E2C(R2) Periodic Benefit-Risk 
Evaluation Report 
____________________________ 
Questions and Answers 
 
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 
ICH 
   
 
E2C(R2) Periodic Benefit-Risk 
Evaluation Report 
____________________________ 
Questions and Answers 
 
Guidance for Industry 
 
 
 
 
 
 
 
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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 
ICH
   
Contains Nonbinding Recommendations 
 
 
 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION (1) ....................................................................................................... 1 
II.  GENERAL GUIDANCE (2) ............................................................................................ 2 
III.  MODULAR FORMAT (3) ............................................................................................... 4 
IV.  INTERNATIONAL BIRTHDATES (4) ......................................................................... 7 
V.  MATURE PRODUCTS (5) .............................................................................................. 7 
VI.  REFERENCE INFORMATION (6) ............................................................................... 8 
VII.  EXPOSURE DATA (7) ..................................................................................................... 9 
VIII.  SUMMARY TABULATIONS (8) ................................................................................... 9 
IX.  CLINICAL TRIALS (9) ................................................................................................. 11 
X.  NONCLINICAL DATA (10) .......................................................................................... 11 
XI.  LITERATURE (11) ........................................................................................................ 12 
XII.  LACK OF EFFICACY (12) ........................................................................................... 12 
XIII.  SIGNAL AND RISK EVALUATION (13) ................................................................... 13 
XIV.  RISK AND BENEFIT SECTIONS (14) ........................................................................ 18 
XV.  BENEFIT EVALUATION (15) ..................................................................................... 18 
   
Contains Nonbinding Recommendations 
 
E2C(R2) Periodic Benefit-Risk Evaluation Report     
Questions and Answers 
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) 
on this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  
You can use an alternative approach if it satisfies the requirements of the applicable statutes and 
regulations.  To discuss an alternative approach, contact the FDA office responsible for this guidance 
as listed on the title page. 
   
 
I.  INTRODUCTION (1)2 
 
The ICH guidance E2C(R2) Periodic Benefit-Risk Evaluation Report (PBRER) is intended to 
be a common standard for periodic benefit-risk evaluation reporting on marketed products 
among the ICH regions.  The ICH E2C(R2) guidance3 introduced new concepts linked to an 
evolution of the traditional Periodic Safety Update Report (PSUR) from an interval safety 
report to a cumulative benefit-risk report.  It changed the focus from individual case safety 
reports to aggregate data evaluation.  In addition, the broadened scope increased the need for 
integrating information within the report. 
 
The benefits of harmonizing technical requirements can only be achieved if the guidance is 
implemented and interpreted in a consistent way across the ICH regions.  In November 2012, 
the ICH Steering Committee endorsed the establishment of an Implementation Working 
Group (IWG) on E2C(R2) to assist with the implementation of the guidance.  The ICH 
E2C(R2) IWG has prepared this question and answer (Q&A) document to support 
implementation of the guidance in practice.  The Q&A document is intended to facilitate 
practical implementation of the PBRER, including points to consider in addressing some of 
the more novel aspects of the new periodic safety report. 
 
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.  The 
Q&As in this document have been endorsed by the ICH Steering Committee at Step 4 of the ICH process, 
March 2014.  At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of 
the European Union, Japan, and North America. 
2 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering 
Committee at Step 4 of the ICH process, March 2014. 
3 The ICH E2C(R2) guidance is available on the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
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Contains Nonbinding Recommendations 
 
 
 
II.  GENERAL GUIDANCE (2) 
 
2.1:  How can a Marketing Authorization Holder (MAH) manage the submission of 
PBRERs when the reporting interval is different across multiple countries or 
regions? 
 
In situations where the MAH is preparing PBRERs on both a 6-month and an annual 
basis for different regulatory authorities, it is possible that a PBRER on a 6-month 
cycle could be submitted as an up-to-date PBRER containing 12-month interval data 
(to fulfill the second 6-month interval of an annual cycle) (see Figure 2 below from 
the E2C(R2) guidance).  The same may be true if a product is on a 6-month cycle in 
one region and a 3-year cycle in another region.  However, the MAH should always  
discuss  the  acceptability  of  this  approach  with  the  relevant  regulatory  authority 
or authorities, noting that this approach is not an attempt to amend local reporting 
periodicity, but rather  an  opportunity to use the 12-month document to fulfill the 
shorter reporting period requirement. 
 
Figure 1:  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. 
 
2.2:  Can Summary Bridging Reports and Addendum Reports still be submitted? 
 
Summary Bridging Reports and Addendum Reports should no longer be submitted 
when following ICH E2C(R2).  Independent of the time interval covered by the 
report, each PBRER should stand alone and reflect new and cumulative information 
currently available to the MAH. 
 
2.3:  Where in the PBRER can we present information on off-label use of the product? 
 
The PBRER should report the evaluation of safety information based on all uses of 
the medicinal product, including uses outside the terms of the reference product 
information (more commonly known as off-label use).  Although the benefit-risk 
evaluation should be conducted across approved indications, it is critical that the risk 
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Contains Nonbinding Recommendations 
 
assessment take into account all uses of the product. 
 
Section I.C (1.3) of the E2C(R2) guidance (Scope of the PBRER) indicates that 
knowledge of a medicinal products safety that is derived from data associated with 
uses other than the approved indication(s) should be reflected in the discussion of risk 
evaluation when it is  available, relevant, and appropriate.  Examples of potential 
sources of information on use outside the approved indication include, but are not 
limited to, spontaneous adverse event reports, investigator-initiated clinical trials, 
drug utilization data/studies, and published literature. 
 
