Format and Content of a REMS Document Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Format and Content of
a REMS Document
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)
January 2023
Drug Safety

Format and Content of
a REMS Document
Guidance for Industry
Additional copies are available from:
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Food and Drug Administration
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and/or
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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)
January 2023
Drug Safety

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
A. 	FDA’s REMS Authority ................................................................................................................ 2
B. 	FDA’s Considerations for Changing the Format of the REMS Document .............................. 3
III. 	FORMAT AND CONTENT OF A REMS DOCUMENT............................................. 4
A. 	Administrative Information .......................................................................................................... 4
B. 	REMS Goals ................................................................................................................................... 4
C. 	REMS Requirements ..................................................................................................................... 4
1. REMS Participant Requirements ..................................................................................................... 5
2. REMS Applicant Requirements ........................................................................................................ 6
D. 	REMS Assessment Timetable ....................................................................................................... 7
E. 	REMS Materials ............................................................................................................................ 7
IV. 	PROCEDURES ................................................................................................................. 8
A. 	Proposed REMS Submissions ....................................................................................................... 8
B. 	Submission Type ............................................................................................................................ 8
C. 	Submission Identification .............................................................................................................. 9
D. 	Posting REMS Documents on the FDA Website ....................................................................... 10

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Format and Content of a REMS Document
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 recommendations for the format and content of a risk evaluation and
mitigation strategy (REMS) document for a prescription drug product, including a biological
drug product.2 A REMS document, which is part of a REMS that is required by FDA,
establishes the goals and requirements of the REMS.
This guidance provides recommendations to applicants on drafting proposed REMS documents
and converting an already-approved REMS document to a new, standardized format that is
clearer, more informative, and supports submission of a REMS document in Structured Product
Labeling (SPL) format.
This guidance provides an overview of the types of information that should be included in a
REMS document. Additional and more detailed information is provided in a separate guide,
REMS Document Technical Conformance Guide, which will be updated periodically and is
available on FDA’s website.3 The guide can be used for drafting a REMS document for single
product and shared system REMS and includes an outline for drafting a Bifurcated4 REMS
document. This guidance and the technical conformance guide are intended to help ensure that
1 This guidance has been prepared by the Office of Medication Error Prevention and Risk Management, Office of
Surveillance and Epidemiology in the Center for Drug Evaluation and Research (CDER) in cooperation with other
Offices within CDER and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug
Administration.
2 For purposes of this guidance, unless otherwise specified, references to drugs and drug products include drugs
submitted for approval or approved under sections 505(b) or (j) of the Federal Food, Drug, and Cosmetic Act
(FD&C Act) (21 U.S.C. 355(b) or (j)) and biological products licensed under section 351 of the Public Health
Service Act (42 U.S.C. 262), 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)). These applications are termed covered applications and refer to new
drug applications (NDAs), abbreviated new drug applications (ANDAs) and biologics license applications (BLAs).
3 See the REMS Document Technical Conformance Guide that includes the REMS Document Template and the
Bifurcated REMS Document Outline. For the most recent version of this technical conformance guide, go to
https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/roles-different-participants-rems.
4 A Bifurcated REMS Document is used when the approval of a shared system REMS may coincide with tentative
approval of an ANDA or section 505(b)(2) application. For more information, refer to the guidance for industry,
Development of a Shared System or Separate Comparable REMS (June, 2018). 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.

