Safety Labeling Changes (Section 505(o)(4) of the FD&C Act)-- Rebuttal Statemen

Guidance for Industry
Safety Labeling Changes —
Implementation of
Section 505(o)(4) of
the FD&C Act

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)
July 2013
Drug Safety

OMB Control Number 0910-0734
Expiration Date: 03/31/2016
(Expiration date will be updated periodically.)
See additional PRA statement in section VII of this guidance.

Guidance for Industry
Safety Labeling Changes —
Implementation of
Section 505(o)(4) of the
FD&C Act
Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
10903 New Hampshire Ave.
Silver Spring, MD 20993-0002
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/or
Office of Communication, Outreach and
Development, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

(Phone) 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)
July 2013
Drug Safety

TABLE OF CONTENTS

I.

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 2

A.

Past Practice ................................................................................................................................... 2

B.

New FDAAA Authorities and Requirements .............................................................................. 3

III.
A.

IMPLEMENTATION OF SAFETY LABELING CHANGES UNDER FDAAA...... 3
What is New Safety Information?.................................................................................................. 3

1. What Does New Safety Information Mean? ................................................................................... 3
2. How Does FDA Learn About New Safety Information? .................................................................. 4
3. How Will FDA Evaluate the New Safety Information?.................................................................... 4
B. What Types of Safety Labeling Changes Could Be Required Under Section 505(o)(4)?........ 5

IV.

PROCEDURES ................................................................................................................. 6

A.

How Will FDA Notify Application Holder(s) of Required Safety Labeling Changes?............ 6

B.

How Should Application Holders Respond to a Notification Letter? ....................................... 7

C.

How Will FDA Review the Required Labeling Supplement or Rebuttal Statement? ............. 8

1. Meaning of Promptly Review and Act............................................................................................. 8
a. Labeling Supplements............................................................................................................... 8
b. Rebuttal Statements .................................................................................................................. 9
2. Additional Information on Review Procedures.............................................................................. 10
a. 30-Day Discussion Periods and Extensions............................................................................ 10
b. Failure to Respond to a Notification Letter ............................................................................ 10
c. Labeling Change Notifications for ANDAs with a Marketed NDA RLD.............................. 11
3. Additional Information on Review Procedures for Safety Labeling Changes that Affect More than
One Application.................................................................................................................................. 11
D. How Will FDA Issue an Order for Labeling Changes?............................................................ 12
E.

When Should New Labeling Be Available? ............................................................................... 13

F.

Will Safety Labeling Changes Letters Be Disclosed? ............................................................... 13

V.

DISPUTE RESOLUTION ............................................................................................. 13

VI.

ENFORCING REQUIREMENTS FOR SAFETY LABELING CHANGES ........... 14

VII.

PAPERWORK REDUCTION ACT OF 1995.............................................................. 15

APPENDIX A: EXAMPLES OF SOURCES OF NEW SAFETY INFORMATION ......... 16
GLOSSARY................................................................................................................................. 17

Contains Nonbinding Recommendations*

Guidance for Industry1
Safety Labeling Changes — Implementation of Section 505(o)(4) of
the Federal Food, Drug, and Cosmetic Act

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.** 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.
** Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21
CFR 314.70 and 601.12, it does have binding effect. If you have any questions about the effect of any
portion of this guidance, contact Kristen Everett, Center for Drug Evaluation and Research, Food and
Drug Administration, 10903 New Hampshire Ave., Building 22, room 6484, Silver Spring, MD 20993.

I.

INTRODUCTION

This guidance provides information on the implementation of section 505(o)(4) of the Federal
Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(o)(4)), which was added by section
901 of the Food and Drug Administration Amendments Act of 2007 (FDAAA). Section
505(o)(4) authorizes FDA to require certain drug and biological product application holders to
make safety-related labeling changes based on new safety information that becomes available
after approval of the drug or biological product.
Section 505(o)(4) of the Act authorizes FDA to require safety labeling changes for the following
products:
 Prescription drug products with an approved new drug application (NDA) under section
505(b) of the Act
 Biological products with an approved biologics license application (BLA) under section
351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262)
 Prescription drug products with an approved abbreviated new drug application (ANDA)
under section 505(j) of the Act, if the NDA reference listed drug (RLD) is not currently
marketed
The safety labeling changes provisions in section 505(o)(4) apply to the above-listed products,
including products that are not marketed, unless approval of the NDA, BLA, or ANDA has been
withdrawn in the Federal Register.
1

This guidance has been prepared by the FDAAA Title IX Working Group in the Center for Drug Evaluation and
Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug
Administration.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
1

Contains Nonbinding Recommendations*

Section 505(o)(4) does not apply to nonprescription (over-the-counter) drugs approved under an
NDA or ANDA or to marketed unapproved drugs. 2
This guidance does not address labeling supplements submitted voluntarily by an application
holder. Application holders may submit labeling supplements for review at any time and without
prior notification to FDA.
FDA’s guidance documents, in general, 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. Insofar as this guidance adjusts reporting categories pursuant to section 506A of the
FD&C Act and 21 CFR 314.70 and 601.12, it does have binding effect. If you have any
questions about the effect of any portion of this guidance, contact Kristen Everett, Center for
Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Building 22, room 6484, Silver Spring, MD 20993.
II.