Specific information relating to off-label use can be included in the following 
sections of the PBRER: 
 
  Section III.E.2 (3.5.2) (Cumulative and Interval Patient Exposure from 
Marketing Experience), paragraph c (Other post-approval use) 
 
The MAH should provide a brief description of patterns of use considered 
relevant for interpretation of safety data.  This can include information on off-
label use, including whether or not such use is supported by clinical guidelines, 
clinical trial evidence, or an absence of approved alternative treatments.  For 
purposes of identifying patterns of use outside the terms of the reference product 
information, the MAH should use the appropriate sections (e.g., approved 
indication(s), contraindication(s)) of the reference product information that was in 
effect at the Data Lock Point (DLP) of the PBRER.  See question 6.1of this Q&A 
document for points to consider in selecting the reference product information 
document. 
 
  Sections III.O (3.15) (Overview of  Signals: New, Ongoing, or Closed) and III.P 
(3.16) (Signal and  Risk Evaluation) 
 
The MAH should include in these sections the signals and risks arising from 
all uses of the product. 
 
  Section III.R.2 (3.18.2) (Benefit-Risk Analysis Evaluation) 
 
Although the evaluation of benefit should be limited to approved use (see section 
III.Q (3.17) of the E2C(R2) guidance), the overall benefit-risk evaluation should take 
into account the risks associated with all uses of the product. 
 
2.4:  What information sources could be used in preparing a PBRER? 
 
The MAH should prepare the PBRER on the active substance(s) using data that the 
MAH might reasonably have access to and that are relevant to the evaluation of the 
safety or benefit-risk profile.  Compared to the product for which the MAH is the 
innovator, there may be less information available to the MAH on a generic product.  
For example, only a published report may be accessible for a clinical trial not 
sponsored by the MAH.  The MAH can consider providing as an appendix to the 
report a list of the information sources used to prepare the PBRER (see Appendix E of 
the E2C(R2) guidance). 
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Contains Nonbinding Recommendations 
 
 
 
III.  MODULAR FORMAT (3) 
 
3.1:  The modular format of the PBRER facilitates using information from other 
regulatory documents.  How can information be reused when the other documents 
do not share the same DLP? 
 
If the regulatory documents are written at different times, it may not always be 
possible to reuse sections, because the information may change from one period to 
another.  For example, this can occur when the PBRER is on a 6-month cycle and the 
Development Safety Update Report (DSUR) is on an annual cycle.  Some of the 
information from the 6-month PBRER could be used as a basis for populating some of 
the sections covering interval information in the annual DSUR.  Appendix D of the 
E2C(R2) guidance lists the PBRER sections that can be shared with other regulatory 
documents. 
 
 3.2:  What practical points should the MAH consider to coordinate preparing DSURs 
and PBRERs? 
 
Depending on the nature of information available at the time of writing, the MAH 
may be able to use information across multiple documents.  The MAH should first 
determine the interval and periodicity for each type of report the MAH is planning to 
produce. 
 
The MAH should assess the extent to which other recently submitted reports (e.g., 
DSUR) can be used as a data source. 
 
The MAH can facilitate the planning and production of PBRERs in association with 
other documents by synchronizing the DLPs for the various documents based on the 
International Birth Date (IBD).  The MAH must obtain approval from the relevant 
regulatory authorities to synchronize the DLPs, and this can make it possible for the 
MAH to reuse information from other documents. 
 
Where it has been established that there is no new and significant information, the 
MAH can consider reusing some sections from recently submitted documents with 
little modification. 
 
If there is new and significant information, the MAH should review sections from 
recently submitted documents and provide updates of the source information, minor 
revisions, or a complete revision. 
 
The reader can also refer to section II.H.1 (2.8.1) (IBD and DLP) and Appendix D of 
the E2C(R2) guidance.  Table 1 provides further clarification. 
 
 
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Contains Nonbinding Recommendations 
 
Table 1 - Sharing Content between PBRER and DSUR 
 
This table is intended to supplement Appendix D (List of PBRER Sections that Can Be Shared With Other Regulatory Documents) and 
sets out the sections that were proposed to be common.  The information to be included in these sections is intended to enable sharing of 
content between the PBRER and DSUR when the birth dates and DLPs are aligned.  In addition, this table identifies additional DSUR 
sections that can be considered information sources for corresponding sections in the PBRER, or vice versa.  The sharing of content 
facilitates the modular approach, ensuring consistency across documents and avoiding duplicated effort when possible.  The MAH should 
review information being shared or used as a data source to ensure that it is current and accurate and reflects the regulatory needs of the 
report in which it is being used. 
 
