Development of a 
Shared System REMS  
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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), Lubna Merchant, Office of 
Surveillance and Epidemiology, at 301-796-5162 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) 
 
June 2018 
Drug Safety
   
Development of a 
Shared System REMS 
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) 
 
June 2018 
Drug Safety
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  Overview of Risk Evaluation and Mitigation Strategies (REMS) ............................................. 2 
B.  Overview of Shared System REMS .............................................................................................. 3 
C.  Benefits of a Shared System REMS.............................................................................................. 3 
D.    Required Use of a Single, Shared System REMS for ANDAs and RLD ................................... 4 
E.    Recommended Use of a Shared System REMS in Other Situations ......................................... 4 
III.  DEVELOPING A SHARED SYSTEM REMS PROGRAM ........................................ 4 
A.  Notification From FDA That a Shared System REMS Is Required or Recommended .......... 5 
B.  Formation of an Industry Working Group ................................................................................. 5 
C.  FDA Role ........................................................................................................................................ 6 
IV.  SHARED SYSTEM REMS ASSESSMENTS ................................................................ 6 
V.  SUBMISSION PROCEDURES ....................................................................................... 6 
A.  General Considerations ................................................................................................................. 7 
B.  Timing of Initial Shared System REMS Submission .................................................................. 7 
C.  RLD Submission of a Bifurcated REMS.................................................................................. 8 
D.  Submission to FDA Using a Type V Drug Master File ............................................................... 8 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
1  Development of a Shared System REMS  
2  Guidance for Industry1 
3   
4  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
5  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
6  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
7  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
8  for this guidance as listed on the title page.   
9   
10   
11   
12   
13  I.  INTRODUCTION  
14   
15  This guidance provides recommendations to industry on the development of a shared system risk 
16  evaluation and mitigation strategy (REMS)2 for multiple prescription drug (including biological) 
17  products.3  This guidance describes some of the possible benefits of a shared system REMS, and 
18  provides general principles and recommendations to assist industry with the development of 
19  these programs.  This guidance does not discuss the process for requesting a waiver of the single, 
20  shared system REMS requirement that applies to abbreviated new drug applications (ANDAs) 
21  referencing a listed drug with an approved REMS.4  FDA issued a separate guidance describing 
22  the process for requesting waivers and the criteria FDA applies in considering them.5 
23   
24  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
25  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
26  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
                                                 
1 This guidance has been prepared by the Office of Surveillance and Epidemiology, Office of New Drugs, Office of 
Generic Drugs, and Office of Regulatory Policy in the Center for Drug Evaluation and Research (CDER), in 
cooperation with the Center for Biologics Evaluation and Research (CBER), at the Food and Drug Administration.  
2 A shared system REMS encompasses multiple prescription drug products and is developed and implemented 
jointly by two or more applicants. 
3 For purposes of this guidance, unless otherwise specified, references to drugs and drug products include 
prescription 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 submitted for licensure or 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)).  
4 See section 505-l(i)(l)(B) of the FD&C Act (21 U.S.C. 355-1(i)(1)(B)). 
5 See the draft guidance for industry Waivers of the Single, Shared System REMS Requirement.  We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs 
guidance web page (available at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm) or Biologics 
guidance web page  
(available at 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).  
When final, this guidance will represent FDAs current thinking on this topic. 
 
