Guidance for Industry

Content and Format for

Geriatric Labeling

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

October 2001

Labeling
Guidance for Industry

Content and Format for

Geriatric Labeling

Additional copies of this Guidance are available from:

 Office of Training and Communications

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

 5600 Fishers Lane,

Rockville, MD 20857

(Tel) 301-827-4573

 http://www.fda.gov/cder/guidance/index.htm.

or

 Office of Communication, Training and

Manufacturers Assistance, HFM-40

Center for Biologics Evaluation and Research

 Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

 http://www.fda.gov/cber/guidelines.htm. 

Fax: 1-888-CBERFAX or 301-827-3844

Phonel: the Voice Information System at 800-835-4709 or 301-827-1800.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

October 2001

Labeling
TABLE OF CONTENTS

I. INTRODUCTION................................................................................................................. 1

II. BACKGROUND.................................................................................................................... 1

III. APPLICATION HOLDERS' RESPONSIBILITY FOR SUBMITTING

REVISED LABELING.......................................................................................................... 2

IV. IMPLEMENTATION OF THE GERIATRIC LABELING RULE................................... 3

V. DESCRIPTION OF REGULATION AND OPTIONAL STANDARD LANGUAGE...... 5

VI. CONTENT AND FORMAT.................................................................................................. 7

A. Cover Letter.......................................................................................................... 7

B. Detailed Table of Contents................................................................................... 7

C. Revised Labeling.................................................................................................... 7

D. Applicable Regulatory Paragraph(s).................................................................... 8

E. User Fee ................................................................................................................. 8

F. Data to Support Geriatric Use Labeling .............................................................. 8

VII. APPLICABILITY OF USER FEES TO GERIATRIC LABELING

SUPPLEMENTS.............................................................................................................. 10

VIII. QUESTIONS REGARDING 21 CFR 201.57(f)(10) ..................................................... 10
GUIDANCE FOR INDUSTRY1

Content and Format for Geriatric Labeling

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does

not create or confer any rights for or on any person and does not operate to bind FDA or the public. An

alternative approach may be used if such approach satisfies the requirements of the applicable statutes and

regulations.

I. INTRODUCTION

In a final rule published in the Federal Register on August 27, 1997 (62 FR 45313), FDA

established the Geriatric Use subsection in the labeling for human prescription drug and

biological products to provide pertinent information about the use of those products in the elderly.

 This guidance is intended to provide industry with information on submitting geriatric labeling of

human prescription drug and biological products. This guidance discusses the following issues

related to the submission of geriatric labeling:

• Who should submit revised labeling

• Implementation dates

• Description of the regulation and optional standard language in proposed labeling

• Content and format for geriatric labeling

• Applicability of user fees to geriatric labeling supplements

II. BACKGROUND

In 1997, FDA established the Geriatric Use subsection, as a part of the PRECAUTIONS section,

in the labeling for human prescription drugs to include more complete information about the use of

a drug or biological product in the elderly (persons aged 65 years and over) (21 CFR 201.57

(f)(10)). As a result, many application holders are required to submit geriatric labeling

supplements under 21 CFR 314.70 or 601.12. These supplements require Agency approval prior

to implementation except (1) in cases where the labeling change adds or strengthens a precaution

 

1

This guidance has been prepared by the Geriatric Subcommittee of the Medical Policy Coordinating Committee

(MPCC), Center for Drug Evaluation and Research (CDER), and the Center for Biologics Evaluation and Research (CBER) at

the Food and Drug Administration.
2

or dosage and administration instruction as outlined in ' 314.70(c)(2) or § 601.12(f)(2)2 and (2)

for labeling changes submitted 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).3 

III. APPLICATION HOLDERS' RESPONSIBILITY FOR SUBMITTING REVISED

LABELING

Under the geriatric labeling regulation, drug products fall into one of three categories with regard

to submission of geriatric labeling supplements (Table 1). For drug products in the first category,

which includes all marketed drug products with an approved new drug application (NDA) or

biologics license application (BLA) and products marketed under an approved abbreviated new

drug application (ANDA) where the ANDA product is the reference listed drug,4 the submission is

to include revised labeling and the data supporting the revision. For drug products in the second

category, which includes marketed drug products for which there is no approved application,

unmarketed drugs with an approved NDA, BLA, or ANDA, and over-the-counter (OTC) drug

products,5 no submission is necessary. For drug products in the third category (i.e., marketed

products with ANDAs that are not the reference listed product), revised labeling should be

submitted based on the approved geriatric labeling of the reference listed drug product in the

Orange Book when that drug's labeling is changed to include a Geriatric Use subsection.