Section #s in DSUR  Section Headings in DSUR (ICH E2F)  Section #s in PBRER  Section Headings in PBRER (ICH E2C(R2)) 
2*  Worldwide Marketing Approval Status  2*  Worldwide Marketing Approval Status 
3*  Actions Taken in the Reporting Period for  3*  Actions Taken in the Reporting Interval for Safety 
Safety Reasons  Reasons 
6.1*  Cumulative Subject Exposure in the  5.1*  Cumulative Subject Exposure in Clinical Trials 
Development Program 
6.2*  Patient Exposure From Marketing  5.2*  Cumulative and Interval Patient Exposure From 
Experience  Marketing Experience (N.B.,Cumulative exposure 
from PBRER could be considered for the 
DSUR Section 6.2) 
7.1  Reference Information  6.1**  Reference Information 
7.3*  Cumulative Summary Tabulations of  6.2*  Cumulative Summary Tabulations of Serious 
Serious Adverse Events  Adverse Events From Clinical Trials 
8.1*  Completed Clinical Trials  7.1*  Completed Clinical Trials 
8.2*  Ongoing Clinical Trials  7.2*  Ongoing Clinical Trials 
8.3*  Long-Term Follow-up  7.3*  Long-Term Follow-up 
8.4*  Other Therapeutic Use of Investigational  7.4*  Other Therapeutic Use of Medicinal Product 
Drug 
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8.5*  New Safety Data Related to Combination  7.5*  New Safety Data Related to Fixed Combination 
Therapies  Therapies 
9*  Safety Findings From Non-interventional  8*  Findings from Non-Interventional Studies 
Studies 
10*  Other Clinical Trial/Study Safety  9.1*  Other Clinical Trials 
Information 
11  Safety Findings From Marketing  15**  Overview of Signals: New, Ongoing, or Closed 
Experience  9.2**  Medication Errors 
5.2   (para.3)**  Other post-approval use 
12*  Nonclinical Data  10*  Nonclinical Data 
13*  Literature  11*  Literature 
14***  Other DSURs  12  Other Periodic Reports 
15*  Lack of Efficacy  13*  Lack of Efficacy in Controlled Clinical Trials 
17*  Late-Breaking Information  14*  Late-Breaking Information 
18.1  Evaluation of the Risks  16.2**  Signal Evaluation 
16.3**  Evaluation of Risks and New Information 
16.4**  Characterization of Risks 
18.2  Benefit-Risk Considerations  18.2**  Benefit-Risk Analysis Evaluation 
19  Summary of Important Risks  16.1**  Summary of Safety Concerns 
20*  Conclusions  19*  Conclusions and Actions 
 
* Sections listed in Appendix D of ICH E2C(R2) as sections that can be shared with other regulatory documents. 
 
** PBRER sections that could be used as an information source for the DSUR. 
 
*** DSUR sections that could be used as a data source for the PBRER. 
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IV.  INTERNATIONAL BIRTHDATES (4) 
 
4.1:  When transitioning to the PBRER, how should the MAH handle medicinal products  
whose current DLP is not synchronized to the new definition of the IBD? 
 
The definition of IBD in the E2C(R2) guidance refers to the date of the first marketing 
approval for any product containing the active substance granted to any company in any 
country in the world.  Provisions are available in many countries, whether through formal 
regulation or informal guidance, for the MAH to synchronize the PBRER DLP with the 
IBD.  The MAH should consult the relevant local/regional regulations for further 
information.  It should also contact the appropriate regulatory authority and request 
adjustment of the PBRER DLP to the IBD, as necessary.   Granting these requests is at 
the discretion of each regulatory authority; experience has shown that most regulatory 
authorities are willing to do so, in the interest of international harmonization. 
 
4.2:  How can the MAH determine the IBD for products based on the definition of IBD in 
the E2C(R2) guidance? 
 
  The definition of IBD in the guidance refers to the date of the first marketing approval for any 
product containing the active substance granted to any company in any country in the world.  If 
the MAH has no information on the actual IBD for a product, the MAH should first refer to 
listings of birth dates that some regions develop and make publicly available.  If the product is 
not included in any listing, the MAH should propose to the regulatory authority a birth date that 
is based on the earliest known marketing approval of the substance and then obtain the regulatory 
authoritys agreement. 
 
4.3:  How can the Development International Birth Date used for DSURs be harmonized 
with the IBD used for PBRERs? 
 
As indicated in the ICH E2F guidance (DSUR - Section II.B (2.2)), the MAH can, if 
desired, submit a DSUR based on the PBRER IBD.  In synchronizing the DLPs for the 
DSUR and PBRER, the period covered by the next DSUR should be no longer than one 
year.  The MAH should obtain approval from the relevant regulatory authorities to 
synchronize the DLPs. 
 
 
V.  MATURE PRODUCTS (5) 
 
5.1:  There can be challenges related to lack of availability of historical information for 
some products.  How should the MAH prepare sections that should include cumulative 
information when preparing PBRERs for these products? 
 
The MAH should provide all information that is available at the time they prepare the 
PBRER.  The MAH should specify what information is not available and fully explain 
why it is not available.  For example, if it is not feasible to obtain precise cumulative 
clinical trial exposure data, the MAH should explain any omission of data from the 
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cumulative data.  When the original clinical study report for a product marketed for many 
years is not accessible, the MAH is advised to base its presentation of 
efficacy/effectiveness on information obtained from publicly available data sources, such 
as the published literature. 
 
5.2:  Should the PBRER for a generic product include information regarding the active 
substance? 
 
The E2C(R2) guidance is applicable to generic products for which a PBRER for a generic 
product is required by national/regional laws and regulations.   A PBRER prepared for a 
generic product should follow the same format and content as outlined in the guidance.  
Sources of information can include information available for the active substance 
(sources of available information are those that the MAH might reasonably have access 
to, and that are relevant to evaluating the safety or benefit-risk profile (see also Appendix 
E of the guidance, Examples of Possible Sources of Information That Can Be Used in the 
Preparation of the PBRER)).  Refer also to ICH E2C(R2), section I.C (1.3) (Scope of the 
PBRER). 
 
