Use of a Drug Master File for  
Shared System REMS Submissions
 
 
Guidance for Industry 
 
 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Gita Toyserkani 301-796-1783 or 
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010. 
 
 
 
 
 
 
 
 
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) 
 
November 2017 
Procedural 
 
   
Use of a Drug Master File for  
Shared System REMS Submissions
 
 
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  
https://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/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
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) 
 
November 2017 
Procedural
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  OVERVIEW OF THE SSR DMF ................................................................................... 4 
A.  Ownership of the SSR DMF.......................................................................................................... 4 
B.  Establishing the SSR DMF ............................................................................................................ 4 
C.  Authorization To Refer to the SSR DMF .................................................................................... 5 
D.  Contents of the SSR DMF ............................................................................................................. 5 
E.  Communication About the SSR DMF .......................................................................................... 6 
IV.  CROSS-REFERENCE SUBMISSIONS FOR SSR APPLICANTS ............................ 6 
V.   CONTACT INFORMATION .......................................................................................... 8 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Use of a Drug Master File for  
2  Shared System REMS Submissions 
3   
1
4  Guidance for Industry  
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page.   
12   
13   
14   
15   
16  I.  INTRODUCTION  
17   
18  This guidance provides recommendations for applicants that are part of a shared system risk 
19  evaluation and mitigation strategy (REMS) on using an electronic Type V2 Drug Master File 
20  (DMF)3 for shared system REMS (SSR) submissions. The recommendations in this guidance are 
21  intended to improve the efficiency of submitting SSR to the Agency.4   
22  The use of a DMF is not a requirement for SSRs.  However, if applicants that are subject to and 
23  participating in an SSR choose to use a DMF, this guidance provides an overview of a 
24  recommended approach for their SSR submissions.  Additional and more-detailed submission 
25  instructions are included in a separate technical guide, Technical Conformance Guide for Shared 
26  System REMS Drug Master File Submissions (the SSR DMF Technical Conformance Guide), 
27  which will be updated periodically.5 
                                                 
1 This guidance has been prepared by the Office of Medication Error Prevention and Risk Management, Office of 
Surveillance and Epidemiology, in collaboration with other Offices in the Center for Drug Evaluation and Research 
and with the Center for Biologics Evaluation and Research (CBER), at the Food and Drug Administration.  
 
2 Type V FDA-Accepted Reference Information DMF. 
 
3 21 CFR 314.420(a)(5). 
 
4 This guidance discusses DMF submissions for the following products: drug products marketed for human use with 
approved new drug applications (NDAs) and abbreviated new drug applications (ANDAs), and biological products 
marketed for human use with approved biologics license applications (BLAs).  
 
5 To make sure you have the most recent version of the SSR DMF Technical Conformance Guide, check the FDA 
website at 
https://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/electronicsubmissions/ucm5
35180.htm. 
 
 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
28  If SSR applicants choose to use the DMF, as of the date specified by FDA, they must submit the 
29  DMFs in the Electronic Common Technical Document (eCTD) format, as previously stated in 
30  the guidance for industry on Providing Regulatory Submissions in Electronic Format  Certain 
31  Human Pharmaceutical Product Applications and Related Submissions Using the eCTD 
32  Specifications (Revision 4).6   
33  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
34  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
35  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
36  the word should in Agency guidances means that something is suggested or recommended, but 
37  not required.  
38   
39   
40  II.  BACKGROUND 
41   
42  A REMS is a required risk management plan that uses tools beyond the FDA-approved 
43  prescribing information to ensure that the benefits of certain drugs7 outweigh their risks.8  FDA 
44  can, under certain circumstances,9 require that the REMS for a drug include one or more 
45  elements to assure safe use (ETASU).10  When ETASUs are required for an innovator drug, any 
46  abbreviated new drug application (ANDA)11 referencing that innovator drug must use an SSR 
47  with the innovator (unless FDA waives the requirement for using a shared system).12  There are 
48  also circumstances under which multiple applicants form an SSR to minimize the burden on the 
49  health care delivery system, such as for a class of similar products.  
________________________ 
 
6 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
or the FDA Biologics guidance web page at  
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryinformation/Guidances/default.htm. 
  