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REMS documents are clear, understandable to stakeholders, and to the extent possible, consistent
in content and format, and support submission of a REMS document in SPL format.
This guidance does not provide detailed information on the format and content of other
documents that are part of a REMS submission, such as the REMS materials5 or the REMS
supporting document.6 Furthermore, the guidance does not include information on how to
design, implement, and evaluate a REMS or to submit revisions and modifications for a REMS.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
A. 	FDA’s REMS Authority
Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C Act)(21 U.S.C. 355-1)
establishes FDA’s REMS authority. A REMS is a required risk management strategy that can
include one or more elements to ensure that the benefits of a drug outweigh its risks.
If FDA determines that a REMS is necessary,
a patient package insert,
7 the Agency may require one or more REMS
elements, which could include a Medication Guide, 	a communication
plan and/or certain packaging and safe disposal technologies for drugs that pose a serious risk of
abuse or overdose.8 FDA may also require elements to assure safe use (ETASU) as part of a
REMS.9 ETASU may be required if the drug has been shown to be effective, but is associated
with a specific serious risk and can be approved only if, or would be withdrawn unless, such
elements are required as part of a strategy to mitigate a specific serious risk(s) listed in the
labeling of the drug. ETASU may be required for drug products initially approved without
ETASU when other elements are not sufficient to mitigate a serious risk.
Specifically, ETASU may include one or any combination of the following requirements:10
5 All proposed materials that are included as part of the REMS (e.g., communication and educational materials,
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.
6 For purposes of this guidance, 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.
7 See guidance for industry FDA’s Application of Statutory Factors in Determining When a REMS Is Necessary
(April 2019).
8 Section 505-1(e)(2)-(4) of the FD&C Act.
9 See section 505-1(f) of the FD&C Act.
10 See section 505-1(f)(3) of the FD&C Act.

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• 	Health care providers who prescribe the drug have particular training or experience, or
are specially certified
• 	Pharmacies, practitioners, or health care settings that dispense the drug are specially
certified
• 	The drug be dispensed to patients only in certain health care settings, such as hospitals
• 	The drug be dispensed to patients with evidence or other documentation of safe use
conditions, such as laboratory test results
• 	Each patient using the drug be subject to monitoring
• 	Each patient using the drug be enrolled in a registry
If a REMS includes certain ETASU, the REMS may also include an implementation system to
enable the applicant to monitor, evaluate, and improve the implementation of the element(s)
(e.g., development of a REMS specific website or call center to facilitate enrollment;
establishment of electronic databases of certified health care settings).11
All REMS should include one or more goals. If the REMS has ETASU, the REMS must include
one or more goals to mitigate a specific serious risk listed in the labeling of the drug and for
which the ETASU are required.12
Finally, REMS generally must include a timetable for submission of assessments of the REMS.13
The timetable for submission of assessments of the REMS must include an assessment by the
dates that are 18 months and 3 years after the REMS is initially approved, and an assessment in
the 7th year after the REMS is approved, or at another frequency specified in the REMS.14
B. 	FDA’s Considerations for Changing the Format of the REMS Document
Since the approval of the first REMS in 2008, FDA has received public feedback on improving
the REMS document.15, 16 FDA has revised its recommendations on the format and content of
the REMS document in response to the public’s feedback and to provide assistance with drafting
a clearer, more informative, and standardized document. Additionally, this format supports
submission of REMS documents in SPL format. 17, 1819
11 See section 505-1(f)(4) of the FD&C Act.
12 See section 505-1(f)(3) of the FD&C Act.
13 NDAs and BLAs must include a timetable for submission of assessments. ANDAs are not subject to the
requirement for a timetable for submission of assessments (section 505-1(i)), but FDA can require any application
holder, including ANDA applicants, to submit REMS assessments under section 505-1(g)(2)(C).
14 See section 505-1(d) of the FD&C Act; see also section 505-1(g)(2) of the FD&C Act.
15 See http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm272170.htm.
16 See http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm350852.htm.
17 Structured product labeling (SPL) is a document markup standard approved by Health Level Seven and adopted
by FDA as a mechanism for exchanging product and facility information.
18 See additional information on REMS SPL, available at
https://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm517343.htm.

