E2C(R2) Periodic Benefit-
Risk Evaluation Report 
(PBRER) 
 
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) 
 
July 2016 
Revision 1 
 
 
  E2C(R2) Periodic Benefit-
Risk Evaluation Report 
(PBRER) 
 
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 
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and/or 
 
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 Food and Drug Administration 
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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) 
 
 
July 2016 
Revision 1  
  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION (1) ....................................................................................................... 3 
A.  Background (1.1) ........................................................................................................................... 4 
B.  Objectives (1.2) .............................................................................................................................. 6 
C.  Scope of the PBRER (1.3) ............................................................................................................. 6 
D.  Relation of the PBRER to Other ICH Documents (1.4) ............................................................. 7 
II.  GENERAL PRINCIPLES (2) .......................................................................................... 8 
A.  Single PBRER for an Active Substance (2.1) .............................................................................. 8 
B.  PBRERs for Fixed-Dose Combination Product (2.2) ................................................................. 8 
C.  Products Manufactured and/or Marketed by More Than One Company (2.3) ...................... 8 
D.  Reference Information (2.4) ......................................................................................................... 9 
E.  Level of Detail Within PBRER (2.5) .......................................................................................... 10 
F.  Efficacy/Effectiveness (2.6) ......................................................................................................... 10 
G.  Benefit-Risk Evaluation (2.7) ..................................................................................................... 11 
H.  Periodicity and PBRER Data Lock Point (2.8) ......................................................................... 11 
1. International Birth Date and Data Lock Point (2.8.1) .................................................................. 11 
2. Managing Different Frequencies of PBRER Submission (2.8.2) .................................................. 11 
3. Time Interval Between Data Lock Point and the Submission (2.8.3) ............................................ 14 
I.  Format and Presentation of PBRER (2.9) ................................................................................. 14 
1. Format (2.9.1) ............................................................................................................................... 14 
2. Presentation (2.9.2) ....................................................................................................................... 14 
III.  GUIDANCE ON CONTENTS OF THE PBRER (3) ................................................... 16 
A.  Introduction (3.1) ......................................................................................................................... 17 
B.  Worldwide Marketing Approval Status (3.2) ........................................................................... 17 
C.  Actions Taken in the Reporting Interval for Safety Reasons (3.3) ......................................... 17 
D.  Changes to Reference Safety Information (3.4) ........................................................................ 19 
E.  Estimated Exposure and Use Patterns (3.5) .............................................................................. 19 
1. Cumulative Subject Exposure in Clinical Trials (3.5.1) ................................................................ 19 
2. Cumulative and Interval Patient Exposure From Marketing Experience (3.5.2) ......................... 20 
F.  Data in Summary Tabulations (3.6) ........................................................................................... 21 
1. Reference Information (3.6.1) ....................................................................................................... 21 
2. Cumulative Summary Tabulations of Serious Adverse Events From Clinical Trials (3.6.2) ........ 21 
3. Cumulative and Interval Summary Tabulations from Post-Marketing Data Sources (3.6.3) ....... 22 
G.  Summaries of Significant Safety Findings From Clinical Trials During the Reporting 
Interval (3.7) ......................................................................................................................................... 23 
1. Completed Clinical Trials (3.7.1) .................................................................................................. 23 
2. Ongoing Clinical Trials (3.7.2) ..................................................................................................... 24 
3. Long-Term Follow-Up (3.7.3) ....................................................................................................... 24 
i  Contains Nonbinding Recommendations 
 
4. Other Therapeutic Use of Medicinal Product (3.7.4) ................................................................... 24 
5. New Safety Data Related to Fixed Combination Therapies (3.7.5) .............................................. 24 
H.  Findings From Non-Interventional Studies (3.8) ...................................................................... 24 
I.  Information From Other Clinical Trials and Sources (3.9) ..................................................... 25 
1. Other Clinical Trials (3.9.1) .......................................................................................................... 25 
2. Medication Errors (3.9.2).............................................................................................................. 25 
J.  Nonclinical Data (3.10) ................................................................................................................ 25 
K.  Literature (3.11) ........................................................................................................................... 25 
L.  Other Periodic Reports (3.12) .................................................................................................... 26 
M.  Lack of Efficacy in Controlled Clinical Trials (3.13) ............................................................... 26 
N.  Late-Breaking Information (3.14) .............................................................................................. 26 
O.  Overview of Signals:  New, Ongoing, or Closed (3.15) ............................................................. 26 
P.  Signal and Risk Evaluation (3.16) .............................................................................................. 28 
1. Summary of Safety Concerns (3.16.1) ........................................................................................... 28 
2. Signal Evaluation (3.16.2) ............................................................................................................. 29 
3. Evaluation of Risks and New Information (3.16.3) ....................................................................... 30 
4. Characterization of Risks (3.16.4)................................................................................................. 31 
5. Effectiveness of Risk Minimization (if applicable) (3.16.5) ........................................................... 33 
Q.  Benefit Evaluation (3.17)............................................................................................................. 33 
1. Important Baseline Efficacy/Effectiveness Information (3.17.1) ................................................... 33 
2. Newly Identified Information on Efficacy/Effectiveness (3.17.2) .................................................. 33 
3. Characterization of Benefits (3.17.3) ............................................................................................ 34 
R.  Integrated Benefit-Risk Analysis for Approved Indications (3.18) ......................................... 34 
1. Benefit-Risk Context  Medical Need and Important Alternatives (3.18.1) ................................ 35 
2. Benefit-Risk Analysis Evaluation (3.18.2) ..................................................................................... 35 
S.  Conclusions and Actions (3.19) .................................................................................................. 36 
T.  Appendices to the PBRER (3.20) ............................................................................................... 36 
IV.  APPENDICES TO THIS GUIDANCE (5) .................................................................... 38 
APPENDIX A  GLOSSARY .................................................................................................... 39 
APPENDIX B  EXAMPLES OF SUMMARY TABULATIONS ......................................... 43 
APPENDIX C  EXAMPLE OF A TABULAR SUMMARY OF SAFETY SIGNALS 
THAT WERE ONGOING OR CLOSED DURING THE REPORTING INTERVAL ....... 46 
APPENDIX D  LIST OF PBRER SECTIONS THAT CAN BE SHARED WITH 
OTHER REGULATORY DOCUMENTS ................................................................................ 48 
APPENDIX E  EXAMPLES OF POSSIBLE SOURCES OF INFORMATION THAT 
CAN BE USED IN THE PREPARATION OF THE PBRER ................................................. 50 
APPENDIX F  MAPPING SIGNALS AND RISKS TO PBRER SECTIONS .................... 51 
  ii  Contains Nonbinding Recommendations 
 
E2C(R2) Periodic Benefit-Risk Evaluation (PBRER)  
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 create 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 (1)2 
  
This guidance defines the recommended format and content of a Periodic Benefit-Risk 
Evaluation Report (PBRER), and provides an outline of points to be considered in the 
preparation and submission of the PBRER.  The PBRER described in this guidance is 
intended to be a common standard for periodic benefit-risk evaluation reporting on marketed 
products (including approved drugs that are under further study) among the ICH regions. 
 
This guidance revises, combines, and replaces two ICH guidances:  E2C Clinical Safety Data 
Management:  Periodic Safety Update Reports for Marketed Drugs (ICH E2C guidance) and 
Addendum to E2C Clinical Safety Data Management:  Periodic Safety Update Reports for 
Marketed Drugs (ICH E2C addendum).3   
   
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.  
 
                                                 
1 This guidance was developed within the Efficacy Implementation Working Group of the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 
(ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process.  This 
document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2012.  At 
Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European 
Union, Japan, and the United States. 
 
2 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering 
Committee at Step 4 of the ICH process, November 2012. 
 
3 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the 
Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or the Vaccines, 
Blood and Biologics Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
3  Contains Nonbinding Recommendations 
 
A.  Background (1.1) 
 
When a new medicinal product is approved for marketing, demonstration of safety and 
efficacy are generally based on data from a limited number of patients, many studied under 
the controlled conditions of randomized trials.  Often, higher risk subgroups and patients with 
concomitant illnesses that require use of other drugs are excluded from clinical trials, and 
long-term treatment data are limited.  Moreover, patients in trials are closely monitored for 
evidence of adverse events.  In clinical practice, monitoring is less intensive, a broader range 
of patients are treated (age, comorbidities, drugs, genetic abnormalities), and events too rare 
to occur in clinical trials might be observed (e.g., severe liver injury).  These factors underlie 
the significance of continuing analysis of relevant safety, efficacy, and effectiveness4 
information throughout the life cycle of a medicinal product  promptly (as important 
findings occur) and periodically  to allow an overall assessment of the accumulating data.  
Although the majority of new information will be safety-related, new information about 
effectiveness, limitations of use, alternative treatments, and many other aspects of the drugs 
place in therapy may be pertinent to its benefit-risk assessment. 
 
The ICH E2C guidance reached Step 4 of the ICH process in 1996, and was intended to 
harmonize the periodic reporting requirements of regulatory authorities and to provide, in a 
common format, the worldwide interval safety experience of a medicinal product at defined 
times post-approval.  At that time, the focus of the Periodic Safety Update Report (PSUR) 
was on relevant new safety information in the context of patient exposure, to determine 
whether changes were called for in the reference safety information*5 (RSI) to optimize the 
continued safe use of the product.  In 2003, ICH incorporated the ICH E2C addendum with 
the ICH E2C guidance to provide important clarification, guidance, and flexibility. 
 
Since that time, the pharmacovigilance environment has evolved, prompting reassessment of 
the role of the PSUR in the spectrum of safety documents submitted to regulatory authorities.  
This reassessment highlighted several factors that led to consensus for revision and refocus of 
the guidance to enhance its usefulness in light of advances in the field: 
 
  Significant progress in the technology and science of pharmacovigilance, including 
electronic submission of individual case safety reports (ICSRs) to regulatory authorities, 
automated data mining techniques, and more attention to benefit-risk evaluation 
 
  Greater emphasis on proactive and documented risk management planning 
 
  Increasing recognition that meaningful evaluation of important new risk information 
should be undertaken in the context of a medicinal products benefits 
  
  Overlap in the content of ICH Guidelines related to pharmacovigilance documentation 
 
As noted above, the primary objective of the PSUR was to provide a comprehensive picture 
of the safety of approved medicinal products.  With recognition that the assessment of the 
risk of a medicinal product is most meaningful when considered in light of its benefits, the 
                                                 
4 The terms efficacy and effectiveness are not standardized and have different meanings across some regions (see 
section II.F (2.6) of this guidance). 
 
5 Definitions of many technical terms used in this guidance are included in a Glossary (Appendix A).  The first 
mention of a term in the guidance is identified with an asterisk (*), and the term appears in bold type. 
  4  Contains Nonbinding Recommendations 
 
proposed report would provide greater emphasis on benefit than the PSUR, particularly when 
risk estimates change importantly.  In such cases, there should be an overall explicit 
evaluation of benefit-risk.  Consequently, the name of the proposed report is the Periodic 
Benefit-Risk Evaluation Report (PBRER).  The PBRER would also provide greater 
emphasis on the cumulative knowledge regarding a medicinal product, while retaining a 
focus on new information. 
 
A formal evaluation of benefit is a new feature of the PBRER; however, it is recognized that 
a concise discussion of benefit will usually be sufficient, unless the safety or benefit-risk 
profile has changed significantly during the reporting interval.  Thus, the level of detail 
provided in certain sections of the PBRER (e.g., evaluation of safety and efficacy data, 
evaluation of safety signals,* and benefit-risk evaluation) should be proportional to the 
medicinal products known or emerging important risks and to evidence of emerging 
important benefits. 
  
As the scope of the PBRER has been extended to include benefit as well as safety, the 
reference information for the report also should take this new factor into account.  It is 
generally impractical for marketing authorization holders (MAHs) to have one reference 
information source that: 
 
  Encompasses all parameters that contribute towards the benefit-risk evaluation (i.e., 
benefit, efficacy/effectiveness, indication(s) and safety information) 
 
  Is common to all ICH regions 
 
  Addresses all circumstances (e.g., generics, products licensed in one country only) 
 
Therefore, this guidance proposes more practical options that MAHs can consider in 
selecting the most appropriate reference product information for the PBRER.  These 
proposals incorporate the original ICH E2C concept of reference safety information (e.g., 
Company Core Safety Information* (CCSI)), with the addition of the approved indications 
for the product.  This reference product information can be the Company Core Data Sheet* 
(CCDS) or another document proposed by the MAH (see section II.D (2.4)). 
 