 
VI.  REFERENCE INFORMATION (6) 
 
6.1:  Which reference product information should the MAH choose to prepare a PBRER for 
different products with different indications that are based on the same active 
substance? 
 
Section II.D (2.4) of the E2C(R2) guidance provides guidance on reference information, 
including when indications vary across countries or regions.  The PBRER should address 
aspects common to all products containing the active substance, with subsections that 
address specific formulations and indications.  For example, consider an MAH that is 
preparing a PBRER for a corticosteroid that can be used to manage asthma and chronic 
obstructive airway disease (inhaler), rhinitis (intranasal spray), Crohns Disease (oral) 
and ulcerative colitis (suppository)   in this situation, the MAH should specify a single 
reference product information document, which in practice is often the Company Core 
Data Sheet (CCDS).  However, if the product does not have a CCDS, then the MAH 
should use the most comprehensive local prescribing text. 
 
6.2:  When preparing the PBRER, where should the MAH include information on patterns 
of use that extend beyond the approved indications in a local label, including situations 
in which the reference product information covers all approved indications? 
 
If patterns of use suggest that a product is being used beyond the local label in one or 
more countries or regions where the PBRER is being submitted, the MAH should 
indicate in Section 5 of the PBRER those countries or regions where the use is considered 
off-label.  If patterns of use give rise to a safety signal, the MAH should include it in the 
signal tabulation (Section 15) and also address it in other relevant sections of the PBRER. 
 
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VII.  EXPOSURE DATA (7) 
 
7.1:  What exposure data from historical clinical trials should the MAH provide for 
products that have been on the market for several years? 
   
Section III.E.1 (3.5.1) of the E2C(R2) guidance describes the information the MAH 
should provide.    If precise exposure data is not available, the MAH should provide its 
best estimate, indicating the basis and the underlying assumptions for this estimate. 
 
7.2:  According to the E2C(R2) guidance, section 5.2 of the PBRER should include patient 
exposure from marketing experience that is presented by various parameters (e.g., 
indication, sex, age, dose, formulation, and region). The guidance also states that 
detailed information should be provided on use in special populations.  How should the 
MAH comply with this request when it cannot obtain the data in these groupings? 
 
The MAH should make reasonable efforts to obtain accurate and complete postmarketing 
exposure data.  Potential sources include, but are not limited to, sales data, registries, and 
healthcare databases. 
 
When available, the MAH should provide these data in section 5.2 of the PBRER and 
describe any limitations regarding the data accuracy.   If data are not available, the MAH 
should state this and indicate why. 
 
 
VIII.  SUMMARY TABULATIONS (8) 
 
8.1:  Should the tabulation referred to in section III.F.2 (3.6.2) of the E2C(R2) guidance 
contain only Serious Adverse Events (SAEs) collected during interventional clinical 
trials in which the investigational drug contains the same active substance as that 
contained in the product(s) represented in the PBRER? 
 
The PBRER tabulation referred to in Section 3.6.2 of the guidance should include only 
the SAEs collected during interventional clinical trials sponsored by the MAH in which 
the investigational drug contains the same active substance as the product or products 
represented in the PBRER.  This tabulation should include data from all such clinical 
trials sponsored by the MAH and is not limited to data from clinical trials that study the 
approved indication(s), approved dose(s), approved population(s), and approved 
formulation(s).  The tabulations should also include data from clinical trials with the 
primary aim of identifying, characterizing, or quantifying a safety hazard, or confirming 
the safety profile.  In addition, the tabulations should include SAEs from clinical trials 
that test unapproved doses or that test the investigational drug in unapproved indications 
or unstudied populations, if relevant and/or appropriate. 
 
Any safety signals or other significant safety information arising from clinical trials using 
the active substance contained in the product(s) represented in the PBRER should be 
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summarized in the applicable sections of the PBRER in order to fully characterize the 
ongoing safety profile of the marketed product.  Any findings from clinical trials that 
study unapproved indications, new formulations, unstudied populations or doses should 
be included if relevant to the marketed product(s). 
 
8.2:  In some instances, the product that is the subject of a PBRER (product A) might have 
been used as a comparator product for a clinical trial regarding another product 
(product B).  Should SAEs related to product A from the clinical trial undertaken for 
product B be included in the comparator column of the Cumulative Tabulation of 
SAEs in the product A PBRER? 
 
No.  The MAH should summarize any clinically important safety findings for product A 
that arise from the clinical trial with product B in sections 7.1, 7.2, or 9.1 of the PBRER, 
as most appropriate (depending on whether or not the MAH was the sponsor of the trial 
program giving rise to the information).  The term comparator in section III.F.2 (3.6.2) of 
the E2C(R2) guidance refers to other drugs used as comparators  in  the  clinical  
development  program  for  the  product  that  is  the  subject  of  the PBRER. 
 
Likewise, the MAH for product B, in preparing a PBRER for product B, should include 
the SAEs for product A in the comparator column when it is used as a comparator in 
clinical trials for product B.  See Appendix B, Table 6, of the guidance, which provides 
an example of a cumulative tabulation of SAEs from clinical trials. 
 
8.3:  Should the MAH include in the summary tabulation SAEs that were collected in 
studies not sponsored by the MAH (e.g., investigator-initiated trials)? 
 
In general, the MAH should include in the summary tabulations only those SAEs that 
were reported during clinical trials sponsored by the MAH, for which the drug is used as 
the investigational medicinal product or active comparator (see also question 8.1 of this 
Q&A document). 
 
The MAH should summarize in section 9.1 of the PBRER the important safety 
information from clinical trials that the MAH has not sponsored.  If applicable, the MAH 
should provide further information and evaluation in sections 15 through 18 of the 
PBRER. 
 
In the interest of transparency, the MAH should provide a statement in section 6.2 of the 
PBRER if the MAH receives SAE case reports from a clinical trial it has not sponsored, 
but the MAH should not include these reports in the SAE summary tabulation. 
 
It is important to note, however, that in some situations the MAH can assume the 
responsibilities of a sponsor on behalf of third parties that conduct clinical trials on the 
MAHs marketed product.  In that case, any SAEs arising from those trials should be 
included in the SAE summary tabulations of the applicable PBRERs and described in the 
background to the tabulations (section 6.2 of the PBRER). 
 
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8.4:  Regarding the summary tabulations from postmarketing data sources, should the MAH 
list all events or all case reports, which can include more than one event?  And should 
seriousness be reflected at the case level or the event level? 
 
The MAH should include both the nonserious and serious Adverse Drug Reactions (ADRs) 
from the case reports in the tabulation of ADRs from postmarketing sources, as exemplified by 
Table 7 in Appendix B of the E2C(R2) guidance. 
 
The seriousness reflected in the summary tabulations should be at the event level. 
 
 
IX.  CLINICAL TRIALS (9) 
 
9.1:  What level of detail should be included on findings from randomized clinical trials and 
other safety information provided by co-development partners or from investigator-
initiated trials? 
 
Information from sources other than MAH-sponsored clinical trials should be briefly 
summarized in section 9.1 (Other Clinical Trials).  If there are new significant safety or 
efficacy findings from such sources, more detail might be appropriate, for example, to 
support a more comprehensive evaluation later in the report. 
 
9.2:  Is section 7.4 of the PBRER intended to capture clinically important safety information 
from clinical trials conducted on other therapeutic uses, or is it meant to capture safety 
information from other programs conducted by the MAH that follow a specific 
protocol, with solicited reporting? 
 
Section 7.4 of the PBRER should include clinically important safety information from 
other programs conducted by the MAH that follow a specific protocol (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).   The MAH should summarize important safety information arising from 
clinical trials conducted on other therapeutic uses of the product represented in the 
PBRER (e.g., a phase IIIb clinical development program for a new indication).  The 
information should be summarized in sections 7.1, 7.2, and 9.1 of the PBRER, as 
applicable, depending on whether or not the MAH was the sponsor of the trial program 
giving rise to the information. 
 
 
X.  NONCLINICAL DATA (10) 
 
10.1:  Does section 10 of the PBRER only refer to nonclinical studies that are sponsored by 
the MAH, or does it also refer to other studies, including those found in the literature? 
 
The intention is that section 10 of the PBRER should summarize or reference major 
safety findings arising from all nonclinical studies conducted and/or reported during the 
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reporting interval, regardless of who sponsored and/or conducted the study.   If such 
findings arise from nonclinical studies conducted by other organizations and published in 
the literature, the MAH should summarize them in section 11 (Literature) and provide a 
suitable cross-reference in section 10 (Nonclinical Data) back to section 11.  In this way, 
unnecessary duplication of information can be avoided. 
 
 
XI.  LITERATURE (11) 
 
11.1:  Section III.K (3.11) of the E2C(R2) guidance states, this section 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.   
Does the phrase relevant to the approved medicinal product refer to the active 
substance or to a specific brand name? 
 
Section 11 of the PBRER should summarize all new and significant safety findings that 
are relevant to the product represented in the PBRER.   This may include safety findings 
related to the same active substance of the product, but not necessarily the brand sold by 
the MAH.   Hence, the guidance indicates that literature searches conducted for PBRERs 
should be wider than those for individual adverse reaction cases (i.e., for expedited 
reporting purposes), and if relevant, the PBRER should address information on active 
substances of the same class. 
 
11.2:  Section III.K (3.11) of the E2C(R2) guidance states, Literature searches for PBRERs 
should be wider than those for individual adverse reaction cases.   What should the 
MAH include in the wider search? 
 
Section 11 of the PBRER should summarize all new and significant safety findings that 
are relevant to the product represented in the PBRER.   This may include safety findings 
related to the same active substance of the product, but not necessarily the brand sold by 
the MAH.   Hence, the guidance indicates that literature searches conducted for PBRERs 
should be wider than those for individual adverse reaction cases (i.e., for expedited 
reporting purposes), and if relevant, the PBRER should address information on active 
substances of the same class. 
 
 
XII.  LACK OF EFFICACY (12) 
 
12.1:  Does the scope of section 13 of the PBRER only include controlled clinical trials? 
 
No.  Although Section 13 of the E2C(R2) guidance is titled Lack of Efficacy in 
Controlled Clinical Trials, the intent of this section is that it should include lack of 
efficacy data arising from all types of clinical trials conducted or completed during the 
reporting interval. 
 
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12.2:  Lack of efficacy in clinical trials should be addressed in section 13 of the PBRER for 
products intended to treat or prevent serious or life-threatening illnesses and in 
section 7 for non-life-threatening diseases.  What parameters should be used to define 
whether the drug is treating a life-threatening or a non-life-threatening condition? 
 
The determination of what is and is not a life-threatening disease or illness is a matter of 
medical judgment.  The primary consideration relates to the degree of morbidity and 
mortality that is a potential consequence of the disease.  Section III.M (3.13) of the 
E2C(R2) guidance provides an example, namely, acute coronary syndrome, to illustrate 
what might be considered a serious or life-threatening illness, and here the key 
consideration is that lack of efficacy could present a significant risk to the population 
treated by the product. 
 
 
XIII.  SIGNAL AND RISK EVALUATION (13) 
 
13.1:  Some sections of the E2C(R2) guidance refer to discussing important safety 
information; this could vary widely based on the interpretation of the word 
important.  What is the guidances intended meaning of important safety 
information in the context of the PBRER? 
 
Important safety information has not been defined, because it is a matter of judgment.  
For example, it could include information that, upon evaluation, might have an impact on 
the understanding of the products safety profile or call for communication through the 
product label.  It could include data that contribute to identifying a new signal.  It could 
also provide information that either supports or refutes a signal. 
 
13.2:  The E2C(R2) guidance states that the PBRER should present safety-related data and 
findings in sections 6 through 14.  How can the MAH (a) avoid repeating data in 
sections 15 and 16 and (b) provide sufficient detail to substantiate conclusions? 
 
(a) Points to Consider in Avoiding Repetition in the PBRER 
 
Although repetition of information across different sections of the PBRER is not entirely 
avoidable and sometimes appropriate, the MAH can consider providing instructions to its 
staff in its internal templates/guidance documents to minimize such repetition.   These 
instructions could recommend cross-referencing earlier sections of the PBRER in which 
the data were initially presented.  However, the MAH should not overuse cross-
referencing, because this could prevent a clear message from being conveyed to the 
reader. 
 
Sections 6 through 14 of the PBRER are intended to present only the data or findings 
from the various sources covered by these sections.  In contrast, sections 15 and 16 are 
intended to present the relevant interpretation and evaluation of the significant data and 
findings from sections 6 through 14. 
 
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For example, if the MAH identifies a new and ongoing signal based on a literature report 
published during the reporting interval, the MAH should summarize the literature report 
in section 11 (Literature) and the identified safety signal should be included in the 
summary tabulation in section 15 (Overview of Signals).  If the MAH refutes an ongoing 
safety signal based on the results of a randomized clinical trial completed during the 
reporting interval, then the MAH should briefly summarize the relevant study findings in 
section 7.1 (Completed Clinical Trials).  In addition, the MAH should update the status of 
the signal in the section 15 signal tabulation, as well as provide a critical analysis of new 
and cumulative data in section 16.2 (Signal Evaluation).  This integrated analysis should 
include the MAHs rationale and conclusions for refuting the signal.  The analysis of the 
refuted signal discussed in section 16.2 should not completely repeat the findings 
included in section 7.1 but should instead provide a high-level summary that focuses on 
the evaluation and interpretation of these findings.  Similarly, the summary analyses 
included in sections 16.2 and 16.3 should not be repeated in section 16.4 
(Characterization of Risks) of the PBRER. 
 
Appendix C of the E2C(R2) guidance provides a format for signal tabulation, including 
two examples; Appendix F provides further guidance on mapping signals and risks to the 
appropriate PBRER sections. 
 
(b) Points to Consider in Providing Sufficient Detail in Sections 15 and 16 of the 
PBRER 
 
General Considerations: 
 
As described in section II.E (2.5) of the guidance, the MAH should tailor the level of 
detail it provides for both the presentation of findings (sections 6 through 14) and 
evaluation sections (sections 15 and 16)  based  upon  the  clinical  significance  of  the  
presented  findings;  this  involves  medical  and scientific judgment.  The level of detail 
should be sufficient to substantiate the MAHs conclusions and any actions taken or 
proposed.  In these sections, the MAH should discuss in greater detail any findings that 
have a substantial medical impact or call for a more in-depth evaluation of causality. 
 
Considerations for Specific Sections: 
 
Section 15: Overview of Signals 
 
The MAH should provide in a summary table an overview of signals ongoing and closed 
in the reporting interval.  Appendix C of the guidance provides an example summary 
table that contains information at a high level, as opposed to detailed data.  For signals 
closed during the reporting interval, the MAH should supplement the information 
appearing in the table with a summary evaluation of available data in section 16.2.   
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 this section if it is negative. 
 
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Section 16.1: Summary of Safety Concerns 
 
For a discussion on this topic, please refer to the answer for question 13.4 of this Q&A 
document. 
 
Sections 16.2 and 16.3: Signal Evaluation and Evaluation of Risks and New 
Information 
 
In sections 16.2 and 16.3 of the PBRER, the MAH should include sufficient information 
and interpretation of the available data to enable a reviewer to understand the rationale 
for the MAHs conclusions and actions (if taken or proposed). 
 
The MAH should present a clear evaluation of the available evidence for or against a 
possible causal relationship in section 16.2.  The focus of the presented analysis should 
support how the MAH came to the conclusion that: 
 
  A signal was refuted based on available evidence against a causal relationship. 
  A signal became an identified risk (adequate evidence of an association). 
  A signal became a potential risk (there is some basis to suspect an association, but the 
association has not been confirmed). 
 
Section 16.3 should contain new information relevant to a previously recognized risk that 
was not already included in section 16.2, i.e., when the new information itself does not 
constitute a signal.  This should include information on important risks and an update on 
important missing information, as well as updates on risks not otherwise categorized as 
important.  The new information may be in response to a regulatory request on a 
previously recognized risk.  Although the MAH should provide concise information, it 
should ensure that sufficient detail is contained in the summary to allow a regulatory 
authority reviewer to determine whether the information has an impact on the 
understanding of the risk and/or its characterization. 
 
