Providing Postmarketing Periodic Safety 
Reports in the ICH E2C(R2) Format 
(Periodic Benefit-Risk Evaluation Report) 
 
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) 
 
November 2016 
Drug Safety 
   
Providing Postmarketing Periodic Safety 
Reports in the ICH E2C(R2) Format 
(Periodic Benefit-Risk Evaluation Report) 
 
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 
http://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 2016 
Drug Safety 
 
 
   
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.    Postmarketing Periodic Safety Reporting Regulations .............................................................. 2 
B.    The PSUR (ICH E2C)(R1) and the PBRER (ICH E2C(R2)) ..................................................... 2 
C.    Precedence for Granting PSUR Waivers ..................................................................................... 3 
III.   PROCEDURES APPLICANTS SHOULD FOLLOW TO SUBMIT A PBRER ....... 4 
A.    Applicants With a PSUR Waiver ................................................................................................. 4 
1. Change in the Date of the DLP for the PBRER  Submit Notification ............................................ 4 
2. Longer PBRER Reporting Intervals But No Change in Frequency  Submit Notification .............. 5 
3. Other Changes to the PSUR Waiver  Submit New Waiver ............................................................ 5 
B.    Applicants Without a PSUR Waiver ............................................................................................ 5 
IV.   SUBMITTING WAIVER REQUESTS .......................................................................... 6 
V.    FORMAT, CONTENT, AND TIMING OF THE PBRER ........................................... 7 
  Contains Nonbinding Recommendations 
 
Providing Postmarketing Periodic Safety Reports in the ICH 
E2C(R2) Format (Periodic Benefit-Risk Evaluation Report) 
1
Guidance for Industry  
 
 
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 describes the conditions under which applicants2 can use an alternative reporting 
format, the International Council for Harmonisation (ICH)3 E2C(R2) Periodic Benefit-Risk 
Evaluation Report (PBRER), in place of the U.S. periodic adverse drug experience report 
(PADER), U.S. periodic adverse experience report (PAER), or ICH E2C Periodic Safety Update 
Report (PSUR), to satisfy the periodic postmarketing safety reporting requirements in  
314.80(c)(2) and 600.80(c)(2) (21 CFR 314.80(c)(2) and 600.80(c)(2)).  This guidance also 
describes the procedures applicants should follow if they wish to submit a PBRER in place of a 
PADER, PAER, or PSUR.4  The steps will differ, depending on whether or not the applicant has 
an approved waiver in place to substitute the PSUR for the PADER/PAER. 
 
                                                 
1 This guidance has been prepared by the Office of Surveillance and Epidemiology 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 This guidance uses the term applicant to mean the holder of an approved new drug application (NDA), abbreviated 
new drug application (ANDA), or biologics license application (BLA), which are referred to collectively in this 
guidance as applications.   
 
3 Formerly the International Conference on Harmonisation.  The ICH was organized to provide an opportunity for 
harmonization initiatives to be developed with input from both regulatory and industry representatives.  ICH is 
concerned with harmonization of technical requirements for the registration of pharmaceutical products for human 
use among regulators around the world (for more information about the ICH and the procedures for adopting 
harmonized guidelines, see http://www.ich.org/).  Guidelines that have been formally endorsed by the ICH are 
implemented by the FDA in the form of FDA guidance documents whose development  follows the procedures 
outlined in FDAs good guidance practices regulation (21 CFR 10.115). 
 
4 FDA accepts all three formats, the PADER/PAER, PSUR, and PBRER, to fulfill the postmarketing periodic safety 
reporting requirements under  314.80(c)(2) and 600.80(c)(2).  Each format must be submitted according to the 
content and timelines specified in the regulations (PADER/PAER) or by ICH (PSUR and PBRER). 
 
   
  1 
 
  Contains Nonbinding Recommendations 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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.    Postmarketing Periodic Safety Reporting Regulations 
 
FDA regulations in  314.80(c)(2) and 600.80(c)(2) require applicants to submit postmarketing 
periodic safety reports in the PADER/PAER format for each approved application.  The reports 
must be submitted quarterly for the first 3 years following the U.S. approval date and annually 
thereafter (see  314.80(c)(2)(i) and 600.80(c)(2)(i)), and must contain the information 
described in  314.80(c)(2)(ii) and 600.80(c)(2)(ii).   
 