The important baseline efficacy and effectiveness information summarized in section 17.1 of 
the PBRER will form the basis (or reference) for the benefit evaluation, irrespective of the 
reference product information used by the MAH. 
 
The frequency of submission of reports to regulatory authorities is subject to national or 
regional regulatory requirements, and may differ, depending on many factors.  The guidance 
includes advice on managing different frequencies of PBRER submission in different 
regions. 
 
One of the motivating factors behind incorporating the ICH E2C addendum with the ICH 
E2C guidance was the desire to enhance efficiency by decreasing the duplication of effort in 
preparing various regulatory documents.  This guidance has been developed, therefore, such 
that corresponding sections of the PBRER, development safety update report (DSUR) (ICH 
E2F guidance), and safety specification of a risk management plan (ICH E2E guidance) can 
be identical in content (see also section I.D (1.4), Relation of the PBRER to Other ICH 
Documents).  This guidance reached step 4 in November 2012. 
5  Contains Nonbinding Recommendations 
 
 
B.  Objectives (1.2) 
 
The main objective of a PBRER is to present a comprehensive, concise, and critical analysis 
of new or emerging information on the risks of the medicinal product, and on its benefit in 
approved indications, to enable an appraisal of the products overall benefit-risk profile.  The 
PBRER should contain an evaluation of new information relevant to the medicinal product 
that has become available to the MAH during the reporting interval, in the context of 
cumulative information by: 
 
  Summarizing relevant new safety information that could have an impact on the benefit-
risk profile of the medicinal product 
 
  Summarizing any important new efficacy/effectiveness information that has become 
available during the reporting interval 
  
  Examining whether the information obtained by the MAH during the reporting interval is 
in accord with previous knowledge of the medicinal products benefit and risk profile  
 
  Where important new safety information has emerged, conducting an integrated benefit-
risk evaluation for approved indications 
 
When appropriate, the PBRER should include proposed action(s) to optimize the benefit-risk 
profile. 
   
Urgent safety information should be reported through the appropriate mechanism; the 
PBRER is not intended to be used to provide initial notification of significant new safety 
information or to provide the means by which new safety concerns* are detected. 
  
C.  Scope of the PBRER (1.3) 
 
The main focus of each PBRER is the evaluation of relevant new safety information from the 
available data sources, placed within the context of any pertinent efficacy/effectiveness 
information that may have become available since the international birth date* (IBD) (the 
date of the first marketing approval in any country in the world) or the development 
international birth date (DIBD) (the date of first authorization for the conduct of an 
interventional clinical trial in any country).6  All pertinent new safety and 
efficacy/effectiveness information discovered during the reporting interval7 should be 
discussed in the appropriate sections of the PBRER. 
   
For the purposes of this guidance, sources of available information refer to data regarding the 
active substance(s) included in the medicinal product or the medicinal product that the MAH 
may reasonably be expected to have access to, and data that are relevant to the evaluation of 
                                                 
6 For the purpose of this document, the terms authorization and authorized refer to clinical trials, and the terms 
approval and approved refer to marketing applications. 
 
7 This guidance should not serve to limit the scope of information to be provided in the evaluation of benefit-risk 
of a medicinal product.  Please refer to the applicable laws and regulations in the countries and regions in which 
the PBRER is to be submitted.  
 
  6  Contains Nonbinding Recommendations 
 
the safety or benefit-risk profile (see also Appendix E, Examples of Possible Sources of 
Information That May Be Used in the Preparation of the PBRER).  For example, there may 
be less information available to the MAH regarding a generic product as compared to a 
product for which the MAH is the innovator, and only a published report may be accessible 
for a clinical trial not sponsored by the MAH.  On the other hand, for a MAH-sponsored 
clinical trial, the MAH will have access to patient-level data towards evaluation of the 
products benefit-risk.  When desired by the MAH, a list of the sources of information used to 
prepare the PBRER can be provided as an appendix to the report. 
 
The PBRER should include cumulative knowledge of the product while retaining focus on 
new information (i.e., the overall safety evaluation and integrated benefit-risk evaluation will 
take into account cumulative information).  Because clinical development of a drug 
frequently continues following marketing approval, relevant information from postmarketing 
studies or clinical trials in unapproved indications or populations should also be included in 
the PBRER.  Similarly, because knowledge of the safety of a medicinal product can be 
derived from evaluation of data associated with uses other than the approved indication(s), 
such knowledge should be reflected in the risk evaluation, where relevant and appropriate. 
 
D.  Relation of the PBRER to Other ICH Documents (1.4) 
 
At present, some ICH countries and regions accept submission of separate types of periodic 
reports to fulfill national and regional requirements within the post-approval period:  the 
PSUR (ICH E2C guidance and E2C addendum) for periodic reporting of the safety of 
approved medicinal products, the DSUR (ICH E2F guidance) for periodic reporting on the 
safety of medicinal products that remain in clinical development, and the safety specification 
component of the ICH E2E guidance that might be submitted at the time of marketing 
application and/or PSUR submission to aid in the planning of pharmacovigilance activities.  
Because these documents have different regulatory purposes, different periodicities, and can 
be reviewed by different divisions within a single regulatory authority, each document should 
be complete in its own right  a comprehensive document that can stand alone.  
Nevertheless, overlap and inconsistencies between the content of the DSUR, PSUR, and 
safety specification can lead to inefficiencies in the production of the documents by the MAH. 
 
Modular Approach 
 
This guidance aims to facilitate flexibility by encouraging the use of individual sections that 
are common to more than one report  modules that can be used for different regulatory 
authorities and for different purposes.  Therefore, the PBRER has been developed in such a 
way that the content of several sections can be used for sections of other documents as a basis 
for a modular approach.  For example, if the DIBD of a DSUR for a medicinal product is 
aligned to the IBD of the PBRER for the same product as suggested in ICH E2F, the content 
of a number of sections of the DSUR can also be used in the PBRER when the data lock 
points (DLPs) are the same (i.e., when each report covers an interval of 1 year based on the 
IBD). 
 
Appendix D of this guidance lists the PBRER sections that can be shared with either the 
DSUR (ICH E2F guidance) or safety specification of a risk management plan (ICH E2E 
guidance), if appropriate.   
 
7  Contains Nonbinding Recommendations 
 
The use of common sections across the PBRER, DSUR, and safety specification as a modular 
approach has a number of advantages: 
 
  Maximizes the utility of the modules across multiple regulatory documents. 
  
  Promotes consistency across the PBRER, DSUR and Safety Specification. 
 
  Avoids unnecessary duplication of effort. 
 
  Is expected to improve efficiency for MAHs in preparing these documents. 
 
  Facilitates flexible utilization of existing sections (modules) when, for example, the 
PBRER covers different time intervals or should be submitted at different times to 
multiple different authorities.  In these circumstances, only modules that include new 
information or new evaluation should be updated when submitting the PBRER. 
  
Although currently out of scope for the ICH E2C(R2) guidance, it is envisioned that the 
modular approach proposed, based on common sections across various documents, will 
ultimately facilitate development of electronic modules for use in future regulatory 
submissions. 
 
 
II.  GENERAL PRINCIPLES (2) 
 
A.  Single PBRER for an Active Substance (2.1) 
 
The PBRER should provide information on all approved indications, dosage forms, and 
regimens for the active substance, with a single DLP.  In some circumstances, it will be 
appropriate to present data by indication, dosage form, dosing regimen, or population (e.g., 
children versus adults) within the relevant section(s) of the PBRER.  In exceptional cases, 
submission of separate PBRERs might be appropriate, for example, an active substance used 
in two formulations for systemic and topical administration in entirely different indications.  
In these cases, the regulatory authorities should be notified and their agreement obtained, 
preferably at the time of approval. 
 
B.  PBRERs for Fixed-Dose Combination Product (2.2) 
 
For combinations of substances also marketed individually, information for the fixed 
combination can be reported either in a separate PBRER or included as separate presentations 
in the report for one of the individual substances, depending on the circumstances.  Listing 
related PBRERs is considered important. 
 
C.  Products Manufactured and/or Marketed by More Than One Company 
(2.3) 
 
Each MAH is responsible for submitting PBRERs for its own products. 
 
  8  Contains Nonbinding Recommendations 
 
When companies are involved in contractual relationships (e.g., licensor-licensee), respective 
responsibilities for preparation and submission of the PBRER to the regulatory authorities 
should be clearly specified in the written agreement. 
 
When data received from a partner company or companies might contribute meaningfully to 
the safety, benefit, and/or benefit-risk analyses and influence the reporting companys 
product information, these data should be included and discussed in the PBRER. 
 
D.  Reference Information (2.4) 
 
An objective of a PBRER is to evaluate whether information obtained during the reporting 
interval is in accord with previous knowledge on the products benefit and risk profile, and to 
indicate whether changes should be made to the reference product information.  Having one 
reference source of information that can be applied across the three ICH regions would 
facilitate a practical, efficient, and consistent approach to the benefit-risk evaluation and 
make the PBRER a unique report accepted in all countries and regions. 
 
The reference product information for the PBRER would include core safety and approved 
indications components.  To facilitate the assessment of benefit and benefit-risk by indication 
in the evaluation sections of the PBRER, the reference product information document should 
list all approved indications in ICH countries or regions.  It is likely that these indications will 
also apply in other countries or regions.  However, when the PBRER is also to be submitted 
to other countries in which there are additional locally approved indications, these indications 
can either be added to the reference product information or handled as regional 
appendix/appendices as considered most appropriate by the MAH. The basis for the benefit 
evaluation should be the baseline important efficacy/effectiveness information summarized in 
section 17.1 of the PBRER. 
 
The following possible options can be considered by MAHs in selecting the most appropriate 
reference product information for a PBRER: 
 
  Company Core Data Sheet (CCDS) 
  
In accordance with the ICH E2C guidance and E2C addendum recommendations, it is a 
common practice for MAHs to prepare their own CCDS, which includes sections relating to 
safety, indications, dosing, pharmacology, and other information concerning the medicinal 
product.  The core safety information contained within the CCDS is referred to as the CCSI.  
A practical option is for MAHs to use the latest CCDS in effect at the end of the reporting 
interval as the reference product information for both the risk sections of the PBRER as well 
as the main approved indications for which benefit is evaluated. 
   
When the CCDS for a medicinal product does not contain information on approved 
indications, the MAH should clearly specify which document is used as the reference 
information for the approved indications in the PBRER. 
   
  Other options for the reference product information 
 
When there is no CCDS or CCSI for a product (e.g., where the product is approved in only 
one country or region, or for established/generic products on the market for many years), the 
MAH should clearly specify the reference information being used.  This might comprise 
9  Contains Nonbinding Recommendations 
 
national or regional product information such as the U.S. Package Insert (USPI) or European 
Summary of Product Characteristics (SmPC), or the Japanese package insert, as appropriate. 
The basis for the benefit evaluation should be the baseline important efficacy/effectiveness 
information summarized in section 17.1 of the PBRER. 
 
Where the reference information for approved indications is a separate document to the RSI, 
the version current at the DLP of the PBRER should be included in Appendix 1. 
 
The MAH should continuously evaluate whether any revision of the reference product 
information/RSI should be made whenever new safety information is obtained throughout the 
reporting interval.  Significant changes to the reference product information/RSI made during 
the interval should be described in section 4 of the PBRER (Changes to Reference Safety 
Information) and include: 
 
  Changes to contraindications, warnings/precautions sections of the RSI 
  Addition of adverse drug reactions (ADR(s)) and interactions 
  Addition of important new information on use in overdose 
  Removal of an indication or other restrictions for safety or lack of efficacy reasons 
 
Significant changes to the RSI made after the DLP but before submission of the PBRER 
should be included in section 14 of the report (Late Breaking Information), if feasible. 
   
If stipulated by applicable regional requirements, the MAH should provide, in a regional 
appendix, information on any final, ongoing, or proposed changes to the national or local 
authorized product information. 
  
E.  Level of Detail Within PBRER (2.5) 
 
The level of detail provided in certain sections of the PBRER should depend on the medicinal 
products known or emerging important benefits and risks.  This approach is applicable to 
those sections of the PBRER in which there is evaluation of safety data, 
efficacy/effectiveness data, safety signals, and benefit-risk.  Therefore, the extent of 
information provided in such PBRER sections will vary among individual PBRERs. 
 
