Risk Evaluation and 
Mitigation Strategies:  
Modifications and Revisions 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
June 2020 
Drug Safety 
 
Revision 2 
 
   
Risk Evaluation and 
Mitigation Strategies:  
Modifications and Revisions 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD  20993-0002  
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https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
and/or 
 
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Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
 
 
 
 
 
 
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) 
 
June 2020 
Drug Safety 
 
Revision 2 
 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  POLICY ............................................................................................................................. 3 
A.  REMS Revisions ............................................................................................................................. 4 
B.  REMS Modifications ..................................................................................................................... 5 
1. Minor REMS Modifications ............................................................................................................. 5 
2. Major REMS Modifications ............................................................................................................. 7 
IV.  SUBMISSION PROCEDURES ..................................................................................... 10 
A.  General Considerations ............................................................................................................... 11 
B.  Content and Format .................................................................................................................... 11 
1. Administrative Content .................................................................................................................. 11 
2. REMS History ................................................................................................................................ 12 
3. Adequate Rationale for REMS Modifications ................................................................................ 12 
C.  Submission of Proposed REMS Changes................................................................................... 13 
V.  FDA TIME FRAMES FOR REMS CHANGES .......................................................... 14 
A.  REMS Revisions ........................................................................................................................... 15 
B.  Minor REMS Modifications ........................................................................................................ 15 
C.  Major REMS Modifications ........................................................................................................ 15 
D.  REMS Modification Due to Safety Labeling Changes ............................................................. 15 
E.  Submissions Containing More Than One Type of REMS Change ......................................... 16 
F.  REMS Modifications Included in Other Submissions .............................................................. 16 
G.  Posting Revised and Modified REMS on the FDA Website ..................................................... 16 
VI.  CONTACT INFORMATION ........................................................................................ 16 
APPENDIX: SUBMISSION PROCEDURES FOR CHANGES TO APPROVED REMS . 18 
  Contains Nonbinding Recommendations 
Risk Evaluation and Mitigation Strategies:   
Modifications and Revisions 
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance provides information on how the FDA defines the types of changes to an approved 
risk evaluation and mitigation strategy (REMS), how application holders2 should submit changes 
to an approved REMS,3 and how the FDA will process submissions from application holders for 
changes to REMS.  Specifically, this guidance provides information, as described in section 505-
1(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), on what types of changes to 
REMS will be considered modifications of the REMS and what types of changes will be 
considered revisions of the REMS (changes that may be implemented following notification to 
the FDA).4  This guidance is issued pursuant to section 505-1(h)(2)(A)(ii), (iii), and (iv) of the 
FD&C Act and section 1132(c) of Public Law 112-144. 
 
                                                 
1 This guidance has been prepared by the Office of New Drugs, the Office of Surveillance and Epidemiology, and 
the Office of Compliance in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center 
for Biologics Evaluation and Research at the Food and Drug Administration. You may submit comments on this 
guidance at any time.  Submit comments to Docket No. FDA-2014-D-1747 (available at 
https://www.regulations.gov/docket?D=FDA-2014-D-1747). 
 
2 Under section 505-1(b)(7) of the Federal Food, Drug, and Cosmetic Act, the term responsible person means the 
person submitting a covered application or the holder of the approved such application.  For ease of reference, this 
guidance refers to a responsible person as an application holder.  
 
3 The REMS is the enforceable document that describes the elements that an application holder is required to 
implement to mitigate a specific, serious risk listed in the labeling of the drug.  All proposed materials that are 
included as part of the REMS (e.g., communication and educational materials, Medication Guide, patient package 
insert, enrollment forms, prescriber and patient agreements) are also approved and are appended to the REMS 
document.  This guidance refers to these materials as REMS materials. 
 
4 See 21 U.S.C. 355-1(h)(2)(A) and P.L. 112-144, 1132(c). 
 
1  Contains Nonbinding Recommendations 
This guidance applies to all types of REMS, including REMS that are part of a shared system 
(SS REMS).5,6   
 
This guidance does not address additional submission procedures that may apply to application 
holders proposing changes to REMS that are part of a shared system and that use a drug master 
file (DMF) for their REMS submissions.7   
 
This guidance is being issued consistent with the FDAs good guidance practices regulation (21 
CFR 10.115).  The guidance represents the Agencys current thinking on changes to REMS.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the 
public.  
 
 
II.  BACKGROUND 
 
A REMS is a required risk management plan that uses tools beyond the prescribing information 
(the package insert) to ensure that the benefits of certain drugs outweigh their risks.8  If the FDA 
determines that a REMS is necessary to ensure that the benefits of a drug outweigh its risks, the 
FDA is authorized to require a REMS for such a drug under section 505-1 of the FD&C Act.9  
Section 505-1(g) and (h) includes provisions regarding the assessment and modification of an 
approved REMS.   
 
An application holder may propose a REMS modification at any time.  In addition, when the 
FDA determines that a modification of a REMS is necessary to ensure that the benefits of a drug 
outweigh its risks, to minimize the burden on the health care delivery system of complying with 
the REMS, or to accommodate different, comparable aspects of the elements to assure safe use 
(ETASU) for a drug that is the subject of an application under section 505(j), and the applicable 
listed drug, the FDA has the authority to require that the application holder submit a proposed 
modification to a REMS under section 505-1(g) of the FD&C Act.    
                                                 
5 For the purposes of this guidance, a shared system REMS (SS REMS) is a program that encompasses multiple 
prescription drugs and is developed and jointly implemented by two or more application holders.  An SS REMS 
includes a single, shared system REMS as defined in section 505-1(i)(1)(C) of the FD&C Act.   
 