1 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
27  the word should in Agency guidances means that something is suggested or recommended, but 
28  not required.  
29   
30   
31  II.  BACKGROUND 
32   
33  A.  Overview of Risk Evaluation and Mitigation Strategies (REMS) 
34   
35  The Food and Drug Administration Amendments Act of 2007 (FDAAA)6 created section 505-1 
36  of the FD&C Act, which authorizes FDA to require a REMS if FDA determines that a REMS is 
37  necessary to ensure that the benefits of the drug outweigh its risks.7  A REMS is a required risk 
38  management strategy that employs tools beyond prescribing information to ensure that the 
39  benefits of a drug outweigh its risks.  A REMS may require a Medication Guide (or patient 
40  package insert) to provide risk information to patients8 and/or a communication plan to 
41  disseminate risk information to health care providers.9  FDA may also require certain Elements 
42  To Assure Safe Use (ETASU) when such elements are necessary to mitigate specific serious 
43  risks associated with a drug.10  ETASU may include, for example, requirements that health care 
44  providers who prescribe the drug have particular training or experience, that patients using the 
45  drug be monitored, or that the drug be dispensed to patients with evidence or other 
46  documentation of safe-use conditions.   
47   
48  Certain REMS with ETASU may also include an implementation system through which the 
49  applicant is able to monitor and evaluate implementation of the ETASU and work to improve 
50  their implementation.11  Finally, REMS generally must have a timetable for submission of 
51  assessments of the strategy.12   
52   
53  FDA can require a REMS before initial approval of a new drug application (NDA) or, should 
54  FDA become aware of new safety information13 about a drug and determine that a REMS is 
55  necessary to ensure that the benefits of the drug outweigh its risks, after the drug has been 
56  approved.14  
57   
                                                 
6 Public Law 110-85.  
7 Section 505-1(a) of the FD&C Act. 
8 Section 505-1(e)(2) of the FD&C Act. 
9 Section 505-1(e)(3) of the FD&C Act. 
10 Section 505-l(f)(3) of the FD&C Act. 
11 Section 505-1(f)(4) of the FD&C Act. 
12 Section 505-1(d) of the FD&C Act. 
13 Section 505-1(b)(3) of the FD&C Act. 
14 Section 505-1(a) of the FD&C Act. 
2 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
58  B.  Overview of Shared System REMS 
59   
60  A shared system REMS encompasses multiple prescription drug products and is developed and 
61  implemented jointly by two or more applicants.15  A REMS that includes more than one product 
62  but only a single applicant is not considered a shared system REMS.  A shared system REMS 
63  can be a program shared by a drug that is the subject of an abbreviated new drug application 
64  (ANDA) and the listed drug, as required in section 505-1(i)(1)(B) of the FD&C Act (described in 
65  subsection I.D below).  It can also involve multiple NDAs or ANDAs, submitted under section 
66  505(b)(1), (b)(2), or (j) of the FD&C Act, or multiple biologics license applications (BLAs), 
67  submitted under section 351(a) or (k) of the PHS Act, that form a shared system voluntarily 
68  (described in subsection I.E below). 
69   
70  A shared system REMS uses a single REMS document,16 supporting document, and REMS 
71  materials, agreed to by all applicants and approved as part of each application.  Applicants 
72  generally share in the implementation and maintenance of any database and infrastructure (e.g., 
73  call center) used for the program, and are jointly responsible for carrying out all or most 
74  components of the REMS assessments (see section IV below).  There may be product-specific 
75  materials (e.g., Medication Guide) that will not be shared across applicants. 
76   
77  C.  Benefits of a Shared System REMS 
78   
79  A shared system for REMS with ETASU may offer benefits to drug applicants and stakeholders 
80  in the health care delivery system.  The benefits may vary, but generally stem from opportunities 
81  for increased efficiencies for stakeholders and applicants.   
82   
83  Impact on Drug Applicants.  Use of a shared system REMS may benefit the applicants by 
84  providing opportunities for sharing the cost of developing and implementing the program, 
85  analyses of adverse events or other safety data, and periodic assessments to determine whether 
86  the REMS is meeting its intended risk management goal(s).  A shared system may also make 
87  modifying a REMS that encompasses multiple products and adding other applicants to the 
88  REMS more efficient. 
89   
90  Impact on Health Care Providers and Patients.  A shared system REMS generally uses a shared 
91  infrastructure for all of the products in the REMS.  This generally provides a single portal for 
92  REMS participants17 to engage in and undertake the activities of the program.  For example, 
                                                 
15 For the purpose of this guidance, applicants includes any person that holds an application approved under section 
505 of the FD&C Act or a license issued under section 351 of the PHS Act for such product, or who submits an 
NDA, an ANDA, a BLA, or an amendment or supplement to an NDA, an ANDA, or a BLA to obtain FDA 
approval.  
16 See the draft guidance for industry Format and Content of a REMS Document.  When final, this guidance will 
represent FDAs current thinking on this topic.   
17 REMS participants are stakeholders who participate in the REMS based on their role in clinical assessment; 
prescribing, dispensing, administering the product; monitoring treatment; or in the distribution process. REMS 
participants can include health care providers who prescribe, patients who receive the drug, health care settings, 
practitioners, pharmacies that dispense, and wholesalers/distributors that distribute. 
 