For example, when there is important new safety information, a detailed presentation of that 
information should be included, plus the relevant benefit information, to facilitate a robust 
benefit-risk analysis.  Conversely, when little new important safety information has become 
available during the reporting interval, a concise summary of baseline benefit information 
should be sufficient, and the benefit-risk evaluation would consist primarily of an evaluation 
of updated interval safety data. 
 
F.  Efficacy/Effectiveness (2.6) 
 
For the purpose of this guidance, evidence on benefits in clinical trials and in everyday 
medical practice should be reported.  Because the terms are not harmonized across regions, 
the terms efficacy/effectiveness are used in this guidance to clarify that information from both 
clinical trials and everyday medical practice are within the scope of the information on 
benefit that should be included within the PBRER.  In some regions, efficacy refers to 
evidence of benefit from controlled clinical trials while effectiveness implies use in everyday 
medical practice.  Conversely, in other regions, this distinction is not made. 
  10  Contains Nonbinding Recommendations 
 
 
G.  Benefit-Risk Evaluation (2.7) 
 
When a drug is approved for marketing, a conclusion has been reached that, when used in 
accordance with approved product information, its benefits outweigh its risks.  As new 
information about the drug emerges during marketing experience, benefit-risk evaluation 
should be carried out to determine whether benefits continue to outweigh risks, and to 
consider whether steps should be taken to improve the benefit-risk balance through risk 
minimization activities (e.g., labeling changes, communications with prescribers, or other 
steps). 
 
H.  Periodicity and PBRER Data Lock Point (2.8) 
 
1.  International Birth Date and Data Lock Point (2.8.1) 
 
Each medicinal product should have an IBD  the IBD is the date of the first marketing 
approval for any product containing the active substance granted to any company in any 
country in the world.  When a report contains information on different dosage forms, 
formulations, or uses (indications, routes and/or populations), the date of the first marketing 
approval for any of the various authorizations should be regarded as the IBD and, therefore, 
determines the DLP for purposes of the PBRER.  The DLP is the date designated as the cut-
off for data to be included in a PBRER.  Through PBRERs prepared with harmonized DLPs 
based on a common IBD, the same updated safety and benefit-risk information can be 
reviewed globally by different regulatory authorities. 
 
When a separate PBRER is prepared for a fixed-dose combination product (see section II.B 
(2.2)), the DLP for that PBRER can be based on either the earliest IBD of one of the 
component active substances, or the IBD of the first marketing approval anywhere in the 
world for the fixed-dose combination. 
   
When clinical development of a medicinal product continues following marketing approval, 
if desired by the sponsor/MAH, the beginning of the DSUR reporting interval can be 
synchronized with the IBD-based cycle so that both the DSUR and PBRER can be prepared 
at the same time, using the same DLP.  This approach will facilitate use of the proposed 
common sections/modules for both the PBRER and DSUR when both are submitted annually 
(see Appendix D). 
 
2.  Managing Different Frequencies of PBRER Submission (2.8.2) 
 
The need for the submission of a PBRER and the frequency of report submission to 
regulatory authorities are subject to national or regional regulatory requirements, and usually 
depend on such factors as approval dates, the length of time the product has been on the 
market, and the extent of knowledge of the benefit-risk profile of the product.  The PBRER 
format and content are intended to apply to periodic reports that cover reporting periods of 6 
months or longer.  Once a drug has been marketed for several years, national or regional 
regulation can allow the frequency of submission to be extended to longer time intervals (e.g., 
greater than 1 year for products considered to have an established and acceptable profile or 
considered to be low risk); however, more frequent PBRERs might be continued in other 
regions.  As a result, MAHs might encounter the following scenarios: 
 
11  Contains Nonbinding Recommendations 
 
  PBRERs can be on 6-month, annual, and less-frequent submission timetables 
simultaneously across different regions. 
 
  Changes in reporting frequency might also apply after important additions or changes in 
clinical use are approved (e.g., new indication(s) and/or new population(s)).  In these 
circumstances, it is possible that the reporting interval will be shortened, even for older 
products with a previously reduced frequency of PBRER submission. 
 
  An ad hoc PBRER might be requested by a regulatory authority (see section II.H.2.a 
(2.8.2.1) of this guidance). 
 
Independent of the length of the interval covered by the report: 
 
  Each PBRER should be stand-alone and reflect new and cumulative information currently 
available to the MAH. 
 
  Regulators will normally accept use of the IBD to determine the DLP for PBRERs.  
Where national or regional requirements differ from this, the MAH may wish to discuss 
with the relevant regulatory authority. Use of a single harmonized IBD and DLP for each 
product is important to reduce the burden of work involved in preparing PBRERs, and 
respects the original purpose of the PBRER  to prepare a single worldwide summary on 
a product that can be submitted to different regulatory authorities. 
 
  For newly approved products, a 6-month periodicity applies in many regions, for at least 
the first 2 years after approval. 
 
  For PBRERs submitted on a routine/regular basis, the reports should be based on 
cumulative data, with interval data sets of 6 months, or multiples of 6 months. 
 
  Sections that provide interval information should be reviewed for updating for each 
PBRER, and the content used in the previous PBRER can be reviewed and reused for 
sections where no new information has arisen since preparation of the last PBRER, if 
appropriate.  Following review, it may be determined that sections providing evaluation 
of cumulative data may not need to be updated if the content remains up to date with 
current information (see Figure 1). 
 
  In situations when an MAH is preparing PBRERs on both a 6-month and an annual basis 
for different regulatory authorities, the regulatory authority receiving a PBRER on a 6-
month cycle might accept PBRERs containing 12-month interval data (see Figure 2).  
MAHs should discuss this approach with the relevant regulatory authority or authorities. 
  12  Contains Nonbinding Recommendations 
 
 
Figure 1:  Submission of PBRERs Based on the Same Data Lock Point, with Various Reporting 
Periods. 
 
Shading indicates period of interval data. 
For all reports, the cumulative data reflect all data from the IBD/DIBD. ** 
           
 
                     
 
           IBD                                                                                            Data  Lock Po int 
 
    IBD   DLP
  Region A 6 months
cumulative 
 
Region B 12 months data are 
 
identical
  Region C longer
 
Region D * ad hoc; PBRERs ongoing in other regions - interval specified in request
 
  Region E ad hoc; PBRER not prepared for other regions
 
  time (years) 0 1 2 3
 
* update the most recent cumulative and interval data, as appropriate
 
** Cumulative Clinical Trial Summary Tabulation of Serious Adverse Events & Clinical Trial 
Exposure data only 
 
Figure 2:  Submission of 6-Month and Annual PBRERs 
 
 
  6-month PBRER A C
 
Annual PBRER B D
 
  Month:    0 6 12 18 24
 
Region 1 requests 6-month PBRER, and receives PBRER A, B, C, and D (assuming agreement has 
been reached with pertinent regulatory authority or authorities). 
Region 2 requests annual PBRER, and receives PBRER B and D. 
 
13 
 
 
     Contains Nonbinding Recommendations 
 
 
a.  Ad hoc (for cause) PBRERs (2.8.2.1) 
 
Ad hoc PBRERs are reports outside the routine reporting requirements, and might be 
requested by some regulatory authorities.  Where an ad hoc report is requested and a PBRER 
has not been prepared for a number of years, it is likely that a completely new report should 
be prepared by the MAH. 
3.  Time Interval Between Data Lock Point and the Submission (2.8.3) 
 
As a result of the expanded scope of the PBRER, the time interval between the DLP and 
submission of PBRERs should be as follows: 
 
  PBRERs covering intervals of 6 or 12 months:  within 70 calendar days 
  PBRERs covering intervals in excess of 12 months:  within 90 calendar days 
  Ad hoc PBRERs:  90 calendar days, unless otherwise specified in the ad hoc request 
 
The day of DLP is day 0 of the 70- or 90-calendar-day interval between the DLP and report 
submission. Where national or regional requirements differ from the above, the MAH should 
discuss the timeline for submission with the relevant regulatory authority. 
 
I.  Format and Presentation of PBRER (2.9) 
1.  Format (2.9.1) 
 
The recommended format and content of the PBRER, including table of contents, section 
numbering, and content of each section, is outlined below. 
 
The full ICH E2C(R2) guidance format should be used for all PBRERs.  When no relevant 
information is available or a PBRER section is not applicable, this should be stated.  
Particular sections of the PBRER might share content with other regulatory reports (e.g., 
documents described in ICH E2E and E2F guidances).  It may be possible for the MAHs to 
take advantage of the modular approach of the PBRER (i.e., sections that can be separated 
and submitted independently or combined with other documents) to facilitate such regulatory 
needs, maximize the utility of the content, and reduce duplicate work. 
 
2.  Presentation (2.9.2) 
 
The recommended table of contents, including section numbering, for the PBRER is provided 
below: 
 
Title Page 
Executive Summary 
Table of Contents 
1.  Introduction 
2.  Worldwide Marketing Approval Status 
3.  Actions Taken in the Reporting Interval for Safety Reasons 
4.  Changes to Reference Safety Information 
  14  Contains Nonbinding Recommendations 
 
5.  Estimated Exposure and Use Patterns 
5.1  Cumulative Subject Exposure in Clinical Trials 
5.2  Cumulative and Interval Patient Exposure from Marketing Experience 
6.  Data in Summary Tabulations 
6.1  Reference Information 
6.2   Cumulative Summary Tabulations of Serious Adverse Events from Clinical 
Trials 
6.3   Cumulative and Interval Summary Tabulations from Postmarketing Data 
Sources 
7.  Summaries of Significant Findings from Clinical Trials during the Reporting Period 
7.1  Completed Clinical Trials 
7.2  Ongoing Clinical Trials 
7.3  Long-Term Follow-up 
7.4  Other Therapeutic Use of Medicinal Product 
7.5  New Safety Data Related to Fixed Combination Therapies 
8.  Findings From Non-Interventional Studies 
9.  Information From Other Clinical Trials and Sources 
9.1  Other Clinical Trials 
9.2  Medication Errors 
10. Nonclinical Data 
11. Literature 
12. Other Periodic Reports 
13. Lack of Efficacy in Controlled Clinical Trials 
14. Late-Breaking Information 
15. Overview of Signals:  New, Ongoing, or Closed 
16. Signal and Risk Evaluation  
16.1  Summary of Safety Concerns 
16.2  Signal Evaluation  
16.3  Evaluation of Risks and New Information  
16.4  Characterization of Risks 
16.5  Effectiveness of Risk Minimization (if applicable) 
17. Benefit Evaluation 
17.1  Important Baseline Efficacy/Effectiveness Information 
17.2  Newly Identified Information on Efficacy/Effectiveness  
17.3  Characterization of Benefits 
18. Integrated Benefit-Risk Analysis for Approved Indications 
15  Contains Nonbinding Recommendations 
 
18.1  Benefit-Risk Context  Medical Need and Important Alternatives  
18.2  Benefit-Risk Analysis Evaluation 
19. Conclusions and Actions 
20. Appendices 
 
 
III.  GUIDANCE ON CONTENTS OF THE PBRER (3) 
 
All sections should be completed, and when no information is available, this should be stated.  
Note that section III.N (3.14) of this guidance provides guidance on the content of section N 
(14) of the PBRER.  For example, Reference Information, described in section III.F.l 
(3.6.1) of this guidance corresponds to section 6.1 of the PBRER. 
 
Title Page 
  
The title page of the PBRER should include the following information: 
 
  Date of the report 
  Medicinal product(s) 
  IBD 
  Reporting interval 
  MAH(s) name(s) and address(es)  
  Any statement on the confidentiality of the information included in the PBRER 
  
Executive Summary 
 
This section should provide a concise summary of the most important information contained 
in the report. 
 