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The current format for the REMS document organizes the REMS requirements by who is
responsible for implementing the requirement, when the requirement is to be implemented, what
action is required, and with what REMS material(s). This format also makes greater use of
tables and bulleted lists to better present and organize the information.
III. 	FORMAT AND CONTENT OF A REMS DOCUMENT
A REMS document establishes the goals and requirements20 of the REMS as they relate to the
required REMS elements. This information is described in more detail in the sections below.
To facilitate the applicant’s implementation of the recommended format, FDA has developed a
technical conformance guide to use in conjunction with this guidance. The REMS Document
Technical Conformance Guide is available on FDA’s website, at https://www.fda.gov/drugs/risk-
evaluation-and-mitigation-strategies-rems/roles-different-participants-rems
As described here, the technical conformance guide contains specific sections and provides
standardized language to describe common REMS requirements. The standardized language was
developed by FDA after review and comparison of existing approved REMS documents,
consideration of stakeholder feedback on REMS documents, and FDA’s experience in reviewing
REMS and implementing its REMS authorities. It is the Agency’s view that where REMS
requirements are the same across REMS, the language used to describe the requirements should
be consistent. FDA recommends that applicants use the standardized language whenever
possible to help ensure consistency and facilitate efficient review of the REMS document. If
alternative language is proposed, FDA recommends that applicants provide an explanation for
their proposed language.
A. 	Administrative Information
The Administrative Information section should include relevant administrative information such
as the application number(s), application holder’s name, the date that the REMS was initially
approved, the date of the most recent revision or modification of the REMS, and the risk(s)
addressed by the REMS.
B. 	REMS Goals
The REMS Goals section should describe the overall, safety-related health outcome(s) that the
REMS is designed to achieve. Because risk mitigation goals cannot always be measured
directly, it is important to also include one or more specific, measurable objectives that, if
achieved, indicate that the REMS is meeting its goals. For example, a REMS for a drug that
causes renal toxicity may include a goal to mitigate the risk of renal failure, and the measurable
objectives could be that patients undergo periodic monitoring of serum creatinine and that
appropriate management steps are undertaken based on the test results.
C. 	REMS Requirements
The REMS Requirements section should establish the requirements of the REMS for both the
REMS participant(s) and the applicant(s). REMS participants are stakeholders who participate
20 Section 505-1 of the FD&C Act (21 U.S.C. 355-1).

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in the REMS based on their role in clinical assessment, prescribing, dispensing, administering, or
monitoring, as well as the distribution process. They can include health care providers who
prescribe, patients who receive the drug, health care settings, practitioners, pharmacies that
dispense, and wholesalers-distributors that distribute.
The REMS Requirements section should be divided into the following subsections:
1. 	REMS Participant Requirements
The REMS Participant Requirements are the activities that REMS participants must
undertake in REMS with ETASU.
If there are no requirements for REMS participants to carry out, the REMS Participant
Requirements section should not be included in a REMS document.
In the REMS document, REMS Participant Requirements should be presented as a series
of tables. There should be a separate table for each type of participant and each table
should be formatted as follows:
1. 	[REMS Participant]
[Timing Category] 	1. 	[REMS Requirement] using [REMS material]
2. 	[REMS Requirement]
[Timing Category] 	3. 	[REMS Requirement]
4. 	[REMS Requirement]
The table describes the participant who is responsible for complying with the
requirement(s), what requirement(s) each participant needs to carry out, when the
participant should perform each requirement(s), and with what REMS material(s). These
items are described in further detail, below.
[REMS Participant]: REMS participants are stakeholders who participate in the REMS
and are described based on their role in clinical assessment, prescribing, dispensing,
administering, or monitoring as well as the distribution process. For example, REMS
participants can include health care providers who prescribe; patients who receive the
drug; health care settings, practitioners, and pharmacies that dispense; and wholesalers-
distributors.
[Timing Category]: The timing category refers to when the participant must carry out
the requirement (e.g., before a patient initiates treatment, during treatment, or after
treatment discontinuation), and generally is associated with either a clinical activity (e.g.,