B.    The PSUR and the PBRER  
 
 In November 1996, the ICH endorsed the ICH E2C Periodic Safety Update Report Guideline 
(ICH E2C(R1) guideline), which established the PSUR as a harmonized format for 
postmarketing periodic safety reports for approved drugs and biologic products, and described 
the format, content, and timing of PSUR submissions.  FDA adopted that guideline and, in May 
1997, published it as FDA guidance for industry E2C Clinical Safety Data Management: 
Periodic Safety Update Reports for Marketed Drugs.5  In February 2003, ICH endorsed and 
made final an addendum that further clarified some aspects of the ICH E2C(R1) guideline.  In 
February 2004, FDA published the addendum as FDA guidance for industry Addendum to E2C 
Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs.6  
 
On April 11, 2012, FDA announced the availability of a draft guidance for industry entitled E2C 
(R2) Periodic Benefit-Risk Evaluation Report,7 which reflected revisions by ICH and described 
the format, content, and timing of the updated version, the PBRER, as presented in the ICH 
EC2(R2)8 step 2 guideline.9  ICH subsequently endorsed a final version of that guideline on 
                                                 
5 62 FR 27470 (May 19, 1997).  We update guidances periodically.  To make sure you have the most recent version 
of a guidance, check the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.      
 
6 69 FR 5551 (Feb. 5, 2004). When final, this guidance will represent FDAs current thinking on this topic. 
 
7 77 FR 21782 (April 11, 2012). 
 
8 The terms R1 and R2 refer to successive revisions in ICH E2C.   
 
9 The term step 2 refers to the point in the ICH process where the draft guideline is agreed and signed by the Expert 
Working Group and the ICH Assembly, which signifies acceptance for consultation by the Members of the ICH 
Association. 
 
   
  2 
 
  Contains Nonbinding Recommendations 
 
November 15, 2012, and published the ICH guideline Periodic Benefit-Risk Evaluation Report 
(PBRER) E2C(R2)10 (ICH E2C(R2) step 4 guideline).11  The step 4 guideline updates and 
combines the E2C(R1) guideline and the addendum to the E2C(R1) guideline.  The step 4 
guideline replaces the PSUR with the PBRER for postmarketing periodic safety reporting, and 
describes the recommended format, content, and timing of PBRER submissions.  Like the PSUR, 
the harmonized PBRER is intended to promote a consistent approach to periodic postmarketing 
safety reporting among the ICH regions and to enhance efficiency by reducing the number of 
reports generated for submission to regulatory authorities.  FDA adopted the step 4 guideline 
and, on July 19, 2016, published it as FDA guidance for industry E2C(R2) Periodic Benefit-Risk 
Evaluation Report (PBRER) (ICH E2C(R2) PBRER guidance).12   
 
In addition to adopting ICH guidelines as described above, on April 28, 2013, FDA made 
available  a draft guidance for industry Providing Postmarket Periodic Safety Reports in the ICH 
E2C(R2) Format (Periodic Benefit-Risk Evaluation Report),13 which FDA is now finalizing in 
this current guidance.  This current guidance describes the procedures that applicants should 
follow to submit a PBRER in place of a PADER, PAER, or PSUR. 
 
C.    Precedence for Granting PSUR Waivers 
 
Since the introduction of the PSUR reporting format, FDA has granted waivers under  
314.90(b) and 600.90(b) (21 CFR 314.90(b) and 600.90(b)) to allow applicants to substitute the 
PSUR for the PADER/PAER (PSUR waiver).  FDA has routinely granted PSUR waivers on the 
condition that applicants provide the following information: 
  The nonexpedited individual case safety reports (ICSRs) received during the reporting 
interval, as required under  314.80(c)(2)(ii)(B) and 600.80(c)(2)(ii)(B), excluding any 
previously submitted nonexpedited ICSRs.  All ICSRs must be submitted electronically 
in a format FDA can process, review, and archive as described  314.80(g) and 
600.80(h) .  
  A list of all ICSRs submitted during the reporting interval and their submission dates. 
  A narrative that identifies any changes made to the approved U.S. labeling based on new 
information in the PSUR, as required under  314.80(c)(2)(ii)(A)(3) and  
________________________ 
 
10 Available at http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html. 
  
11  The term step 4 refers to the point in the ICH process at which consensus is reached and the guideline is 
recommended for adoption by the regulatory agencies.   
 
12 81 FR 17009 
 
13 78 FR 20926 (April 8, 2013).   
 