BACKGROUND

Before the enactment of FDAAA, FDA had the ability to request safety-related changes to
the labeling of approved drug products. Upon the enactment of FDAAA, FDA received
express authority to require safety labeling changes in certain circumstances as described
in this guidance.
A.

Past Practice

In the past, FDA requested that holders of applications for approved products make labeling
changes related to safety to address serious risks. FDA typically learned of the potential for such
serious risks from a variety of sources, including FDA’s adverse events reporting systems (see
list of sources in Appendix A). In most cases, application holders responded to these requests for
labeling changes by negotiating appropriate language with FDA staff to address the concerns and
then submitting a supplement or amended supplement to obtain approval of the changes.
Negotiations were often protracted, and FDA had few tools at its disposal to end negotiations and
require the changes.
Before FDAAA, if the application holder did not respond to FDA’s request or did not agree with
the requested labeling changes, FDA could take the following actions:

2

Section 505(o)(4) of the FD&C Act does not apply to unapproved drugs, which do not, by definition, have
approved labeling. However, FDA may prioritize action against unapproved drugs for which safety issues have
been identified. When FDA becomes aware of the need for safety labeling changes that could affect unapproved
drugs, the responsible review division in the Office of New Drugs (OND) will contact the Unapproved Drugs
Coordinator in the Immediate Office, OND, and the Office of Unapproved Drugs and Labeling Compliance
(OUDLC) to initiate appropriate actions.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
2

Contains Nonbinding Recommendations*


FDA could initiate proceedings to withdraw approval of the drug 3 — an action not normally
desirable if some patients were benefitting from the drug despite its risks.



FDA could notify the public about the safety information through mechanisms such as Public
Health Advisories or notifications on the FDA web site describing the safety information and
the need for labeling changes.



If in FDA’s judgment the absence of the new safety information from the drug’s label
rendered the product misbranded, FDA could take appropriate enforcement action.

Congress recognized the limitations of FDA’s authority in this area and, in FDAAA, gave FDA
new authorities to require safety labeling changes in certain circumstances.
B.

New FDAAA Authorities and Requirements

On September 27, 2007, the President signed FDAAA (Public Law 110-85). Section 901 of
Title IX of FDAAA amended the FD&C Act by adding new section 505(o). Section 505(o)(4)
authorizes FDA to require and, if necessary, order labeling changes if FDA becomes aware of
new safety information that FDA believes should be included in the labeling of the drug. Section
505(o)(4) of the FD&C Act imposes time frames for application holders to submit and for FDA
staff to review such changes, and gives FDA new enforcement tools to bring about timely and
appropriate safety labeling changes.

III.

IMPLEMENTATION OF SAFETY LABELING CHANGES UNDER FDAAA

The following sections answer key questions about the implementation of the safety
labeling changes provisions that were added to the FD&C Act by FDAAA.
A.

What is New Safety Information?
1.

What Does New Safety Information Mean?

Section 505(o)(2)(C) of the FD&C Act states that, for the purposes of section 505(o), the phrase
new safety information has the meaning given in section 505-1(b) of the FD&C Act (21 U.S.C.
355-1(b)), which defines new safety information as “information derived from a clinical trial, an
adverse event report, a postapproval study (including a study under section 505(o)(3)), peerreviewed biomedical literature, data derived from the postmarket risk identification and analysis
system under section 505(k); or other scientific data deemed appropriate by [FDA]” about:


“A serious risk or an unexpected serious risk associated with use of the drug that [FDA]
has become aware of (that may be based on a new analysis of existing information)
since the drug was approved, since the risk evaluation and mitigation strategy (REMS)
was required, or since the last assessment of the approved [REMS] for the drug”
(emphasis added), or

3

For the purposes of this guidance, all references to drugs mean human drugs, including biological products,
regulated by CDER or CBER unless otherwise specified.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
3

Contains Nonbinding Recommendations*


“The effectiveness of the approved [REMS] for the drug obtained since the last
assessment of [the REMS].”

The phrases serious risk and unexpected serious risk are also defined in section 505-1(b) of the
FD&C Act and are included in the Glossary at the end of this guidance.
It is FDA’s view that the statutory definition of new safety information is broad to enable FDA to
require application holders to add information about serious risks to the labeling of a drug when
the Agency determines that such information should be included.
2.

How Does FDA Learn About New Safety Information?

FDA may learn about new safety information from many sources, including, but not limited to,
those listed in Appendix A. Once FDA has learned about the potential for new safety
information, FDA may derive new safety information through various means, including, but not
limited to, the following:


A new analysis of existing information



An assessment of the risks and benefits of the drug as it pertains to a new use of the drug,
a new indication for the drug, or the use of the drug in a new population



Information on the effectiveness of a previously approved REMS obtained since the last
assessment of that REMS
3.

How Will FDA Evaluate the New Safety Information?