6 See the draft guidance for industry Development of a Shared System REMS (June 2018).  When final, this guidance 
will represent the FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
7 For submission procedures for changes to SS REMS that use a DMF for submissions, see the draft guidance for 
industry Use of a Drug Master File for Shared System REMS Submissions (November 2017).  When final, this 
guidance will represent the FDAs current thinking on this topic.   
 
8 For the purposes of this guidance, unless otherwise specified, references to drugs include drugs approved under the 
FD&C Act and biological products licensed under the Public Health Service Act (PHS Act), other than biological 
products that also meet the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)). 
 
9 Section 505-1 applies to applications for prescription drugs submitted under FD&C Act subsections 505(b) (i.e., 
new drug applications (NDAs)) or (j) (i.e., abbreviated new drug applications (ANDAs)), and applications under 
section 351 of the PHS Act (i.e., biologics license applications). 
 
2  Contains Nonbinding Recommendations 
 
The Food and Drug Administration Safety and Innovation Act (FDASIA) amended the REMS 
modification provisions under section 505-1(g) and (h) of the FD&C Act.  Section 505-1(h), as 
amended by FDASIA, requires the FDA to review and act on proposed minor modifications, as 
defined in guidance, within 60 days.10  It also requires the FDA to establish, through guidance, 
that certain modifications can be implemented following notification to the FDA.11  In addition, 
section 505-1(h) requires the FDA to review and act on REMS modifications to conform the 
strategy to approved safety labeling changes, or to a safety labeling change that the FDA has 
directed the application holder make pursuant to section 505(o)(4) of the FD&C Act, within 60 
days.12  Finally, section 505-1(g)(4)(A) of the FD&C Act as amended by FDASIA specifies that 
proposed REMS modifications no longer require submission of a REMS assessment; instead, 
proposed modifications must include an adequate rationale for the proposed changes.     
 
Existing FDA regulations describe how to make changes to approved applications and include a 
mechanism for rapid implementation of certain changes.13  Some changes must be submitted as a 
prior approval supplement (PAS) and be approved before they are implemented.  Changes-being-
effected (CBE) supplements may be implemented at the time they are submitted or 30 days 
following submission.14  If a supplement was inappropriately submitted as a CBE, the FDA will 
notify the application holder that the proposed change(s) require FDA approval before 
implementation.  A description of how these existing submission requirements apply to proposed 
REMS changes is provided below in greater detail. 
 
 
III.  POLICY 
 
Changes to REMS will be categorized as REMS revisions, minor REMS modifications, or major 
REMS modifications, based on the degree of their potential effect on (1) the information 
provided in the REMS related to the serious risk(s) associated with the drug; (2) the safe use of 
                                                 
10 See section 505-1(h)(2)(A)(ii) of the FD&C Act.  Section 1132(c) of FDASIA also provides that the FDA shall 
issue guidance that, for purposes of section 505-1(h)(2)(A) of the [FD&C Act], describes the types of modifications 
to approved risk evaluation and mitigation strategies that shall be considered to be minor modifications of such 
strategies. 
 
11 See section 505-1(h)(2)(A)(iv) of the FD&C Act.  The FDA interprets certain modifications that can be 
implemented upon notification to the FDA to be changes to a REMS that are editorial in nature or appropriate for 
submission in an annual report, and therefore, the FDA calls these REMS changes revisions to differentiate these 
changes from modifications that require the submission of a supplement and the FDA review and action. 
 
12 See section 505-1(h)(2)(A)(iii) of the FD&C Act.  
 
13 See 21 CFR 314.70 and 601.12.  
 
14 PAS-proposed changes must be approved by the FDA before implementation (21 CFR 314.70(b) and 21 CFR 
601.12(b)(3) and (f)(1)).  CBE supplements contain changes that may be implemented by the application holder 
either immediately upon FDA receipt of the supplement (CBE-0 supplements) (21 CFR 314.70(c)(6) and 
601.12(c)(5) and (f)(2)(ii)) or 30 days after FDA receipt of the supplement (CBE-30 supplements) (21 CFR 
314.70(c) and 601.12(c)(3)). 
3  Contains Nonbinding Recommendations 
the drug; and/or (3) the actions that the application holder, patients, health care providers, and 
other stakeholders must take to comply with the REMS.   
 
Tables 1 through 4 provide examples of REMS revisions and minor and major REMS 
modifications.  These tables are intended to be a representative, rather than comprehensive, list 
of examples. 
 
A.  REMS Revisions 
 
REMS revisions are defined as editorial changes that do not affect: 
 
  The information contained in the REMS document and/or REMS materials about the 
serious risk or safe use of the drug 
 
  The actions application holders, patients, health care providers, or other stakeholders 
must take to comply with the REMS, or the REMS materials that support those actions 
 
Examples of REMS revisions are provided in Table 1. 
 