7 For the purpose of this guidance, unless otherwise specified, references to drugs include drugs submitted for 
approval or approved under section 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 (PHS 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)). 
 
8 Section 505-1 of the FD&C Act (21 U.S.C. 355-1), as amended by the Food and Drug Administration 
Amendments Act of 2007. 
 
9 Section 505-1(f)(1) of the FD&C Act. 
 
10 Section 505-1(f)(3) of the FD&C Act. 
 
11 Abbreviated new drug application (ANDA) refers to an application submitted or approved under section 505(j) of 
the FD&C Act. 
 
12 Section 505-1(i)(1)(B) of the FD&C Act. 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
50  A DMF is a voluntary submission that may be used to provide confidential detailed information 
51  to the Agency.13  The DMF holder may authorize other applicants to reference information in the 
52  holders DMF.  A DMF is submitted solely at the discretion of the DMF holder, and the 
53  technical contents of a DMF are customarily reviewed by FDA only in connection with the 
54  review of an application.  There are several types of DMFs; a Type V is used for FDA-accepted 
55  reference information.14 
56  As part of an SSR, multiple applicants need to coordinate the submission of identical REMS-
57  related documents by each applicant to its own application.  To improve the efficiency of the 
58  submission and review process for SSRs, FDA recommends that applicants use a Type V DMF 
59  for their SSR submissions.  As noted above, as of the date specified by FDA, applicants who 
60  choose to use a Type V DMF for an SSR must make the DMF submissions electronically, as 
61  required in the binding guidance for industry on Providing Regulatory Submissions in Electronic 
62  Format  Certain Human Pharmaceutical Product Applications and Related Submissions Using 
63  the eCTD Specifications (Revision 4). 
64  In addition to the recommendations provided in this guidance, FDA advises stakeholders to refer 
65  to other relevant FDA resources to help create their submissions, such as the following: 
66   
67    Technical Conformance Guide for Shared System REMS Drug Master File Submissions15  
68   
69    Guideline for Drug Master Files16 
70   
71    FDAs DMF web page17  
72   
73    Draft guidance for industry Format and Content of a REMS Document18 
                                                 
13 Confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, 
packaging, and storing of one or more human drugs (see Guideline for Drug Master Files, available at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/
ucm073164.htm).  
 
14 21 CFR 314.420(a)(5). 
 
15 SSR DMF Technical Conformance Guide is available at 
https://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/electronicsubmissions/ucm5
35180.htm. 
 
16Available at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/
ucm073164.htm. 
 
17 See the FDA DMF web page for additional DMF information including various letter templates (e.g., letter of 
authorization), at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/
default.htm. and at 
https://www.fda.gov/biologicsbloodvaccines/developmentapprovalprocess/newdrugapplicationndaprocess/ucm2116
04.htm. 
 
18 When final, this guidance will represent FDAs current thinking on this topic. 
 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
74   
75    Guidance for industry Risk Evaluation and Mitigation Strategies: Modifications and 
76  Revisions 
77   
78   
79  III.  OVERVIEW OF THE SSR DMF 
80    
81  This section provides an overview of how a Type V DMF can be used for an SSR (SSR DMF).  
82  Detailed submission instructions for each type of REMS submission or cross-reference 
83  submission to the SSR DMF (e.g., minor REMS modification, REMS assessment) are provided 
84  in the SSR DMF Technical Conformance Guide, which will be updated periodically.19  
85  A.  Ownership of the SSR DMF 
86  The owner of the SSR DMF is the DMF holder who is jointly designated by the SSR applicants. 
87  Only one company should be listed as the DMF holder.  The DMF holder will make submissions 
88  to the DMF on behalf of the SSR applicants.  Therefore, FDA will consider any submission to 
89  the SSR DMF to represent the views of the participating SSR applicants.  
90  B.  Establishing the SSR DMF  
91  As with any Type V DMF, the DMF holder must submit a letter of intent to the FDA DMF staff 
92  at dmfquestion@fda.hhs.gov to request preclearance.20  The letter should include the name of the 
93  FDA project manager who has been assigned as the point-of-contact for the SSR in addition to 
94  the necessary information that should be included in the request.21 
95  The DMF holder should also request from FDA a pre-assigned DMF number for the new 
96  DMF.22  Once the number is obtained, the DMF holder should submit a DMF Original 
97  submission containing a cover letter and complete administrative and technical information (e.g., 
________________________ 
 
19 See footnote 15. 
 
20 21 CFR 314.420(a)(5). 
 