FDA will form a multidisciplinary team to evaluate information that may be new safety
information that should be incorporated into a drug’s labeling under section 505(o)(4). 4 The
composition of the team will vary depending on the nature of the safety concern. Within the
Center for Drug Evaluation and Research (CDER), the relevant review division(s) from Office of
New Drugs will be included, and the Office of Surveillance and Epidemiology (OSE), the Office
of Generic Drugs (OGD), the Unapproved Drugs Coordinator, and the Office of Unapproved
Drugs and Labeling Compliance (OUDLC) may also be notified, as appropriate. Within the
Center for Biologic Evaluation and Research (CBER), staff in the appropriate product office, the
Office of Biostatistics and Epidemiology, and others as warranted will work together. The
team’s discussions and evaluations of the new safety information may include, but are not
limited to, presentations at internal FDA meetings, Drug Safety Oversight Board meetings, or
Advisory Committee meetings. More information about FDA’s policies and procedures for drug
safety issues is available in several Manuals of Policies and Procedures (MAPPs). 5 Public
4

If the safety information is relevant to more than one drug, the multidisciplinary review team will identify the
affected applications and include staff from all relevant review divisions and offices. Review of new safety
information that is relevant to more than one drug will follow the same procedures as for new safety information that
is relevant only to an individual drug.
5

See Manual of Policies and Procedures (MAPP) 6700.7, Safety Labeling Changes Under Section 505(o)(4) of the
FD&C Act; MAPP 4121.2, Tracking of Significant Safety Issues in Marketed Drugs — Use of the DARRTS

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
4

Contains Nonbinding Recommendations*
communication about drug safety issues is further described in a separate guidance. 6
B.

What Types of Safety Labeling Changes Could Be Required Under Section
505(o)(4)?

FDA expects that information that meets the standard of new safety information that should be
included in labeling, thereby triggering safety labeling changes under section 505(o)(4),
generally will include, but is not limited to, information that would be described in new or
revised language in the following sections of the prescribing information:






BOXED WARNINGS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
DRUG INTERACTIONS
ADVERSE REACTIONS

FDA expects that labeling changes that address new safety information about serious risks
associated with a drug, including those that affect a class of drugs, will be required under the
authority of section 505(o)(4) of the FD&C Act.
If certain changes to the prescribing information are required under section 505(o)(4), other
changes to the product labeling, including changes to an existing Medication Guide or creation
of a new Medication Guide, may also be required to ensure that all labeling for the product is
consistent. Medication Guides are part of the product labeling and are also potential elements of
a REMS.
Changes to prescribing information required under section 505(o)(4) may necessitate changes to
REMS documents and REMS materials. When that is the case, these changes should be
submitted as REMS modifications pursuant to section 505-1 of the FD&C Act.
FDA does not anticipate that all labeling changes that may be related to safety will be required
and reviewed under section 505(o)(4) of the FD&C Act. For other labeling changes, application

Tracked Safety Issue (TSI), and MAPP 6700.9, FDA Posting of Potential Signals of Serious Risks Identified by the
Adverse Event Reporting System. FDA MAPPs are available at
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProce
dures/default.htm.
6

See FDA guidance for industry on Drug Safety Information—FDA’s Communication to the Public.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072281.pdf.
FDA guidances are available on FDA’s guidance web page at
http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234622.htm.

We update guidance documents periodically. To make sure you have the most recent version of a guidance, check
the Guidances (Drug) Web page.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
5

Contains Nonbinding Recommendations*
holders may continue to submit labeling supplements using standard procedures (See 21 CFR
314.70 and 601.12).
FDA expects that information that results in changes made only to the ADVERSE REACTIONS
section, but does not warrant inclusion in other sections of labeling (such as WARNINGS AND
PRECAUTIONS), would not normally trigger required safety labeling changes under section
505(o)(4). In addition, minor revisions to risk information that is already in the labeling (e.g.,
updating information about the well known risk of neutropenia in the label of a cytotoxic
chemotherapy drug or updating information about the well known risk of hypoglycemia for an
antidiabetic agent) may not trigger required safety labeling changes under section 505(o)(4) in all
circumstances. FDA also anticipates that minor editorial changes to any part of the labeling
would not trigger required safety labeling changes under section 505(o)(4).
IV.

PROCEDURES

A.

How Will FDA Notify Application Holder(s) of Required Safety Labeling Changes?

Once FDA has determined that there is new safety information that should be included in
labeling, FDA plans to send a safety labeling change notification letter (notification letter) to the
application holder(s). A holder of an approved NDA, BLA, or ANDA without a marketed NDA
reference listed drug (RLD) will be notified and required to make the safety labeling changes,
unless approval of the application has been formally withdrawn in a Federal Register notice. 7 If
the new safety information applies to more than one application holder, FDA plans to send a
letter on the same day to each holder of an approved NDA, BLA, and/or ANDA without a
marketed NDA RLD.
FDA will include the following information in the notification letter:
 The source from which the new safety information was derived
 A brief description of what the new safety information is about (a serious risk or an
unexpected serious risk associated with the use of the drug, or the effectiveness of the
REMS)
 Proposed labeling changes
 Instructions regarding the circumstances in which the application holder should
respond by submitting proposed labeling changes as a prior approval supplement 8 or
as a changes-being-effected supplement 9
7

Requirements under section 505(o)(4) apply to NDAs, BLAs, and ANDAs without a currently marketed reference
listed drug approved under an NDA, including discontinued products, unless approval of an application has been
withdrawn in the Federal Register. Therefore, requirements described in a safety labeling change notification letter
apply unless approval of the application has been withdrawn in the Federal Register.