Table 1.  REMS Revisions (Submitted as REMS Revisions and Summarized in the Annual 
Report)15 
Examplesa 
  Changes in the application holder name or address to reflect transfer of application 
ownershipb 
  Updates to the application holders contact information (e.g., mailing address, telephone 
number, fax number, email address) 
  Editorial changes, such as: 
  Changes in International Classification of Diseases code(s) in the REMS materials or 
on the REMS website 
  Changes to the application holders internal tracking information (e.g., tracking 
numbers) on REMS forms 
  Changing the application holders signatory for a Dear Health Care Provider letter that 
is part of the REMS materials 
  Changing a trademark symbol, designated by TM, to the registered trademark symbol, 
designated by  
  Changes to the approved package count configuration that result in changes to the 
REMS materials (e.g., a change in the national drug code number(s)) 
continued 
                                                 
15 See section IV., Submission Procedures. 
4  Contains Nonbinding Recommendations 
Table 1, continued 
Examplesa 
  Correction of grammatical, formatting, and/or typographical errors, for example: 
[DRUG] are is associated with the potential risk risks of seizure and hepatotoxicity. 
Health care prviders providers who prescribe [DRUG] must be specally specially 
certified. 
  The following changes to a Medication Guide that is an element of a REMS:c 
  Changes in the application holders name and/or place of businessd 
  Insertions of the date of the most recent revision of the Medication Guidee  
  Addition of the side effects statement and toll-free number for reporting adverse events 
to a Medication Guidef 
  Addition of an authorized generic for a drug in a shared system (SS) REMS when product-
specific information is not included in the REMS document and/or REMS materials 
a The types of REMS changes in italic font are provided for illustrative purposes.  Additions are noted by underline, 
and deletions are noted by strikethrough. 
b Application holders are responsible for reporting a transfer of ownership in accordance with Federal regulations.  
The FDA must be notified in writing by the new and former application holders at the time of transfer in ownership 
of a new drug application (NDA), abbreviated new drug application (ANDA), or biologics license application 
(BLA) (21 CFR 314.72; 21 CFR 601.12(f)(1)).    
c See 21 CFR 314.70(b)(2)(v)(B) for NDAs and 21 CFR 601.12(f)(3)(C) for BLAs. 
d See 21 CFR 208.20(b)(8)(iii). 
e See 21 CFR 208.20(b)(8)(iv). 
f See the guidance for industry Medication Guides  Adding a Toll-Free Number for Reporting Adverse Events 
(June 2009).  We update guidances periodically.  For the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
B.  REMS Modifications 
 
Proposed REMS modifications are divided into two categories:  minor modifications and major 
modifications.   
 
1.  Minor REMS Modifications 
 
Minor REMS modifications are defined as changes that have a limited effect on: 
 
  The information contained in the REMS document and/or REMS materials about the 
serious risk or safe use of the drug  
 
  The actions application holders, patients, health care providers, or other stakeholders 
must take to comply with the REMS, or the REMS materials that support those actions 
 
These modifications should be submitted as CBE-30 supplements (see section IV., Submission 
Procedures).  Examples of minor REMS modifications are provided in Table 2. 
 
5  Contains Nonbinding Recommendations 
Table 2.  Minor REMS Modifications (Submitted as CBE-30 Supplements16) 
Type of Change  Examples 
Minor modifications    Addition of an approved new strength or dosage regimen of the 
that have a limited  druga 
effect on information 
  Removal of a strength or dosage form of the drug (other than 
contained in the 
from the Medication Guide) because either 
REMS about the 
  FDA approval has been withdrawn and documented 
serious risk or safe use  o
by publication of a Federal Register notice for the 
of the drug 
strength/dosage form, or  
  The FDA has determined that the strength/dosage 
o
form was withdrawn from sale for reasons of safety or 
effectiveness 
  Addition of an authorized generic to a single drug REMS 
  Addition of an authorized generic for a drug in a shared system 
(SS) REMS when product-specific information is in the REMS 
document and/or REMS materials. 
  Adding, removing, or changing information about another drug 
that is mentioned in the REMS document and/or materials, but is 
not the drug for which the REMS was required 
  Adding a new, recently approved drug to a class of drugs 
already mentioned in the REMS materials as having the 
potential to cause drug-drug interactions 
  Adding information previously reviewed and approved for one 
application that is part of an SS REMS to the REMS document 
and/or REMS materials for the other applications in the SS 
REMS 
  Adding a new, recently approved drug in a class to the REMS 
document and/or REMS materials for the other applications in 
the SS REMS 
  Adding new information about an existing drug in a class to 
the REMS document and/or REMS materials for the other 
applications in the SS REMS 
  Changes to graphics, including changes to the existing 
manufacturers logo or the logo for the REMS program 
continued 
                                                 
16 See section IV., Submission Procedures. 
6  Contains Nonbinding Recommendations 
Table 2, continued 
Type of Change  Examples 
Minor modifications    Adding a professional society to the list of required recipients of a 
that have a limited  Dear Health Care Provider letter required in the REMS materials  
effect on the actions 
  Converting an existing prescriber enrollment form into another 
application holders, 
format to allow for online registration, in addition to paper 
patients, health care 
enrollment via email or fax, without altering the prescriber 
providers, and other 
certification requirements  
stakeholders must take 
  Creating or converting an existing health care facility enrollment 
to comply with the 
form to allow closed (i.e., self-contained) health care systems to 
REMS 
enroll 
  Changing an existing health care provider or patient enrollment 
form to collect additional demographic information 
  Changes to the hours of operation for the REMS call center 
  Limited changes to the REMS website to improve functionality 
(ease of use) for stakeholders 
  Limited changes to the REMS website to clarify current processes 
required of stakeholders (e.g., changes to clarify how health care 
providers should navigate the website to complete enrollment in 
the REMS) 
  Adding approved REMS materials (new or modified) to the 
REMS website 
  Changing the timetable for submission of assessment for REMS 
involving multiple drugs in the same class and owned by the 
same application holder to synchronize the assessment due date(s) 
  Reordering the risk information in the REMS materials 
a Proposals for a new dose regimen or strength of a drug are submitted as supplemental efficacy or chemistry, 
manufacturing, and controls (CMC) applications.  Proposed REMS modifications submitted or required as part of 
an efficacy or CMC supplement will be reviewed and acted on as part of that supplement, and not according to the 
time frames described above for REMS revisions, minor modifications, or major modifications.  See section V.F., 
REMS Modifications Included in Other Submissions. 
 
