Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations 45313

This incorporation by reference was

approved by the Director of the Federal

Register in accordance with 5 U.S.C. 552(a)

and 1 CFR part 51. Copies may be obtained

from Hartzell Propeller Inc., One Propeller

Place, Piqua, OH 45356–2634, ATTN:

Product Support; telephone (937) 778–4200,

fax (937) 778–4321. Copies may be inspected

at the FAA, New England Region, Office of

the Assistant Chief Counsel, 12 New England

Executive Park, Burlington, MA; or at the

Office of the Federal Register, 800 North

Capitol Street, NW., suite 700, Washington,

DC.

(j) This amendment becomes effective on

September 11, 1997.

Issued in Burlington, Massachusetts, on

August 15, 1997.

James C. Jones,

Assistant Manager, Engine and Propeller

Directorate, Aircraft Certification Service.

[FR Doc. 97–22677 Filed 8–26–97; 8:45 am]

BILLING CODE 4910–13–P

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.

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 (§ 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
45314 Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations

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

§ 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 § 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,

§ 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, § 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,

§ 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 drugdrug and drug-disease interactions. For

example, § 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 § 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 § 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, § 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 § 201.57(f)(10)(vi), must provide

reasons for omitting the specific

geriatric use information and statements
Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations 45315

in § 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 § 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 * * *’’

(§ 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 § 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
45316 Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations

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

§ 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 § 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
Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations 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

§ 201.57(f)(10)(iii)(A), data about drugdisease and drug-drug interactions are

ordinarily included in the ‘‘Clinical

Pharmacology’’ section (§ 201.57(b)) and

‘‘Drug interactions’’ subsection of the

‘‘Precautions’’ section (§ 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

§ 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 § 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

§ 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

§ 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 § 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 § 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

§ 201.57(f)(10)(ii)(C)).

FDA advises that, with regard to the

phrases ‘‘sufficient numbers of subjects

aged 65 and over’’ in

§ 201.57(f)(10)(ii)(A) and ‘‘enough

elderly subjects’’ in

§ 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

§ 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 § 201.57(f)(10)(ii)(A), while

a finding of no difference in a larger

population could lead to the statement

in § 201.57(f)(10)(ii)(B). A finding of

difference, whatever the population,

would lead to labeling as in

§ 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
45318 Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations

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 § 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 § 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

§ 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 § 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

§ 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 § 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, CockroftGault (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.
Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations 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 § 314.70(b) (21 CFR

314.70(b)) or § 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 § 314.70(c). Labeling

changes should be implemented

immediately under § 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

§ 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

§ 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 § 601.12. In the Federal Register of

July 24, 1997 (62 FR 39890), FDA

revised the requirements in § 601.12 for

the reporting of changes, including the

reporting of changes in labeling, to an

approved license application. With the

revision of § 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
45320 Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations

products, and the potential for drugdrug 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 § 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

§ 201.100. In addition, under § 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 § 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
Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations 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
45322 Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations

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

Geriatric Use and Data Availability Pre-1975

1975 to 1984

1985 to 1991 Totals

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

Totals1 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.
Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations 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 personweeks 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

Geriatric Use and Data

Availability Pre-1975

1975 to 1984

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

Geriatric Use and Data Availability Pre-1975

1975 to 1984

1985 to 1991 Totals

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
45324 Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations

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 onetime 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 § 201.57(f)(10)(ii)(A),

and much of the labeling language

under § 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.
Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations 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, 360gg360ss, 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:

§ 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 wellcontrolled 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 welldocumented 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 drugdisease 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
45326 Federal Register / Vol. 62, No. 166 / Wednesday, August 27, 1997 / Rules and Regulations

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

DEPARTMENT OF TRANSPORTATION

Federal Highway Administration

23 CFR Parts 140 and 646

[FHWA Docket No. FHWA–97–2681]

RIN 2125–AD86

Railroad/Highway Projects

AGENCY: Federal Highway

Administration (FHWA), DOT.

ACTION: Interim final rule; request for

comments.

SUMMARY: The FHWA is amending its

regulations on railroad/highway projects

and reimbursement for railroad work on

Federal-aid highway projects. The

amendments require railroads to:

Submit final billings within one year

following completion of the railroad

work; remove the requirement of a

State’s certification that work is

complete; remove the ‘‘G’’ Funds

terminology; increase the ceiling for

lump sum agreements from $25,000 to

$100,000; incorporate changes brought

about by the Intermodal Surface

Transportation Efficiency Act of 1991

(ISTEA), Public Law 102–240, 105 Stat.

1914; and show dimensions for

participation limits in metric units. The

FHWA makes these changes to conform

the existing railroad/highway

regulations to more recent laws or

regulations, and to provide State

highway agencies with clarification and

more flexibility in implementing the

current law. This rulemaking is part of

the FHWA’s effort to implement the

President’s Regulatory Reinvention

Initiative.