21 See 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/
default.htm. 
 
22 See 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/u
cm114027.htm). See CBER SOPP 8117: 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm1
09641.htm.  
 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
98  the SSR submission that is the subject of the DMF) in the appropriate sections of the eCTD 
99  format.23  
100  C.  Authorization To Refer to the SSR DMF 
101  The DMF holder must submit letters of authorization (LOAs) to the DMF that permit FDA to 
102  review information in the DMF in support of the SSR applicants applications.24  The DMF 
103  holder should submit a separate LOA to the DMF for each SSR applicant.  If an SSR applicant is 
104  also the DMF holder, an LOA should still be submitted to the DMF.  The DMF holder does not 
105  need to submit a new LOA for each new submission to the DMF unless there is a change in the 
106  DMF holder name or the authorized party name.   
107  The DMF holder should also send a copy of the LOA to each SSR applicant who has been 
108  authorized to incorporate the information contained in the DMF by reference.  Each SSR 
109  applicant should then submit the copy of the LOA to its own application.25  SSR applicants only 
110  need to submit this LOA to their application one time unless there is a change in the DMF holder 
111  name or the authorized party name. 
112  D.  Contents of the SSR DMF  
113  In general, only information related to the SSR should be submitted, through the DMF holder, to 
114  the SSR DMF.  Information that is application-specific should be submitted by an applicant to its 
115  own individual application. 
116  Items that should be submitted to the SSR DMF include, but are not limited to, the following: 
117    The REMS Document26 
118    The REMS Materials  
119    The REMS Supporting Document 
                                                 
23 See section IV.B. Administrative Information of the Guideline for Drug Master Files, available at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/
ucm073164.htm. 
 
24 21 CFR 314.420(b); see also section V.A. Letter of Authorization to FDA of the Guideline for Drug Master Files, 
available at  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/
ucm073164.htm. 
 
25 See section V.B Copy to Applicant, Sponsor, or Other Holder of the Guideline for Drug Master Files, available at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/
ucm073164.htm. 
 
26 See draft guidance for industry Format and Content of a REMS Document. When final, this guidance will 
represent FDAs current thinking on this topic. 
 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
120    REMS Assessment Methodologies and REMS Assessments27  
121    REMS Correspondence  
122    REMS History 
123    Any interim versions of documents that need FDAs review  
124    Any responses to FDA requests for information concerning the SSR 
125    Documents that are submitted to all DMFs, such as the DMF Amendments and LOAs 
126  Items that should not be submitted to the SSR DMF (and instead should be submitted to each 
127  applicants individual application) include, but are not limited to, the following: 
128    Labeling, including Medication Guides that are part of a REMS (See section IV of this 
129  document, Cross-Reference Submissions for SSR Applicants) 
130    Product-specific information, such as REMS Assessment Adverse Event summaries28 
131    REMS changes29 that apply to only one application in the SSR (e.g., efficacy supplement 
132  for new indication for use) 
133  E.  Communication About the SSR DMF  
134  FDA will contact the DMF holder regarding DMF technical issues and questions about the 
135  administrative content (e.g., information in eCTD section 1.4).  FDA will contact the SSR 
136  applicants designated point-of-contact30 with questions about the REMS content in the DMF 
137  (e.g., information in eCTD section 1.16).  It is up to the SSR applicants to decide who else, if 
138  anyone, should be involved in each of these types of discussions. 
139   
140   
141  IV.  CROSS-REFERENCE SUBMISSIONS FOR SSR APPLICANTS 
142   
                                                 
27 FDA may ask applicants to submit product-specific adverse event summaries as part of a REMS assessment. 
These product-specific summaries should be submitted to each applicants individual application, and not to the SSR 
DMF.  
 