2.  Major REMS Modifications 
 
Major REMS modifications are defined as changes that have a substantial effect on: 
 
  The information contained in the REMS document and/or REMS materials about the 
serious risk or safe use of the drug 
 
  The actions application holders, patients, health care providers, or other stakeholders 
must take to comply with the REMS, or the REMS materials that support those actions 
 
7  Contains Nonbinding Recommendations 
Major REMS modifications include changes to provide new information about the serious risk(s) 
or safe use of the drug.  In addition, modifications to the strategy due to approved safety labeling 
changes, or to a safety labeling change that the FDA has directed the application holder to make 
pursuant to section 505(o)(4) of the FD&C Act, are considered major REMS modifications.  The 
FDA interprets REMS modifications that conform to safety labeling changes in section 505-
1(h)(2)(A)(iii) of the FD&C Act to refer to modifications that transfer the newly approved 
labeling language into the existing REMS and/or REMS materials.  Overall design, 
programmatic, and/or implementation changes to the REMS that result from approved (or 
ordered) safety labeling changes are not considered conforming REMS modifications.   
 
Examples of major REMS modifications are provided in Tables 3 and 4.  Major REMS 
modifications should be submitted as a PAS (see section IV., Submission Procedures).  
 
Table 3.  Major REMS Modifications (Submitted as a PAS17) 
Type of Change  Examples 
Major modifications    Addition, removal, or change to a REMS goal 
that have a substantial 
  Addition of new information about the serious risks associated 
effect on information 
with the drug  
contained in the REMS 
  Addition of a new indication for use that may alter the serious 
about the serious risk 
risks (in relation to benefits) of the drug for the new patient 
or safe use of the drug  
populationa 
 
    Addition of new information about drug administration that 
  affects patient safety 
 
  Changing the type, frequency, and/or timing of patient 
laboratory testing required as part of the documentation of safe-
use conditions 
  Any change to a Medication Guide that is an element of a REMS 
and for which FDA approval of the change is requiredb 
continued 
                                                 
17 See section IV., Submission Procedures. 
8  Contains Nonbinding Recommendations 
Table 3, continued 
Type of Change  Examples 
Major modifications    Removing or adding an element of the REMS  
that have a substantial 
  Substantially modifying an existing REMS element, including: 
effect on the actions 
  Changes to the timetable for submission of assessments of 
application holders, 
the REMS that alter the frequency and/or number of the 
patients, health care 
assessments 
providers, and other 
stakeholders must take    Changes to an ETASUc that modify the verification process 
to comply with the  required for the drug to be dispensed to patients 
REMS  
  Adding a new letter to health professional societies to the 
REMS materials to describe new or clarified information 
about a serious risk 
  Adding/removing the REMS website from the 
communication plan or an ETASU 
  Substantial changes to a REMS tool, including: 
  Changing the prescriber enrollment form to add/remove an 
attestation that the prescriber understands the serious risk(s) 
of the drug 
  Extensive changes to a patient brochure to better educate 
patients about the serious risk(s) of the drug 
  Adding or removing a prescriber educational tool, such as a 
slide deck or safety information brochure 
  Modification that proposes releasing the REMS requirement  
  Changing a REMS for an individual drug to a shared system 
(SS) REMSd 
a See section V.F., REMS Modifications Included in Other Submissions. 
b See 21 CFR 314.70(b)(2)(v)(B) and 601.12(f)(1).  For a Medication Guide that is an element of a REMS, if the 
changes are required under section 505(o)(4) of the FD&C Act, the changes should be submitted in accordance 
with the procedures described in the guidance for industry Safety Labeling Changes  Implementation of Section 
505(o)(4) of the FD&C Act (July 2013). 
c ETASU = elements to assure safe use 
d See the draft guidance for industry Development of a Shared System REMS (June 2018) for additional policies and 
procedures for modifying the REMS for an individual drug to an SS REMS.  When final, this guidance will 
represent the FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
9  Contains Nonbinding Recommendations 
Table 4.  REMS Modifications Due to Safety Labeling Changes (Type of Major 
Modification, Submitted as a PAS18) 
Type of Change  Examples 
Changes that are    Updating language in the existing prescriber or pharmacy 
considered conforming  training materials to reflect approved safety labeling changes 
(i.e., modifications that  made to the WARNINGS AND PRECAUTIONS section of the 
transfer the newly  package insert. 
approved labeling 
  Addition of newly approved language from the product labeling 
language into the 
describing new adverse reactions and drug-drug interactions to 
existing REMS and/or 
the REMS patient education brochure 
REMS materials (60-
 
day review)) 
Changes that are not    Addition of a new ETASUa requiring the documentation of safe-
considered conforming  use conditions, based on the newly approved language in the 
(i.e., overall  BOXED WARNING and CONTRAINDICATIONS sections of 
programmatic and/or  the package insert 
implementation 
  Addition of a new Dear Health Care Provider letter to the REMS 
changes to the REMS 
materials that describes a new serious risk added to the product 
that result from 
labeling 
approved (or ordered) 
  Extensive changes to prescriber training materials to add new 
safety labeling changes 
patient monitoring procedures necessary to address a new 
(180-day review)) 
serious risk described in approved product labeling 
a ETASU = elements to assure safe use 
 
 
IV.  SUBMISSION PROCEDURES 
 
This section provides an overview of submission procedures that apply to all REMS changes 
(revisions and modifications).  The Appendix summarizes the relevant information that should 
be included in these submissions.19 
 
                                                 
18 See section IV., Submission Procedures. 
 
19 The Electronic Submissions Gateway web page (available at https://www.fda.gov/industry/electronic-
submissions-gateway) provides email addresses to which application holders can send questions about electronic 
submissions (e.g., location of REMS materials in the electronic common technical document) and general questions 
about sending electronic submissions through the electronic submissions gateway.  Application holders also can 
refer to the guidance for industry Providing Regulatory Submissions in Electronic Format  General 
Considerations (January 1999).   
 
 
10  Contains Nonbinding Recommendations 
A.  General Considerations 
 
When the FDA requires a REMS change,20 the FDA will describe the required change and the 
type of submission that is needed (CBE-30 supplement or PAS).   
 
Application holders who wish to seek advice from the FDA before submission of a proposed 
REMS modification may do so in accordance with established FDA procedures.21  
 
B.  Content and Format  
 
1.  Administrative Content  
 
Submissions should include: 
 
a)  The appropriate submission identifier in bold capital letters at the top of the first page 
of the submission and completed Form FDA 356h (see the Appendix).   
 
b)  A detailed description of the REMS changes to allow the FDA to determine quickly if 
the appropriate submission category has been used.  This information can be included 
in the submission or the cover letter. 
 
c)  A clean (without track changes) Word version of the changed REMS and REMS 
materials. 
 
d)  A redlined (track changes) Word version of the changed REMS and REMS materials.  
 
e)  One PDF file that includes a clean version of the changed REMS document and 
REMS materials. 
 
f)  A clean (without track changes) Word version of the updated REMS supporting 
document22 to align with changes made to the REMS document and REMS materials, 
as appropriate. 
 
g)  A redlined (track changes) Word version of the updated REMS supporting document. 
                                                 
20 See section 505-1(g)(4)(B) of the FD&C Act. 
 
21 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (December 2017).  When final, this guidance will represent the FDAs current thinking on this topic.  
Application holders seeking FDA advice about proposed modifications to REMS for drugs approved under an 
ANDA should contact the Office of Bioequivalence in the Office of Generic Drugs in CDER (see section VI., 
Contact Information).  
 
22 The REMS supporting document expands on information in the REMS document and provides additional 
information about the REMS, such as the rationale for, and supporting information about, the design, 
implementation, and assessment of the REMS.  See the draft guidance for industry Format and Content of a REMS 
Document (October 2017).  When final, this guidance will represent the FDAs current thinking on this topic.  The 
statutory requirements for REMS revisions and modifications do not apply to the REMS supporting document (i.e., 
changes to the REMS supporting document are neither REMS revisions nor modifications). 
11  Contains Nonbinding Recommendations 
 
h)  A REMS history of all changes to the REMS since originally approved (see section 
IV.B.2., REMS History). 
 
i)  For REMS modifications only:  An adequate rationale for the proposed 
modifications (see section IV.B.3., Adequate Rationale for REMS Modifications). 
 
2.  REMS History 
 
For all REMS changes, the FDA recommends application holders include a REMS history that 
outlines all changes made to the REMS since its original approval. 
 
The REMS history should be similar in format to the history of labeling changes provided in 
submissions containing new labeling.23,24  The REMS history should be in a tabular format that 
lists all approved and/or pending REMS changes with the approval or submission date 
(respectively), a summary of the changes (revisions and/or modifications), and a list of affected 
REMS materials.  
 
3.  Adequate Rationale for REMS Modifications 
 
All proposed REMS modifications (minor or major) initiated by the application holder must 
include an adequate rationale.25  The rationale may include, but is not limited to, the reason(s) 
why the proposed modification is necessary; the potential effect of the proposed modification on 
how the REMS addresses the serious risk(s) for which the REMS was required, on patient access 
to the drug, and/or on the burden on the health care delivery system; and other appropriate 
evidence or data to support the proposed change.  If a REMS assessment was submitted in the 
previous 18 months and includes data to support the proposed modifications, then it can be 
referenced as the adequate rationale. 
 
When considering a proposed REMS modification as part of an efficacy supplement for a new 
indication for use (see section IV.C., Submission of Proposed REMS Changes), the REMS 
assessment that is required in accordance with section 505-1(g)(2)(A) of the FD&C Act will be 
considered the adequate rationale to support the proposed REMS modification.  This adequate 
rationale should include:   
 
  In every case:  An evaluation of how the benefit-risk profile will or will not change with 
the new indication and the implications of any changes on the currently approved REMS 
                                                 
23 See the eCTD Technical Conformance Guide, Technical Specifications Document available at 
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-technical-document-
ectd.  This document is incorporated by reference in the guidance for industry Providing Regulatory Submissions in 
Electronic Format  Certain Human Pharmaceutical Product Applications and Related Submissions Using the 
eCTD Specifications (February 2020).  
 
24 For an example of a REMS history, see the draft guidance for industry Use of a Drug Master File for Shared 
System REMS Submissions.  When final, this guidance will represent the FDAs current thinking on this topic.   
 
25 See section 505-1(g)(4)(A) of the FD&C Act. 
12  Contains Nonbinding Recommendations 
 
  If the new, proposed indication for use introduces unexpected risks:  A description of 
those risks and an evaluation of whether those risks can be appropriately managed with 
the currently approved REMS   
 
  If the proposed REMS modification is based on a change in the benefit-risk profile or 
because of the new indication of use:  Explanation of the reason(s) why the proposed 
REMS modification is necessary; the potential effect of the proposed changes on how the 
REMS addresses the serious risk(s) for which the program was required, on patient 
access to the drug, and/or on the burden on the health care delivery system; and other 
appropriate evidence or data to support the proposed change  
 
  If a REMS assessment was submitted in the 18 months before submission of the 
supplemental application for a new indication for use:  A statement about whether the 
REMS was meeting its goals at the time of the last assessment and if any modifications of 
the REMS have been proposed since that assessment  
 
  If a REMS assessment was not submitted in the 18 months before submission of the 
supplemental application for a new indication for use:  Include as many of the currently 
listed assessment plan items as feasible 
 
If the proposed REMS modifications are submitted in accordance with an FDA requirement to 
modify the REMS,26 submission of an adequate rationale is not required as long as the proposed 
changes are identical to or consistent with those specified by the FDA.  If the proposed REMS 
modification supplement includes changes that differ from the modifications described by the 
FDA, an adequate rationale is required for those proposed changes in accordance with section 
505-1(g)(4)(A) of the FD&C Act. 
 
If the proposed REMS modifications are due to approved safety labeling changes or to safety 
labeling changes that the FDA has ordered the application holder to make, the adequate rationale 
can consist of a statement that the REMS changes are submitted due to the approved or ordered 
safety labeling changes (see section V.D., REMS Modification Due to Safety Labeling Changes). 
 
C.  Submission of Proposed REMS Changes  
 
Revisions should be submitted as REMS Revision, a submission type similar to drug 
correspondence.  REMS revisions should be documented in the next annual report27 and 
submitted at the time the revisions are implemented so that the current REMS document and 
                                                 
26 See section 505-1(g)(4)(B) of the FD&C Act. 
 
27 A summary of REMS revisions should be included under section c of the next NDA, biologics license application, 
(BLA), or ANDA annual report (21 CFR 314.81(b)(2)(iii)(c)). 
 
13  Contains Nonbinding Recommendations 
REMS materials are publicly displayed on the FDA web page of approved REMS.28,29  Because 
REMS revisions are not submitted as supplemental applications, they do not require FDA action 
and can be implemented following receipt by the FDA. 
 
Proposed minor REMS modifications should be submitted as a CBE-30 supplement; proposed 
major modifications should be submitted as a PAS.  
 
Proposed REMS modifications submitted to conform a REMS to approved or ordered safety 
labeling changes are major modifications and should be submitted as a PAS.  However, these 
modifications are subject to a different time frame for review than other major modifications and 
safety labeling changes supplements submitted under section 505(o)(4) (see section V.D., REMS 
Modification Due to Safety Labeling Changes).   
 
Application holders can submit multiple proposed REMS modifications of the same type (e.g., 
multiple minor modifications) in a single submission.  
 
Application holders also can submit a single submission that contains REMS changes of 
different types (e.g., REMS revisions and minor (or major) modifications; or minor 
modifications and major modifications).  However, a single submission with multiple REMS 
changes will affect the time frame for review of the submission (see section V.E., Submissions 
Containing More Than One Type of REMS Change). 
 
A REMS assessment, supplemental efficacy application, or a supplemental chemistry, 
manufacturing, and controls (CMC) application may result in changes to an approved REMS.30  
REMS modifications included in these applications should include the relevant information for 
the submission and should be submitted according to the instructions described in the Appendix.  
 
 
V.  FDA TIME FRAMES31 FOR REMS CHANGES 
 
The FDA will promptly assess submissions that contain proposed REMS changes to determine 
whether the proposed changes meet the criteria for the type of submission used (i.e., CBE-30 for 
minor REMS modifications or a PAS for major REMS modifications, including REMS 
modifications due to safety labeling changes).  If the FDA determines that the REMS changes 
are not appropriately categorized and submitted, the FDA will notify the application holder, in 
writing, within 14 days of receipt of the submission, and as described in the following 
subsections.  
                                                 
28 See section 505-1(h)(2)(C) of the FD&C Act.   
 
29 See the FDA web page Approved Risk Evaluation and Mitigation Strategies (REMS)  REMS@FDA, available 
at https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm.  
 
30 Examples of REMS modifications that may result from efficacy supplements include addition of a new dosing 
regimen or a new indication for use (see Tables 2 and 3).  An example of a REMS modification that may result from 
a CMC supplement is addition of a new packaging to the REMS document and/or the appended REMS materials. 
 
31 The time frames described in this section refer to calendar days.  
14  Contains Nonbinding Recommendations 
 
A.  REMS Revisions  
 
REMS revisions are not submitted as supplemental applications; therefore, they do not require 
FDA action.  Application holders can implement REMS revisions following receipt by the FDA. 
 
B.  Minor REMS Modifications  
 
The FDA will review and act on proposed minor REMS modifications within 60 days of 
receipt.32  Although the application holder can implement the modified REMS 30 days after 
receipt by the FDA, the changes to the REMS are not considered final until approved by the 
FDA.  
 
If the FDA informs the application holder (within 14 days of receipt) that information necessary 
for the FDA to act on the submission is missing, the application holder should delay 
implementation.  The missing information should be submitted as soon as possible, but no later 
than 10 days after notification.  If the missing information is not received within 10 days of the 
FDA request, the FDA may issue a complete response letter. 
 
C.  Major REMS Modifications  
 
The FDA will review and act on proposed major REMS modifications within 180 days of 
receipt.33  Proposed major REMS modifications must not be implemented before FDA 
approval.34 
 
D.  REMS Modification Due to Safety Labeling Changes   
 
The FDA will review and act on proposed conforming REMS modifications within 60 days of 
receipt and will review and act on modifications not considered conforming within 180 days of 
receipt.  Proposed major REMS modifications, including modifications due to safety labeling 
changes, must not be implemented before FDA approval.35 
 
The 60- or 180-day review time frame does not begin until the FDA receives the REMS 
modification to conform or align with the approved (or ordered) safety labeling changes.  Even if 
a REMS modification due to a safety labeling changes supplement is submitted at the same time 
as the corresponding proposed safety labeling changes, or after submission but before the 
                                                 
32 See section 505-1(h)(2)(A)(ii) of the FD&C Act. 
 
33 See section 505-1(h)(2)(A)(i) of the FD&C Act.  The 180-day review time frame does not apply if the dispute 
resolution process described in section 505-1(h)(4) applies. 
 
34 See 21 CFR 314.70(b) and 21 CFR 601.12(b)(3) and (f)(1). 
 
35 See 21 CFR 314.70(b)(3).  It is the FDAs view that the labeling changes process under 21 CFR 314.70 and 
601.12 continues to be available to application holders in situations in which application holders become aware of 
newly acquired information, including in circumstances that meet the criteria for submission of a CBE-0.   
 
15  Contains Nonbinding Recommendations 
approval of the labeling supplement (see section IV.C., Submission of Proposed REMS 
Changes), the 60- or 180-day review time frame does not begin until the associated labeling 
supplement is approved (or ordered)36 and the REMS modification supplement is amended, if 
necessary, to accurately reflect the approved labeling.   
 
E.  Submissions Containing More Than One Type of REMS Change 
 
Because the FDA takes one action per supplement, submissions that contain REMS changes of 
different types will be reviewed and acted on based on the time frame for the longer review 
clock.  Therefore, the FDA will review and act on submissions that include both minor and major 
REMS modifications within 180 days of receipt (to allow sufficient time for review of the major 
modifications).  The FDA will review and act on submissions containing both minor 
modifications and REMS revisions within 60 days (to allow sufficient time for review of the 
minor modifications).  
 
F.  REMS Modifications Included in Other Submissions 
 
Proposed REMS modifications submitted with a REMS assessment required in accordance with 
the timetable for submission of assessments of the REMS will be reviewed concurrently with the 
REMS assessments.  Action on the proposed REMS modifications will follow review of the 
REMS assessment.  
 
Proposed REMS modifications submitted in an efficacy or CMC supplement will be reviewed 
and acted on as part of that supplement, and not according to the time frames described above.37  
REMS modifications submitted as part of an efficacy or CMC supplement may not be 
implemented until approved. 
 
G.  Posting Revised and Modified REMS on the FDA Website 
 
The FDA intends to post updated REMS reflecting REMS revisions on the website within 14 
days of receipt of the submission.38 
 
The FDA intends to post updated REMS reflecting REMS modifications on the website within 3 
days of approval. 
 
 
VI.  CONTACT INFORMATION 
 
The contacts for questions about a proposed REMS revision or modification are as follows: 
                                                 
36 See section 505-1(h)(2)(A)(iii) of the FD&C Act. 
 
37 For more information on the FDAs review of efficacy supplements, see the guidance for industry Standards for 
the Prompt Review of Efficacy Supplements, Including Priority Efficacy Supplements (May 1998).  For more 
information on the FDAs review of CMC supplements, see the guidance for industry Changes to an Approved NDA 
or ANDA (April 2004).  
 
38 See https://www.accessdata.fda.gov/scripts/cder/rems/.  
16  Contains Nonbinding Recommendations 
 
  Center for Drug Evaluation and Research: 
 
  For a drug under a new drug application or biologics license application:  the 
regulatory project manager in the Office of New Drugs review division responsible 
for that drug  
 
  For a drug under an abbreviated new drug application:  the REMS coordinator in the 
Office of Bioequivalence in the Office of Generic Drugs  
 
  For modifications of SS REMS:  the regulatory project manager in the Project 
Management Staff, Office of Surveillance and Epidemiology 
 
  Center for Biologics Evaluation and Research: 
 
  The regulatory project manager in the office responsible for that drug  
 
 
17  Contains Nonbinding Recommendations 
APPENDIX: 
SUBMISSION PROCEDURES FOR CHANGES TO APPROVED REMS 
 
Table A summarizes the relevant information to include in submissions for changes (revisions 
and modifications) to approved risk evaluation and mitigation strategies (REMS). 
 