 The following information should be included in the Executive Summary: 
 
  Introduction 
 
  Reporting interval 
 
  Medicinal product(s)  mode(s) of action, therapeutic class(es), indication(s), dose(s), 
route(s) of administration, formulation(s) 
 
  Estimated cumulative exposure of clinical trial subjects; interval and cumulative post-
approval exposure 
 
  Number of countries in which the medicinal product is approved 
 
  Summary of overall benefit-risk evaluation (based on section 18.2 of the PBRER)  
 
  Actions taken or proposed for safety reasons (e.g., significant changes to the reference 
product information, other risk minimization activities 
 
  16  Contains Nonbinding Recommendations 
 
  Conclusions 
 
Table of Contents 
 
A.  Introduction (3.1) 
 
Section 1 of the PBRER should include the following information: 
 
  IBD 
 
  Reporting interval 
 
  Medicinal product(s)  mode(s) of action, therapeutic class(es), dose(s), route(s) of 
administration, formulation(s) 
 
  A brief description of the approved indication(s) and population(s) 
 
  A brief description and explanation of any information that has not been included in the 
PBRER 
 
  The rationale for submission of multiple PBRERs for the medicinal product, if applicable 
 
B.  Worldwide Marketing Approval Status (3.2) 
  
Section 2 of the PBRER should provide a brief narrative overview, including date of first 
approval, indication(s), approved dose(s), and where approved, if applicable. 
 
C.  Actions Taken in the Reporting Interval for Safety Reasons (3.3)  
 
Section 3 of the PBRER should include a description of significant actions related to safety 
that have been taken during the reporting interval, related to either investigational uses or 
marketing experience by the MAH, sponsor of a clinical trial(s), regulatory authorities, data 
monitoring committees, or ethics committees that had: 
 
  A significant influence on the benefit-risk profile of the approved medicinal product, 
and/or 
 
  An impact on the conduct of a specific clinical trial(s) or on the overall clinical 
development program. 
 
The reason(s) for each action should be provided, if known, and additional relevant 
information should be provided when appropriate.  Relevant updates to previous actions 
should also be summarized in this section.  Examples of significant actions taken for safety 
reasons include: 
 
Actions related to investigational drugs:* 
 
  Refusal to authorize a clinical trial for ethical or safety reasons 
 
17  Contains Nonbinding Recommendations 
 
  Partial8 or complete clinical trial suspension or early termination of an ongoing clinical 
trial* because of safety findings or lack of efficacy 
 
  Recall of investigational drug or comparator 
 
  Failure to obtain marketing approval for a tested indication, including voluntary 
withdrawal of a marketing application 
 
  Risk management activities, including: 
 
  Protocol modifications because of safety or efficacy concerns (e.g., dosage changes, 
o
changes in study inclusion/exclusion criteria, intensification of subject monitoring, 
limitation in trial duration) 
 
  Restrictions in study population or indications 
o
 
  Changes to the informed consent document relating to safety concerns 
o
 
  Formulation changes 
o
 
  Addition by regulators of a special safety-related reporting requirement 
o
 
  Issuance of a communication to investigators or healthcare professionals 
o
 
  Plans for new studies to address safety concerns 
o
 
Actions related to marketed drugs: 
 
  Failure to obtain or apply for a marketing approval renewal 
 
  Withdrawal or suspension of a marketing approval 
 
  Suspension of supply by the MAH 
 
  Risk management activities, including: 
 
  Significant restrictions on distribution or introduction of other risk minimization 
o
measures 
 
  Significant safety-related changes in labeling documents that could affect the 
o
development program, including restrictions on use or population treated 
 
  Communications to healthcare professionals 
o
 
  New postmarketing study requirement(s) imposed by regulator(s) 
o
 
                                                 
8 Partial suspension might include several actions (e.g., suspension of repeat-dose studies, but continuation of 
single-dose studies; suspension of trials in one indication, but continuation in another; and/or suspension of a 
particular dosing regimen in a trial, but continuation of other doses). 
  18  Contains Nonbinding Recommendations 
 
D.  Changes to Reference Safety Information (3.4) 
 
Section 4 of the PBRER should list any significant changes to the reference safety 
information within the reporting interval.  Such changes might include information relating to 
contraindications, warnings, precautions, ADRs, overdose, and interactions; important 
findings from ongoing and completed clinical trials;* and significant non-clinical findings 
(e.g., carcinogenicity studies).  Specific information relevant to these changes should be 
provided in the appropriate sections of the PBRER.   
 
A clean version of the reference document that is current at the DLP of the PBRER should be 
included in Appendix 1.  A track change version of the reference information is not required. 
 
E.  Estimated Exposure and Use Patterns (3.5) 
 
Sections 5.1 and 5.2 of the PBRER should provide estimates of the size and nature of the 
population exposed to the medicinal product.  Section 5.1 of the PBRER should provide 
information on cumulative exposure in clinical trials.  Section 5.2 should provide cumulative 
and interval exposure in the marketed setting.  Brief descriptions of the method(s) used to 
estimate the subject/patient exposure should be provided, as well as the limitations of the 
methods.  Consistent methods for calculating patient exposure should be used across 
PBRERs for the same product.  If a change in the method is appropriate, both methods and 
calculations should be provided in the PBRER introducing the change. 
 
1.  Cumulative Subject Exposure in Clinical Trials (3.5.1) 
 
Section 5.1 of the PBRER should include the following information, if applicable, presented 
in tabular format (see Appendix B, Tables 1, 2, and 3, for examples): 
 
  Cumulative numbers of subjects from ongoing and completed clinical trials exposed to 
the investigational medicinal product, placebo, and/or active comparator(s) since the 
DIBD.  It is recognized that for older products, precise data might not be available. 
 
  More detailed information on cumulative subject exposure in clinical trials should be 
presented, if available (e.g., subgrouped by age, sex, and racial/ethnic group) for the 
entire development program. 
 
  Important differences among trials in dose, routes of administration, or patient 
populations can be noted in the tables, if applicable, or separate tables can be considered. 
 
  If clinical trials have been or are being performed in special populations (e.g., pregnant 
women; patients with renal, hepatic, or cardiac impairment; or patients with relevant 
genetic polymorphisms), exposure data should be provided, as appropriate. 
 
  When there are substantial differences in duration of exposure between subjects 
randomized to the investigational medicinal product or comparator(s), or disparities in 
duration of exposure between clinical trials, it can be useful to express exposure in 
subject-time (subject-days, -months, or -years). 
 
  Investigational drug exposure in healthy volunteers might be less relevant to the overall 
safety profile, depending on the type of adverse reaction, particularly when subjects are 
19  Contains Nonbinding Recommendations 
 
exposed to a single dose.  Such data can be presented separately with an explanation, as 
appropriate. 
 
  If the serious adverse events (SAEs) from clinical trials are presented by indication in the 
summary tabulations, the patient exposure should also be presented by indication, where 
available. 
 
  For individual trials of particular importance, demographic characteristics should be 
provided separately. 
 
2.  Cumulative and Interval Patient Exposure From Marketing Experience (3.5.2) 
 
Separate estimations should be provided for interval exposure (since the DLP of the previous 
PBRER) and, when possible, cumulative exposure (since the IBD).  See Appendix B, Tables 
4 and 5, for examples.  The estimated number of patients exposed should be provided when 
possible, along with the method(s) used to determine the estimate.  If an estimate of the 
number of patients is not available, alternative estimated measures of exposure should be 
presented along with the method(s) used to derive them, if available.  Examples of alternative 
measures of exposure include patient-days of exposure and number of prescriptions.  
Measures of drug sales, such as tonnage or dosage units, can be used only if  it is not possible 
to provide the measures described above.  The concept of a defined daily dose can also be 
used to estimate patient exposure. 
 
The data should be presented according to the following categories: 
 
a.  Post-approval (nonclinical trial) exposure: 
  
An overall estimation of patient exposure should be provided. 
 
In addition, the data should be routinely presented by indication, sex, age, dose, formulation, 
and region, where applicable. 
 
Depending upon the product, other variables may be relevant, such as number of vaccination 
courses, route(s) of administration, and duration of treatment. 
 
When there are patterns of reports indicating a safety signal, exposure data within relevant 
subgroups should be presented, if possible. 
 
b.  Post-approval use in special populations: 
 
Where post-approval use has occurred in special populations, available information regarding 
cumulative patient numbers exposed and the method of calculation should be provided.  
Sources of such data include non-interventional studies designed to obtain this information, 
including registries.  Populations to be considered for discussion include, but might not be 
limited to: 
 
  Pediatric population 
  Elderly population 
  Pregnant or lactating women 
  Patients with hepatic and/or renal impairment 
  20  Contains Nonbinding Recommendations 
 
  Patients with other relevant co-morbidity 
  Patients with disease severity different from that studied in clinical trials 
  Sub-populations carrying relevant genetic polymorphism(s) 
  Patients of different racial and/or ethnic origins 
 
c.  Other post-approval use: 
 
If the MAH becomes aware of patterns of use of the medicinal product considered relevant 
for the interpretation of safety data, the PBRER should provide a brief description of them.  
Examples of such patterns of use can include overdose, drug abuse, misuse, and use beyond 
that recommended in the reference product information (e.g., an anti-epileptic drug used for 
neuropathic pain and/or prophylaxis of migraine headaches).  Such patterns can be regional.  
If known, the MAH can briefly comment on whether use beyond that recommended in the 
reference product information is supported by clinical guidelines, clinical trial evidence, or an 
absence of approved alternative treatments.  Quantitative use information should be provided, 
if available.  For purposes of identifying patterns of use outside the terms of the reference 
product information, the MAH should use the appropriate sections of the reference product 
information that was in effect at the DLP of the PBRER (e.g., approved indication, 
contraindications). 
 
F.  Data in Summary Tabulations (3.6) 
 
PBRER sections 6.1 to 6.3 should present cumulative summary tabulations of SAEs from 
clinical trials and postmarketing sources that have been reported to the MAH since the DIBD.  
At the discretion of the MAH, graphical displays can be used to illustrate specific aspects of 
the data when useful to enhance understanding. 
 
1.  Reference Information (3.6.1) 
 
Section 6.1 of the PBRER should specify the version(s) of the coding dictionary used for 
analyses of adverse reactions. 
 
2.  Cumulative Summary Tabulations of Serious Adverse Events From Clinical 
Trials (3.6.2) 
 
Section 6.2 of the PBRER should provide background for the appendix that provides a 
cumulative summary tabulation of SAEs reported in the MAHs clinical trials, from the 
DIBD to the DLP of the current PBRER.  The MAH should explain any omission of data 
(e.g., clinical trial data might not be available for products marketed for many years).  The 
tabulation(s) should be organized by system organ class (SOC), for the investigational drug, 
as well as for the comparator arm(s) (active comparators, placebo) used in the clinical 
development program.  Data can be integrated across the program.  Alternatively, when 
useful and feasible, tabulations of SAEs can be presented by trial, indication, route of 
administration, or other variables.  This section should not serve to provide analyses or 
conclusions based on the SAEs. 
   
Appendix B, Table 6, of this guidance provides an example of summary tabulations of SAEs 
from clinical trials.  The following points should be considered: 
 
21  Contains Nonbinding Recommendations 
 
  In general, the tabulation(s) of SAEs from clinical trials should include only those terms 
that were used in defining the case as serious; they should not include nonserious events. 
 
  When the Medical Dictionary for Regulatory Activities (MedDRA) terminology is used 
for coding the adverse event/reaction terms, the Preferred Term level and SOC should be 
presented in the summary tabulations. 
 
  The tabulations should include blinded and unblinded clinical trial data.  Unblinded SAEs 
might originate from completed trials and individual cases that have been unblinded for 
safety-related reasons (e.g., expedited reporting), if applicable.  Sponsors/MAHs should 
not unblind data for the specific purpose of preparing the PBRER. 
 
  Certain adverse events in clinical trials can be excluded from the clinical trials summary 
tabulations, but such exclusions should be explained in the report.  For example, adverse 
events that have been defined in the protocol as exempt from special collection and 
entry into the safety database because they are anticipated in the patient population, and 
those that represent study endpoints, can be excluded (e.g., deaths reported in a trial of a 
drug for congestive heart failure where all-cause mortality is the primary efficacy 
endpoint, disease progression in cancer trials). 
 
  Causality assessment is generally useful for the evaluation of individual rare ADRs.  
Individual case causality assessment has less value in the analysis of aggregate data, 
where group comparisons of rates are possible.  Therefore, the summary tabulations 
should include all SAEs for the investigational drug, active controls, and placebo.  It may 
be useful to give rates by dose. 
 