   
  3 
 
  Contains Nonbinding Recommendations 
 
600.80(c)(2)(ii)(A)(3), along with a copy of the U.S. labeling in effect on the data lock 
point (DLP)14 date.   
 
FDA has routinely granted waivers to permit applicants to change the date of the DLP from the 
U.S. approval date, as required under  314.80(c)(2)(i) and 600.80(c)(2)(i), to a different date 
for harmonization purposes.  These waivers have been granted on the condition that the applicant 
ensures that there are no gaps in reporting resulting from the date change.  FDA has also 
permitted applicants to include multiple products with the same active moiety or active 
ingredient in a single report as recommended in the ICH E2C(R1) guidance. 
   
Generally, FDA has not waived the reporting frequencies required under  314.80(c)(2)(i) and 
600.80(c)(2)(i).  However, FDA has permitted applicants to submit PSURs at longer intervals, 
consistent with the ICH guidelines, on the condition that the applicant submit a periodic safety 
report as needed to fulfill the reporting frequency requirements.   
 
Example: FDA granted an applicant a waiver to submit a PSUR for its drug product 
every 3 years.  FDA granted this waiver on the condition that the applicant also submit 
an annual PADER for years 1 and 2 of the 3-year PSUR cycle. 
 
III.   PROCEDURES APPLICANTS SHOULD FOLLOW TO SUBMIT A PBRER 
 
A.    Applicants With a PSUR Waiver  
 
If applicants already have a PSUR waiver for an approved application, FDA will consider the 
existing PSUR waiver to permit applicants to submit a PBRER instead of a PSUR under the 
conditions described below, because the PBRER replaces the PSUR for postmarketing periodic 
safety reporting.  If applicants wish to substitute the PBRER for the PSUR with no changes in 
the DLP or frequency of reporting, applicants can do so without submitting a new waiver 
request.  However, if applicants wish to change any conditions of their PSUR waiver other than 
the format, applicants should submit either a notification or new waiver request, depending on 
the circumstances described below.     
 
1.  Change in the Date of the DLP for the PBRER  Submit Notification  
 
If applicants wish to use a DLP date for the PBRER that is different than the DLP date used 
for the PSUR, applicants should ensure there are no gaps in reporting intervals resulting from 
the change in DLP.  Examples of appropriate alternatives include the following: 
  Submit overlapping reports to cover the gap.  
  Submit a one-time PADER/PAER to cover the gap.  
  Extend the reporting interval of the applicants upcoming PADER/PAER by up 
to 3 months to cover the gap. 
                                                 
14 The term data lock point refers to the date designated as the cut-off for data to be included in the PSUR or 
PBRER. 
   
  4 
 
  Contains Nonbinding Recommendations 
 
   
Applicants should submit written notification to the application(s), indicating the change in 
DLP date and describing the measures taken to ensure that there are no resulting gaps in 
reporting.   
2.  Longer PBRER Reporting Intervals But No Change in Frequency  Submit 
Notification  
 
If applicants wish to submit the PBRER less frequently than is permitted under their PSUR 
waiver, the continued validity of the applicants waiver will be conditioned on the applicants 
submission of a PADER/PAER as needed to fulfill the reporting frequency requirement under 
our regulations.    
 
Applicants should submit written notification to the application, indicating this change and 
describing the measures taken to ensure that the periodicity requirements are being met.   
 
Example:  If the applicants PSUR waiver specifies annual PSUR submission but the 
applicant wishes to submit a PBRER every 3 years, the applicant can substitute the 
PBRER for the PSUR, provided the applicant submits a PADER/PAER for years 1 
and 2 of the 3-year PBRER cycle to maintain the annual reporting frequency 
required under the regulations and as specified in its PSUR waiver. 
 
3.  Other Changes to the PSUR Waiver  Submit New Waiver  
 
If applicants wish to change any other condition of their PSUR waiver beyond what is 
described in sections III.A.1 and III.A.2 above, then applicants should submit a new waiver 
request.  For example, a new waiver request should be submitted to change the overall 
reporting frequency or to add or remove products covered by the report. 
 
B.    Applicants Without a PSUR Waiver  
 
If applicants do not already have a PSUR waiver and wish to submit in the PBRER format, a 
waiver request must be submitted under  314.90(a) or 600.90(a) in order to submit a PBRER 
instead of the PADER/PAER (PBRER waiver).  In accordance with the ICH E2C(R2) PBRER 
guidance, applicants can prepare a single PBRER for multiple products with the same active 
moiety or ingredient.  
 
