Providing Regulatory 
Submissions in Electronic 
Format  Content of the Risk 
Evaluation and Mitigation 
Strategies Document Using 
Structured Product Labeling 
 
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) 
 
December 2020 
Electronic Submissions 
   
Providing Regulatory 
Submissions in Electronic 
Format  Content of the Risk 
Evaluation and Mitigation 
Strategies Document Using 
Structured Product Labeling 
 
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 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002 
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) 
 
December 2020 
Electronic Submissions 
  Contains Binding Provisions 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  REQUIREMENT TO SUBMIT ELECTRONICALLY UNDER THIS GUIDANCE 2 
A.  Types of Submissions That Must Adhere to the Electronic Submission Requirement 
Described in This Guidance ................................................................................................................... 2 
B.  Requirements That Must Be Followed for Electronic Submission of the Content of REMS 
Documents ............................................................................................................................................... 3 
C.  Types of Submissions That Are Exempt From the Electronic Submission Requirement 
Described in This Guidance ................................................................................................................... 4 
D.  SPL Specifications .......................................................................................................................... 4 
E.  Contact Information ...................................................................................................................... 4 
i  Contains Binding Provisions 
Providing Regulatory Submissions in Electronic Format  Content 
of the Risk Evaluation and Mitigation Strategies Document Using 
Structured Product Labeling  
Guidance for Industry1 
 
 
I.  INTRODUCTION  
 
Under section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 
379k-1(a)), beginning no earlier than 24 months after the issuance of this final guidance in which 
the Food and Drug Administration (FDA or Agency) has specified the electronic format for 
submitting certain submission types to the Agency, the content of such submission types must be 
submitted electronically and in the format specified by FDA.  This guidance describes the format 
requirements for the electronic submission of the content of a risk evaluation and mitigation 
strategy (REMS) document2 under section 745A(a) of the FD&C Act. This guidance describes 
how FDA will implement the requirements for the electronic submission of REMS documents as 
part of submissions under new drug applications (NDAs), abbreviated new drug applications 
(ANDAs), and, as described in Section III below, certain biologics license applications (BLAs).  
Consistent with section 745A(a) of the FD&C Act, beginning 24 months after the issuance of 
this final guidance, REMS documents must be submitted to FDA in SPL format.  
 
In section 745A(a) of the FD&C Act, Congress granted explicit authorization to FDA to 
implement the statutory electronic submission requirements in guidance.  Accordingly, as 
indicated by the use of the words must or required, this guidance establishes legally enforceable 
responsibilities3 and is not subject to the usual restrictions in FDAs good guidance practices 
(GGP) regulation (see 21 CFR 10.115(d)).  To comply with the GGP regulations and make sure 
that regulated entities and the public understand that guidance documents are nonbinding, FDA 
guidances ordinarily contain standard language explaining that guidance documents should be 
viewed only as recommendations unless specific regulatory or statutory requirements are cited.  
FDA is not including this standard language in this guidance because it is not an accurate 
description of all the effects of this guidance.  This guidance specifies the format for electronic 
submission of REMS documents under section 745A(a) of the FD&C Act, and will have binding 
effect 24 months from the date the notice of availability for this guidance is published in the 
Federal Register. 
 
 
                                                 
1 This guidance has been prepared by the Center for Drug Evaluation and Research and the Center for Biologics 
Evaluation and Research (CBER) at the Food and Drug Administration.  
2 See page 3 for more detail on which component of a REMS submission needs to be submitted in SPL format.  
3 See also guidance for industry Providing Regulatory Submissions in Electronic Format  Submissions Under 
Section 745A(a) of the Federal Food, Drug, and Cosmetic Act (December 2014). We update guidances periodically.  
To make sure you have the most recent version of a guidance, check the FDA Drugs Guidance website at 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.  
 
  1 Contains Binding Provisions 
II.  BACKGROUND 
 
FDA engaged stakeholders over a 3-year time frame and analyzed their feedback regarding 
REMS standardization.  The Agencys findings were published as a report: Standardizing and 
Evaluating Risk Evaluation and Mitigation Strategies (REMS).4 As the report describes, some 
stakeholders expressed concern about the clarity and consistency with which information about 
REMS materials and requirements are communicated to stakeholders.  They told FDA that 
REMS materials and requirements may be difficult to locate, and that specific activities and 
requirements of various stakeholders (e.g., prescriber, pharmacist) are not always clearly 
outlined.  Some stakeholders expressed the need to have better ways to integrate REMS 
materials and procedures into their existing health information systems and health care delivery 
processes.  Stakeholders also expressed the desire to avoid spending excessive time trying to 
locate, understand, and comply with different REMS requirements while ensuring safe use of 
drugs with REMS.  To help address these concerns, applicants of NDAs, ANDAs, and certain 
BLAs will be required to submit the content of their REMS documents in Structured Product 
Labeling (SPL) format. SPL can be used to capture and present REMS information in a format 
that is easily shared with stakeholders and readily incorporated into health information 
technology.  For more general background information on REMS, as well as a more 
comprehensive discussion of the issues mentioned in this paragraph, please refer to the 
Background Materials for the July 2013 REMS Standardization and Evaluation Public 
Meeting.5 
 
 
III.  REQUIREMENT TO SUBMIT ELECTRONICALLY UNDER THIS GUIDANCE 
 
Twenty-four months after the publication of this guidance in the Federal Register, applicants 
must submit REMS documents in electronic format consistent with the requirements set forth 
below. 
 