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initiating treatment or discontinuing treatment), or an administrative activity (e.g.,
becoming certified to prescribe21).
[Requirement]: Participant requirements generally include clinical or administrative
activities that the participant must comply with as part of the REMS. An example of a
clinical requirement is “Monitor the patient for injection site reactions.” An example of
an administrative requirement is “Enroll the patient in the REMS.”22 In addition, some
administrative requirements refer to “documentation of safe use conditions,”23 which are
activities that help ensure that health care providers or patients meet specified criteria
before the drug is dispensed. For example, documentation of safe use conditions can
include verifying that the prescriber is certified or that a required lab test was completed.
[REMS Material(s)]: Materials, such as enrollment forms and educational materials,
refer to the specific documents that participants need to use to comply with a
requirement. They should be included as a hyperlink in the REMS document within the
requirement text that directs readers to the material. 24
2. 	REMS Applicant Requirements
The REMS Applicant Requirements are generally the requirements for applicants to: (1)
develop and provide REMS training; (2) develop and provide packaging and disposal
systems; (3) develop and disseminate REMS communications; (4) support REMS
operations; and (5) ensure participants’ compliance with the REMS. A REMS may
include some or all of these types of requirements.
Requirements related to training can include the requirement for the applicant to develop
REMS training materials, to provide training to health care providers, and to develop a
knowledge assessment for health care providers to complete as part of the training. The
REMS training requirements should include information about how the training is being
provided (e.g., website, mailing, in-person) and whether the training is being provided by
a continuing education provider.
Requirements related to packaging and disposal can include requirements for the
applicant to make a drug available for dispensing in certain packaging (e.g., unit dose) or
implement a requirement that a disposal system be dispensed (for the purpose of
rendering the drug nonretrievable). The packaging and disposal requirements can be
21 Certification requires that health care providers, pharmacies, or health care settings meet certain REMS
requirements to be able to prescribe, dispense, or order a drug. Once the health care provider, pharmacy, or
setting has met these requirements, they are referred to as “certified.” For health care providers who prescribe the
drug, the process for obtaining this certification is referred to as “prescriber certification,” and for health care
providers, pharmacies, and settings that dispense the drug, this process is referred to as “dispenser certification.”
22 For purposes of this guidance, REMS enrollment is the process by which participants provide basic identifying
and demographic information to the REMS program, allowing the applicant to track and communicate with
REMS participants.
23 See section 505-1(f)(3)(D) of the FD&C Act.
24 A comprehensive list of all REMS materials is also included at the end of the REMS document (See section III.E
REMS Materials of this guidance).

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required if they might mitigate a serious adverse event occurring from abuse or
overdose.25
Requirements related to communication can include requirements for the applicant to
develop materials about the REMS and/or the risks and safe use of the drug, and to
disseminate the materials to health care professionals and professional organizations or
societies. The following information should be included: the target audience, the type of
materials to be disseminated, how the materials will be disseminated, the timing of the
dissemination(s) and whether there is any follow-up required.
Requirements related to operations can include requirements for the applicant to develop,
establish, and implement systems and infrastructure (e.g., databases, websites, call
centers, distribution processes) to support the REMS requirements that enable access to
and participation in the REMS.
Requirements related to compliance with the REMS can include requirements for the
applicant to monitor and evaluate REMS participants’ compliance with the REMS and
address any noncompliance to ensure the REMS requirements are being met. For
example, if a REMS includes a requirement for prescribers of a drug to complete training,
the applicant is required to ensure that prescribers comply with the requirement to
complete the training. These requirements include ensuring (e.g., through audits) that all
REMS processes and procedures to support the REMS requirements are in place,
functioning, and are being complied with.
D. 	REMS Assessment Timetable
The REMS Assessment Timetable section of the REMS document should describe the timetable
for submission of assessments of the REMS by the applicant. REMS are generally required to
include a timetable for submission of assessments, and applicants are required to submit
assessments of the REMS at the specified intervals.26
E. 	REMS Materials
The REMS Materials section should provide a comprehensive list of all the materials that are
required for the REMS (e.g., enrollment forms, educational materials, counseling tools,
monitoring forms, and patient-provider agreements). The list should be organized by the REMS
participant(s) to which the materials apply and the type of REMS material.
F. 	Statutory Elements
The Statutory Elements section should provide a list of the elements, as outlined in section 505-1
of the FD&C Act, that FDA has determined are necessary to ensure that the benefits of the drug
outweigh its risks. The list is organized by the order the element appears in the FD&C Act.
25 See section 505-1(e)(4) of the FD&C Act.
26 See section 505-1(d) of the FD&C Act.