If the applicants waiver request is for several products, the applicant can submit a single waiver 
request letter that references multiple applications.    
 
Each PBRER waiver request should include the following information: 
 
1.  The product name(s) and application number(s). 
2.  Email address and telephone number for the individual FDA may contact should the Agency 
need additional information regarding the waiver request. 
   
  5 
 
  Contains Nonbinding Recommendations 
 
3.  A brief description of the justification for the request. 
4.  The U.S. approval date for the product(s) and current reporting interval used. 
5.  The reporting interval of the last PADER/PAER submitted for the product(s). 
6.  The date of the DLP that applicants intend to use for each PBRER.  If applicants propose a 
DLP date other than one aligned to the U.S. approval date, applicants should describe their 
plan to ensure there are no gaps in reporting intervals.  Examples of appropriate alternatives 
include: 
  Submitting overlapping reports to cover the gap; 
  Submitting a one-time PADER/PAER to cover the gap; or 
  Extending the reporting interval of the applicants final PADER/PAER by up to 3 
months to close the gap. 
7.  The frequency with which applicants intend to submit reports. 
 
The time period from the products U.S. approval date is less than or equal to 3 years:   
Applicants can ask FDA to consider waiving the quarterly reporting requirement under  
314.80(c)(2)(i) and 600.80(c)(2)(i), and instead propose to submit the PBRER less frequently 
during this period (e.g., every 6 or 12 months).  FDA will grant or deny the request on an 
application-specific basis.  
 
The time period from the products U.S. approval date is greater than 3 years: 
Applicants must submit a postmarketing periodic safety report annually, as required under  
314.80(c)(2)(i) and 600.80(c)(2)(i).  Alternatively, applicants can submit a PBRER less 
frequently on the condition that applicants also submit an annual periodic safety report in one 
of the other acceptable formats (i.e., PADER/PAER or PSUR) as needed to fulfill the annual 
requirement.  See the example in section II.C. 
 
IV.   SUBMITTING WAIVER REQUESTS 
 
The applicants waiver request letter should be submitted to each of the applications for which a 
waiver is being requested.  Requests submitted electronically should be sent via FDAs 
Electronic Submissions Gateway (ESG) to the electronic common technical document (eCTD)15 
for the applications for which a waiver is being requested. 
 
Requests submitted on paper should be sent to the appropriate address below: 
 
For CDER-regulated drug and biological products: 
 
Central Document Room 
Center for Drug Evaluation and Research 
Food and Drug Administration 
                                                 
15 Guidance for industry, Providing Regulatory Submissions in Electronic Format Certain Human Pharmaceutical 
Product Applications and Related Submissions Using the eCTD Specifications (May 2015). 
   
  6 
 
  Contains Nonbinding Recommendations 
 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
 
For CBER-regulated biological products: 
 
U.S. Food and Drug Administration 
Center for Biologics Evaluation and Research  
Office of Biostatistics and Epidemiology  
Document Control Center 
10903 New Hampshire Ave. 
Bldg. 71, Rm. G112 
Silver Spring, MD 20993-0002
 
   
V.    FORMAT, CONTENT, AND TIMING OF THE PBRER  
 
When preparing and submitting the PBRER, the applicant should follow the format, content, and 
timing recommendations described in the ICH E2C(R2) PBRER guidance.   
 
As part of the applicants PBRER submission to FDA, the applicant should provide a list of all 
ICSRs submitted during the reporting interval, a narrative that identifies any changes made to the 
approved U.S. labeling, and a copy of the U.S. labeling in effect on the DLP, as specified in the 
bulleted list in section II.C.  Applicants must also electronically submit nonexpedited ICSRs 
received during the reporting interval, as required under  314.80(c)(2)(ii)(B) and 
600.80(c)(2)(ii)(B), excluding any previously submitted nonexpedited ICSRs.16,17  
 
The applicant can submit 6-month and 12-month PBRERs within 70 calendar days following the 
DLP, and the applicant can submit PBRERs covering a longer reporting interval within 90 
calendar days following the DLP. 
 
                                                 
16 Draft guidance for industry, Providing Submissions in Electronic Format  Postmarketing Safety Reports      
(June 2014).  When final, this guidance will represent FDAs current thinking on this topic.  
 
17 Guidance for industry, Providing Submissions in Electronic Format  Postmarketing Safety Reports for Vaccines 
(August 2015).  
 
   
  7