3.  Cumulative and Interval Summary Tabulations from Post-Marketing Data 
Sources (3.6.3) 
 
Section 6.3 of the PBRER should provide background for the appendix that provides 
cumulative and interval summary tabulations of adverse reactions, from the IBD to the DLP 
of the current PBRER.  As described in the ICH E2D guidance, for marketed medicinal 
products, spontaneously reported* adverse events usually imply at least a suspicion of 
causality by the reporter, and should be considered to be adverse reactions for regulatory 
reporting purposes.  The tabulation should include: 
 
  Serious and nonserious adverse drug reactions from spontaneous ICSRs, including reports 
from healthcare professionals, consumers, scientific literature, and regulatory authorities 
 
  Serious adverse reactions from non-interventional studies 
 
  Solicited reports* of serious adverse reactions 
 
The tabulation should include interval and cumulative data presented side-by-side (see 
Appendix B, Table 7), and should be organized by SOC. 
   
For special issues or concerns, additional tabulations of adverse reactions can be presented by 
indication, route of administration, or other variables.  This section should not serve to 
provide analyses or conclusions based on the data presented. 
   
  22  Contains Nonbinding Recommendations 
 
G.  Summaries of Significant Safety Findings From Clinical Trials During the 
Reporting Interval (3.7) 
 
Section 7 of the PBRER should provide a brief summary of clinically important emerging 
efficacy/effectiveness and safety findings obtained from the MAHs sponsored clinical trials 
that have become available during the reporting interval of the report.  The safety signals 
arising from clinical trial sources should be tabulated in section 15 of the PBRER. Evaluation 
of the signals (whether or not categorized as refuted signals or either potential risks* or 
identified risks*) that were closed during the reporting interval should be presented in 
Section 16.2 of the PBRER.  New information in relation to any previously known potential 
or identified risks and not considered to constitute a newly identified signal should be 
evaluated and characterized in sections 16.3 and 16.4, respectively.  Findings from clinical 
trials not sponsored by the MAH should be described in the relevant sections of the PBRER.  
 
When relevant to the benefit-risk evaluation, information on lack of efficacy from clinical 
trials for treatments of non-life-threatening diseases in approved indications should also be 
summarized in this section.  Information on lack of efficacy from clinical trials with products 
intended to treat or prevent serious or life-threatening illnesses should be summarized in 
section 13 of the PBRER. 
 
When possible and relevant, data categorized by sex and age (particularly children versus 
adult), indication, dose, and region should be presented. 
 
A listing of any MAH-sponsored postmarketing interventional trials with the primary aim of 
identifying, characterizing, or quantifying a safety hazard, or confirming the safety profile of 
the medicinal product that were completed or ongoing during the reporting interval should be 
included in an appendix. The listing should include the following information for each trial: 
 
  Study identification (e.g., protocol number or other identifier)  
 
  Study title (abbreviated study title, if applicable) 
 
  Study type (e.g., randomized clinical trial, cohort study, case-control study)  
 
  Population studied (including country and other relevant population descriptors, e.g., 
pediatric population or trial subjects with impaired renal function)  
 
  Study start (as defined by the MAH) and projected completion dates  
 
  Status:  
 
  Ongoing (clinical trial has begun)  
o
 
  Completed (clinical study report is finalized); 
o
 
1.  Completed Clinical Trials (3.7.1) 
 
Section 7.1 of the PBRER should provide a brief summary of clinically important emerging 
efficacy and safety findings obtained from clinical trials completed during the reporting 
23  Contains Nonbinding Recommendations 
 
interval.  This information can be presented in narrative format or as a synopsis.9  It could 
include information that supports or refutes previously identified safety concerns, as well as 
evidence of new safety signals. 
 
2.  Ongoing Clinical Trials (3.7.2) 
 
If the MAH is aware of clinically important information that has arisen from ongoing clinical 
trials (e.g., learned through interim safety analyses or as a result of unblinding of subjects 
with adverse events), section 7.2 should briefly summarize the concern(s).  It could include 
information that supports or refutes previously identified safety concerns, as well as evidence 
of new safety signals. 
 
3.  Long-Term Follow-Up (3.7.3) 
 
Where applicable, section 7.3 should provide information from long-term follow-up of 
subjects from clinical trials of investigational drugs, particularly advanced therapy products. 
  
4.  Other Therapeutic Use of Medicinal Product (3.7.4) 
 
Section 7.4 of the PBRER should include clinically important safety information from other 
programs conducted by the MAH that follow a specific protocol, with solicited reporting as 
per the ICH E2D guidance (e.g., expanded access programs, compassionate use programs, 
particular patient use, single-patient investigational new drug applications (INDs), treatment 
INDs, and other organized data collection). 
 
5.  New Safety Data Related to Fixed Combination Therapies (3.7.5) 
 
Unless otherwise specified by national or regional regulatory requirements, the following 
options can be used to present data from combination therapies: 
 
  If the product that is the subject of a PBRER is also approved or under development as a 
component of a fixed combination product or a multidrug regimen, this section should 
summarize important safety findings from use of the combination therapy. 
 
  If this PBRER is for a fixed combination product, this section should summarize 
important safety information arising from the individual components. 
 
The information specific to the combination can be incorporated into a separate section(s) of 
the PBRER for one or all of the individual components of the combination. 
 
H.  Findings From Non-Interventional Studies (3.8) 
 
Section 8 should summarize relevant safety information or information having potential 
impact on the benefit or risk evaluations, from MAH-sponsored, non-interventional studies 
that have become available during the reporting interval (e.g., observational studies, 
epidemiological studies, registries, and active surveillance programs).  This should include 
relevant information from drug use studies when applicable to multiple regions. 
                                                 
9 Examples of synopses are provided in the ICH E3 guidance and by the Council for International Organizations 
of Medical Sciences (CIOMS) VII. 
  24  Contains Nonbinding Recommendations 
 
 
A listing of any MAH-sponsored, postmarketing non-interventional study or studies with the 
primary aim of identifying, characterizing, or quantifying a safety hazard; confirming the 
safety profile of the medicinal product; or measuring the effectiveness of risk management 
measures that were completed or ongoing during the reporting interval should be included in 
an appendix (see section III.G (3.7) of this guidance for the information that should be 
included in the listing).   
 
Final study reports completed during the reporting interval for the studies mentioned in the 
paragraph above should also be included in the regional appendix of the report where 
stipulated by regional requirements. 
  
I.  Information From Other Clinical Trials and Sources (3.9) 
 
1.  Other Clinical Trials (3.9.1) 
 
Section 9.1 of the PBRER should summarize information accessible to the MAH with 
reasonable and appropriate effort from any other clinical trial/study sources, including results 
from pooled analyses or meta-analyses of randomized clinical trials, and safety information 
provided by co-development partners or from investigator-initiated trials. 
 
2.  Medication Errors (3.9.2) 
 
Section 9.2 should summarize relevant information on patterns of medication errors and 
potential medication errors, even when not associated with adverse outcomes.  A potential 
medication error is the recognition of circumstances that could lead to a medication error, and 
might or might not involve a patient.  Such information could be relevant to the interpretation 
of safety data or the overall benefit-risk evaluation of the medicinal product.  A medication 
error can arise at any stage in the medication use process, and can involve patients, 
consumers, or healthcare professionals. 
 
This information can be received by the MAH via spontaneous reporting systems, medical 
information queries, customer complaints, screening of digital media, patient support 
programs, or other available information sources.  
 
Signals or risks identified from any information source and/or category of reports should be 
presented and evaluated in the relevant section of the PBRER. 
  
J.  Nonclinical Data (3.10) 
 
Section 10 of the PBRER should summarize major safety findings from nonclinical in vivo 
and in vitro studies (e.g., carcinogenicity, reproduction, or immunotoxicity studies) ongoing 
or completed during the reporting interval.  Results from studies designed to address specific 
safety concerns should be included in the PBRER, regardless of the outcome.  Implications of 
the findings presented in PBRER section 10 should be discussed in the relevant evaluation 
sections of the report. 
   
K.  Literature (3.11) 
 
25  Contains Nonbinding Recommendations 
 
Section 11 should summarize new and significant safety findings, either published in the 
peer-reviewed scientific literature or made available as unpublished manuscripts, relevant to 
the approved medicinal product that the MAH has become aware of during the reporting 
interval.  Literature searches for PBRERs should be wider than those for individual adverse 
reaction cases, and include studies reporting safety outcomes in groups of subjects.  If 
relevant, information on active substances of the same class should be considered. 
 
L.  Other Periodic Reports (3.12) 
 
Unless otherwise specified by national or regional regulatory requirements, the MAH should 
prepare a single PBRER for a single active substance.  However, if an MAH prepares 
multiple PBRERs for a single active substance (e.g., covering different indications, or 
formulations), section 12 should summarize significant findings from the other periodic 
reports if they are not presented elsewhere within this report. 
 
When available, based on contractual agreements, the MAH should summarize significant 
findings from periodic reports provided during the reporting interval by other parties (e.g., 
sponsors, MAHs, other contractual partners). 
 
M.  Lack of Efficacy in Controlled Clinical Trials (3.13)  
 
Data from clinical trials indicating lack of efficacy, or lack of efficacy relative to established 
therapy or therapies for products intended to treat or prevent serious or life-threatening 
illnesses (e.g., excess cardiovascular adverse events in a trial of a new anti-platelet drug for 
acute coronary syndromes) could reflect a significant risk to the treated population and 
should be summarized in section 13. 
 
N.  Late-Breaking Information (3.14) 
 
Section 14 of the PBRER should summarize information on potentially important safety and 
efficacy/effectiveness findings that arise after the DLP but while the PBRER is in 
preparation.  Examples include clinically significant new publications; important follow-up 
data; clinically relevant toxicological findings; and any action that the MAH, a data 
monitoring committee, or a regulatory authority has taken for safety reasons.  New individual 
case reports should not be included unless they are considered to constitute an important 
index case (i.e., the first instance of an important event), an important safety signal, or where 
they may add information to the evaluation of safety concerns already presented in the 
PBRER (e.g., a well-documented and unconfounded case report of aplastic anemia in a 
medicinal product known to be associated with adverse effects on the bone marrow). 
 
Any significant change proposed to the reference product information that has occurred after 
the DLP of the report but before submission should also be included in this section, where 
feasible.  Such changes could include a new contraindication, warning/precaution, or new 
adverse drug reaction.   
 
The data presented in this section should also be taken into account in the evaluation of risks 
and new information (see section III.P.3 (3.16.3) of this guidance).  
 
O.  Overview of Signals:  New, Ongoing, or Closed (3.15) 
 
  26  Contains Nonbinding Recommendations 
 
The general location for presentation of information on signals and risks within the PBRER is 
shown in Appendix F of this guidance.  Section 15 of the PBRER should provide a high-level 
overview of safety signals that were closed (i.e., the evaluation was completed) during the 
reporting interval as well as ongoing signals* that were undergoing evaluation, at the end of 
reporting interval.  For the purposes of the PBRER, a signal should be included once it has 
undergone the initial screening or clarification step, and a determination made to conduct 
further evaluation by the MAH.  It should be noted that a safety signal is not synonymous 
with a statistic of disproportionate reporting for a specific drug/event combination because a 
validation step is called for.  Signals can be qualitative (e.g., a pivotal individual safety case 
report, case series) or quantitative (e.g., a disproportionality score, findings of a clinical trial 
or epidemiological study).  Signals can arise in the form of an information request or inquiry 
on a safety issue from a regulatory authority.    
 
Decisions regarding the subsequent classification of these signals and the conclusions of the 
evaluation involve medical judgment and scientific interpretation of available data, which is 
presented in section 16 of the PBRER.  
 
A new signal is a signal that the MAH has become aware of during the reporting interval. 
New clinically important information on a previously closed signal* that has become 
available during the reporting period of the PBRER (i.e., a new aspect of a previously refuted 
signal or recognized risk likely to warrant further action to verify) would also constitute a 
new signal.  New signals can be classified as closed or ongoing, depending on the status of 
signal evaluation at the DLP of the PBRER.  Examples would include new information on a 
previously: 
 
  Closed and refuted signal, which would result in the signal being reopened 
  
  Identified risk that is indicative of a clinically significant difference in the severity of the 
risk (e.g., transient liver enzyme increases are identified risks, and new information is 
received indicative of a more severe outcome such as hepatic failure; neutropenia is an 
identified risk and a well-documented and unconfounded case report of agranulocytosis is 
received) 
  
  Identified risk for which a higher frequency of the risk is newly found (e.g., in a 
subpopulation) 
   
  Potential risk* that, if confirmed, would warrant a new warning, precaution, new 
contraindication or restriction in indication(s) or population, or other risk minimization 
activities 
 
Within this section or as an appendix, a tabular listing of all signals, ongoing or closed, at the 
DLP of the PBRER should be included.  This table should include the following information 
(see Appendix C for an example). 
  