 

2

See 62 FR 45313 at 45319 for further clarification.

3

See 62 FR 45313 at 45316 for further clarification.

4

See Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book), FDA, sec. 1.4.

5

For drugs that are available as both OTC and prescription drug products, the holders of applications for the

prescription drug products are responsible for submitting revised geriatric labeling.
3

Table 1. Categories for Revised Geriatric Labeling

Type of Drug Product Submission

$ Approved NDA and BLA marketed products

$ Approved ANDA marketed drug products where the ANDA is the

 reference listed drug in the publication Approved Drug Products with

 Therapeutic Equivalence Evaluations A

Revised labeling and supporting data as

outlined in the geriatric labeling final rule

$ Drug Products for which there is no approved application (e.g., pre-

 1938 drug products without an approved application)

$ Unmarketed drug products of approved NDA, BLA or ANDA B

$ OTC Drug Products

None

$ Approved ANDA marketed drug products that are not the marketed

 reference listed drug

Revised labeling based on reference listed

drug=s Geriatric Use subsection

 

A

 Some ANDA products may be designated as a reference listed drug solely because they have a different dosage form

compared to the innovator product (e.g., tablet versus capsule) but their labeling still conforms to the innovator product labeling

(i.e., changes in the NDA holder's (innovator’s) labeling result in changes in the ANDA holder's labeling). For this situation, the

ANDA holder is responsible for submitting a supplement providing any information regarding the use of its product in the elderly

or to acknowledge that it has no information and it will conform to changes in the innovator's labeling. In cases where the ANDA

is the reference listed drug and there is no marketed innovator drug product, the ANDA holder is responsible for submitting a

Geriatric Use subsection.

 

B

 If the application holder decides to resume marketing of a drug product, a geriatric labeling supplement should be submitted

prior to marketing.

IV. IMPLEMENTATION OF THE GERIATRIC LABELING RULE

The geriatric labeling final rule (62 FR 45313) provides for staggered implementation dates for

products approved prior to the effective date of the rule, August 27, 1998. Because certain classes

of drugs were thought to pose potential problems for geriatric patients, labeling changes for these

drugs were subject to priority implementation and were to be submitted to the FDA by August 27,

1998 (62 FR 45320). The Agency selected the following drug classes for priority implementation:

• Psychotropic drugs (antidepressants, anxiolytics, hypnotics, and antipsychotics)

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Digoxin, antiarrhythmics, and calcium channel blockers

• Oral hypoglycemic agents

• Anticoagulants

• Quinolones
4

For marketed drugs not in the priority categories, the implementation schedule is based on the year

in which the drug product's new molecular entity (NME) (active moiety) or biological product

license was first approved. Table 2 summarizes the dates for submitting geriatric labeling. Any

application submitted after August 27, 1998, must include a Geriatric Use subsection in the

proposed labeling (' 201.57(f)(10)). Sponsors of applications for new drug products currently

under review should provide Geriatric Use subsections for their proposed labeling as an

amendment to pending applications.

Table 2. Dates for Submitting Geriatric Labeling

Drug Categories Type of Submission Date

New Applications

Applications submitted after August 27, 1998 NDA or BLA Submissions $ With application

Applications submitted after August 27, 1997, and

 before August 27, 1998

Amendment (if pending)

Supplement (if approved)

$ August 27, 1998

Marketed Priority DrugsA

NME first approved prior to August 27, 1998 Supplement $ August 27, 1998

Marketed Drugs Not on the Priority Implementation Schedule

NME or biological product

 first approved from 1989 to August 27, 1997

Supplement $ August 27, 1999

NME or biological product

 first approved from 1982 through 1988

Supplement $ August 28, 2000

NME or biological product

 first approved from 1975 through 1981

Supplement $ August 27, 2001

NME or biological product

 first approved from 1963 through 1974

Supplement $ August 27, 2002

NME or biological product first approved prior to 1963 Supplement $ August 27, 2003