Table A:  Information to Include in Submissions of Proposed REMS Changes 
Type of 
Instructions for 
REMS  Other   Adequate 
Submission  Completing  REMS 
Change/  Administrat Rationale
Identifier   Form FDA  History3  
Submission  ive Content2  4 
356h1 
Type 
Field 21  Select 
Other and 
enter REMS 
REMS  Revision  Not 
REMS REVISION  Items5 b-h  Recommended 
Revision  required 
Field 25  Enter 
REMS 
Revision 
NEW 
SUPPLEMENT 
Field 21  Select 
FOR [NDA/BLA/ 
REMS 
ANDA]6  
Supplement 
[assigned #] 
Minor  Field 23  Select 
CHANGES 
REMS  CBE-30  Items b-i  Recommended  Required 
BEING 
Modification 
EFFECTED IN 30 
Field 25  Enter 
DAYS 
Proposed Minor 
REMS 
PROPOSED 
Modification 
MINOR REMS 
MODIFICATION 
continued 
18  Contains Nonbinding Recommendations 
Table A, continued 
Type of 
Instructions for 
REMS  Other   Adequate 
Submission  Completing  REMS 
Change/  Administrat Rationale
Identifier   Form FDA  History3  
Submission  ive Content2  4  
356h1 
Type 
NEW 
Field 21  Select 
SUPPLEMENT 
REMS 
FOR [NDA/BLA/ 
Supplement 
ANDA] 
[assigned #] 
Field 23  Select 
Major REMS  Prior Approval 
PRIOR  Items b-i   Recommended  Required  
Modification  (PA) 
APPROVAL 
SUPPLEMENT 
Field 25  Enter 
Proposed Major 
PROPOSED 
REMS 
MAJOR REMS 
Modification 
MODIFICATION 
NEW 
Field 21  Select 
SUPPLEMENT 
REMS 
FOR [NDA/BLA/ 
Supplement 
ANDA]  
[assigned #]  
REMS  Field 23  Select 
Modification  Prior Approval 
PRIOR 
Due to  (PA) 
APPROVAL 
Safety 
SUPPLEMENT 
Field 25  Enter 
Labeling 
Items b-i   Recommended  Required  
Proposed 
Changes   PROPOSED 
REMS 
REMS 
(Major  Modification 
MODIFICATIONS 
REMS  Due to Safety 
DUE TO SAFETY 
Modification)  Labeling 
LABELING 
Changes 
CHANGES 
Submitted in 
SUBMITTED IN 
Supplement 
SUPPLEMENT 
[supplement #] 
[supplement #] 
continued 
19  Contains Nonbinding Recommendations 
Table A, continued 
Type of 
Instructions for 
REMS  Other   Adequate 
Submission  Completing  REMS 
Change/  Administrat Rationale
Identifier   Form FDA  History3  
Submission  ive Content2  4  
356h1 
Type 
NEW 
SUPPLEMENT  Field 21  Select 
FOR [NDA/BLA/  REMS 
ANDA]   Supplement 
[assigned #]  
Field 23  Select 
Multiple 
PRIOR  Prior Approval 
Types of 
APPROVAL  (PA) or CBE-
REMS 
SUPPLEMENT or  30   Items b-i   Recommended  Required 
Changes in 
CHANGES 
Same 
BEING  Field 25  Enter 
Submission 
EFFECTED IN 30  Proposed 
DAYS  REMS 
Modification 
PROPOSED 
REMS   
MODIFICATIONS 
continued 
20  Contains Nonbinding Recommendations 
Table A, continued 
Type of 
Instructions for 
REMS  Other   Adequate 
Submission  Completing  REMS 
Change/  Administrat Rationale
Identifier   Form FDA  History3  
Submission  ive Content2  4  
356h1 
Type 
NEW 
SUPPLEMENT 
FOR [NDA/BLA]  Field 21  Select 
[assigned #]  Efficacy 
Supplement 
PRIOR  and REMS 
APPROVAL  Supplement 
Efficacy  SUPPLEMENT 
Supplement  Field 23  Select 
With  < other supplement  Prior Approval 
Items b-i   Recommended  Required  
Proposed  identification >  (PA) 
REMS 
Modifications  [EFFICACY  Field 25  Enter 
SUBMISSION  Efficacy 
CONTENT  Supplement 
INFORMATION]  and Proposed 
REMS 
PROPOSED  Modification 
REMS 
MODIFICATION 
continued 
21  Contains Nonbinding Recommendations 
Table A, continued 
Type of 
Instructions for 
REMS  Other   Adequate 
Submission  Completing  REMS 
Change/  Administrat Rationale
Identifier   Form FDA  History3  
Submission  ive Content2  4  
356h1 
Type 
NEW 
SUPPLEMENT 
FOR [NDA/BLA/ 
ANDA]  
[assigned #]  Field 21  Select 
CMC 
PRIOR  Supplement 
APPROVAL  and REMS 
SUPPLEMENT or  Supplement 
CMC6  CHANGES 
BEING  Field 23  Select 
Supplement 
EFFECTED in 30  CBE-30 or 
With 
Days  Prior Approval  Items b-i   Recommended  Required 
Proposed 
(PA) 
REMS 
< other supplement 
Modifications 
identification >  Field 25  Enter 
CMC 
[CMC  Supplement 
SUBMISSION  and Proposed 
CONTENT  REMS 
INFORMATION]  Modification 
PROPOSED 
REMS 
MODIFICATION 
continued 
22  Contains Nonbinding Recommendations 
Table A, continued 
Type of 
Instructions for 
REMS  Other   Adequate 
Submission  Completing  REMS 
Change/  Administrat Rationale
Identifier   Form FDA  History3  
Submission  ive Content2  4  
356h1 
Type 
Field 21  Select 
NEW 
REMS 
SUPPLEMENT 
Supplement 
FOR [NDA/BLA/  Required: 
and Other; 
ANDA]   The 
then enter 
[assigned #]  required 
REMS 
REMS 
Assessment 
REMS  PRIOR  assess-
Assessment  APPROVAL  ment 
Field 23  Select 
With  SUPPLEMENT or  included 
CBE-30 or  Items b-i   Recommended 
Proposed  CHANGES  with the 
Prior Approval 
REMS  BEING  supple-
(PA) 
Modifications  EFFECTED in 30  ment is 
Days   Field 25  Enter  considered 
the 
REMS 
REMS  adequate 
Assessment 
MODIFICATION/  rationale 
and Proposed 
REMS 
REMS 
ASSESSMENT 
Modification 
1 The field numbers in this column correspond to the number boxes on Form FDA 356h, Application to Market a 
New or Abbreviated New Drug or Biologic for Human Use. 
2 See section IV.B.1., Administrative Content, of the guidance. 
3 See section IV.B.2., REMS History, of the guidance. 
4 See section IV.B.3., Adequate Rationale for REMS Modifications, of the guidance. 
5 Items as listed in section IV.B.1., Administrative Content, of the guidance. 
6 NDA = new drug application; BLA = biologics license application; ANDA = abbreviated new drug application; 
CMC = chemistry, manufacturing, and controls 
23