  A brief description of the signal 
  Date when the MAH became aware of the signal 
  Status of the signal (closed or ongoing at the DLP) 
  Date when the signal was closed, if applicable 
  Source of the signal 
27  Contains Nonbinding Recommendations 
 
  A brief summary of key data 
  Plans for further evaluation 
  Actions taken or planned 
 
Detailed signal evaluations for closed signals should not to be included in this section, but 
instead should be presented in section 16.2 (Signal Evaluation) of the PBRER.  Evaluation of 
new information in relation to any previously known identified and potential risks and not 
considered to constitute a newly identified signal* should be provided in section 16.3 
(Evaluation of Risks and New Information) of the PBRER.  
 
When a regulatory authority has requested that a specific topic (not considered a signal) be 
monitored and reported in a PBRER, the MAH should summarize the result of the analysis in 
PBRER section 15 if it is negative.  If the specific topic becomes a signal, it should instead be 
included in the signal tabulation and discussed in PBRER section 16.2. 
   
P.  Signal and Risk Evaluation (3.16) 
 
Section 16 of the PBRER should provide: 
 
  A succinct summary of what is known about important identified and potential risks and 
important missing information* at the beginning of the reporting interval covered by 
the report (16.1) 
 
  An evaluation of  all signals closed  during the reporting interval (16.2) 
 
  An evaluation of new information with respect to previously recognized identified and 
potential risks (16.3) 
   
  An updated characterization of important potential and identified risks, where applicable 
(16.4)  
 
  A summary of the effectiveness of risk minimization activities in any country or region 
that might have utility in other countries or regions (16.5)  
 
Appendix F of this guidance provides a flowchart to illustrate the mapping of signals and 
risks to specific sections of the PBRER. 
 
The evaluation subsections should not summarize or repeat information presented in previous 
sections of the PBRER, but should instead provide an interpretation of the information, with a 
view towards characterizing the profile of those risks assessed as important.  As a general 
rule, it is not necessary to include individual case narratives in the evaluation sections of the 
PBRER; however, when integral to the scientific analysis of a signal or risk, a clinical 
evaluation of pivotal or illustrative cases (e.g., the first case of suspected agranulocytosis with 
an active substance belonging to a class known to be associated with this adverse reaction) 
should be provided. 
 
1.  Summary of Safety Concerns (3.16.1) 
 
Section 16.1 should provide a summary of safety concerns at the beginning of the reporting 
interval, against which new information and evaluations can be made.  These comprise: 
  28  Contains Nonbinding Recommendations 
 
 
  Important identified risks* 
  Important potential risks* 
  Important missing information 
 
The following factors should be considered when determining whether or not a risk is 
important: 
 
  Medical seriousness of the risk, including the impact on individual patients 
  Its frequency, predictability, preventability, and reversibility 
  Potential impact on public health (frequency; size of treated population) 
  Potential for avoidance of a medical product with a preventive benefit as a result of public 
perception of risk 
 
For products with an existing safety specification, this section can be either the same as, or be 
derived from, the safety specification summary (according to the ICH E2E guidance) at the 
start of the reporting interval of the current PBRER.  For products without an existing safety 
specification, this section should provide information on the important identified and 
potential risks and important missing information associated with use of the product, based 
on pre-approval and post-approval experience.  Important identified and potential risks may 
include, for example: 
 
  Important adverse reactions 
  Interactions with other medicinal products 
  Interactions with foods and other substances 
  Medication errors 
  Effects of occupational exposure  
  Pharmacological class effects 
 
The summary on important missing information should take into account whether there are 
critical gaps in knowledge for specific safety issues or populations that use the medicinal 
product. 
 
2.  Signal Evaluation (3.16.2) 
 
Section 16.2 of the PBRER should summarize the results of evaluations of all safety signals 
(whether or not classified as important) that were closed during the reporting interval.  A 
safety signal can be closed either because it is refuted or because it is determined to be a 
potential or identified risk following evaluation. Therefore, the two main categories that 
should be included in this section are: 
 
1.  Those signals that, following evaluation, have been refuted as false signals based on 
medical judgment and a scientific evaluation of the currently available information 
  
2.  Those signals that, following evaluation, have been categorized as either a potential or 
identified risk, including lack of efficacy 
  
29  Contains Nonbinding Recommendations 
 
For both categories of closed signals, a concise description of each signal evaluation should 
be included to provide to the regulatory authorities the basis upon which the signal was either 
refuted or considered to be a potential or identified risk by the MAH.  
 
It is recommended that the level of detail provided in the description of the signal evaluation 
be proportionate to the medical significance of the signal, its public health importance, and 
the extent of the available evidence.  When multiple evaluations are included under both 
categories of closed signals, they can be presented in the following order: 
  
  Closed and refuted signals 
  Closed signals that are categorized as important potential risks 
  Closed signals that are categorized as important identified risks 
  Closed signals that are potential risks not categorized as important 
  Closed signals that are identified risks not categorized as important 
 
Where applicable, the closed signal evaluations can be presented by indication or population. 
 
The description(s) of the signal evaluations can be included in this section of the PBRER, or 
in an appendix.  Each signal evaluation should include the following information, as 
appropriate: 
 
  Source of the signal 
 
  Background relevant to the evaluation 
 
  Method(s) of evaluation, including data sources, search criteria (where applicable, the 
specific MedDRA terms (e.g., PTs, HLTs, SOCs) or Standardized MedDRA Queries 
(SMQs) that were reviewed), and analytical approaches 
  
  Results  a summary and critical analysis of the data considered in the signal evaluation; 
where integral to the assessment, this may include a description of a case series or an 
ICSR (e.g., an index case of well-documented agranulocytosis or Stevens Johnson 
syndrome) 
 
  Discussion 
  
  Conclusion 
 
3.  Evaluation of Risks and New Information (3.16.3) 
 
Section 16.3 should provide a critical appraisal of new information relevant to previously 
recognized risks that is not already included in section 16.2 of the PBRER, Signal Evaluation.   
 
New information that constitutes a signal with respect to a previously recognized risk or 
previously refuted signal should be presented in the tabular summary in Appendix C and 
evaluated in section 16.2 of the PBRER, if the signal is also closed during the interval of the 
PBRER. 
 
  30  Contains Nonbinding Recommendations 
 
Updated information on a previously recognized risk that does not constitute a signal should 
be included in this section.  Examples include information that confirms a potential risk as an 
identified risk, or information that allows further characterization of a previously recognized 
risk.  
 
New information can be organized as follows: 
 
1.  New information on important potential risks 
2.  New information on important identified risks 
3.  New information on other potential risks not categorized as important 
4.  New information on other identified risks not categorized as important  
5.  Update on important missing information 
 
The focus of the evaluation(s) is on new information that has emerged during the reporting 
interval of the PBRER.  This should be concise and interpret the impact, if any, on the 
understanding and characterization of the risk.  Where applicable, the evaluation will form 
the basis for an updated characterization of important potential and identified risks in section 
16.4 of the report.  It is recommended that the level of detail of the evaluation included in this 
section be proportional to the available evidence on the risk and its medical significance and 
public health relevance. 
 
The evaluation(s) of new information and missing information update(s) can be included in 
this section of the PBRER, or in an appendix.  Each evaluation should include the following 
information, as appropriate: 
 
  Source of the new information 
 
  Background relevant to the evaluation 
 
  Method(s) of evaluation, including data sources, search criteria, and analytical approaches 
 
  Results  a summary and critical analysis of the data considered in the risk evaluation 
  
  Discussion 
 
  Conclusion including whether or not the evaluation supports an update of the 
characterization of any of the important potential and identified risks in section 16.4 of 
the PBRER 
 
Any new information on populations exposed or data generated to address previously missing 
information should be critically assessed in this section.  Unresolved concerns and 
uncertainties should be acknowledged. 
 
4.  Characterization of Risks (3.16.4) 
 
Section 16.4 of the PBRER should characterize important identified and important potential 
risks based on cumulative data (i.e., not restricted to the reporting interval), and describe 
important missing information. 
 
31  Contains Nonbinding Recommendations 
 
Depending on the nature of the data source, the characterization of risk can include, where 
applicable: 
 
  Frequency 
 
  Numbers of cases (numerator); precision of estimate, taking into account the source of the 
data 
  
  Extent of use (denominator) (expressed in, e.g., numbers of patients, patient-time) and 
precision of estimate 
 
  Estimate of relative risk; precision of estimate 
 
  Estimate of absolute risk; precision of estimate 
 
  Impact on the individual patient (effects on symptoms, quality or quantity of life) 
 
  Public health impact 
 
  Patient characteristics relevant to risk (e.g., age, pregnancy/lactation, disease severity, 
hepatic/renal impairment, relevant comorbidity, genetic polymorphism) 
 
  Dose, route of administration 
 
  Duration of treatment, risk period 
 
  Preventability (i.e., predictability, ability to monitor for a sentinel adverse reaction or 
laboratory marker) 
 
  Reversibility 
 
  Potential mechanism 
 
  Strength of evidence and its uncertainties, including analysis of conflicting evidence, if 
applicable 
 
When missing information could constitute an important risk, it should be included as a 
safety concern.  The limitations of the safety database (in terms of, e.g., number of patients 
studied, cumulative exposure or long-term use) should be discussed. 
 
For PBRERs for products with several indications, formulations, or routes of administration, 
where there might be significant differences in the identified and potential risks, it might be 
appropriate to present risks by indication, formulation, or route of administration.  Headings 
that could be considered include: 
 
  Risks relating to the active substance 
 
  Risks related to a specific formulation or route of administration (including occupational 
exposure) 
  32  Contains Nonbinding Recommendations 
 
 
  Risks relating to a specific population 
 
  Risks associated with non-prescription use (for substances that are available as both 
prescription and non-prescription products) 
 
5.  Effectiveness of Risk Minimization (if applicable) (3.16.5) 
 
Section 16.5 of the PBRER should summarize relevant information that has become available 
during the reporting interval concerning the effectiveness and/or limitations of specific risk 
minimization activities for important identified risks. 
 
Insights into the effectiveness of risk minimization activities in any country or region that 
might have utility in other countries or regions are of particular interest.  Information can be 
summarized by region, if applicable and relevant. 
 
When reporting in a PBRER the results of evaluations that are relevant to only one region and 
that have become available during the reporting interval, the results should be provided in 
regional appendices. 
 
Q.  Benefit Evaluation (3.17) 
 
PBRER sections 17.1 and 17.2 should provide the baseline (17.1) and newly identified 
(17.2) benefit information that support the characterization of benefit described in section 
17.3 that in turn supports the benefit-risk evaluation in section 18. 
  
1.  Important Baseline Efficacy/Effectiveness Information (3.17.1) 
 
Section 17.1 should summarize information on the efficacy/effectiveness of the medicinal 
product as of the beginning of the reporting interval, and should provide the basis for the 
benefit evaluation.  This information should relate to the approved indication(s) of the 
medicinal product listed in the reference product information (see section II.D (2.4) of this 
guidance). 
 
For medicinal products with multiple indications, populations, and/or routes of 
administration, the benefit should be characterized separately by these factors, where 
relevant. 
 
The level of detail provided in this section should be sufficient to support the characterization 
of benefit in PBRER section 17.3 and the benefit-risk assessment in section 18. 
 
2.  Newly Identified Information on Efficacy/Effectiveness (3.17.2) 
  
New information on efficacy/effectiveness in approved indications that may have become 
available during the reporting interval should be presented in PBRER section 17.2.  For 
approved indications, new information on efficacy/effectiveness under conditions of actual 
use should also be described in this section, if available.  New information about 
efficacy/effectiveness in uses other than the approved indication(s) should not be included, 
unless relevant for the benefit-risk evaluation in the approved indication.  Information on 
indications approved during the reporting interval should also be included in this section.  
33  Contains Nonbinding Recommendations 
 
The level of detail provided in this section should be sufficient to support the characterization 
of benefit in section 17.3 and the benefit-risk assessment in section 18. 
 