8

A prior approval supplement proposes changes that require supplement submission and approval prior to the
distribution of the product with those changes. See 21 CFR 314.70(b) and 601.12(f)(1).

9

A supplement - changes-being-effected (CBE-0) proposes changes that do not require FDA approval prior to
distribution of the product; for such changes, the application holder may distribute the product with the changes
upon FDA’s receipt of the supplement (see 21 CFR 314.70(c)(6) and 601.12(f)(2)).

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
6

Contains Nonbinding Recommendations*

B.

How Should Application Holders Respond to a Notification Letter?

Section 505(o)(4)(B)(i) and (ii) states that, after receiving notification of the required safety
labeling changes, the application holder(s) must either:



submit a supplement with proposed labeling changes to reflect the new safety
information; or
notify FDA that it does not believe a labeling change is warranted and submit a statement
detailing the reasons why such a change is not warranted (a rebuttal statement).

If the application holder submits a supplement proposing labeling changes identical to those that
FDA included in the notification letter, the application holder may submit a supplement changes-being-effected (CBE-0). In all other situations, the application holder(s) should submit
a prior approval supplement to propose alternative labeling changes that reflect the new safety
information. As mentioned in section IV.A above, in the notification letter, FDA will provide
instructions regarding the circumstances in which the application holder should submit a
supplement - changes-being-effected (CBE-0) or a prior approval supplement.
It is FDA’s view that the labeling changes process under 21 CFR 314.70 and 601.12 continues to
apply to application holders 10 in situations in which the application holder becomes aware of
newly acquired information, including in circumstances that meet the criteria for submission of a
supplement - changes-being-effected (CBE-0). 11
Following notification, the labeling supplement or rebuttal statement must be submitted within
30 days (section 505(o)(4)(B)). FDA has interpreted within 30 days to mean within 30 calendar
days of the date that the notification letter is issued. FDA will generally forward copies of safety

10

To implement the statutory prohibition against marketing a misbranded product, 21 CFR 201.57(c)(6) requires
that prescription drug labeling be “revised to include a warning about a clinically significant hazard as soon as there
is reasonable evidence of a causal association with a drug” (see also sections 502(a),(f),(j), and (n) of the FD&C
Act).
Under existing FDA regulations, ANDA holders cannot make labeling changes through the formal supplement
process under 21 CFR 314.70 in all circumstances in which NDA holders can because an ANDA’s labeling must be
the same as the NDA RLD’s labeling (with some exceptions, as described in 21 CFR 314.94(a)(8)(iv)).
Accordingly, the changes-being-effected supplement process under 21 CFR 314.70(c) is not expressly available to
ANDA holders except to match the RLD labeling or to respond to FDA’s specific request to submit a labeling
change under this provision. ANDA holders, however, are obligated to provide FDA with information about
labeling concerns, including a concern that new information should be added to a product’s labeling. See 57 FR
17950, 17961 (April 28, 1992). An ANDA holder may submit a prior approval supplement to request a change to
product labeling, and “FDA will determine whether the labeling for the generic and [reference] listed drugs should
be revised” (57 FR 17950, 17961). ANDA holders also have a duty to inform FDA of certain adverse events in
compliance with postmarket reporting requirements, to develop written procedures for the surveillance, receipt,
evaluation, and reporting of postmarket adverse drug experiences and to annually report “information…that might
affect the safety, effectiveness, or labeling of the drug product” (see 21 CFR 314.80, 314.81, and 314.98).
11

See section 505(o)(4)(I) of the FD&C Act.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
7

Contains Nonbinding Recommendations*
labeling change letters (including notification letters and orders) by fax or e-mail so that they
will be received on the date the document is issued.
An application holder’s prior approval supplement may contain proposed edits or
counterproposals to the language recommended by FDA. When FDA notifies an application
holder that safety labeling changes are needed, FDA is aware of the new safety information that
the changes are intended to address. Therefore, application holders should provide explanations
(often referred to as “annotated labeling”) only for counterproposals or proposed edits to the
language recommended by FDA in the notification letter. 12
If FDA notifies an application holder that, under section 505(o)(4), a new Medication Guide
must be created, the application holder must respond within 30 days, as required by section
505(o)(4)(B). FDA recognizes that if a new Medication Guide is required and a Medication
Guide for the individual drug or its class does not already exist, it could be challenging to create
a Medication Guide that adequately describes risks and benefits in patient friendly language
within the submission timeframe (30 days) required under section 505(o)(4) of the FD&C Act.
In addition, Medication Guide language is generally derived from approved prescribing
information. Therefore, FDA may consider a request from the application holder to extend the
discussion period on a case-by-case basis.
C.

How Will FDA Review the Required Labeling Supplement or Rebuttal Statement?

Section 505(o)(4)(C) of the Act directs FDA to “promptly review and act upon” a safety labeling
changes supplement or rebuttal statement responding to a notification letter.
1.

Meaning of Promptly Review and Act

This section describes the process FDA intends to use to review labeling supplements and
rebuttal statements, the actions that FDA will take, and the time frame in which FDA expects to
take those actions.
a.