28 See footnote 27. 
 
29 See guidance for industry Risk Evaluation and Mitigation Strategies: Modifications and Revisions. 
   
30 Early in the SSR development process, and to facilitate communication between FDA and the SSR applicants, 
FDA asks the SSR applicant group to designate a single point-of-contact for their group. 
 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
143  For the purposes of this guidance, a cross-reference submission is the submission that an SSR 
144  applicant will make to its individual application to incorporate by reference information that the 
145  DMF holder has submitted to the SSR DMF.31  
146  This section provides a brief overview of cross-reference submissions.   
147    A cross-reference submission will be needed after any of the following has been 
148  submitted to the SSR DMF: 
149    REMS Original 
o
150    Minor REMS Modification 
o
151    Major REMS Modification 
o
152    REMS Modification Due to Safety Label Changes 
o
153    REMS Revision 
o
154    REMS Assessment32  
o
155  The cross-reference submission for a REMS Original,33 minor REMS modification, 
156  major REMS modification, and REMS modification due to safety label changes should 
157  be submitted to the individual application as an amendment, if applicable, or a 
158  supplement.  Submissions of REMS revisions34 and REMS assessments are not 
159  supplemental applications. Therefore, the cross-reference submissions should also not be 
160  submitted as supplements.  
                                                 
31 The cross-reference submission serves to incorporate the material in the DMF by reference. See section VI.B of 
the Guideline for Drug Master Files, available at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/
ucm073164.htm.  
 
32 To the extent that REMS Assessments are not required for ANDAs, a cross-reference submission for REMS 
Assessments is also not required; see section 505-1(g) of the FD&C Act. 
 
33 If the REMS Original submission is part of the Original Application, the cross-reference submission will be an 
amendment to a pending application. 
 
34 See guidance for industry Risk Evaluation and Mitigation Strategies: Modifications and Revisions.   
 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
161    A cross-reference submission will not be needed after the following have been submitted 
162  to the SSR DMF: 
163    REMS Assessment Methodology 
o
164    REMS Correspondence 
o
165    Interim versions of REMS documents, REMS materials, or REMS supporting 
o
166  documents 
167    Responses to FDA Requests for Information  
o
168   
169    In most cases, the cross-reference submission will only include a cover letter, Form FDA 
170  356h, and, as applicable, a Medication Guide.35  
171    An SSR applicant should submit a copy of the DMF holders LOA to its application 
172  either before or at the time of the applicants first cross-reference submission.  As 
173  previously described in section III.C Authorization To Refer to the SSR DMF, the SSR 
174  applicant should submit this LOA only once, unless there is a change in the DMF holder 
175  name or the authorized party name.  
176    To facilitate tracking of the cross-reference submissions, FDA recommends that SSR 
177  applicants submit their cross-reference submissions as soon as possible after the DMF 
178  holder has made the corresponding submission to the SSR DMF.  In addition, FDA 
179  recommends that SSR applicants work together to make their cross-reference 
180  submissions on the same day. 
181   
182   
183  V.   CONTACT INFORMATION 
184   
185  For questions about providing electronic submissions according to the recommendations in this 
186  guidance, you should contact FDAs REMS Team at REMS@fda.hhs.gov for CDER products, 
187  and contact Review Management at ESUBPREP@fda.hhs.gov for CBER products.  Specific 
188  questions about the content of applications should be directed to the appropriate review division 
189  or office. 
                                                 
35 Medication Guides that are part of a REMS should be included in each applicants cross-reference submission to 
its NDA/BLA/ANDA. Please note that if changes have been made to the Medication Guide that is part of a REMS, a 
REMS supplement should be submitted to the application, as well as a cross reference to the DMF. If a product has a 
Medication Guide that is not part of the REMS, it does not need to be included in any REMS submission.  
  8