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IV. 	PROCEDURES
A. 	Proposed REMS Submissions
Proposed REMS submissions should include two parts: the REMS (REMS document and REMS
materials) and the REMS supporting document.
• 	REMS document and REMS materials:
The REMS document should use the format and content described in section III above. With
the exception of the prescribing information and Medication Guide, the REMS materials
should be appended to the REMS document. Foreign-language versions of REMS materials
are not considered part of the approved REMS, and are not reviewed by FDA.27,,,,,
,28
• 	REMS supporting document:
The REMS supporting document should expand on information in the REMS document, and
provide additional information about the REMS, such as the rationale for and supporting
information about the design, implementation, and assessment of the REMS (e.g., why a
REMS is necessary based on application of the statutory factors,29 how the REMS would
ensure that the benefits of the drug outweigh the risks, implementation processes, compliance
and enforcement policies and procedures, definitions, knowledge assessment analysis
approach, and the REMS assessment plan).
Proposed REMS modifications to convert an already-approved REMS document to the new
format should be submitted in accordance with the procedures outlined in the guidance for
industry, Risk Evaluation and Mitigation Strategies: Modifications and Revisions (June 2020).
FDA does not expect application holders of approved REMS to submit a proposed REMS
modification solely to convert their REMS document to the new format. Changing the REMS
document to the new format should be done in conjunction with other REMS modifications.30,31
B. 	Submission Type
A proposed REMS can be included in the initial submission of an original or supplemental
application (NDA, ANDA, and BLA), or submitted as an amendment to an existing original or
supplemental application. All supplemental applications32 that include a new proposed REMS
should be submitted as prior approval supplements. A proposed REMS submitted after product
27 Consistent with CDER’s approach to foreign-language labeling, when applicants distribute foreign-language
versions of a currently approved REMS, applicants are responsible for ensuring that such materials are complete
and accurate (see 21 CFR 201.15(c)).
28 See manual of policies and procedures 6020.7 Foreign Language Labeling (October 2014).
29 See guidance for industry FDA’s Application of Statutory Factors in Determining When a REMS Is Necessary
(April 2019).
30 See guidance for industry Providing Regulatory Submissions in Electronic Format – Content of Risk Evaluation
and Mitigation Strategies Document Using Structured Product Labeling Format (December 2020).
31 See guidance for industry Risk Evaluation and Mitigation Strategies: Modifications and Revisions (June 2020).
32 See 21 CFR 314.70, 314.97 and 601.12.

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approval and not associated with an existing supplemental application should be submitted as a
new supplemental application.33
C. 	Submission Identification
The first page of a proposed REMS submission should prominently identify the submission as
PROPOSED REMS in bold capital letters at the top of the page. This wording on the first page
of the submission should be combined with any other applicable content identification, for
example:
When the proposed REMS is submitted as part of an original application:
NDA/BLA/ANDA [assigned #]
NEW ORIGINAL APPLICATION FOR <name of drug>
PROPOSED REMS
When the original proposed REMS is submitted as an amendment to an existing original or
supplemental application:
PROPOSED REMS for NDA ######, ANDA ######, BLA ######
PROPOSED REMS for NDA ######/S-000, ANDA ######/S-000, BLA ###### -
AMENDMENT
When the original proposed REMS is submitted postapproval as a new supplemental application:
NEW SUPPLEMENT FOR NDA ######/S-000, ANDA ######/S-000, BLA ######
PRIOR APPROVAL SUPPLEMENT
PROPOSED REMS
When the original proposed REMS is submitted postapproval with a new supplemental
application:
NEW SUPPLEMENT FOR NDA ######/S-000, BLA ######
PRIOR APPROVAL SUPPLEMENT
PROPOSED REMS
On the first page of subsequent submissions related to an already-submitted proposed REMS,
prominently identify the submission by including this wording in bold capital letters at the top of
the letter:
PROPOSED REMS for NDA ######, ANDA ######, BLA ###### -AMENDMENT
33 For instructions on submission of REMS modifications, see the guidance for industry Risk Evaluation and
Mitigation Strategies: Modifications and Revisions (June 2020).

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D. 	Posting REMS Documents on the FDA Website
All approved REMS documents and their approved REMS materials are posted on FDA’s
website.34 REMS supporting documents are not made available on FDA’s website.
34 Available at https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm.