Guidance for Industry 
 
 
E2F Development Safety 
Update Report 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
August 2011 
ICH 
 
   
Guidance for Industry 
 
 
E2F Development Safety 
Update Report
 
 
 
 
 
 
 
Additional copies are available from: 
 
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Division of Drug Information, WO51, Room 220 
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 Food and Drug Administration1 
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Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
and/or 
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Development, HFM-40  
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 Food and Drug Administration 
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(Tel) 800-835-4709 or 301-827-1800 
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) 
 
August 2011 
ICH  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION (1)........................................................................................................1 
A.  Background (1.1)............................................................................................................................2 
B.  Objectives (1.2)...............................................................................................................................2 
C.  Scope of the DSUR (1.3).................................................................................................................3 
D.  Relation of the DSUR to the Periodic Safety Update Report (1.4)............................................3 
E.  Recipients of the DSUR (1.5).........................................................................................................4 
II.  GENERAL PRINCIPLES (2)...........................................................................................4 
A.  Single DSUR for an Active Substance (2.1).................................................................................4 
B.  Periodicity and DSUR Data Lock Point* (2.2)............................................................................4 
C.  Duration of DSUR Submissions (2.3)...........................................................................................5 
D.  Responsibilities for Preparing and Submitting a DSUR (2.4)....................................................5 
1. Sponsors Responsibilities (2.4.1)....................................................................................................5 
2. Responsibilities of Multiple Parties (2.4.2)......................................................................................5 
E.  DSURs for Combination Therapies (2.5).....................................................................................6 
F.  Reference Safety Information (2.6)...............................................................................................7 
G.  Format and Presentation of DSUR (2.7)......................................................................................7 
1. Format (2.7.1)..................................................................................................................................7 
2. Presentation (2.7.2)..........................................................................................................................7 
III.  GUIDANCE ON CONTENTS OF A DSUR (3).............................................................8 
1.  Introduction (3.1)...........................................................................................................................9 
2.  Worldwide Marketing Approval Status (3.2)..............................................................................9 
3.  Actions Taken in the Reporting Period for Safety Reasons (3.3).............................................10 
4.  Changes to Reference Safety Information (3.4).........................................................................11 
5.  Inventory of Clinical Trials Ongoing and Completed During the Reporting Period (3.5)....11 
6.  Estimated Cumulative Exposure (3.6)........................................................................................12 
6.1.  Cumulative Subject Exposure in the Development Program (3.6.1)........................................12 
6.2.  Patient Exposure From Marketing Experience (3.6.2)............................................................13 
7.  Data in Line Listings and Summary Tabulations (3.7).............................................................13 
7.1.  Reference Information (3.7.1)..................................................................................................14 
7.2.  Line Listings of Serious Adverse Reactions During the Reporting Period (3.7.2)...................14 
7.3.  Cumulative Summary Tabulations of Serious Adverse Events (3.7.3).....................................15 
8.  Significant Findings from Clinical Trials During the Reporting Period (3.8)........................15 
  i Contains Nonbinding Recommendations 
8.1.  Completed Clinical Trials (3.8.1).............................................................................................15 
8.2.  Ongoing Clinical Trials (3.8.2)................................................................................................16 
8.3.  Long-Term Follow-up (3.8.3)...................................................................................................16 
8.4.  Other Therapeutic Use of Investigational Drug (3.8.4)...........................................................16 
8.5.  New Safety Data Related to Combination Therapies (3.8.5)...................................................16 
9.  Safety Findings From Noninterventional Studies (3.9).............................................................16 
10.  Other Clinical Trial/Study Safety Information (3.10)..............................................................17 
11.  Safety Findings From Marketing Experience (3.11).................................................................17 
12.  Nonclinical Data (3.12).................................................................................................................17 
13.  Literature (3.13)...........................................................................................................................17 
14.  Other DSURs (3.14).....................................................................................................................17 
15.  Lack of Efficacy (3.15).................................................................................................................18 
16.  Region-Specific Information (3.16).............................................................................................18 
17.  Late-Breaking Information (3.17)..............................................................................................19 
18.  Overall Safety Assessment (3.18)................................................................................................19 
18.1.  Evaluation of the Risks (3.18.1).............................................................................................19 
18.2.  Benefit-Risk Considerations (3.18.2).....................................................................................20 
19.  Summary of Important Risks (3.19)...........................................................................................21 
20.  Conclusions (3.20)........................................................................................................................21 
IV.  APPENDICES TO THIS GUIDANCE..........................................................................23 
APPENDIX A  Glossary...................................................................................................................23 
APPENDIX B  Examples of Tables and Table Headings for Clinical Trial Listings.................26 
APPENDIX C  Examples of the Summary of Important Risks...................................................29 
 
  ii Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
 
E2F Development Safety Update Report 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
 
I.  INTRODUCTION (1)2 
 
The development safety update report (DSUR) proposed in this guidance is intended to be a 
common standard for periodic reporting on drugs under development (including marketed drugs 
that are under further study) among the ICH regions. U.S. and European Union (EU) regulators 
consider that the DSUR, submitted annually, would meet national and regional requirements 
currently met by the U.S. investigational new drug application (IND) annual report and the EU 
annual safety report, respectively, and can therefore take the place of these existing reports.3 This 
guidance defines the recommended content and format of a DSUR and provides an outline of 
points to be considered in its preparation and submission. 
 
Definitions of the technical terms used in the guidance are included in a glossary (Appendix A); 
the first mention of a term in the guidance is identified with an asterisk (*). 
 
                                                 
1 This guidance was developed within the Efficacy 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, August 2010.  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, August 2010. 
 
3 Japan will consider existing regulations on periodic safety reporting in implementing the DSUR. 
 
  1 Contains Nonbinding Recommendations 
A.  Background (1.1) 
 
During the clinical development of an investigational drug,*4 periodic analysis of safety 
information is crucial to the ongoing assessment of risk to trial subjects.5,6  It is also important to 
inform regulators and other interested parties (e.g., ethics committees) at regular intervals about 
the results of such analyses and the evolving safety profile of an investigational drug, and apprise 
them of actions proposed or being taken to address safety concerns. Currently, laws and 
regulations of some ICH countries and regions require submission of a periodic report to 
regulatory authorities to provide this information.  However, significant differences in the 
content, format, and timing of these reports highlight the importance of a common standard 
report in promoting consistency and enhancing efficiency.  Some national and regional laws and 
regulations also require a periodic report that describes the status of ongoing individual 
investigations, manufacturing changes, and overall development status and plans.  To be broadly 
useful, the DSUR should also include this information, in addition to safety-related information. 
The harmonization of the content, format, and timing of periodic safety reports will help to 
ensure that regulators in the three ICH regions receive a uniform, high-quality, comprehensive 
report.  
 
B.  Objectives (1.2) 
 
The main objective of a DSUR is to present a comprehensive, thoughtful annual review and 
evaluation of pertinent safety information collected during the reporting period related to a drug 
under investigation, whether or not it is marketed, by:  
(1) examining whether the information obtained by the sponsor during the reporting period is 
in accord with previous knowledge of the investigational drugs safety;  
(2) describing new safety issues that could have an impact on the protection of clinical trial 
subjects;  
(3) summarizing the current understanding and management of identified and potential 
risks;* and  
(4) providing an update on the status of the clinical investigation/development program and 
study results.  
 
A DSUR should be concise and provide information to assure regulators that sponsors are 
adequately monitoring and evaluating the evolving safety profile of the investigational drug. All 
safety issues discovered during the reporting period should be discussed in the text of the DSUR; 
however, it should not be used to provide the initial notification of significant new safety 
information or provide the means by which new safety issues are detected.  
 
                                                 
4 The term investigational drug is used in this guidance to indicate only the experimental product under study or 
development. 
 
5 For detailed discussion see The Development Safety Update Report (DSUR): Harmonizing the Format and Content 
for Periodic Safety Reporting During Clinical Trials: Report of CIOMS Working Group VII, Council for 
International Organizations of Medical Sciences (CIOMS), Geneva 2006.  
 
6 ICH E6 Good Clinical Practice: Consolidated Guidance, at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf. 
  2 Contains Nonbinding Recommendations 
C.  Scope of the DSUR (1.3) 
 
The main focus of the DSUR is data and findings from interventional clinical trials* (hereafter 
referred to as clinical trials) of drugs and biologicals that are under investigation, whether or not 
they have a marketing approval. Because clinical development of a drug frequently continues 
following marketing approval,7 relevant information from postmarketing studies should also be 
included in the DSUR. The DSUR should concentrate primarily on the investigational drug, 
providing information on comparators only where relevant to the safety of trial subjects.  
 
The DSUR should provide safety information from all ongoing clinical trials and other studies 
that the sponsor is conducting or has completed during the review period including: 
  Clinical trials using an investigational drug (i.e., human pharmacology, therapeutic 
exploratory and therapeutic confirmatory trials (Phase 13));8 
  Clinical trials conducted using marketed drugs in approved indications (i.e., therapeutic 
use trials (Phase 4));  
  Therapeutic use of an investigational drug (e.g., expanded access programs, 
compassionate use programs, particular patient use, single patient INDs, and treatment 
INDs); and 
  Clinical trials conducted to support changes in the manufacturing process of medicinal 
products.  
 
The DSUR should also include significant other findings pertinent to the safety of the 
investigational drug, including findings from: 
  Observational or epidemiological studies; 
  Nonclinical studies (toxicological and in vitro studies); 
  Related DSURs, if applicable to the investigational drug;  
  Manufacturing or microbiological changes;  
  Studies recently published in the literature; 
  Clinical trials with results indicating lack of efficacy that could have a direct impact on 
subject safety (e.g., worsening of the underlying condition if the indication is serious or 
life-threatening); 
  Any other source of relevant safety findings for products in the same therapeutic class; 
  Clinical trials conducted by a co-development partner, if permitted by the contractual 
agreement. 
 
D.  Relation of the DSUR to the Periodic Safety Update Report (1.4) 
 
At present, some ICH countries and regions accept submission of a periodic safety update report 
(PSUR) to fulfill national and regional requirements for periodic reporting on the safety of 
approved drugs. Although the focus of the DSUR is on investigational drugs, there can be 
                                                 
7 For the purposes of this document, we use the terms authorization or authorized to refer to approvals of clinical 
trials and approved or marketing approval to refer to marketing authorizations. 
 
8 For classification of clinical trials, see ICH E8 General Considerations for Clinical Trials, at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073132.pdf.   
  3 Contains Nonbinding Recommendations 
overlap between the content of the DSUR and PSUR, and some repetition is expected. For 
example, information from marketing experience (reported in the PSUR) might be relevant to 
clinical development, and therefore reported in the DSUR. Safety findings from clinical trials 
conducted using marketed drugs would be included in the DSUR, but would also be pertinent to 
postmarketing safety and would be reported in the PSUR. Both the DSUR and PSUR should be 
comprehensive and stand alone as they focus on different subject matter and have differing 
periodicities and recipients. 
 
E.  Recipients of the DSUR (1.5) 
 
The DSUR is intended to serve as an annual report to regulatory authorities. Where national or 
regional laws or regulations require submission of an annual safety report on an investigational 
drug to ethics committees/institutional review boards, the DSUR Executive Summary might be 
appropriate, supplemented with line listings of serious adverse reactions9 (SARs) as warranted. 
 
II.  GENERAL PRINCIPLES (2) 
 
A.  Single DSUR for an Active Substance (2.1) 
 
In order to promote a comprehensive analysis and presentation of the safety profile of the 
investigational drug, a sponsor should prepare a single DSUR with data pertinent to all dosage 
forms and strengths, all indications, and all patient populations under study with the 
investigational drug, wherever feasible. If this is not possible (e.g., when the data are not 
available to the sponsor), an explanation should be provided in the introduction section of the 
DSUR. 
 
If more than one sponsor is involved in drug development, particularly in a co-development or 
other contractual agreement, a single DSUR can be submitted (see section II.D.2 (2.4.2)). 
 
B.  Periodicity and DSUR Data Lock Point* (2.2) 
 
The Development International Birth Date* (DIBD) is used to determine the start of the annual 
period for the DSUR. This date is the sponsors first authorization to conduct a clinical trial in 
any country worldwide. The start of the annual period for the DSUR is the month and date of the 
DIBD.  
 
When the sponsors first clinical trial is conducted in a country without a formal authorization 
process, the sponsor should designate an appropriate date linked to the commencement of the 
first clinical trial. Where clinical trials are ongoing in one country and are later initiated in 
another country, the original DIBD should be maintained and used for all countries in preparing 
the DSUR. 
 
                                                 
9 Serious adverse reaction, serious adverse event, and adverse drug reaction are defined in ICH E2A Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073087.pdf.  
  4 Contains Nonbinding Recommendations 
The data lock point of the DSUR should be the last day of the one-year reporting period. For 
administrative convenience, if desired by the sponsor, the data lock point of the DSUR can be 
designated as the last day of the month prior to the month of the DIBD.  
 
When clinical development of a drug continues following a marketing approval in any country 
worldwide, both a PSUR and a DSUR should be submitted as specified by national or regional 
laws or regulations. If desired by the sponsor, a DSUR can be prepared based on the PSUR 
International Birth Date (IBD) so that the DSUR and the PSUR can be synchronized. In 
synchronizing the data lock points for the DSUR and PSUR, the period covered by the next 
DSUR should be no longer than one year.  
 
The DSUR should be submitted to all concerned regulatory authorities no later than 60 calendar 
days after the DSUR data lock point. 
 
C.  Duration of DSUR Submissions (2.3) 
 
DSURs should continue to be submitted for as long as indicated by national or regional laws or 
regulations.10 When submission of an annual report is no longer required in an individual 
country or region, the sponsor should indicate that the final DSUR serves as the last annual 
report for the investigational drug in that country or region. The sponsor should also indicate 
whether or not clinical trials are continuing elsewhere. 
 
D.  Responsibilities for Preparing and Submitting a DSUR (2.4) 
 
1.  Sponsors Responsibilities (2.4.1) 
 
The sponsor* of a clinical trial is considered responsible for the preparation, content and 
submission of a DSUR. The sponsor can delegate the preparation of the DSUR to a third party 
(e.g., a contract research organization). 
 
In situations where the sponsor does not have access to the information to be included in specific 
sections (e.g., sponsor-investigators* might not have information on manufacturing issues, 
nonclinical data, and marketing status), this should be stated in the DSUR. 
 
2.  Responsibilities of Multiple Parties (2.4.2) 
 
When there is more than one sponsor of a clinical trial or drug development program, the parties 
should arrange to prepare a single DSUR, if possible. This includes situations where a sponsor is 
in a formal co-development or licensing relationship with one or more partners, or where 
individual clinical trials or a drug development program involve collaboration with public or 
private institutions, business partners, or other parties. Written agreements should be in place 
specifying how data will be exchanged and detailing the responsibilities for preparation and 
submission of the DSUR.  
 
                                                 
10 For example, in the United States, sponsors might keep an IND open even if no clinical trials are ongoing or 
planned. Annual reports are submitted for as long as the IND remains open. 
  5 Contains Nonbinding Recommendations 
When a single DSUR cannot be arranged, multiple sponsors can agree to prepare separate 
DSURs for the same investigational drug. This can occur where different indications, routes of 
administration, or formulations are being investigated by different parties. In this situation, the 
rationale for separate DSURs should be provided in each report. 
 
E.  DSURs for Combination Therapies (2.5) 
 
Given the potential complexities of clinical development involving combination therapies, it is 
not possible to provide guidance that addresses all such situations. The sponsor should select the 
most appropriate option based on judgment, taking into account patient population, indication, 
formulation, etc., as well as the circumstances in which the clinical trials are being conducted 
and national or regional laws or regulations. The rationale for this decision should be provided in 
the report.  
 
In general, a single DSUR should be prepared for clinical trials involving a fixed combination 
product (i.e., a product consisting of at least two active ingredients in a fixed dose that is 
administered in a single dosage form). If the sponsor is also conducting clinical trials with 
individual component(s) of the fixed combination product, separate DSUR(s) should be 
submitted for each component. Relevant findings from each DSUR should be summarized in 
section 8.5 of the other DSUR(s). 
 
For trials involving multi-drug therapy, i.e., combinations of drugs that are not fixed, the sponsor 
can prepare either: 
(1) a DSUR for the multi-drug therapy, or  
(2) DSUR(s) for one or more of the individual components; in this case information on the 
multidrug therapy trials can be included in the DSURs of one or all of the components.  
 
The following table provides examples of strategies for preparation of DSURs for multi-drug 
therapies.  
 
Multi-drug therapy used in clinical  DSUR 
trial(s) 
Either a single DSUR focusing on (A+X+Y+Z) 
Investigational drug (A) + marketed  or  
drug(s) (X, Y, Z)  A single DSUR focusing on (A) 
including data on the multi-drug therapy 
Either a single DSUR focusing on (A + B) 
or 
Two investigational drugs (A) + (B) 
Two separate DSURs (A) and (B), each including 
data on the multi-drug therapy 
Two (or more) marketed drugs as an 
investigational drug combination   A single DSUR focusing on the multi-drug 
(X, Y, Z)  therapy (X + Y + Z) 
 
 
  6 Contains Nonbinding Recommendations 
F.  Reference Safety Information (2.6) 
 
The Investigators Brochure (IB) in effect at the start of the reporting period should serve as the 
reference safety information to determine whether the information received during the reporting 
period remains consistent with previous knowledge of the safety profile of the investigational 
drug. Section 7.1 of the DSUR should clearly indicate the version number and date of the IB 
used for this purpose. When an IB is not required by national or regional laws or regulations, the 
applicable national or regional product label11 should serve as the reference safety information. 
 
Usually, a single document should serve as the reference safety information. However, in certain 
circumstances, it might be appropriate to use more than one reference document to support the 
DSUR (e.g., for a DSUR providing information on an investigational drug used in combination 
and as monotherapy). 
 
If the IB has been revised during the reporting period and not previously submitted to the 
relevant regulatory authority, the sponsor should provide a copy of the current version of the IB 
as an attachment to the DSUR.  
 
G.  Format and Presentation of DSUR (2.7) 
 
1.  Format (2.7.1) 
 
The recommended format and content of the DSUR, including table of contents, section 
numbering, and content of each section, is outlined below. For each heading where information 
is available, the information should be presented concisely; when no information is available or a 
DSUR section is not applicable, this should be stated.  
 
If a sponsor intends to submit a DSUR in eCTD format, the sponsor should consult with the 
relevant regulatory authority regarding the appropriate placement of the DSUR in the eCTD 
structure. 
 
2.  Presentation (2.7.2) 
 
The recommended table of contents, including section numbering, for the DSUR is provided 
below: 
 
  Title page 
  Executive Summary 
  Table of Contents 
1.  Introduction 
2.  Worldwide Marketing Approval Status 
3.  Actions Taken in the Reporting Period for Safety Reasons 
4.  Changes to Reference Safety Information 
5.  Inventory of Clinical Trials Ongoing and Completed during the Reporting Period  
                                                 
11 In the EU, this would be the Summary of Product Characteristics (SmPC); in Japan, this would be the Japanese 
Package Insert; and in the United States, this would be the U.S. Package Insert. 
  7 Contains Nonbinding Recommendations 
6.  Estimated Cumulative Exposure  
6.1  Cumulative Subject Exposure in the Development Program 
6.2  Patient Exposure from Marketing Experience 
7.  Data in Line Listings and Summary Tabulations 
7.1  Reference Information 
7.2  Line Listings of Serious Adverse Reactions During the Reporting    
    Period 
7.3  Cumulative Summary Tabulations of Serious Adverse Events 
8.  Significant Findings from Clinical Trials during the Reporting Period 
8.1  Completed Clinical Trials 
8.2  Ongoing Clinical Trials 
8.3  Long-term Follow-up  
8.4  Other Therapeutic Use of Investigational Drug 
8.5  New Safety Data Related to Combination Therapies 
9.  Safety Findings from Noninterventional Studies 
10.  Other Clinical Trial/Study Safety Information 
11.  Safety Findings from Marketing Experience 
12.  Nonclinical Data 
13.  Literature 
14.  Other DSURs  
15.  Lack of Efficacy 
16.  Region-Specific Information 
17.  Late-Breaking Information 
18.  Overall Safety Assessment 
18.1.  Evaluation of the Risks 
18.2  Benefit-risk Considerations  
19.  Summary of Important Risks 
20.  Conclusions 
  Appendices to the DSUR 
 
 
III.  GUIDANCE ON CONTENTS OF A DSUR (3)12 
 
All sections should be completed; when no information is available, this should be stated. 
 
Title page 
 
The title page of the DSUR should include the following information: 
  DSUR number (reports should be numbered sequentially)  
  Investigational drug(s) 
  Reporting period 
  Date of the report 
  Sponsor(s) name(s) and address(es) 
                                                 
12 Headings in this section on guidance on the contents of a DSUR are numbered to correspond to the numbering of 
an actual DSUR. 
  8 Contains Nonbinding Recommendations 
  Statement on the confidentiality of the information included in the DSUR  
  A cautionary statement that the DSUR includes unblinded information, if applicable 
 
Executive Summary 
 
This section should provide a concise summary of the important information contained in the 
report. Together with the title page, it can serve as a stand-alone document suitable for 
submission to ethics committees and other stakeholders, if required by national or regional laws 
or regulations. The following information should be included in the Executive Summary: 
  Introduction  report number and reporting period 
  Investigational drug(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 
  Marketing approval(s)? (yes/no)  If yes, number of countries 
  Summary of overall safety assessment (based on section 18 of the DSUR)  
  Summary of important risks (based on section 19 of the DSUR) 
  Actions taken for safety reasons including significant changes to IB 
  Conclusions 
 
Table of Contents 
 
1.  Introduction (3.1) 
 
This section should include: 
  DIBD or IBD (as applicable) 
  Reporting period and sequential number of the report 
  Investigational drug(s)  mode(s) of action, therapeutic class(es), dose(s), route(s) of 
administration, formulation(s); 
  A brief description of the indication(s) and population(s) being studied 
  A short summary of the scope of the clinical trials covered by the report (e.g., all trials 
with the investigational drug, indication-specific trials, trials with combination products) 
  A brief description and explanation of any information that has not been included in the 
DSUR (e.g., when written agreements with a partner company do not provide for 
exchange of all safety data) 
  The rationale for submission of multiple DSURs for the investigational drug, if 
applicable 
 
2.  Worldwide Marketing Approval Status (3.2) 
 
This section should provide a brief narrative overview including: date of first approval, 
indication(s), approved dose(s), and where approved, if applicable.  
 
  9 Contains Nonbinding Recommendations 
3.  Actions Taken in the Reporting Period for Safety Reasons (3.3) 
 
This section should include a description of significant actions related to safety that have been 
taken during the reporting period by the sponsor, regulators, data monitoring committees* 
(DMC) or ethics committees that had 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. Relevant updates to previous actions should also be summarized in this section (e.g., 
resumption of a clinical trial after suspension).  
 
Changes to the Investigators Brochure should be discussed separately in the Changes to 
Reference Safety Information (see section III.4 (3.4)). 
 
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 
  Partial13 or complete clinical trial suspension or early termination of an ongoing 
clinical trial because of safety findings or lack of efficacy (see section III.15 (3.15)) 
  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: 
o  Protocol modifications due to safety or efficacy concerns (e.g., dosage changes, 
changes in study inclusion/exclusion criteria, intensification of subject 
monitoring, limitation in trial duration) 
o  Restrictions in study population or indications 
o  Changes to the informed consent document relating to safety issues 
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 issues  
Actions related to marketed drugs: 
  Failure to obtain a marketing approval renewal 
  Withdrawal or suspension of a marketing approval 
  Risk management activities including: 
o  Significant restrictions on distribution or introduction of other risk minimization 
measures 
o  Significant safety-related changes in labeling documents that could affect the 
development program, including restrictions on use or population treated 
o  Communications to health care professionals 
o  New postmarketing study requirement(s) imposed by regulators 
 
                                                 
13 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). 
  10 Contains Nonbinding Recommendations 
This section should also summarize requests from regulatory authority(ies) that place a specific 
limitation on current or future development (e.g., a request to conduct long-term animal studies 
before initiating a long-term clinical trial, specification of a maximum dose to be evaluated, a 
request for specific safety data before initiating trials in pediatric subjects). A cumulative listing 
of such requests from regulatory authorities should be provided, including any updates if 
applicable. This can be provided as a table, in an appendix, or in this section. 
 
4.  Changes to Reference Safety Information (3.4) 
 
This section should list any significant safety-related changes to the IB or other reference safety 
information within the reporting period. Such changes might include information relating to 
exclusion criteria, contraindications, warnings, precautions, serious adverse drug reactions, 
adverse events of special interest,* interactions, and any important findings from nonclinical 
studies (e.g., carcinogenicity studies).  Specific information relevant to these changes should be 
provided in the appropriate sections of the DSUR. 
 