New information on efficacy/effectiveness might also include changes in the therapeutic 
environment that could have an impact on efficacy/effectiveness over time (e.g., vaccines, 
emergence of resistance to anti-infective agents). 
 
3.  Characterization of Benefits (3.17.3) 
 
Section 17.3 of the PBRER should provide an integration of the baseline benefit information 
(see section III.Q.l (3.17.1) of this guidance) and any relevant new benefit information (see 
section III.Q.2 (3.17.2)) that has become available during the reporting interval for approved 
indications. 
 
This section should provide a concise but critical evaluation of the strengths and limitations 
of the evidence on efficacy/effectiveness, considering the following, when available: 
 
  A brief description of the strength of evidence of benefit, considering comparator(s), 
effect size, statistical rigor, methodological strengths and deficiencies, and consistency of 
findings across trials/studies 
 
  New information that challenges the validity of a surrogate endpoint, if used 
 
  Clinical relevance of the effect size 
  
  Generalizability of treatment response across the indicated patient population (e.g., 
information that demonstrates lack of treatment effect in a subpopulation) 
 
  Adequacy of characterization of dose-response 
 
  Duration of effect 
 
  Comparative efficacy 
 
  A determination of the extent to which efficacy findings from clinical trials are 
generalizable to patient populations treated in medical practice 
 
The level of detail provided in PBRER section 17.3 should be sufficient to support the 
analysis of benefit-risk in section 18. 
 
When there are no new relevant benefit data, section 17.3 should provide a characterization 
of the information in section 17.1 of the PBRER. 
 
When there is new positive benefit information and no significant change in the risk profile in 
this reporting interval, the integration of baseline and new information in this section should 
be succinct. 
 
R.  Integrated Benefit-Risk Analysis for Approved Indications (3.18) 
 
  34  Contains Nonbinding Recommendations 
 
Whereas PBRER sections 16.4 and 17.3 present the risks and benefits, respectively, section 
18 should provide an integration and critical analysis of the key information in these sections 
as described below.  Section 18 provides the benefit-risk analysis, and should not simply 
duplicate the benefit and risk characterization presented in sections 16.4 and 17.3. 
1.  Benefit-Risk Context  Medical Need and Important Alternatives (3.18.1) 
  
Section 18.1 should provide a brief description of the medical need for the medicinal product 
in the approved indications, and summarize alternatives (medical, surgical, or other, 
including no treatment). 
 
2.  Benefit-Risk Analysis Evaluation (3.18.2) 
 
A benefit-risk profile is specific to an indication and population.  For products approved for 
more than one indication, benefit-risk profiles should be evaluated and presented for each 
indication individually.  If there are important differences in the benefit-risk profiles among 
populations within an indication, benefit-risk evaluation should be presented by population, if 
possible.  The evaluation should be presented and discussed in a way that facilitates the 
comparison of benefits and risks, and should take into account the following points: 
 
  Whereas previous sections should include all important benefit and risk information, not 
all benefits and risks contribute importantly to the overall benefit-risk evaluation.  
Therefore, the key benefits and risks considered in the evaluation should be specified.  
The key information presented in the previous benefit and risk sections should be carried 
forward for integration in the benefit-risk evaluation. 
 
  The context of use of the medicinal product should be considered: the condition to be 
treated, prevented, or diagnosed; its severity and seriousness; and the population to be 
treated. 
 
  With respect to a key benefit(s), the following factors should be considered:  its nature, 
clinical importance, duration, and generalizability, as well as evidence of efficacy in 
nonresponders to other therapies and alternative treatments.  The effect size should also 
be considered.  If there are individual elements of benefit, all of them should be 
considered (e.g., for therapies for arthritis, reduction of symptoms and inhibition of 
radiographic progression of joint damage). 
 
  With respect to risk, its clinical importance should be considered (e.g., nature of toxicity; 
seriousness; frequency; predictability; preventability; reversibility; impact on patients; 
and whether it arose from off-label use, a new use, or misuse). 
 
  The strengths, weaknesses, and uncertainties of the evidence should be considered when 
formulating the benefit-risk evaluation.  A description of how the uncertainties in the 
benefits and risks have an impact on the evaluation should be provided.  Limitations of 
the assessment should be discussed. 
 
A clear explanation of the methodology and reasoning used to develop the benefit-risk 
evaluation should be provided: 
  
  The assumptions, considerations, and judgment or weighting that support the conclusions 
of the benefit-risk evaluation should be clear. 
35  Contains Nonbinding Recommendations 
 
 
  If a formal quantitative or semi-quantitative assessment of benefit-risk is provided, a 
summary of the methods should be included. 
 
Economic considerations (e.g., cost-effectiveness) should not be included in the benefit-risk 
evaluation. 
 
When there is important new information or an ad hoc PBRER has been requested, a detailed 
benefit-risk analysis should be provided.   
 
Conversely, where little new information has become available during the reporting interval, 
the primary focus of the benefit-risk evaluation might consist of an evaluation of updated 
interval safety data. 
 
S.  Conclusions and Actions (3.19) 
 
Section 19 of the PBRER should provide a conclusion about the implications of any new 
information that has arisen during the reporting interval, in terms of the overall benefit-risk 
evaluation, for each approved indication, as well as for relevant subgroups, if appropriate. 
 
Based on the evaluation of the cumulative safety data and the benefit-risk analysis, the MAH 
should assess the importance of further changes to the reference product information and 
propose changes, as appropriate. 
 
In addition and as applicable, the conclusion should include preliminary proposal(s) to 
optimize or further evaluate the benefit-risk balance, for further discussion with the relevant 
regulatory authorities.  This might include proposals for additional risk minimization 
activities.  
 
These proposals should also be considered for incorporation into the risk management plan 
(e.g., the E2E pharmacovigilance plan and/or risk minimization plan, as appropriate). 
 
If required by applicable regional laws and regulations, the MAH should provide, in a 
regional appendix, information on any final, ongoing, or proposed changes to the national or 
local authorized product information. 
 
T.  Appendices to the PBRER (3.20) 
 
The PBRER should be accompanied by the following appendices, as appropriate, numbered 
as follows: 
 
1.  Reference Information 
 
2.  Cumulative Summary Tabulation of Serious Adverse Events From Clinical Trials and 
Interval/Cumulative Summary Tabulations From Marketed Experience 
 
3.  Tabular Summary of Safety Signals (if not included in the body of the report) 
 
4.  Listing of Interventional and Non-Interventional Studies With a Primary Objective of 
Post-Authorization Safety Monitoring 
  36  Contains Nonbinding Recommendations 
 
 
5.  List of the Sources of Information Used to Prepare the PBRER (when desired by the 
MAH) 
 
The PBRER can also be accompanied by regional appendices, as appropriate, to fulfill 
national and regional requirements. 
 
 
 
 
37  Contains Nonbinding Recommendations 
 
IV.  APPENDICES TO THIS GUIDANCE (5) 
 
APPENDIX A  Glossary 
  
APPENDIX B  Examples of Summary Tabulations 
 
APPENDIX C  Example of a Tabular Summary of Safety Signals That Were Ongoing or 
Closed During the Reporting Interval 
 
APPENDIX D  List of PBRER Sections That Can Be Shared With Other Regulatory 
Documents 
 
APPENDIX E  Examples of Possible Sources of Information That Can Be Used in the 
Preparation of the PBRER 
 
APPENDIX F  Mapping of Signals and Risks to PBRER Sections 
  38  Contains Nonbinding Recommendations 
 
APPENDIX A  GLOSSARY 
 
Whenever possible, the Working Group has used terms in use in other ICH guidances, or 
those previously proposed by the Council for International Organizations of Medical 
Sciences (CIOMS) working groups.  Generally, the definitions of terms previously defined in 
ICH documents are not repeated in this glossary, except for those of particular importance to 
the PBRER.
Source of 
Item  Glossary Term  Definition/Commentary 
Definition 
1.    Closed signal  ICH E2C(R2) guidance  A signal for which an evaluation was completed 
during the reporting interval. 
2.    Company Core  ICH E2C guidance  A document prepared by the MAH containing, in 
Data Sheet  addition to safety information, material related to 
(CCDS)  indications, dosing, pharmacology, and other 
information concerning the product. 
3.    Company Core  ICH E2C guidance  All relevant safety information contained in the 
Safety Information  CCDS prepared by the MAH and that the MAH 
(CCSI)  requests to be listed in all countries where the 
company markets the drug, except when the local 
regulatory authority specifically requests a 
modification.  It is the reference information by 
which listed and unlisted are determined for 
periodic reporting for marketed products, but not 
by which expected and unexpected are determined 
for expedited reporting. 
4.    Completed clinical  ICH E2F guidance  Clinical trial for which a final study report is 
trial  available. 
5.    Identified risk  ICH E2F guidance  An untoward occurrence for which there is 
  adequate evidence of an association with the 
medicinal product of interest. 
Examples of identified risks include the following: 
 An adverse reaction adequately demonstrated in 
nonclinical studies and confirmed by clinical 
data 
 An adverse reaction observed in well-designed 
clinical trials or epidemiological studies for 
which the magnitude of the difference compared 
with the comparator group (placebo or active 
substance) on a parameter of interest suggests a 
causal relationship 
 An adverse reaction suggested by a number of 
well-documented spontaneous reports where 
causality is strongly supported by temporal 
relationship and biological plausibility, such as 
anaphylactic reactions or application site 
reactions 
39  Contains Nonbinding Recommendations 
 
Source of 
Item  Glossary Term  Definition/Commentary 
Definition 
6.    Important  ICH E2C(R2) guidance  An identified risk or potential risk that could have 
identified risk,  an impact on the risk-benefit profile of the product 
important potential  or have implications for public health.  What 
risk  constitutes an important risk will depend upon 
  several factors, including the impact on the 
  individual, the seriousness of the risk, and the 
impact on public health.  Normally, any risk that is 
likely to be included in the contraindications or 
warnings and precautions section of the product 
labeling should be considered important. 
7.    Important missing  ICH E2C(R2) guidance  Critical gaps in knowledge for specific safety 
information  issues or populations that use the marketed product.   
8.    International Birth  ICH E2C guidance  The date of the first marketing authorization for 
Date  any product containing the active substance granted 
to any company in any country in the world. 
9.    Investigational  ICH E2F guidance  The term investigational drug is used in this 
drug  guidance to indicate only the experimental product 
under study or development.  Note: This term is 
more specific than investigational medicinal 
product, which includes comparators and placebos. 
10.    Newly identified  ICH E2C(R2) guidance  A signal first identified during the reporting 
signal  interval, prompting further actions or evaluation. 
This term could also apply to a previously closed 
signal for which new information becomes 
available in the reporting interval prompting further 
action or evaluation. 
11.    Ongoing clinical  ICH E2F guidance  Trial where enrollment has begun, whether a hold 
trial  is in place or analysis is complete, but for which a 
final clinical study report is not available. 
12.    Ongoing signal  ICH E2C(R2) guidance  A signal that remains under evaluation at the DLP.   
  40  Contains Nonbinding Recommendations 
 
Source of 
Item  Glossary Term  Definition/Commentary 
Definition 
13.    Potential risk  ICH E2F guidance  An untoward occurrence for which there is some 
  basis for suspicion of an association with the 
medicinal product of interest but where this 
association has not been confirmed.  Examples of 
potential risks include the following: 
 Nonclinical safety concerns that have not been 
observed or resolved in clinical studies 
 Adverse events observed in clinical trials or 
epidemiological studies for which the 
magnitude of the difference, compared with the 
comparator group (placebo or active substance, 
or unexposed group), on the parameter of 
interest raises a suspicion of, but is not large 
enough to suggest, a causal relationship 
 An event that is known to be associated with 
other products of the same class or that could be 
expected to occur based on the properties of the 
medicinal product 
14.    Reference safety  ICH E2C(R2) guidance  All relevant safety information contained in the 
information  reference product information (e.g., CCDS) 
prepared by the MAH and that the MAH requests 
to be listed in all countries where the company 
markets the drug, except when the local regulatory 
authority specifically requests a modification.  It is 
a subset of information contained within the 
MAHs reference product information for the 
PBRER.  Where the reference product information 
is the Company Core Data Sheet (CCDS), the 
reference safety information is the Company Core 
Safety Information (CCSI). 
15.    Safety concern  ICH E2C(R2) guidance  An important identified risk, important potential 
risk, or important missing information. 
16.    Signal  ICH E2C(R2) guidance  Information that arises from one or multiple 
sources (including observations and experiments), 
that suggests a new potentially causal association, 
or a new aspect of a known association, between an 
intervention and an event or set of related events, 
either adverse or beneficial, that is judged to be of 
sufficient likelihood to justify further action to 
verify.  For section 16.2 of the PBRER, signals 
relate to adverse effects. 
41  Contains Nonbinding Recommendations 
 
Source of 
Item  Glossary Term  Definition/Commentary 
Definition 
17.    Solicited reports  ICH E2D guidance  Solicited reports are those derived from organized 
data collection systems, which include clinical 
trials, registries, post-approval named patient use 
programs, other patient support and disease 
management programs, surveys of patients or 
healthcare providers, or information gathering on 
efficacy or patient compliance.   
18.    Spontaneous  ICH E2D guidance  An unsolicited communication to a company, 
report or  regulatory authority, or other organization that 
spontaneous  describes an adverse drug reaction (ADR) in a 
notification  patient given one or more medicinal products and 
that does not derive from a study or any organized 
data collection scheme. 
  42  Contains Nonbinding Recommendations 
 
APPENDIX B  EXAMPLES OF SUMMARY TABULATIONS 
 
Note:  MAHs can modify these examples to suit specific situations, as appropriate. 
 