3 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
93  prescribers and pharmacists can complete certification and other administrative requirements 
94  once for multiple drugs, rather than separately for each individual drug.  A shared infrastructure 
95  can also allow for a single set of REMS materials and information about the program.  
96   
97  D.    Required Use of a Single, Shared System REMS for ANDAs and RLD 
98   
99  As noted above, section 505-l(i)(l)(B) of the FD&C Act requires that a holder of an ANDA 
100  approved under section 505(j) use a single, shared system with the reference listed drug (RLD) 
101  for any ETASU, unless FDA waives this requirement and permits the ANDA to use a separate, 
102  comparable aspect of the ETASU.18  
103   
104  E.    Recommended Use of a Shared System REMS in Other Situations  
105   
106  The requirement under section 505-1(i)(1)(B) regarding a single, shared system only applies to 
107  ANDAs.  However, FDA recognizes that it may be in the interest of public health to have a 
108  shared system REMS in other cases because it may increase efficiencies for applicants and 
109  stakeholders.   
110   
111  For example, we recommend the applicants for a product submitted under section 505(b)(2) of 
112  the FD&C Act or section 351(k) of the PHS Act work together with the applicant for the product 
113  they are referencing to establish a shared system REMS.  If an applicant of a product submitted 
114  under section 505(b)(2) of the FD&C Act or section 351(k) of the PHS Act seeks to develop a 
115  shared system REMS, we encourage the applicant to contact the applicant of the product they are 
116  referencing and begin joint development of the shared system REMS as early as possible.  
117   
118  Additionally, FDA may request that applicants for a class of products with a similar risk profile 
119  develop a shared system REMS.  Applicants that are interested in developing a shared system 
120  REMS for a class of products should seek the advice of FDA.19 
121   
122   
123  III.  DEVELOPING A SHARED SYSTEM REMS PROGRAM 
124   
125  This section outlines the process and recommendations for developing a shared system REMS 
126  program. 
127   
                                                 
18 For more information on waivers of the single, shared system requirement in section 505-1(i)(1)(B), see the draft 
guidance for industry Waivers of the Single, Shared System REMS Requirement.  This guidance, when final, will 
represent FDAs current thinking on this topic. 
19 See the guidance for industry Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or 
Applicants.  See also the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants 
of PDUFA Products.  When final, this guidance will represent FDAs current thinking on this topic. 
 
4 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
128  A.  Notification From FDA That a Shared System REMS Is Required or 
129  Recommended 
130   
131  FDA will initiate discussions about the formation of a shared system REMS under the following 
132  circumstances: 
133   
134    When FDA has received an ANDA that references an RLD that has a REMS with 
135  ETASU20 
136   
137    When FDA has received an NDA or a BLA for a product that references an NDA or a 
138  BLA that is subject to REMS with ETASU, and has determined that the proposed product 
139  also would require the same ETASU21 
140   
141    When FDA has determined for drugs and biologics in a class with similar, serious risks 
142  that a shared system REMS may minimize the burden of having multiple unique REMS 
143  programs 22  
144   
145  The Agency will, where appropriate, request that applicants of the pending applications submit 
146  an authorization for disclosure that will allow the Agency to hold meetings between multiple 
147  applicants. FDA will provide contact information for the product being referenced by the 
148  pending applications to facilitate the development of a shared system REMS.  
149   
150  B.  Formation of an Industry Working Group 
151   
152  Applicants may consider forming a working group, commonly referred to as an industry working 
153  group (IWG).  Some applicants have used an IWG to facilitate negotiations and agreements 
154  among the applicants to develop a shared system REMS on issues such as confidentiality, 
155  governance, voting structure, cost-sharing, any potential changes to the drug distribution model, 
156  and any other issues that may come up during the collaboration.  Some applicants have used 
157  third-party vendors to aid in implementation and management of the program.  The applicants 
158  must comply with the requirements of the REMS regardless of whether they use a third-party 
159  vendor. 
160   
161  If an IWG is formed, the IWG applicants should identify a single point of contact (POC) to 
162  represent the IWG in communication with FDA.  This POC will facilitate communication 
163  between the Agency and the IWG about the status of developing the shared system.  FDA 
164  generally requests that the Agency receive updates from the IWG POC on the status of 
165  negotiations and on any barriers to developing the shared system REMS based on timelines that 
166  have been communicated by the Agency early in the process.  The updates are typically 
167  submitted to each respective application as a REMS correspondence. 
                                                 
