J:\!Guidanc\7113dft 

9/18/2006 

Guidance for Industry 

Public Availability of Labeling 

Changes in “Changes Being 

Effected” Supplements 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact (CDER) Meredith Francis 301-594-2041. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

September 2006 

Labeling 
J:\!Guidanc\7113dft 

9/18/2006 

Guidance for Industry

Public Availability of Labeling 

Changes in “Changes Being 

Effected” Supplements 

Additional copies 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 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

September 2006 

Labeling 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

J:\!Guidanc\7113dft 

9/18/2006 

TABLE OF CONTENTS 

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

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

III. DISCUSSION ....................................................................................................................... 2 
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1

Guidance for Industry1

Public Availability of Labeling Changes 

in “Changes Being Effected” Supplements 

This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 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. You can use an alternative approach if the approach satisfies the requirements of 

the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

the appropriate number listed on the title page of this guidance. 

I. INTRODUCTION 

This guidance announces to holders of a new drug application (NDA), an abbreviated new drug 

application (ANDA), or a biologics license application (BLA), who intend to submit a “Changes 

Being Effected” supplement (CBE supplement) to make a postapproval labeling change, that 

FDA will make labeling revisions identified in a CBE supplement publicly available upon 

receipt of the supplement by FDA.2 This guidance does not have any bearing on supplements 

that relate to chemistry, manufacturing, and controls changes. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

II. BACKGROUND 

FDA has begun an initiative to facilitate computerized access to drug information by consumers, 

pharmacists, and healthcare providers so that they will have faster and more comprehensive 

 

1

 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at the Food ad Drug 

Administration. 

2

 While the FDA will make labeling revisions submitted via a CBE supplement publicly available when they are 

received by the FDA, this action should not be construed as an endorsement of the revised labeling by the FDA. As 

noted in section III, after revised labeling is submitted, the FDA carefully reviews the proposed change and then 

either approves it or sends a letter identifying the deficiencies with the proposed change. Of particular note, the 

Agency will not permit a labeling change that would misbrand the product (see footnote 4). 
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2

access to drug information. As part of this initiative, the Agency has been involved in an 

initiative known as DailyMed. DailyMed is a computerized repository of a broad array of drug 

information, which is maintained by the National Library of Medicine. Among other things, 

DailyMed contains the information referred to as “content of labeling,” which includes all the 

information found in prescription drug labeling and over-the-counter (OTC) drug facts labeling, 

including all text, tables, and figures (see 21 CFR 314.50(l)(i)). To maximize its ability to serve 

as a useful resource to consumers, pharmacists, and healthcare providers, DailyMed must contain 

the most up-to-date and comprehensive drug information available. This guidance discusses 

FDA policy with regard to the timing of our release of revised drug labeling information. 

 

Sections 314.70 and 601.12 (21 CFR 314.70 and 601.12) of FDA’s regulations describe the types 

of supplemental applications that must be submitted to FDA to effect a labeling change to 

approved NDAs, ANDAs, and BLAs. Certain types of changes to labeling must receive FDA 

approval before the changes are implemented. These include all labeling changes that do not fall 

under § 314.70(c)(6)(iii), (d)(2)(ix), or (d)(2)(x), or under § 601.12(f)(2) or (f)(3). Other changes 

may be implemented by a sponsor upon the Agency’s receipt of a CBE supplement (§§ 

314.70(c)(6)(iii) and 601.12(f)(2)(i)). Under §§ 314.70(c)(6)(iii) and 601.12(f)(2)(i), the labeling 

changes appropriate for CBE supplements are those that: (1) add or strengthen a 

contraindication, warning, precaution, or adverse reaction; (2) add or strengthen a statement 

about abuse, dependence, psychological effect, or overdosage; (3) add or strengthen an 

instruction about dosage and administration that is intended to increase the safe use of the 

product; (4) delete false, misleading, or unsupported indications for use or claims for 

effectiveness; or (5) normally require a supplement submission and approval before distribution 

of the product and that FDA specifically requests be submitted under these provisions.3

 

III. DISCUSSION 

After a CBE supplement is submitted, FDA reviews the proposed change and either approves it 

or sends a letter identifying the deficiencies with the proposed change.4 Historically, most 

sponsors have implemented the proposed labeling changes at the time of, or shortly after, the 

Agency’s receipt of the CBE supplement. However, some have delayed implementation until 

they receive FDA feedback before implementing any change. 

In the past, FDA has not made any labeling change proposed in a CBE supplement publicly 

available until it has been approved. However, this policy could lead to situations where a 

 

3

 As explained in the final rule, “Requirements on Content and Format of Labeling for Human Prescription Drug and 

Biological Products,” that we published in the Federal Register on January 24, 2006 (71 FR 3922), a sponsor may 

not use a CBE supplement to change the “Highlights of Prescribing Information” section except for editorial or 

similar minor changes. For a more complete discussion on this point, see 71 FR at 3932 and 3934. 

4

 Congress has charged FDA with ensuring, among other things, that drugs sold in the United States are not 

misbranded (21 U.S.C. 331(a), (b), and (k); 321(n); 352; and 355(c) and (d)(7)). Consistent with the Federal Food, 

Drug, and Cosmetic Act, FDA will not permit a change to labeling that would misbrand the product. For example, 

FDA would not allow a change to labeling to add a warning in the absence of reasonable evidence of an association 

between the product and an adverse event. 
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company, in compliance with the regulations, is distributing labeling that contains updated safety 

information while FDA is not making the updated version of the labeling available. 

To avoid this situation and to facilitate the DailyMed initiative, FDA wants to make the most 

current labeling submitted to FDA available to healthcare practitioners and the public. 

Therefore, FDA is announcing its intention to change its practice with regard to making labeling 

changes submitted in CBE supplements -- but not in prior approval supplements -- publicly 

available. 

This guidance announces that the Agency will make the revised labeling proposed in a CBE 

supplement publicly available on its Web site and through the DailyMed shortly after the CBE 

supplement is received and before FDA has necessarily reviewed or approved it. If, after 

reviewing the CBE supplement, FDA decides it should not be approved, FDA will either (1) 

remove the labeling submitted with the CBE supplement from the FDA Web site and from the 

DailyMed and replace that labeling with the previous labeling or (2) recommend the sponsor 

amend its labeling and, after the sponsor submits the amended labeling, post this amended 

labeling on FDA’s Web site and provide it to the DailyMed promptly.5

Given this new procedure, we recommend that a sponsor not submit a CBE supplement to FDA 

until the sponsor is ready to distribute the labeling that it proposes in that CBE supplement. FDA 

will consider the submission of a CBE supplement to be consent by the sponsor to post the 

proposed labeling on FDA’s Web site and on the DailyMed. The Agency welcomes discussions 

with sponsors before they submit a CBE supplement. 

 

5

 Nothing in this guidance is intended to expand the circumstances in which an applicant may effect labeling 

changes via a CBE supplement, and particularly, those pertaining to generic drugs.