 

A

 Priority Drugs are psychotropic drugs; nonsteroidal anti-inflammatory drugs (NSAIDs); digoxin, antiarrhythmics, and

calcium channel blockers; oral hypoglycemic agents; anticoagulants; and quinolones. There are no priority biological products.
5

Holders of ANDAs designated as the reference listed drug in the Orange Book are responsible for

submitting a geriatric labeling supplement provided their labeling does not conform to an

innovator product's labeling. All holders of ANDAs that are not listed as the reference listed drug

in the Orange Book should revise their labeling in accordance with the last approved labeling of

the reference listed drug.6 If an ANDA holder receives a reference listed drug designation

subsequent to the release of this guidance, it is the responsibility of that holder to supplement the

application(s) in the manner described in the guidance.

V. DESCRIPTION OF REGULATION AND OPTIONAL STANDARD LANGUAGE

The geriatric labeling regulation (§ 201.57(f)(10)) includes six paragraphs ((i) through (vi)). 

These paragraphs outline various options for statements in the Geriatric Use subsection based on

the type of information available and the interpretation of that information. In addition, paragraphs

(ii)(A), (ii)(B) and (iii)(B) provide standard language to be used in the Geriatric Use subsection. 

A geriatric labeling supplement or amendment should include a cover letter that clearly indicates

that the submission is for geriatric labeling and cites the specific paragraph(s) in the regulation that

pertains to the labeling submitted. More than one paragraph may apply to a labeling submission. 

Table 3 summarizes the requirements of paragraphs (i) through (vi).

 

6

 See the guidance for industry Revising ANDA Labeling Following Revision of the RLD Labeling (May 2000).
6

Table 3. Paragraphs (i) Through (vi) in 21 CFR 201.57(f)(10)

 Paragraph in

' 201.57(f)(10)

Information in the Geriatric Use Subsection

(i) A specific geriatric indication is included in the INDICATIONS AND USAGE section with more detailed discussion

in appropriate sections (e.g., CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS).

(ii) A statement on use in the geriatric population is included for the same indication approved for adults in general. The

statement must reflect all relevant information available to the sponsor pertaining to use in the geriatric population and

be one of the following three kinds.

(ii)(A) Standard language for paragraph (ii) labeling if the clinical studies do not provide a sufficient numberA of geriatric

subjects to determine whether elderly respond differently.

(ii)(B) Standard language for paragraph (ii) labeling if the clinical studies did include a sufficient number of geriatric subjects

to determine whether elderly respond differently and no difference in response was detected.

(ii)(C) If evidence from clinical studies and experience suggests that use in the elderly is associated with differences in safety

or effectiveness, a brief description of the differences with reference to appropriate sections (e.g., CLINICAL

PHARMACOLOGY, WARNINGS, PRECAUTIONS) in the labeling for more detailed discussion must be

included.

(iii)(A) Information from a pharmacokinetic or pharmacodynamic study performed in elderly subjects must be briefly

described with reference to the appropriate sections (e.g., CLINICAL PHARMACOLOGY, DRUG

INTERACTION, PRECAUTIONS) in the labeling for more detailed discussion.

(iii)(B) Standard language for drugs that are substantially excretedB by the kidney.

(iv) A statement describing a specific hazard with use of the drug in the elderly that references appropriate sections (e.g., 

CONTRAINDICATIONS, WARNINGS, PRECAUTIONS) in the labeling for more detailed discussion.

(v) A statement that enhances safe use of the drug based on good clinical practice or past experience.

(vi) If none of the requirements in (i) through (v) are appropriate or relevant to labeling, the sponsor must provide the

reasons for the omission of the statements and may propose an alternative statement.

 

A

 Fewer than 100 geriatric subjects. (See discussion in 62 FR 45313 at 45317.)

 

B

 The final rule does not provide a definition for substantially excreted. (See discussion in 62 FR 45313 at 45318.)

Because there are currently no approved applications that have a specific geriatric indication, the

FDA does not expect any application holders to submit geriatric labeling supplements under

' 201.57(f)(10)(i). Paragraph (i) pertains to future NDA or BLA submissions for a specific

geriatric indication and to those applications currently under review. In either case, the review

clock will not be reset because the data in support of geriatric labeling would be provided as part

of an original submission or be submitted as an amendment to an NDA or BLA currently under

review.
7

In cases where a drug product is unlikely to be used by the geriatric population, the application

holder may submit a supplement under ' 201.57(f)(10)(vi) that requests omission of the Geriatric

Use subsection or proposes an alternative statement with reasons supporting the request.