Table 1  Estimated Cumulative Subject Exposure From Clinical Trials 
Estimates of cumulative subject exposure, based upon actual exposure data from completed 
clinical trials and the enrollment/randomization schemes for ongoing trials.  
Treatment  Number of subjects 
Medicinal product    
Comparator   
Placebo   
Table 2  Cumulative Subject Exposure to Investigational Drug From Completed 
Clinical Trials by Age and Sex* 
  Number of subjects 
Age range  Male  Female  Total 
       
       
* Data from completed trials as of [date]. 
Table 3  Cumulative Subject Exposure to Investigational Drug From Completed 
Clinical Trials by Racial Group* 
Racial group  Number of subjects 
Asian   
Black   
Caucasian   
Other   
Unknown   
Total   
* Data from completed studies as of [date]. 
43  Contains Nonbinding Recommendations 
 
Table 4  Cumulative Exposure From Marketing Experience 
Dose 
Indication  Sex  Age (years)  (milligrams  Formulation  Region 
(mg)/day) 
  Male  Female  2  >16  >  un <40  40  u IV  Oral  EU J MU o
to  to 65  65 kn n a e S t
16  o k p x / h
w n a i C e
n  o n  c a r 
w o n
n  a
d
a 
Overall                                 
Depression                                 
Migraine                                 
Table 4 includes cumulative data obtained from month/day/year through month/day/year. 
Table 5  Interval Exposure from Marketing Experience 
Dose 
Indication  Sex  Age (years)  Formulation  Region 
(mg/day) 
  Male  Female  2  >16  >  u <40  40  u IV  Oral  E J M U o
to  to  65  n n U  a e S t
1 65  k k p x / h
6  n n a i C e
o o n  c a r 
w w o  n
n  n  a
d
a 
Depression                                 
Migraine                                  
Table 5 includes interval data obtained from month/day/year through month/day/year, where available. 
Table 6  Cumulative Tabulations of Serious Adverse Events From Clinical Trials 
System Organ Class  Investigational  Blinded  Active  Placebo 
Medicinal  comparator 
Preferred Term 
product 
Investigations         
Alanine aminotransferase         
increased 
Aspartate aminotransferase         
increased 
 
  44  Contains Nonbinding Recommendations 
 
System Organ Class  Investigational  Blinded  Active  Placebo 
Medicinal  comparator 
Preferred Term 
product 
Nervous System Disorders         
Syncope         
Headache         
 
Table 7 - Numbers of Adverse Drug Reactions by Term From Postmarketing Sources 
Non-interventional 
  postmarketing study 
 
Spontaneous, including regulatory authority and literature  and reports from other 
solicited sources* 
Total 
  Serious  Nonserious  Serious 
Spontaneous 
  Interval  Cumulative  Interval  Cumulative  Cumulative  Interval  Cumulative 
SOC 1               
  MedDRA 
             
PT 
MedDRA 
             
PT 
MedDRA 
             
PT 
               
SOC 2               
MedDRA 
             
PT 
MedDRA 
             
PT 
MedDRA 
             
PT 
MedDRA 
             
PT 
 
*This does not include interventional clinical trials. 
45  Contains Nonbinding Recommendations 
 
APPENDIX C  EXAMPLE OF A TABULAR SUMMARY OF SAFETY SIGNALS 
THAT WERE ONGOING OR CLOSED DURING THE REPORTING INTERVAL 
 
Reporting Interval: DD-MMM-YYYY to DD-MMM-YYYY 
Signal  Date  Status  Date closed  Source of  Reason for  Method of  Action(s) 
term  detected  (ongoing or  (for closed  signal  evaluation &  signal  taken or 
closed)  signals)  summary of key  evaluation  planned 
data 
Stroke  month/  ongoing  month/year  meta-analysis  statistically  review meta- pending 
year  (published  significant  analysis and  
trials)  increase in  available data 
frequency  
SJS  month/  closed  month/year  spontaneous  Rash already an  targeted follow  RSI 
year  case reports &  identified risk  up of reports  updated 
one case report  with site visit to with a 
SJS not reported 
in phase 4 trial  one hospital.  Warning 
in pre-
Full review of  and 
authorization 
cases by MAH  Precaution 
CTs. 
dermatologist 
DHPC  
4 apparently  and literature 
sent to                 
unconfounded  searches 
oncologists 
reports within 6 
months of  Effectivene
approval;  ss survey 
plausible time to  planned 6 
onset.  months 
post 
DHPC. 
RMP 
updated. 
 
Explanatory notes 
 Signal term 
A brief descriptive name of a medical concept for the signal.  The description might evolve 
and be refined as the signal is evaluated.  The concept and scope may, or may not, be 
limited to specific MedDRA term(s), depending on the source of signal.    
 Date detected (month/year) 
Month and year the MAH became aware of the signal. 
 Status 
Ongoing: Signal under evaluation at the DLP of the PBRER.  Provide anticipated 
completion date, if known.  
Closed: Signal for which evaluation was completed before the DLP of the PBRER.   
  46  Contains Nonbinding Recommendations 
 
Note: A new signal of which the MAH became aware during the reporting interval can be 
classified as closed or ongoing, depending on the status of signal evaluation at the DLP of 
the PBRER. 
 
 Date closed (month/year) 
Month and year the signal evaluation was completed. 
  
 Source of signal 
Data or information source from which a signal arose.  Examples include, but might not be 
limited to, spontaneous adverse event reports, clinical trial data, scientific literature, 
nonclinical study results, or information requests or inquiries from a regulatory authority. 
 
 Reason for evaluation 
A brief summary of key data and rationale for further evaluation. 
 
 Actions taken or planned 
It should be stated whether or not a specific action has been taken or is planned for all 
closed signals that have been classified as potential or identified risks.  If any further 
actions are planned for newly or previously identified signals under evaluation at the DLP, 
these should be listed.  Otherwise leave blank for ongoing signals. 
47  Contains Nonbinding Recommendations 
 
APPENDIX D  LIST OF PBRER SECTIONS THAT CAN BE SHARED WITH 
OTHER REGULATORY DOCUMENTS  
Potential 
    shared module 
with 
1  Introduction   
2  Worldwide Marketing Approval Status  E2F 
Parts can be 
Actions Taken in the Reporting Interval for Safety 
3  common to 
Reasons 
E2E and E2F 
4  Changes to Reference Safety Information   
5  Estimated Exposure and Use Patterns   
5.1  Cumulative Subject Exposure in Clinical Trials  E2E and E2F 
E2E and E2F 
Cumulative and Interval Patient Exposure From 
5.2  (cumulative 
Marketing Experience 
only) 
6  Data in Summary Tabulations   
6.1  Reference Information   
Cumulative Summary Tabulations of Serious 
6.2  E2F 
Adverse Events From Clinical Trials 
Cumulative and Interval Summary Tabulations 
6.3   
from Postmarketing Data Sources 
Summaries of Significant Findings From Clinical 
7   
Trials During the Reporting Period 
7.1  Completed Clinical Trials  E2F 
7.2  Ongoing Clinical Trials  E2F 
7.3  Long-Term Follow-up  E2F 
7.4  Other Therapeutic Use of Medicinal Product  E2F 
New Safety Data Related to Combination 
7.5  E2F 
Therapies 
8  Findings from Non-Interventional Studies  E2F 
9  Information from Other Clinical Trials and Sources  E2F 
10  Nonclinical Data  E2F 
11  Literature  E2F 
12  Other Periodic Reports   
13  Lack of Efficacy in Controlled Clinical Trials  E2F 
E2F, if reports 
cover same 
14  Late-Breaking Information  period and 
submitted at 
same time 
15  Overview of Signals: New, Ongoing, or Closed   
16  Signal and Risk Evaluation   
  48  Contains Nonbinding Recommendations 
 
Potential 
    shared module 
with 
16.1  Summary of Safety Concerns   
16.2  Signal Evaluation   
16.3  Evaluation of Risks and New Information   
16.4  Characterization of Risks   
16.5  Effectiveness of Risk Minimization (if applicable)   
17  Benefit Evaluation   
Important Baseline Efficacy/Effectiveness 
17.1   
Information 
Newly Identified Information on Efficacy/ 
17.2   
Effectiveness 
17.3  Characterization of Benefits   
Integrated Benefit-Risk Analysis for Approved 
18   
Indications 
Benefit-Risk Context  Medical Need and 
18.1   
Important Alternatives 
18.2  Benefit-Risk Analysis Evaluation   
19  Conclusions and Actions  E2F 
20  Appendices to the PBRER   
49  Contains Nonbinding Recommendations 
 
APPENDIX E  EXAMPLES OF POSSIBLE SOURCES OF INFORMATION THAT 
CAN BE USED IN THE PREPARATION OF THE PBRER 
 
This list is not intended to be all inclusive; additional data sources can be used by the MAH 
to present safety and efficacy/effectiveness data in the PBRER and to evaluate the benefit-
risk profile, as appropriate to the product and its known and important emerging benefits and 
risks (see also Introduction, subsection I.C (1.3) of this guidance, Scope of the PBRER, 
regarding sources of available information).   
 
Examples of sources of information potentially relevant to the evaluation of benefits and risks 
that, if relevant, should be used in the preparation of the PBRER, include but are not limited 
to the following: 
 
  Nonclinical studies 
  
  Clinical trials, including research in unapproved indications or populations 
 
  Spontaneous reports (for example, on the MAHs safety database) 
 
  MAH-sponsored Web sites (for additional information, see the ICH E2D guidance Post-
Approval Safety Data Management:  Definitions and Standards for Expedited Reporting) 
 
  Observational studies such as registries 
 
  Product usage data and drug use information 
 
  Published scientific literature or reports from abstracts, including information presented at 
scientific meetings 
 
  Unpublished manuscripts 
 
  Active surveillance systems (for example, sentinel sites) 
 
  Systematic reviews and meta-analyses 
 
  Information arising from licensing partners, other sponsors, or academic 
institutions/research networks 
 
  Patient support programs 
 
  Investigations of product quality 
 
  Information from regulatory authorities 
  50  Contains Nonbinding Recommendations 
 
 APPENDIX F  MAPPING SIGNALS AND RISKS TO PBRER SECTIONS 
 
Safety data from available information sources
New 
Previously  information 
recognised risk? constituting 
Y
signal?
N N
Y
No further 
Safety signal 
documentation in 
detected?
PBRER N
Y
Safety signal  - Section 15
Safety signal ongoing 
Closed?
Section 15 N
Y
Section 16.3
Section 16.2
New information on 
previously recognised 
Refuted Signal Potential  or identified/potential risk 
 Identified Risk or missing information 
Important?
N
Y
Section 16.4
Key to benefit-
risk evaluation?
N
Y
Section 18.2
No further documentation 
Action(s) 
in PBRER
proposed?
N
Y
Consider update to E2E 
Section 19 document, if applicable.  
Update RSI as appropriate.
51