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.   IMPLEMENTATION OF SAFETY LABELING CHANGES UNDER FDAAA......3 
A.   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* 
1
Guidance for Industry  
 
Safety Labeling Changes  Implementation of Section 505(o)(4) of 
the Federal Food, Drug, and Cosmetic Act  
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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. 
 
FDAs guidance documents, in general, do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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 FDAs 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 FDAs 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 drug3  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 FDAs judgment the absence of the new safety information from the drugs label 
rendered the product misbranded, FDA could take appropriate enforcement action. 
Congress recognized the limitations of FDAs 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)), 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 [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 FDAs 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 drugs 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 
teams 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 FDAs 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 InformationFDAs Communication to the Public.  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072281.pdf.  
FDA guidances are available on FDAs 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 supplement8 or 
as a changes-being-effected supplement9 
                                                 
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 FDAs 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 FDAs view that the labeling changes process under 21 CFR 314.70 and 601.12 continues to 
apply to application holders10 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 ANDAs labeling must be 
the same as the NDA RLDs 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 FDAs 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 products 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 holders 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, FDAs 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, FDAs 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 holders 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 holders 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 holders 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, FDAs 
review team will conduct a preliminary review of the rebuttal statement, consider whether FDA 
accepts the application holders reasons why labeling changes are not warranted or whether the 
rebuttal statement requires further discussion, and proceed as follows:   
 
  If FDA accepts the application holders reasons why labeling changes are not warranted, 
FDA will promptly notify the application holder.  In such situations, FDAs goal is to take 
action within 30 calendar days of receipt of the rebuttal statement. 
  If FDA does not accept the application holders 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 holders 
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 FDAs web site, consistent with 
FDAs 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 holders 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 FDAs 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.  FDAs reasons may include, but are not limited to, the need to 
consider and discuss the application holders 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-being-
effected (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 FDAs 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 holders 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 holders proposed labeling changes do not adequately address the 
new safety information or finds unacceptable the application holders 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 holders 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 FDAs formal dispute resolution process as described in 21 
CFR 10.75 and the guidance for industry on Formal Dispute Resolution: Appeals Above 
the Division Level15 (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 holders Web site 
within 10 calendar days of approval of the labeling supplement, or FDAs receipt of a changes-
being-effected labeling supplement.  In addition, approved updates to labeling are posted on 
FDAs 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 FDAs 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 FDAs 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 person19 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 applicants 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 20993-
0002. 
 
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 FDAs 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 CDCs 
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