The geriatric labeling statements provided in the final rule are not applicable for most topical

ophthalmic drug products. As a general rule, clinical differences in response between the geriatric

and younger populations, from both an efficacy and safety perspective, have not been demonstrated

to occur in clinical studies of topical ophthalmic drug products. The systemic absorption of

topical ophthalmic drug products is usually minimal, and consequently, systemic interactions are

unlikely and have been observed very infrequently. Where clinical differences between the

geriatric and younger populations are not demonstrated, sponsors of new drug applications for

topical ophthalmic drug products should request an alternative statement for the Geriatric Use

subsection under ' 201.57(f)(10)(vi), such as “No overall differences in safety or effectiveness

have been observed between elderly and younger patients.”

VI. CONTENT AND FORMAT

In the Federal Register of February 11, 1998 (63 FR 6854), FDA amended the NDA format and

content regulations to require safety and effectiveness data for important demographic subgroups,

including age subgroups (21 CFR 314.50(d)(5)(v) and (vi)(a)). The regulation, effective August

10, 1998, also amends IND regulations to require sponsors to tabulate in their annual reports the

number of subjects enrolled to date in clinical studies for drug and biological products according

to certain subgroups, including age (21 CFR 312.33(a)(2)).

All supplements submitted to comply with the geriatric labeling final rule should be noted as

"Geriatric Labeling Supplement" in the "Reason for Submission" block on FDA Form 356h for

submissions to CDER or CBER. The following information should be included in the supplement

in the order shown.

A. Cover Letter C A cover letter should include the following information.

1. Indicate that the submission is a geriatric labeling supplement.

2. Specify the paragraph(s) of the regulation pertinent to the supplement.

3. Include the user fee identification number if applicable.

4. If no user fee is required, explain the reason for the exception.

B. Detailed Table of Contents

C. Revised Labeling
8

1. Include a draft of the revised labeling.7

2. Include a marked-up copy of the last approved labeling,8 clearly showing all

additions and deletions,9 with annotations of where the supporting data are located

in the submission.

3. Submissions to CBER should use form FDA 2567 C Transmittal of Labels and

Circulars. 

D. Applicable Regulatory Paragraph(s)

Indicate under which paragraph(s) in ' 201.57(f)(10) (i) through (vi) the labeling is being revised

and explain how the regulation applies .

E. User Fee

If applicable, the appropriate user fee needs to be submitted (21 U.S.C. 379h) and should be sent

to the designated bank. A user fee cover sheet (Form FDA 3397) should be included in each

submission (OMB No. 0910-0297). If no user fee is applicable, the sponsor should so indicate on

the user fee cover sheet. (See section VII.)

F. Data to Support Geriatric Use Labeling

Data by type (e.g., efficacy, pharmacokinetic/pharmacodynamic, safety) should be presented,

analyzed, and summarized, including data taken from published literature, using applicable parts of

the format described in the Format and Content of the Clinical and Statistical Sections of New

Drug Applications (FDA 1988).10 In addition, the following points should be noted.

 

7 In the case where the applicant is submitting a supplement under § 201.57(f)(10)(vi) that requests omission of the

Geriatric Use subsection or proposes an alternative statement, the applicant is required to include reasons to support the request.

8

 Current labeling may differ from last approved labeling because the current labeling may include additions and/or

deletions made before FDA approval (§ 314.70(c) or § 601.12(f)(2) and (3)) that have not yet undergone FDA review

9

Show all changes being effected under § 314.70(c) or § 601.12(f)(2) and (3) that have not received an approval letter

at the time of the Geriatric Use submission. Annotations for these changes should include the date and serial number or reference

of the submission. It is not necessary to resubmit the data or analysis that supported the change.

10 For additional information, consult the following International Conference on Harmonisation (ICH) guidances:

ICH E3 Structure and Content of Clinical Study Reports (July 1996).

ICH M4 Common Technical Document. (In November 2000, ICH endorsed ICH M4, which describes the content

and format of a common application (CTD) for new products (including biotechnology-derived products) for submission to

regulatory authorities. The efficacy or clinical section (ICH M4E) contains information on study reports and key literature

references. FDA published the draft ICH M4 guidance in August 2000. The final M4 guidance will be published in the coming

months.)
9

1. The source of the data should be described (e.g., sponsor's clinical data, medical

literature, MedWatch).

2. Safety data should include the extent of exposure, duration of exposure, and adverse

events.

3. Labeling that simply relocates information already in the approved labeling does

not require a re-analysis of the original data that supported this information.

4. The analysis and source data that support any change from the currently approved

labeling for the use of the drug product in the geriatric population should be

submitted. For some supplements, the amount of potentially relevant data may be

quite voluminous. In these instances, it will usually be useful to contact the FDA

division where the application resides to discuss which data should be submitted.

5. The submission should state how the medical literature was searched (e.g.,

Medline), the beginning and ending dates covered by the search (month/year to

month/year), and the date(s) the search was performed. A complete listing of

literature reports reviewed by the sponsor should be included.11 A summary of

each literature article is not necessary. Only those articles that support the labeling

change should be summarized as outlined in the Format and Content of the

Clinical and Statistical Sections of New Drug Applications, and a copy of the

article should be included in the submission.12 The FDA reviewer of the

supplement may request copies of other literature articles included in the listing that

are not provided in the submission.

 

11 The listing should be formatted as outlined in Annals of Internal Medicine, 126:36-47, 1997. (See discussion on

References, pp. 40-42.) 

12 For additional information, see the guidance for industry entitled Providing Clinical Evidence of Effectiveness for

Human Drugs and Biological Products (FDA, 1998).
10

VII. APPLICABILITY OF USER FEES TO GERIATRIC LABELING

SUPPLEMENTS

The Prescription Drug User Fee Act of 1992 as amended by the Food and Drug Administration

Modernization Act of 1997 provides no specific waivers of user fees for geriatric labeling

supplements, although a supplement may qualify for a waiver based on one or more of the grounds

for granting waivers listed in section 736(d) of the Federal Food, Drug, and Cosmetic Act (the

Act) (21 U.S.C. 379h(d)). It is expected, however, that very few geriatric labeling supplements

will require the payment of user fees because they will not require clinical data for approval, and

only supplements for which clinical data are required for approval are assessed fees. 

Manufacturers should contact the appropriate review division if there is any question regarding a

specific submission. The review division will determine whether approval of a specific geriatric

labeling supplement requires clinical data.13 Supplements that require clinical data are normally

liable for user fees and, therefore, must be covered by either a fee or a waiver, unless otherwise

excluded (section 736(a)(1) of the Act). Supplements that do not require clinical data are

acceptable for consideration for filing without payment of a fee. Supplements that contain clinical

data not required for approval because the supplement does not propose to modify statements in

the existing approved labeling would generally not be assessed a user fee. For example, most

' 201.57(f)(10)(ii)(A) and (B) supplements would not pay a fee.

Supplements that lessen or remove WARNINGS, PRECAUTIONS, or CONTRAINDICATIONS

relative to the geriatric population should be supported by data. If those data meet the definition of

clinical data for purposes of assessing user fees, the supplement will likely be assessed a user fee.

VIII. QUESTIONS REGARDING 21 CFR 201.57(f)(10)

Questions regarding any aspect of the implementation of the geriatric labeling final rule that are not

addressed in this guidance should be directed to CDER or CBER as follows:

• CDER Executive Secretariat at FAX 301-594-5493 or by mail to CDER Executive Secretariat,

HFD-006, 5600 Fishers Lane, Rockville, Maryland 20857, or

• CBER, Office of Communication, Training and Manufacturers Assistance, HFM-40, CBER,

FDA, 1401 Rockville Pike, Rockville, MD 20852-1448. 

Questions regarding specific applications should be directed to the division where the application

resides.

 

13 FDA recently published a draft guidance for industry entitled Separate Marketing Applications and Clinical Data for

Purposes of Assessing User Fees (66 FR 11175, February 22, 2001). Until this guidance is issued in final form, questions

concerning the definition of clinical data for user fee purposes should be directed to the User Fee Staff (CDER) at 301-594-

2041.