20 Section 505-l(i)(l)(B) of the FD&C Act requires that a holder of an ANDA approved under section 505(j) use a 
single, shared system with the reference listed drug (RLD). 
21 For products submitted under section 505(b)(2) of the FD&C Act or section 351(k) of the PHS Act. 
22 If applicants for a class of products have not received a notification from FDA but are interested in developing a 
shared system REMS, they may seek further advice from FDA. 
5 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
168   
169  C.  FDA Role  
170   
171  FDA does not advise on the business arrangements being negotiated or arbitrate substantive 
172  disputes about the terms of contracts.  FDA will set forth expectations of the applicants for the 
173  development of the shared system REMS, which may include suggested timeframes for various 
174  milestones in the process of developing the shared system, and the process for submission of the 
175  proposed REMS.  FDA may facilitate collaborations between applicants when necessary to 
176  achieve a shared system REMS.  For example, FDA may host teleconferences to encourage 
177  communications between applicants.   
178   
179  FDA will identify an Agency POC for a shared system REMS that is under development and will 
180  provide this information to the IWG.  If obstacles arise that impede the development of a shared 
181  system REMS, the Agency POC should be notified.  
182   
183   
184  IV.  SHARED SYSTEM REMS ASSESSMENTS  
185   
186  Information about the performance of REMS programs is important in determining whether the 
187  program is meeting its intended risk mitigation goals.  All approved REMS for NDA and BLA 
188  products are required to include a timetable for submission of assessments of the REMS.23  The 
189  proposed REMS assessment plan for a shared system REMS, which specifies the nature and 
190  content of the periodic assessments, is generally included in the REMS supporting document.   
191   
192  The assessments for shared system REMS apply collectively to all products that are subject to 
193  the REMS.  The Agency generally does not require submission of the shared REMS assessment 
194  reports for ANDAs that are part of a shared system REMS with an RLD.  However, FDA may 
195  require that ANDA applicants submit REMS assessment reports when product-specific 
196  utilization information or adverse event data is necessary to evaluate whether the program should 
197  be modified to ensure the benefits of the drug outweigh the risks or to minimize the burden on 
198  the health care delivery system of complying with the REMS.24 
199   
200  Generally, FDA expects to assess any separate REMS for ANDAs at the same intervals and with 
201  the same metrics as the RLD REMS to ensure that the separate REMS is meeting its goals. 
202   
203   
204  V.  SUBMISSION PROCEDURES 
205   
206  This section provides an overview of submission procedures that apply to shared system REMS.  
207   
                                                 
23 See section 505-1(d) of the FD&C Act.  Section 505-1(i) states that the only REMS elements to which ANDAs 
are subject are a Medication Guide or patient package insert and any ETASU.  ANDAs are not subject to the 
requirement for a timetable for submission of assessments. 
24 See section 505-1(g)(2)(C) of the FD&C Act. 
6 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
208  A.  General Considerations 
209   
210  In addition to the recommendations provided in this guidance, FDA advises applicants to refer to 
211  other relevant FDA resources to help create their REMS submissions, such as the following: 
212   
213    Guidance for industry on Providing Regulatory Submissions in Electronic Format  
214  Certain Human Pharmaceutical Product Applications and Related Submissions Using 
215  the eCTD Specifications (Revision 4) 
216   
217    Electronic Common Technical Document (eCTD) web page25 
218   
219    Draft guidance for industry Format and Content of a REMS Document26 
220   
221    Guidance for industry Risk Evaluation and Mitigation Strategies: Modifications and 
222  Revisions 
223   
224    Draft guidance for industry Providing Regulatory Submissions in Electronic Format  
225  Content of the Risk Evaluation and Mitigation Strategies Document Using Structured 
226  Product Labeling27 
227   
228    eCTD Technical Conformance Guide28  
229   
230  B.  Timing of Initial Shared System REMS Submission29 
231   
232  Applicants that are developing a shared system REMS should submit their REMS by application 
233  midpoint for pending applications, or another time frame specified by the Agency.  To facilitate 
234  submission tracking, FDA recommends that shared system REMS applicants work together to 
235  coordinate their submissions on the same day, if possible.  
236   
                                                 