Section 16.4: Characterization of Risks 
 
In characterizing the risk for section 16.4 of the PBRER, the MAH should consider 
whether the risk is important or not.  A risk may not be important if it is infrequent, 
nonserious, reversible, and readily managed with no significant impact on the individual 
patient or public health.  Even a common ADR may not constitute an important risk if it 
is not linked to clinically significant adverse sequelae. 
 
Unlike sections 15, 16.2, and 16.3, which cover all signals and risks, section 16.4 only 
includes important risks.   In section 16.4, the MAH should present more detailed 
information on the parameters outlined in the guidance to illustrate why the risk should 
be considered important. 
 
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13.3:  When a regulatory authority has requested that a specific topic be monitored and 
reported in a PBRER, where in the PBRER should the MAH summarize the results of 
the analysis? 
 
If the MAH determines that the specific topic constitutes a signal, the MAH should 
include it in the signal tabulation, evaluate it as such, and handle it in accordance with the 
usual approach for summarizing signals within the PBRER. 
 
If the MAH does not consider the specific topic to constitute a signal, the MAH should 
summarize its analysis on the requested monitoring topic in section 15 of the PBRER. 
 
13.4:  Section III.P.1 (3.16.1) of the E2C(R2) guidance states that the PBRER should include 
a summary of important risks and missing information that are known at the 
beginning of the reporting interval. However, for products that have existing safety 
specifications submitted to different countries, it is not unusual for the particular safety 
concerns to differ across countries or regions. 
For example, a local regulatory authority might request that certain additional safety 
concerns be addressed.  In addition, what is considered an important potential risk 
by the regulatory authority in one region might be considered an important 
identified risk by the regulatory authority in another region. 
Section 16.4 of the PBRER (Characterization of Risks) could be similarly affected.     
How should the MAH handle this situation? 
 
The MAH should tailor the way it handles this situation based on the number of 
additional concerns or the range of different regional or national requests from the 
different regulatory authorities.  One approach is detailed below, but it may not be 
optimal in every situation.  If the MAH is unsure about which approach is best for its 
product, the MAH should seek guidance from the relevant regulatory authorities, 
particularly if there are substantial regional differences in the safety specifications. 
One approach to handling such a situation is described below: 
 
  When a PBRER will be submitted to regulatory authorities with previously different 
assessment conclusions on how a risk should be classified (potential or identified) or 
on the scope of information that should be documented in a risk management plan as 
missing information, the MAH can include all risks and missing information in the 
summary of safety concerns and clarify, using footnotes, those that are specific to 
only one country or region, indicating the country or region to which this additional 
safety concern applies. 
  If  a  safety concern  is  considered to  be  an  important  identified  risk in  one region  
and  an important potential risk in another region, then the risk should appear under 
both categories within this section of the PBRER (see sample tabulation below). 
  In addition to the categorization from the different regulatory authorities, the MAH 
may wish to indicate the company core position on categorizing the various risks. 
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  Other approaches to presentation, such as the use of individual tables for each region 
within this section, can be used, and the guiding principle should be to ensure a clear 
and transparent presentation of information. 
     An example is given below: 
    Summary of Safety Concerns 
 
Important Identified Risks    Important Risk A1 
  Important Risk B 
  Important Risk C2 
Important Potential Risks    Important Risk A1 
  Important Risk D 
  Important Risk E 
  Important Risk F3 
Important Missing Information    Important Missing Information G4  
  1Important identified risk in the European Union (EU) and Switzerland; important potential risk in 
Canada. 
  2 Important identified risk in Japan, Korea, and Switzerland. 
  3 EU only. 
  4 United States, Canada, and Australia only. 
 
If this method is used, all the safety concerns listed in section 16.1 should be 
characterized in section 16.4 of the PBRER, including a description of the important 
missing information. 
 
From a practical perspective, if this suggested approach is used, section 16.1 of the 
PBRER should remain common across multiple PBRERs that are submitted to different 
regulatory agencies at the same time.  As such, this approach promotes transparency and 
avoids creating different sections in the main body of the PBRER to meet different 
regulatory requirements, which may be regional. 
 
13.5:  In section III.P.4 (3.16.4) (Characterization of Risks) of the E2C(R2) guidance, 
public health impact is listed as one of the points that can be included in 
characterizing an important risk.  What factors should the MAH consider in providing 
this information for the purposes of section 16.4 of the PBRER? 
 
It is outside the scope of the guidance and this Q&A document to provide advice on how 
to conduct a public health impact assessment because, in reality, this is a complex 
undertaking that takes into account multiple factors and considerations. 
 
In section 16.4 of the PBRER, the MAH should present its evaluation of the public health 
impact of the risk as part of the characterization of important risk(s) for the purposes of 
the PBRER.  In assessing the public health impact of individual risks, the MAH should 
consider the following points that are intended to be illustrative rather than 
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comprehensive:  extent of product use (size of treated population), frequency, and health 
consequences (including consideration of seriousness, preventability, and reversibility). 
 
Characterization of risk should include consideration of the impact on the individual 
patient, as well as on the overall population. 
 
 
XIV.  RISK AND BENEFIT SECTIONS (14) 
 
14.l:  Regarding section III.P.5 (3.16.5) (Effectiveness of Risk Minimization), the wording of 
the E2C(R2) guidance implies that the MAH should include information relevant to 
the effectiveness and/or limitations of specific risk minimization activities that have 
become available during the reporting period.   
 
If the MAH communicated the risk with a Dear Healthcare Professional 
Communication (or local equivalent) during the reporting interval, should the MAH 
address the effectiveness of that risk communication in the PBRER? 
 
Reporting on the effectiveness of such activities is driven by the standards of the risk 
management plan, or as agreed with the regulatory authorities.  The MAH should include 
information on the effectiveness of such risk minimization activities in section 16.5 of the 
PBRER if the results are applicable across different regions; otherwise this information 
should be included in the appropriate regional appendix. 
 
 
XV.  BENEFIT EVALUATION (15) 
 
15.1:  What is meant by the terms efficacy and effectiveness? 
 
Because the use of these words is not harmonized across regions, the phrase 
efficacy/effectiveness is used in the E2C(R2) guidance to clarify that information from 
both clinical trials and everyday medical practice is within the scope of the information 
on benefit that should be included in the PBRER.  In some regions, efficacy refers to 
evidence of benefit from controlled clinical trials, while effectiveness refers to use of the 
product in everyday medical practice.  However, in other regions this distinction is not 
made. 
 
For the purposes of the PBRER, any pertinent efficacy/effectiveness information from 
clinical trials and from everyday medical practice should be included. 
 
15.2:  What efficacy/effectiveness information should be presented in section 17.1 (Important 
Baseline Efficacy/Effectiveness Information) of the PBRER? 
 
In addition to the guidance provided in section III.Q.1 (3.17.1) of the E2C(R2) guidance, 
the MAH may wish to consider the following points when presenting 
efficacy/effectiveness information in section 17.1 of the PBRER. 
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The MAH should present any efficacy/effectiveness information on approved indications 
that is relevant and supports the characterization of benefit presented in section 17.3 of 
the PBRER. The content should focus on important evidence that supports the benefit of 
the product. The MAH can use tables, graphs, and/or narrative descriptions to 
communicate this information. 
 
The following are examples of points to consider for information that might be included 
in section 17.1 of the PBRER: 
 
  A statement about the intended purpose and impact of the product on the outcome(s) 
of each approved indication in the populations treated, including the nature of the 
benefit (diagnostic, preventative, symptomatic, or disease-modifying treatment).  
  Evidence including (but not limited to) clinical trial data, systematic reviews, meta-
analyses, clinical pharmacology, relevant outcome studies.  
  Information described in Appendix E in the guidance (Examples of Possible Sources 
of Information that May Be Used in the Preparation of the PBRER).  The MAH 
should also consider the following:  
  Evidence that the benefits are applicable to subpopulations, for example, 
o
pediatric, elderly, pregnant, vulnerable populations. 
 
  Information about multiple efficacy endpoints, where they support 
o
efficacy/effectiveness. 
 
  Evidence of efficacy/effectiveness from various sources (e.g., placebo-
o
controlled trials, active controlled trials, meta-analyses, observational 
studies). 
 
  Trends, patterns, and/or evidence of benefit or lack of benefit in important 
o
subgroups. 
 
 
15.3:  What new information should be included in section 17.2 (newly identified information on 
efficacy/effectiveness) of the PBRER? 
 
In section 17.2 of the PBRER, the MAH should present information that is data driven 
and scientifically based. 
 
What constitutes new information is efficacy/effectiveness information that might alter 
the known benefit profile of the product in the approved indication. As such, the MAH 
should not include new efficacy/effectiveness information that only confirms what was 
already known for the product. The same principle applies to other sections of the 
PBRER in which the MAH provides summaries of new, clinically important 
efficacy/effectiveness information that became available during the interval covered by 
the PBRER. 
 
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15.4:  Section III.Q.2 (3.17.2) of the E2C(R2) guidance states, 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. 
Please provide the definition of relevant. 
 
It is not possible to define relevant because this is a matter of judgment. The MAH 
should consider whether or not new efficacy/effectiveness information relating to an 
unapproved indication may have an impact on the benefit-risk profile for the approved 
indication(s) and, if so, should summarize the new information accordingly. 
 
15.5:  What is meant by key risk and key benefit in the context of the PBRER? 
 
Key risks and key benefits are those benefits and risks that contribute importantly to the 
overall benefit-risk evaluation and may not necessarily include all important benefits and 
risks included in the PBRER, as described in section III.R.2 (3.18.2) of the E2C(R2) 
guidance. The particular risks and benefits the MAH should consider as key is a matter of 
medical judgment. 
 
15.6:  Are there specific methods for performing a formal quantitative or semi-quantitative 
assessment of benefit-risk? 
 
It is beyond the scope of the E2C(R2 guidance to provide definitive advice on specific 
methods for performing a formal quantitative or semi-quantitative analysis.  If the MAH 
provides a formal quantitative or semi-quantitative assessment of benefit-risk, the MAH 
should include a summary of the analytical methods used. 
 
15.7:  Can the PBRER include a benefit-risk evaluation in the context of the local label? 
 
In general, the MAH should perform the benefit-risk assessment within the context of the 
applicable reference product information for the PBRER.  The E2C(R2) guidance does 
make provision for the MAH to use regional product information as the reference 
document.   As such, the guidance does not exclude the possibility of a benefit-risk 
assessment within the context of a local label, which would most likely occur at the 
request of a specific regulatory authority for a specific product.  The MAH could provide 
the assessment either within a suitable subsection of the PBRER or as an appendix. 
20