DATES: This interim final rule is

effective August 27, 1997. Written

comments must be submitted on or

before October 27, 1997.

ADDRESSES: Submit written, signed

comments to the docket number that

appears in the heading of this document

to the Docket Clerk, U.S. DOT Dockets,

Room PL–401, 400 Seventh Street, SW.,

Washington, D.C. 20590–0001. All

comments received will be available for

examination at the above address

between 10 a.m. and 5 p.m., e.t.,

Monday through Friday, except Federal

holidays. Those desiring notification of

receipt of comments must include a selfaddressed, stamped envelope or

postcard.

FOR FURTHER INFORMATION CONTACT:

Robert Winans, Office of Engineering,

(202) 366–0450, or Wilbert Baccus,

Office of the Chief Counsel, (202) 366–

0780, FHWA, 400 Seventh Street, SW.,

Washington, D.C. 20590. Office hours

are from 7:45 a.m. to 4:15 p.m., e.t.,

Monday through Friday, except Federal

holidays.

SUPPLEMENTARY INFORMATION: Present

FHWA regulations regarding railroad/

highway projects and reimbursement for

railroad work on Federal-aid highway

projects have evolved from basic

principles established decades ago, with

many of the policies remaining

unchanged. The present regulations are

found at 23 CFR part 140, subpart I, and

part 646, subpart B. The FHWA amends

these regulations in the following

manner and for the reasons set forth

below.

In part 140, subpart I, § 140.904,

paragraph (b)(1) is amended to clarify

that the approved program of projects is

the approved statewide transportation

improvement program, as is now

required under 23 U.S.C. 135.

In § 140.922, paragraph (b) is

amended to require railroads to submit

final billings within one year following

completion of the railroad work.

Otherwise, previous payments to

railroads may be considered final and

projects may be closed out. This change

will assist highway agencies in their

efforts to obtain timely final billings

from the railroads. Prior to this action,

it had been common for some railroad

bills to be received years after the work

was completed, thus delaying audit

activity and project closure. With the

amended language, billings received

from railroads after one year following

completion of the railroad work can be

paid at the discretion of the highway

agency. Paragraph (b) is further

amended to remove the requirement for

State certification that the work is

complete, acceptable, and in accordance

with the terms of the agreement. The

FHWA believes that such certificates are

not necessary on individual projects.

Instead, compliance can be reviewed on

a program basis.

In part 646, subpart B, § 646.200,

paragraph (c) is amended to refer to

current sections of highway law. Section

405 of title 23, U.S.C., was repealed and

section 203 of the Highway Safety Act

of 1973 (Pub. L. 93–87, 87 Stat. 282) was

codified as part of 23 U.S.C. 130.

Paragraph (f) is removed because part

170 of title 23, CFR, no longer exists.

Section 646.202, Authority, is

removed and reserved. This section is

removed because the authority citation

is placed at the part level and, therefore,

redundant as a separate section in

subpart B.

Section 646.204 is amended to

remove paragraph (d) which defines

obsolete terminology, to remove the

paragraph designations from all

definitions, and to place the definitions

in alphabetical order.

In § 646.208, paragraphs (a) and (b)

are revised to describe only funding

sources for rail/highway crossing

projects. Information contained in this

section on Federal share is moved to

§ 646.212.

The current text of § 646.212,

paragraph (b) is removed. Section

1012(a) of the ISTEA amended 23 U.S.C.

120 by removing subsection (d)

concerning Federal share payable for

reconstruction of existing grade

separation projects on railway/highway

crossings. Such projects are no longer

eligible for 100 percent Federal funding.

Regulatory text from § 646.208(b) is

redesignated and revised as a new

paragraph (b) in § 646.212 in order to

provide information on Federal share in

one place.

In § 646.214, paragraph (a)(2) is

amended to clarify that the FHWA no

longer is required to approve standards

for all Federal-aid projects. Section

1016(d) of the ISTEA amended 23

U.S.C. 109 by adding a new subsection

(p) which provided that non-NHS

projects now follow State approved

standards.

In § 646.216, paragraph (d)(3)(ii) is

amended to increase the ceiling from

$25,000 to $100,000 for using the lump

sum payment arrangement for

reimbursement for railroad adjustments

(other than installation or improvement

of grade crossing warning devices and/

or grade crossing surfaces) on Federalaid and direct Federal highway projects.

The amendment provides the States

greater flexibility in utilizing the lump

sum payment arrangement. The purpose

of allowing lump sum agreements, in

lieu of agreements based on an

accounting of actual costs, is to reduce

the administrative burden associated