Labeling Supplements

When an application holder submits a labeling supplement, FDA’s review team will conduct a
preliminary review of the supplement, consider whether the proposed language in the
supplement can be approved or requires further discussion, and proceed as follows:


If the proposed language can be approved without changes, 13 FDA will approve the
supplement promptly and notify the application holder by sending a supplement approval

12

Including the proposed text of the label as a clean copy and as a marked up or track changes version facilitates
timely review and discussion of the counter proposed or edited language.
13

Language that can be approved without changes may include language that is identical to the language that FDA
included in the notification letter, or language that differs from what was included in the notification letter.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
8

Contains Nonbinding Recommendations*
letter. 14 For supplements that propose acceptable wording, FDA’s goal is to take action
within 30 calendar days of receipt of the supplement.


If the proposed revised language cannot be approved without changes, the Agency will
initiate a discussion period to review and discuss the proposed revisions (section
505(o)(4)(C)). The discussion period will begin on the date that FDA receives the
application holder’s submission and last no more than 30 calendar days (unless an extension
is warranted) (section 505(o)(4)(D)).



If the notification letter was issued for more than one application, and one or more
application holders in the class submit proposed language that differs from what FDA
included in the notification letter, FDA will inform all application holders that received a
notification letter that a discussion period will be initiated to review and consider alternative
wording that was submitted. The discussion period will begin on the date that FDA receives
the application holder’s submission and last no more than 30 calendar days (unless an
extension is warranted) (section 505(o)(4)(D)).

Within 15 calendar days of the conclusion of the 30-day discussion period (and any extension
period, if applicable), FDA will proceed as follows:


If FDA and the application holder reach consensus on the proposed labeling, FDA will notify
the application holder by sending a supplement approval letter.



If FDA does not agree with the application holder’s proposed labeling changes and FDA and
the application holder cannot reach consensus, under section 505(o)(4)(E), FDA can order
the application holder to make the required labeling changes (see section IV.E for further
discussion of safety labeling changes orders).
b.

Rebuttal Statements

Similar to the process for supplements, when an applicant submits a rebuttal statement, FDA’s
review team will conduct a preliminary review of the rebuttal statement, consider whether FDA
accepts the application holder’s reasons why labeling changes are not warranted or whether the
rebuttal statement requires further discussion, and proceed as follows:


If FDA accepts the application holder’s reasons why labeling changes are not warranted,
FDA will promptly notify the application holder. In such situations, FDA’s goal is to take
action within 30 calendar days of receipt of the rebuttal statement.



If FDA does not accept the application holder’s reasons why labeling changes are not
warranted, the Agency will initiate a discussion period (section 505(o)(4)(C)). The
discussion period would begin on the date that FDA receives the application holder’s
rebuttal statement and last no more than 30 calendar days (unless an extension is warranted)
(section 505(o)(4)(D)). If the sponsor agrees to submit a labeling supplement during the

14

Supplement approval letters for required safety labeling changes are posted on FDA’s web site, consistent with
FDA’s policy for all approval letters.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
9

Contains Nonbinding Recommendations*
discussion period, the supplement should be submitted before the end of the discussion
period (and any extension period, if applicable), and FDA will follow the procedure as
outlined above in IV.C.1.a.
Within 15 calendar days of the conclusion of the 30-day discussion period (and any extension
period, if applicable), FDA will proceed as follows:


If FDA and the application holder reach consensus on the reasons why labeling changes are
not needed, FDA will notify the application holder.



If FDA does not agree with the application holder’s rebuttal statement and FDA and the
application holder cannot reach consensus on the submission of a labeling supplement, under
section 505(o)(4)(E), FDA can order the application holder to make the required labeling
changes (see section IV.D for further discussion of safety labeling changes orders).
2.

Additional Information on Review Procedures

The following sections provide additional information on FDA’s review procedures for safety
labeling changes supplements or rebuttal statements responding to a notification letter.
a.

30-Day Discussion Periods and Extensions

As explained above in IV.C.1, if FDA does not agree with the wording in the submitted
supplement or the reasoning of the rebuttal statement, FDA must initiate discussions that do not
extend for more than 30 days after the receipt of the submission (section 505(o)(4)(C) and (D)).
Under section 505(o)(4)(D), FDA may extend the discussion period for more than 30 days, if
FDA determines that an extension of the discussion period is warranted. FDA expects that an
extension of the discussion period (usually for another 30 days) will be warranted when a 30-day
discussion period may not suffice to adequately address all outstanding issues (e.g., the labeling
change involves a drug class or the supplement contains significantly revised language). In such
cases, before the conclusion of the discussion period, FDA may notify the application holder in
writing that the 30-day discussion period has been extended and, when possible, briefly state the
reason(s) for the extension. FDA’s reasons may include, but are not limited to, the need to
consider and discuss the application holder’s alternative language, consider additional
information, obtain consensus at a higher level within CDER or CBER or among involved
offices, or receive input from the Drug Safety Oversight Board or an Advisory Committee.
FDA does not anticipate more than one extension to the 30-day discussion period for most
labeling changes.
b.

Failure to Respond to a Notification Letter

If the application holder does not submit a labeling supplement or a rebuttal statement within 30
calendar days of the date of the notification letter, the application holder will be considered to

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
10

Contains Nonbinding Recommendations*
have forfeited the review and discussion period, and FDA can issue an order directing that the
labeling be changed (see section IV.D for further discussion of safety labeling changes orders).
c.