25 To make sure you have the most recent version of related technical specifications (CDER and CBER), check the 
eCTD web page at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/u
cm153574.htm.   
26 When final, this guidance will represent FDAs current thinking on this topic. 
27 When final, this guidance will represent FDAs current thinking on this topic. 
28 Includes information to assist applicants on where to place REMS documents under the eCTD Module 1 REMS 
1.16 sub-headings using the DTD v3.3 of the us-regional.xml.file.  
29 Submission includes the REMS document, supporting document, and appended materials. 
7 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
237  C.  RLD Submission of a Bifurcated REMS 
238   
239  In some cases, the approval of a single, shared system REMS between an ANDA and its RLD 
240  may coincide with tentative approval of the ANDA.30  Tentative approval for an ANDA is a 
241  notification to an applicant that an ANDA meets the requirements for approval but cannot be 
242  approved because of unexpired patents or exclusivity.31  A drug product that is granted tentative 
243  approval is not an approved drug and will not be approved until FDA issues an approval letter 
244  after any necessary additional review of the ANDA.  In such cases, it would not be appropriate 
245  for the single, shared system to be operational yet, because the generic product would not yet be 
246  approved.   
247   
248  For the Agency to approve the single, shared system but postpone its operation until the approval 
249  of the ANDA(s), FDA will request that the RLD holder submit a REMS modification that 
250  proposes a single, two-part REMS, sometimes referred to as a "bifurcated REMS."  Part A would 
251  consist of the current REMS that applies only to the RLD and would be operational before the 
252  first ANDA receives approval.  Part B would be the single, shared system REMS that would be 
253  operational once the first ANDA receives approval.  In this circumstance, the approval letter for 
254  the RLD holders REMS modification, as well as the REMS document itself, would state that the 
255  single, shared system REMS (Part B) becomes operational automatically upon approval of the 
256  first ANDA.  If approval of the single, shared system REMS coincides with approval of the first 
257  ANDA, rather than tentative approval, the single, shared system REMS (Part B) would 
258  automatically be operational.   
259   
260  D.  Submission to FDA Using a Type V Drug Master File 
261   
262  To improve the efficiency of the submission and review process for shared system REMS, FDA 
263  recommends that applicants use a Type V32 Drug Master File (DMF) for their shared system 
264  REMS submissions.  Using a DMF allows applicants that are part of a shared system REMS to 
265  submit one set of files on behalf of the application holders to the Agency and eliminates the need 
266  for each applicant to submit identical REMS-related documents to its own application. The DMF 
267  holder of the shared systems REMS DMF is jointly designated by the application holders.  The 
268  DMF holder will make submissions to the DMF on behalf of the application holders.  
269   
If applicants that are participating in a shared system REMS choose to use a DMF, they should 
refer to the draft guidance for industry Use of a Drug Master File for Shared System REMS 
Submissions.33  Additional, and more-detailed, submission instructions are also included in a 
separate technical guide.34  
                                                 
30 There may also be instances where the approval of a shared system REMS between multiple NDAs may coincide 
with one or more NDAs receiving tentative approval. 
31 Section 505(j)(5)(B)(iv)(II)(dd)(AA) of the FD&C Act; 21 CFR 314.3(b) and 314.107. 
32 Type V FDA-Reference Information DMF. 
33 When final, this guidance will represent FDAs current thinking on this topic. 
34 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. 
8