A.  Types of Submissions That Must Adhere to the Electronic Submission 
Requirement Described in This Guidance  
 
Section 745A(a) of the FD&C Act applies to submissions under section 505(b), (i), or (j) of the 
FD&C Act (21 U.S.C. 355(b), (i), or (j)) and under section 351(a) or (k) of the Public Health 
Service Act (PHS Act) (42 U.S.C. 262(a) or (k)).  For the purposes of this guidance, these 
submissions include the following types: 
 
  NDAs 
  ANDAs 
                                                 
4 Available at: http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM415751.pdf. 
5 Available at: http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM362078.pdf. 
 
  2 Contains Binding Provisions 
  Certain BLAs6,7 
 
As stated in the guidance for industry Providing Regulatory Submissions in Electronic Format 
Submissions Under Section 745A(a) of The Federal Food, Drug, and Cosmetic Act, [s]ection 
745A(a) also applies to all subsequent submissions, including amendments, supplements, and 
reports, to the submission types identified above.  Because they are part of a drugs approval, 
REMS submissions are submissions under section 505(b), (i), or (j) of the FD&C Act or under 
section 351(a) or (k) of the PHS Act.  Therefore, REMS submissions fall within the scope of 
requirements set forth in section 745A(a) of the FD&C Act. 
 
Applicants must submit the content of their REMS document electronically using the format 
described in this guidance beginning 24 months from the date the notice of availability for this 
guidance is published. Accordingly, because the guidance issued on the date of publication of the 
notice of availability, December 28, 2020, all REMS documents submitted to FDA on or after 
December 28, 2022 must be in SPL format.  This would include REMS documents associated 
with new REMS as well as REMS documents submitted as part of REMS modifications.  In 
addition, beginning December 28, 2022, REMS revision submissions that include REMS 
documents that are already in SPL format must remain in SPL format, while REMS revision 
submissions that include REMS documents that have not yet been converted to SPL format do 
not need to be converted to SPL format until their next modification is submitted. 
 
 
B.  Requirements That Must Be Followed for Electronic Submission of the 
Content of REMS Documents 
 
Under section 745A(a) of the FD&C Act, electronic submissions shall be submitted in such 
electronic format as specified by [FDA].  This guidance addresses electronic submission 
requirements for certain documents that are part of a REMS.  A REMS document, which is part 
of the REMS that is approved by FDA, concisely describes the goals and requirements of the 
REMS.  FDA has determined that the content of a REMS document must be submitted 
electronically in SPL format, using specifications outlined in the FDA Data Standards Catalog.8  
REMS materials are all materials that are included as part of the REMS (e.g., communication and 
educational materials, enrollment forms, prescriber and patient agreements) that are also 
approved and enforceable, and are appended to the REMS document.  REMS materials must be 
                                                 
6 This guidance does not apply to those devices that are regulated by CBER as biological products under section 351 
of the PHS Act, including those that do not require the submission of an investigational new drug application before 
the submission of a BLA. Although a discussion of which devices CBER regulates as biological products under 
section 351 of the PHS Act is outside the scope of this guidance, as a general matter, this category would include 
those reagents used in determining donor/recipient compatibility in transfusion medicine.  
7 Specifically, this guidance is not applicable to submissions for blood and blood components, including Source 
Plasma. 
8 The most current version of the Data Standard Catalog is available at https://www.fda.gov/industry/fda-resources-
data-standards.   
 
  3 Contains Binding Provisions 
referenced in the SPL file.  REMS supporting documents9are not required to be submitted in SPL 
format.  The table below shows which components of a REMS will be required to be filed in 
SPL format.  Additional details for creating REMS document SPL files for submission to FDA 
can be found in the Structured Product Labeling (SPL) Implementation Guide with Validation 
Procedures (SPL Implementation Guide) on FDAs SPL website.10  Details for the placement of 
the REMS document SPL files in the Electronic Common Technical Document (eCTD) can be 
found in the eCTD Technical Conformance Guide.11   
 
 
Component of a REMS Submission  Submitted in SPL Format? 
REMS document  Yes
REMS supporting document  No
REMS materials   Referenced in SPL file12 
 
 
C.  Types of Submissions That Are Exempt From the Electronic Submission 
Requirement Described in This Guidance  
 
Section 745A(a) of the FD&C Act allows FDA to establish exemption and waiver criteria from 
the electronic submission requirements. For a discussion of current exemption and waiver 
criteria, please see Guidance for Industry, Providing Regulatory Submissions in Electronic 
FormatCertain Human Pharmaceutical Product Applications and Related Submissions Using 
the eCTD Specifications (Revision 7, February 2020).    
 
D.  SPL Specifications  
 
Applicants must submit electronic submissions using the version of SPL currently supported by 
FDA as specified in the FDA Data Standards Catalog13 and further described in the SPL 
Implementation Guide. 
 
E.  Contact Information 
 
For questions about providing electronic submissions according to the requirements in this 
guidance, you should contact FDAs REMS Web site management team at 
FDAREMSwebsite@fda.hhs.gov.  Specific questions about the content of applications should be 
directed to the appropriate review division or office. 
                                                 
9 For purposes of this guidance, a REMS supporting document is a document that 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. 
10 Available at: 
https://www.fda.gov/downloads/ForIndustry/DataStandards/StructuredProductLabeling/UCM321876.pdf. 
11 Available at: https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-
technical-document-ectd. 
12 See SPL Implementation Guide for more information. 
13  Available at: https://www.fda.gov/industry/fda-resources-data-standards.  
  4