Labeling Change Notifications for ANDAs with a Marketed NDA RLD

Holders of ANDAs with a marketed NDA RLD would usually be notified by OGD of the
required safety labeling changes after approval of the labeling supplement for the NDA RLD.
ANDA holders should submit the required labeling changes as a supplement- changes-beingeffected (CBE-0) within 30 days of the date of the written notification from FDA.
3.
Additional Information on Review Procedures for Safety Labeling Changes that
Affect More than One Application
a.

Labeling Supplements, Rebuttal Statements, and Discussion Period(s)

For class labeling changes, it is FDA’s policy that labeling decisions should wait until all
supplements and rebuttal statements submitted within 30 days of notification have been
reviewed. FDA intends to approve a labeling change common to all class members on the same
day unless there is a well-justified, scientific rationale to support different wording for different
drug labels. To carefully review supplements and rebuttal statements from all application
holders and to consider the differences and commonalities between products, FDA anticipates
that a 30-day extension of the discussion period may be warranted.
To enable consensus on wording of the labeling change, FDA may propose to the application
holders specific language to include in the labeling during the discussion period. If agreement is
reached, application holders should submit an amendment to their previously submitted
supplement, or submit supplement-changes-being-effected (CBE-0) if they previously submitted
a rebuttal statement, with the agreed-upon wording before the end of the discussion period.
If FDA does not agree with one or more application holder’s proposed labeling changes or
rebuttal statement, and FDA and the application holder(s) cannot reach agreement, under section
505(o)(4)(E), FDA can order the application holder(s) to make the required labeling changes (see
section IV.D for further discussion of safety labeling changes orders).
If FDA and the remaining application holders agree on the proposed labeling, FDA will notify
these application holders by sending supplement approval letters. An order issued to one or
more application holder(s) will not delay approval of labeling changes for the rest of the class.
For class labeling changes, FDA will send approval letters or Order letters, as needed, to all
affected application holders of NDAs, BLAs, and ANDAs without a marketed NDA RLD, on the
same day.
b.

Failure to Respond to a Notification Letter

One or more application holders in a class may fail to respond to the notification letter within the
required 30-day time frame, or may fail to respond at all, while others submit labeling

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
11

Contains Nonbinding Recommendations*
supplements or rebuttal statements within the required 30-day time frame. FDA will follow the
processes described in IV. C.2.b. for the application holders who do not respond (or do not
respond within the required time frame). If one or more application holders in a class fail to
respond (or fail to respond within the required time frame), it will not delay approval of required
safety labeling changes for the other application holders in the class that respond within the
required time frame.
D.

How Will FDA Issue an Order for Labeling Changes?

If, at the conclusion of the 30-day discussion period (or extension, if applicable), FDA
determines that the application holder’s proposed labeling changes do not adequately address the
new safety information or finds unacceptable the application holder’s reasons why the labeling
changes are not warranted, FDA can issue an order to change the product labeling (section
505(o)(4)(E)). FDA can also issue an order if a supplement or rebuttal statement is not
submitted within 30 calendar days of the date of the notification letter.
FDA anticipates that orders for labeling changes will be rare and that such actions will first
involve discussion with the appropriate CDER or CBER senior managers.
Order letters will be issued within 15 calendar days of the conclusion of the 30-day discussion
period (or extension, if applicable) (section 505(o)(4)(E)). FDA plans to include the following in
the order letters:







Approval of any sections of labeling on which the application holder and FDA reached
agreement during the discussion period
A Complete Response action for the sections of labeling on which the application holder
and FDA could not agree during the discussion period
A brief explanation why the application holder’s proposed labeling changes or rebuttal do
not adequately address the new safety information
An order to submit a changes-being-effected supplement within 15 calendar days of the
date of the order for specified changes to the sections of labeling on which the application
holder and FDA cannot agree (FDA plans to include specific wording for these required
labeling changes in the order letter)
Brief instructions explaining that within 5 calendar days of the date of the order letter,
instead of submitting a changes-being-effected supplement, the application holder may
appeal the order, through FDA’s formal dispute resolution process as described in 21
CFR 10.75 and the guidance for industry on Formal Dispute Resolution: Appeals Above
the Division Level 15 (section 505(o)(4)(F)) (see section V for further discussion of
dispute resolution procedures).

After the application holder submits the changes-being-effected supplement, FDA intends to
promptly review the supplement, and if it addresses the new safety information adequately as
15

This guidance is available on the Internet at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update guidance documents
periodically. To make sure you have the most recent version of a guidance, check the Guidances (Drug) Web page.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
12

Contains Nonbinding Recommendations*
directed, FDA will approve the supplement, generally within 15 calendar days of receipt
(section IV.D.1). As with other approval letters, the document will be posted on the FDA Web
site.
Under section 505(o)(4)(F), if the application holder neither submits a supplement within 15
calendar days of the date of the order nor initiates dispute resolution within 5 calendar days of
the date of the order, the application holder will be in violation of the statute. This may result in
enforcement actions, which are described in section VI.
E.

When Should New Labeling Be Available?

FDA expects that new approved labeling will be available on the application holder’s Web site
within 10 calendar days of approval of the labeling supplement, or FDA’s receipt of a changesbeing-effected labeling supplement. In addition, approved updates to labeling are posted on
FDA’s Web site. 16
FDA acknowledges that incorporating labeling changes into printed material included in drug
shipments usually requires more time than incorporating changes to a Web site. FDA intends to
issue guidance outlining its expectations regarding time frames for the availability of labeling
changes for printed package inserts, patient package inserts, and Medication Guides.
F.

Will Safety Labeling Changes Letters Be Disclosed?

Safety labeling changes notification letters that apply to more than one application will be posted
on FDA’s Web site to provide rapid communication to the public of a serious safety risk.
Notification letters that apply to a single application are considered confidential commercial
information and are not posted; however, the resulting supplement is approved and posted.
All safety labeling changes order letters may be posted on FDA’s Web site. 17
V.

DISPUTE RESOLUTION

An application holder may appeal an order to make a safety labeling change using the usual
dispute resolution procedures (guidance for industry on Formal Dispute Resolution: Appeals
Above the Division Level) 18 (see section 505(o)(4)(F) of the Act). The appeal should be
submitted as correspondence to the NDA, BLA, or ANDA.
Under section 505(o)(4)(F), the application holder must make its appeal of the order within 5
days of receiving that order. FDA has interpreted “5 days” to mean “5 calendar days.” Appeals
received by FDA later than 5 calendar days after the date that the order letter was received will
16

See http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

17

Safety labeling changes order letters are available at:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm189280.htm.
18

This guidance is available on the Internet at

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
13

Contains Nonbinding Recommendations*
not be entertained. Similarly, for appeals to higher levels, such as the Center Director,
application holders should appeal a written determination made by a previous level within 5
calendar days of receiving that determination. The dispute process will be considered to be
concluded if an appeal of a written determination is not received within this time frame.
At the conclusion of the dispute resolution process, if FDA determines that a labeling
supplement is required, the labeling supplement must be submitted within 15 days of the date of
that determination (section 505(o)(4)(G)). FDA has interpreted “15 days” to mean “15 calendar
days.” If the labeling supplement is not submitted within 15 days, the application holder will be
in violation of the statute.
VI.

ENFORCING REQUIREMENTS FOR SAFETY LABELING CHANGES

Section 902 of FDAAA gave FDA authority to enforce the section 505(o)(4) requirements for
safety labeling changes. If the responsible person 19 or, when applicable, the holder of the
approved application under section 505(j) neither submits a supplement within 15 calendar days
of the date of a safety labeling change order nor initiates dispute resolution within 5 days, the
responsible person or application holder will be in violation of section 505(o)(4) of the Act. In
addition, if at the conclusion of any dispute resolution process, the Secretary determines that a
supplement must be submitted and such supplement is not submitted within 15 days of the date
of the determination, the responsible person or application holder will be in violation of section
505(o)(4) of the Act.
Enforcement action could include one or more of the following:
● Charges under section 505 of the FD&C Act. A responsible person may not introduce or
deliver into interstate commerce the drug involved if the application holder is in violation of
section 505(o) safety labeling changes requirements (see section 505(o)(1) of the FD&C
Act).
● Misbranding charges. A drug is misbranded under section 502(z) of the FD&C Act (21
U.S.C. 352(z)) if the application holder for that drug violates safety labeling change
requirements.
● Civil monetary penalties. Under section 303(f)(4) of the FD&C Act (21 U.S.C.
333(f)(4)(A)), an application holder that violates safety labeling changes requirements may
be subject to civil monetary penalties of up to $250,000 per violation, but no more than $1
million for all violations adjudicated in a single proceeding. These penalties increase if the
violation continues more than 30 days after FDA notifies the application holder of the
violation. The penalties double for the following 30-day period and continue to double for
subsequent 30-day periods, up to $1 million per period and $10 million for all violations
adjudicated in a single proceeding. In determining the amount of a civil penalty, FDA will
consider the applicant’s efforts to correct the violation (see section 303(f)(4)(B) of the FD&C
Act).
19

Defined at section 505(o)(2)(A) of the Act.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
14

Contains Nonbinding Recommendations*
Such violations may also be subject to additional enforcement action, including but not limited
to, seizure of the product and injunction.
VII.

PAPERWORK REDUCTION ACT OF 1995

This guidance 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 expiration date of the OMB control number will be updated periodically.
The time required to complete this information collection is estimated to average 4hours per
response, including the time to review instructions, search existing data sources, gather the data
needed, and complete and review the information collection. Send comments regarding this
burden estimate or suggestions for reducing this burden to:
The Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg.22, Rm. 6303, Silver Spring, MD 209930002.
This guidance also refers to previously approved collections of information found in FDA
regulations. Specifically, the guidance describes: labeling supplements for NDAs, ANDAs, and
BLAs submitted under 21 CFR 314.70, 314.71, 314.97 and 601.12; and the content and format
of prescription drug labeling submitted under 21 CFR 201.56 and 201.57. These collections of
information are subject to review by OMB under the Paperwork Reduction Act and are approved
under OMB control numbers 0910-0001, 0910-0338, and 0910-0572. Section V of the guidance
refers to the guidance entitled “Formal Dispute Resolution: Appeals Above the Division Level,”
which describes collections of information approved under OMB control number 0910-0430.
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. The
OMB control number for this information collection is 0910-0638 (expires 3/31/16).

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
15

Contains Nonbinding Recommendations*
APPENDIX A: EXAMPLES OF SOURCES OF NEW SAFETY INFORMATION
FDA may learn of new safety information from various sources including, but not limited to:














Routine monitoring of Adverse Event Reporting System (AERS) or Vaccine Adverse Event
Reporting System (VAERS) in-boxes (by the CDER Office of Surveillance and
Epidemiology (OSE) or CBER Office of Biostatistics and Epidemiology (OBE) Safety
Evaluators)
Data mining of AERS or VAERS databases, either through routine practice or triggered by a
specific issue, by OSE and OBE
Systematic data mining of all division products
Safety-related data in a new drug application (NDA), biologics license application (BLA),
supplements, or investigational new drug application (IND)
FDA inspections and investigations, including postmarket adverse drug experience (ADE)
inspections
Reports received through established drug quality reporting systems
Medical literature submitted by application holders or external stakeholders or identified by
FDA staff
Submissions from an application holder, including but not limited to:
— Periodic safety reports, including periodic adverse drug experience reports (21 CFR
314.80(c)(2), 314.98(a)), periodic adverse experience reports (21 CFR 600.80(c)(2)), and
periodic safety update reports (PSURs)
— Reports of preclinical, toxicological, or pharmacokinetic studies, clinical trials, or
observational studies
— Studies and clinical trials that may or may not have been conducted as postmarket
requirements or commitments or with FDA’s knowledge
— REMS assessments as required under section 505-1 of the FD&C Act
— Field alert reports (FARs) as required under 21 CFR 314.81(b)(1) and 314.98(c) or
Postmarketing 15-day Alert reports as required under 21 CFR 314.80(c)(1), 314.98(a),
and 600.80(c)(1)
— Reports of fatalities related to blood collection or transfusion, as required under 21 CFR
606.170(b)
— Biological product deviation reports as required under 21 CFR 600.14 and 606.171
— Annual reports as required under 21 CFR 314.81(b)(2) and 314.98(c)
Communications with Centers for Disease Control and Prevention (CDC) about CDC’s
analysis of VAERS reports and the Vaccine Safety Datalink database
Communications with foreign regulatory authorities regarding postmarket analysis of adverse
reactions associated with drugs approved in their countries
Meta-analyses of safety information, or new analyses of previously submitted information

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
16

Contains Nonbinding Recommendations*
GLOSSARY
The following definitions of terms are from section 505-1(b) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 355-1(b)).
New safety information with respect to a drug, means information derived from a clinical trial,
an adverse event report, a post-approval study (including a study under section 505(o)(3)), or
peer-reviewed biomedical literature; data derived from the postmarket risk identification and
analysis system under section 505(k); or other scientific data deemed appropriate by the
Secretary (of Health and Human Services) about —
(A) a serious risk or unexpected serious risk associated with use of the drug that the
Secretary has become aware of (that may be based on a new analysis of existing
information) since the drug was approved, since the risk evaluation and mitigation
strategy was required, or since the last assessment of the approved risk evaluation and
mitigation strategy for the drug; or
(B) the effectiveness of the approved risk evaluation and mitigation strategy for the drug
obtained since the last assessment of such strategy.
Adverse drug experience means any adverse event associated with the use of a drug in humans,
whether or not considered drug related, including—
(A) an adverse event occurring in the course of the use of the drug in professional
practice;
(B) an adverse event occurring from an overdose of the drug, whether accidental or
intentional;
(C) an adverse event occurring from abuse of the drug;
(D) an adverse event occurring from withdrawal of the drug; and
(E) any failure of expected pharmacological action of the drug.
Serious adverse drug experience is an adverse drug experience that —
(A) results in —
(i) death;
(ii) an adverse drug experience that places the patient at immediate risk of death
from the adverse drug experience as it occurred (not including an adverse drug
experience that might have caused death had it occurred in a more severe form);
(iii) inpatient hospitalization or prolongation of existing hospitalization;
(iv) a persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions; or
(v) a congenital anomaly or birth defect; or
(B) based on appropriate medical judgment, may jeopardize the patient and may require a
medical or surgical intervention to prevent an outcome described under subparagraph
(A).
Serious risk means a risk of a serious adverse drug experience.
Signal of a serious risk means information related to a serious adverse drug experience
associated with use of a drug and derived from —

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
17

Contains Nonbinding Recommendations*
(A) a clinical trial;
(B) adverse event reports;
(C) a postapproval study, including a study under section 505(o)(3);
(D) peer-reviewed biomedical literature;
(E) data derived from the postmarket risk identification and analysis system under section
505(k)(4);
(F) other scientific data deemed appropriate by the Secretary.
Unexpected serious risk means a serious adverse drug experience that is not listed in the
labeling of a drug, or that may be symptomatically or pathophysiologically related to an
adverse drug experience identified in the labeling, but differs because of greater severity,
specificity, or prevalence.

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the FD&C Act and 21 CFR
314.70 and 601.12, it does have binding effect.
18