 
geriatric labeling that was found on the surveyed labels did not 
typically comply fully with the regulation, FDA has used the survey 
results in this analysis as an indicator of potential data 
availability, rather than an indicator of compliance with the 
regulation.
    A detailed comparison of the incidence of the geriatric labeling 
data with the geriatric use data showed that products falling in the 
middle range of geriatric use have a higher incidence of geriatric 
labeling than those products with relatively low and relatively high 
geriatric use. (See FDA's ``Threshold Assessment of Requirements for 
Geriatric Labeling'' for a graphical illustration of these respective 
distributions (Ref. 3).) This finding was unexpected. Particularly 
curious was the low incidence of geriatric labeling among the high 
geriatric use products. One possible explanation is that a high degree 
of geriatric use was assumed, but discussions with industry 
representatives could not confirm this hypothesis.
4. Products By Cost Category
    As noted in section VI.B.2 of this document, the geriatric use of 
75 percent of the products surveyed is less than 50 percent. FDA 
assumed that the availability of geriatric data (at least some 
analyzable data) would not exceed the incidence of geriatric labeling 
found in the previously described labeling survey. For the 25 percent 
of the surveyed products for which geriatric use constituted more than 
50 percent of total use (high use), the agency assumed that analyzable 
data exists for the proportion of products that currently have 
geriatric labeling and that at least some data exist for the remaining 
products. These distributions led to the construction of four distinct 
groups of products based on the degree of geriatric use and the 
availability of geriatric data, roughly defined as follows:
     (1) Low geriatric use products with no data available (no 
incidence of geriatric labeling)--about half of the low elderly use 
products.
     (2) Low geriatric use products with some data available (at least 
some geriatric labeling)--about half of the low elderly use products.
     (3) High geriatric use products with limited data available (no 
incidence of geriatric labeling)--about half of the high elderly use 
products.
     (4) High geriatric use products with data available (at least some 
geriatric labeling)--about half of the high elderly use products.
    These four product label groups, combined with the distribution of 
new drug approvals shown in Table 1, provide the basis for FDA's 
estimated costs. Table 2 displays the estimated number of product 
labels falling into each of 16 cost categories. The two low geriatric 
use categories account for three-quarters (three-eights each) of the 
products in each column and the high use categories account for one-
fourth (one-eighth each) of the products. The two columns under the 
1975 to 1984 heading account for the differences in the way the data 
are likely to be stored--half in a form readable by the computer 
technology used today and half in a form that will require some effort 
to reformat.

                                  Table 2--Innovator Products per Cost Category                                 
----------------------------------------------------------------------------------------------------------------
                                                     1975 to 1984                                               
Geriatric Use and Data      Pre-1975     ------------------------------------   1985 to 1991         Totals     
     Availability                          Formatted Data   Unformatted Data                                    
----------------------------------------------------------------------------------------------------------------
Low Use/ No Data                447                38                37                71               592     
Low Use/ Some Data              447                38                37                71               592     
High Use/ Limited Data          149                13                12                24               197     
High Use/ Some Data             149                13                12                24               197     
Totals<SUP>1                       1,191               100                99               188             1,578     
----------------------------------------------------------------------------------------------------------------
\1\ Column totals may not add due to rounding                                                                   

    Table 3 provides estimates of the average cost per product of 
complying with the regulation for each geriatric use/geriatric data 
category shown in Table 2. These values were arrived at after 
discussing anticipated industry effort to comply with the regulation 
with several industry officials, and after considering FDA's own 
experience conducting short-term studies requiring data retrieval, data 
formatting, and data analysis. The category costs, therefore, are based 
on subjective, but reasonable, estimates of the levels of effort likely 
to be involved.

[[Page 45323]]

    The highest costs ($24,000) are for drug products approved before 
1975 for which extensive geriatric data exist, but such data are not 
available in a computer readable format. In this case, at a minimum, 
the data would have to be extracted from subject records, entered into 
a computer file, and analyzed. The results would be compared with 
summary data on all remaining subjects included in the clinical trials 
to detect any significant geriatric differences.
    Calculations assume that this process, including a literature 
search and label and supplement preparation, would take about three 
person-months (the amount of time a person works in 3 months) at a 
loaded cost of about $50 per person-hour. The least complicated case 
($4,000), would be for drug products with no data available on 
geriatric patients. A literature search would have to be conducted, the 
label revised, and a supplement submitted to reflect the revision. This 
process was estimated to take about two person-weeks at the same hourly 
rate. The remaining cost categories fall between the two just described 
with differing levels of effort requiring differing levels of costs.

                                                Table 3--Innovator Costs Per Product by Product Category                                                
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                 1975 to 1984                                           
         Geriatric Use and Data Availability               Pre-1975     --------------------------------------------------------------    1985 to 1991  
                                                                                 Formatted Data                Unformatted Data                         
--------------------------------------------------------------------------------------------------------------------------------------------------------
Low Use/ No Data                                           $4,000                         $4,000                         $4,000             $4,000      
Low Use/ Some Data                                         $8,000                         $6,000                         $8,000             $6,000      
High Use/ Limited Data                                    $16,000                         $6,000                         $8,000             $6,000      
High Use/ Some Data                                       $24,000                         $6,000                         $8,000             $6,000      
--------------------------------------------------------------------------------------------------------------------------------------------------------

C. Total Costs of Compliance

    The category costs in Table 3 were multiplied by the numbers of 
labels shown in Table 2 and summed over all categories to arrive at the 
estimated total costs of compliance for the innovator products. These 
results are shown in Table 4. Clearly, the greatest costs of the 
regulation will be for products approved before 1975. These products 
account for $11,314,500, or 84 percent of the total $13,470,000 
estimated costs for innovators, as shown in Table 4.

                              Table 4--Total Innovator Compliance Costs by Category                             
----------------------------------------------------------------------------------------------------------------
                                                  1975 to 1984                                                  
Geriatric Use and       Pre-1975     --------------------------------------    1985 to 1991          Totals     
Data Availability                       Formatted Data    Unformatted Data                                      
----------------------------------------------------------------------------------------------------------------
Low Use/ No Data    $1,786,500           $150,000           $148,500           $282,000         $2,367,000      
Low Use/ Some                                                                                                   
 Data               $3,573,000           $225,000           $297,000           $423,000         $4,518,000      
High Use/ Limited                                                                                               
 Data               $2,382,000            $75,000            $99,000           $141,000         $2,697,000      
High Use/ Some                                                                                                  
 Data               $3,573,000            $75,000            $99,000           $141,000         $3,888,000      
Totals             $11,314,500           $525,000           $643,500           $987,000        $13,470,000      
----------------------------------------------------------------------------------------------------------------

    FDA's estimates the cost of relabeling each generic product to be 
$2,000, which accounts for the supplement preparation, the revision and 
printing of labels based on changes made to innovator product labels, 
and the destruction of small stocks of existing labels. Thus, the total 
estimated cost of relabeling 2,417 generic products is $4,834,000, 
bringing the total estimated cost of the regulation to $18,304,000. 
Manufacturers of innovator products will incur about 74 percent and 
manufacturers of generic products about 26 percent of this total.
    Although these projections are the best available to the agency, 
FDA notes that there are reasons to believe that they overstate the 
likely consequences of the rule. For example:
    (1) Part of the analysis is based on data that are several years 
old, and a greater percentage of products now on the market are thought 
to be close to compliance with the final rule. Many recently approved 
NME's (those approved since 1991) contain a geriatric labeling section 
and already comply with the rule. Moreover, several of the older drug 
products that would not comply with the rule have been removed from the 
market since 1991.
    (2) The rule applies only to approved products that are actually 
marketed. This cost analysis, however, assumes that all approved NME's 
would be subject to the provisions of the rule. Adjusting for these 
differences would substantially reduce the estimated costs to industry.

D. Effects on Small Entities

    The affected pharmaceutical companies can be classified into three 
industry sectors: Large innovator firms (more than 750 employees), 
small innovator firms (fewer than 750 employees), and independent 
generic firms (fewer than 750 employees). Within the two innovator 
sectors, almost all of the costs will be borne by the large innovators 
because large firms sponsor almost all innovator product applications. 
Although the occasional product sponsored by a small innovator firm may 
require additional research and analysis to support geriatric labeling, 
it is unlikely that any one small firm would have more than one or two 
such products or that any one of these products would be marketed if it 
could not generate over several hundred thousand dollars of revenue per 
year. As firms have up to 6 years to comply with the rule for all 
products, the estimated one-time cost per product of $6,000 to $24,000 
would be extremely low relative to the income generated from such 
product(s) during this period.
    Most of the small firms affected by the rule will be independent 
manufacturers of generic drugs. These firms will incur the cost of 
changing the labels of numerous drug products. The following example 
illustrates that even the largest of these small firms would not likely 
incur significant costs in comparison to company revenues. For example, 
one of the largest independent generic manufacturers (350 employees) 
held ANDA's in 1995 for approximately 250

[[Page 45324]]

products containing 95 chemical entities. According to their 10-k 
filing with the Securities and Exchange Commission, the company 
marketed only 37 drug products containing 21 chemical entities in mid-
1995. Therefore, the firm would need to make about 21 label changes at 
a total cost of about $42,000. Not all of these costs would be incurred 
during the same year, however, because the regulation will be phased in 
over a 6-year period. Considering these circumstances, the $42,000 cost 
to this small entity would not be a significant fraction of the 
company's $200 million in annual sales.
    Although the previous example applies to just one firm, given the 
estimated $2,000 compliance cost for each marketed generic drug, it is 
difficult to construct a scenario in which the cost of the required 
label changes could constitute a significant portion of a company's 6-
year revenue stream. As a result, although most manufacturers of 
generic drugs will be affected, very few, if any, will incur costs that 
are significant in comparison with company revenues. FDA therefore 
certifies that this rule will not have a significant effect on a 
substantial number of small entities.

VII. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(11) that this 
action is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VIII. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
following title, description, and respondent description of the 
information collection provisions are shown with an estimate of the 
annual reporting burden. This estimate includes the time needed for 
reviewing instructions, gathering and maintaining the data needed, and 
completing and reviewing the collection of information.
    Most of the paperwork burden imposed by this final rule will be a 
one-time reporting burden associated with gathering data and designing 
and manufacturing new labeling that includes a geriatric use subsection 
in the ``Precautions'' section of the labeling. The paperwork burden 
will vary widely, with the most significant burden, up to 480 hours, 
estimated for some innovator drug products approved before 1975. By 
contrast, the burden for most generic drug products is estimated at 80 
hours or less.
    In response to comments and on its own initiative, FDA has made a 
number of changes in the final rule to ease the paperwork burden. 
First, for the great majority of products affected by this regulation, 
the revised implementation dates will permit manufacturers sufficient 
time to design and print new labeling and deplete existing stocks of 
old labeling before the geriatric subsection is required for the 
product. Second, FDA will not require geriatric labeling to be 
submitted for approved products that are not currently marketed. Third, 
all of the labeling language under Sec. 201.57(f)(10)(ii)(A), and much 
of the labeling language under Sec. 201.57(f)(10)(ii)(B) and 
(f)(10)(ii)(C) are provided in the regulation. Fourth, as discussed in 
section IV of this document, many NME's approved since 1991 contain a 
geriatric labeling section and are already in compliance, and the 
labeling of a substantial number of drug products approved before 1991 
contains some geriatric information.
    Title: Geriatric Use Labeling for Human Prescription Drugs.
    Description: FDA is amending its regulations governing the content 
and format of labeling for human prescription drug products, including 
biological products, to include information on the appropriate use of 
drugs for persons 65 and older.
    Description of Respondents: Business and other for-profit 
organizations, including small businesses and manufacturers.
    Because labeling was not considered collection of information under 
the Paperwork Reduction Act of 1980, the agency did not provide a 
paperwork comment period for the proposed rule. However, the agency is 
providing an opportunity for public comment under the Paperwork 
Reduction Act of 1995, which was enacted after the publication of the 
proposed rule and applies to this final rule. Therefore, FDA now 
invites comments on: (1) Whether the proposed collection of information 
is necessary for the proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology. Individuals and organizations may submit 
comments on the information collection provisions of this final rule by 
October 27, 1997. Comments should be directed to the Dockets Management 
Branch (address above).
    At the close of the 60-day comment period, FDA will review the 
comments received, revise the information collection provisions as 
necessary, and submit these provisions to OMB for review and approval. 
FDA will publish a notice in the Federal Register when the information 
collection provisions are submitted to OMB, and an opportunity for 
public comment to OMB will be provided at that time. Prior to the 
effective date of this final rule, FDA will publish a notice in the 
Federal Register of OMB's decision to approve, modify, or disapprove 
the information collection provisions. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

                                   Table 5--Estimated Annual Reporting Burden                                   
----------------------------------------------------------------------------------------------------------------
   21 CFR Section      Annual no. of respondents          Hours per response             Total burden hours     
----------------------------------------------------------------------------------------------------------------
201.57(f)(10)                            290                            120                         34,800      
----------------------------------------------------------------------------------------------------------------

IX. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Rochon, P. A., and J. H. Gurwitz, ``Drug Therapy,'' Lancet 
346(8966):32-36, 1995.
    2. Schneider, J. K., L. C. Mion, and J. D. Frengley, ``Adverse 
Drug Reactions in an Elderly Outpatient Population,'' American 
Journal of Hospital Pharmacy, 49(1):90-96, 1992.

[[Page 45325]]

    3. Food and Drug Administration, ``Threshold Assessment of 
Requirements for Geriatric Labeling,'' June 30, 1997.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR part 201 is amended as follows:

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority:  Secs. 201, 301, 501, 502, 503, 505, 506, 507, 508, 
510, 512, 530-542, 701, 704, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 358, 
360, 360b, 360gg-360ss, 371, 374, 379e); secs. 215, 301, 351, 361 of 
the Public Health Service Act (42 U.S.C. 216, 241, 262, 264).
     2. Section 201.57 is amended by adding new paragraph (f)(10) to 
read as follows:

Sec. 201.57   Specific requirements on content and format of labeling 
for human prescription drugs.

* * * * *
    (f) * * *
    (10) Geriatric use. (i) A specific geriatric indication, if any, 
that is supported by adequate and well-controlled studies in the 
geriatric population shall be described under the ``Indications and 
Usage'' section of the labeling, and appropriate geriatric dosage shall 
be stated under the ``Dosage and Administration'' section of the 
labeling. The ``Geriatric use'' subsection shall cite any limitations 
on the geriatric indication, need for specific monitoring, specific 
hazards associated with the geriatric indication, and other information 
related to the safe and effective use of the drug in the geriatric 
population. Unless otherwise noted, information contained in the 
``Geriatric use'' subsection of the labeling shall pertain to use of 
the drug in persons 65 years of age and older. Data summarized in this 
subsection of the labeling shall be discussed in more detail, if 
appropriate, under ``Clinical Pharmacology'' or the ``Clinical 
Studies'' section. As appropriate, this information shall also be 
contained in ``Contraindications,'' ``Warnings,'' and elsewhere in 
``Precautions.''
    (ii) Specific statements on geriatric use of the drug for an 
indication approved for adults generally, as distinguished from a 
specific geriatric indication, shall be contained in the ``Geriatric 
use'' subsection and shall reflect all information available to the 
sponsor that is relevant to the appropriate use of the drug in elderly 
patients. This information includes detailed results from controlled 
studies that are available to the sponsor and pertinent information 
from well-documented studies obtained from a literature search. 
Controlled studies include those that are part of the marketing 
application and other relevant studies available to the sponsor that 
have not been previously submitted in the investigational new drug 
application, new drug application, biological license application, or a 
supplement or amendment to one of these applications (e.g., 
postmarketing studies or adverse drug reaction reports). The 
``Geriatric use'' subsection shall contain the following statement(s) 
or reasonable alternative, as applicable, taking into account available 
information:
     (A) If clinical studies did not include sufficient numbers of 
subjects aged 65 and over to determine whether elderly subjects respond 
differently from younger subjects, and other reported clinical 
experience has not identified such differences, the ``Geriatric use'' 
subsection shall include the following statement:
    ``Clinical studies of (name of drug) did not include sufficient 
numbers of subjects aged 65 and over to determine whether they 
respond differently from younger subjects. Other reported clinical 
experience has not identified differences in responses between the 
elderly and younger patients. In general, dose selection for an 
elderly patient should be cautious, usually starting at the low end 
of the dosing range, reflecting the greater frequency of decreased 
hepatic, renal, or cardiac function, and of concomitant disease or 
other drug therapy.''
    (B) If clinical studies (including studies that are part of 
marketing applications and other relevant studies available to the 
sponsor that have not been submitted in the sponsor's applications) 
included enough elderly subjects to make it likely that differences in 
safety or effectiveness between elderly and younger subjects would have 
been detected, but no such differences (in safety or effectiveness) 
were observed, and other reported clinical experience has not 
identified such differences, the ``Geriatric use'' subsection shall 
contain the following statement:
    Of the total number of subjects in clinical studies of (name of 
drug), -- percent were 65 and over, while -- percent were 75 and 
over. (Alternatively, the labeling may state the total number of 
subjects included in the studies who were 65 and over and 75 and 
over.) No overall differences in safety or effectiveness were 
observed between these subjects and younger subjects, and other 
reported clinical experience has not identified differences in 
responses between the elderly and younger patients, but greater 
sensitivity of some older individuals cannot be ruled out.
    (C) If evidence from clinical studies and other reported clinical 
experience available to the sponsor indicates that use of the drug in 
elderly patients is associated with differences in safety or 
effectiveness, or requires specific monitoring or dosage adjustment, 
the ``Geriatric use'' subsection of the labeling shall contain a brief 
description of observed differences or specific monitoring or dosage 
requirements and, as appropriate, shall refer to more detailed 
discussions in the ``Contraindications,'' ``Warnings,'' ``Dosage and 
Administration,'' or other sections of the labeling.
     (iii)(A) If specific pharmacokinetic or pharmacodynamic studies 
have been carried out in the elderly, they shall be described briefly 
in the ``Geriatric use'' subsection of the labeling and in detail under 
the ``Clinical Pharmacology'' section. The ``Clinical Pharmacology'' 
section and ``Drug interactions'' subsection of the ``Precautions'' 
section ordinarily contain information on drug-disease and drug-drug 
interactions that is particularly relevant to the elderly, who are more 
likely to have concomitant illness and to utilize concomitant drugs.
    (B) If a drug is known to be substantially excreted by the kidney, 
the ``Geriatric use'' subsection shall include the statement:
    ``This drug is known to be substantially excreted by the kidney, 
and the risk of toxic reactions to this drug may be greater in 
patients with impaired renal function. Because elderly patients are 
more likely to have decreased renal function, care should be taken 
in dose selection, and it may be useful to monitor renal function.''
    (iv) If use of the drug in the elderly appears to cause a specific 
hazard, the hazard shall be described in the ``Geriatric use'' 
subsection of the labeling, or, if appropriate, the hazard shall be 
stated in the ``Contraindications,'' ``Warnings,'' or ``Precautions'' 
section of the labeling, and the ``Geriatric use'' subsection shall 
refer to those sections.
    (v) Labeling under paragraphs (f)(10)(i) through (f)(10)(iii) of 
this section may include statements, if they would be useful in 
enhancing safe use of the drug, that reflect good clinical practice or 
past experience in a particular situation, e.g., for a sedating drug, 
it could be stated that:
    ``Sedating drugs may cause confusion and over-sedation in the 
elderly; elderly patients generally should be started on low doses 
of (name of drug) and observed closely.''
    (vi) If the sponsor believes that none of the requirements 
described in

[[Page 45326]]

paragraphs (f)(10)(i) through (f)(10)(v) of this section is appropriate 
or relevant to the labeling of a particular drug, the sponsor shall 
provide reasons for omission of the statements and may propose an 
alternative statement. FDA may permit omission of the statements if FDA 
determines that no statement described in those paragraphs is 
appropriate or relevant to the drug's labeling. FDA may permit use of 
an alternative statement if the agency determines that such statement 
is accurate and appropriate.
* * * * *

    Dated: July 31, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-22701 Filed 8-26-97; 8:45 am]
BILLING CODE 4160-01-F