5.  Inventory of Clinical Trials Ongoing and Completed During the Reporting 
Period (3.5) 
  
This section should provide a brief overview of the clinical trials ongoing* and completed* by 
the sponsor in the reporting period, with detailed information presented in a table as an appendix 
(see examples in Appendix B, Table 1 of this guidance). Separate tables can be provided by 
indication, formulation, and study population, if appropriate. In addition, where required by 
national or regional laws or regulations, similar information should be provided for other 
therapeutic use of an investigational drug in the reporting period. The table(s) should include the 
following information for each clinical trial: 
  Study ID (e.g., protocol number or other identifier) 
  Phase (1, 2, 3, or 4) 
  Status: 
o  Ongoing (clinical trial has begun; has begun but is currently on hold; has concluded 
but clinical study report has not been finalized) 
o  Completed (clinical study report is finalized) 
  Countries/regions where there is at least one investigational site for the protocol 
  Abbreviated study title 
  Design (uncontrolled, controlled, open, single blind, double blind, parallel, cross-over, 
etc., including treatment arms) 
  Dose and regimen of investigational drug and any comparators 
  Study population as appropriate (age; sex; indication(s); specific patient groups, e.g., trial 
subjects with impaired renal function or trial subjects resistant to treatment) 
  Date of clinical trial start (as defined by the sponsor, e.g., first visit of first patient 
(FVFP)) 
  11 Contains Nonbinding Recommendations 
  Planned enrollment for study as a whole 
  Estimates of cumulative numbers of exposed subjects for each treatment arm, where 
available. The actual enrollment numbers for open or completed trials, and/or an estimate 
based on the randomization scheme for blinded trials, should be provided. 
Appendix B, Table 1 of this guidance provides an example of the column headings for such 
tables. 
6.  Estimated Cumulative Exposure (3.6) 
  
Sections 6.1 and 6.2 of the DSUR should provide information on cumulative exposure in clinical 
trials and the marketed setting, respectively.  
 
An estimation of cumulative subject exposure can help provide context for the cumulative 
summary tabulations of serious adverse events (SAEs) and the overall assessment of safety. The 
accuracy of the estimation of clinical trial exposure might be limited because of a number of 
factors, including the rapidity of subject enrolment and the number of ongoing trials where 
treatment assignment remains blinded.  
 
The optimal method of data presentation will depend on a number of factors, and the following 
general points should be considered in the preparation of the estimated exposure for the DSUR: 
  Data should be presented in tabular format. 
  When there are important differences among trials in dose, route of administration, or 
patient population, these differences can be noted in the tables, or separate tables can be 
considered. 
  If the summary tabulations of SAEs are presented by indication, the exposure data should 
also be presented by indication, when available. 
  When there are substantial differences in time of exposure between subjects randomized 
to the investigational drug and comparator(s), or disparities in length of exposure 
between clinical trials, it can be useful to express exposure data in subject-time (subject-
days, -months, or -years). 
  Investigational drug exposure in healthy volunteers might be less relevant to the overall 
safety profile, particularly when volunteers are exposed to only a single dose. Such data 
can be presented separately with explanation, when appropriate. 
  For marketed drugs that are under clinical investigation, it might not be feasible or useful 
to obtain precise cumulative clinical trial exposure data (e.g., when the drug has been 
marketed for a number of years and/or has many indications). In these circumstances, the 
sponsor should provide an explanation. 
 
6.1.  Cumulative Subject Exposure in the Development Program (3.6.1) 
 
This section should include the following information, in tabular format (see Appendix B, Tables 
2-4 of this guidance for examples): 
  The cumulative number of subjects from ongoing and completed clinical trials; the 
number exposed to the investigational drug, placebo, and/or active comparator(s) since 
  12 Contains Nonbinding Recommendations 
the DIBD (Note: When treatment assignment is blinded, numbers of subjects can be 
estimated based on the randomization scheme.) 
  Cumulative number of subjects exposed to the investigational drug from ongoing and 
completed clinical trials, subgrouped by age range, sex, and racial group for the 
development program when the data are available  
  Demographic characteristics for a single trial if the trial is of particular importance (e.g., 
a pivotal Phase 3 trial).  
 
The specific categorization of age might be dependent on the subject population and indication. 
 
This section should also include an explanation of the sponsors rationale for selecting the 
method to estimate subject exposure, and the limitations of that method, based on the points 
above. 
 
6.2.  Patient Exposure From Marketing Experience (3.6.2) 
 
If the investigational drug is marketed by the sponsor, the DSUR should include an estimate of 
the cumulative patient exposure in the marketed setting, based on the information provided in the 
most recent PSUR or other suitable data source, with an explanation of the method(s) used to 
determine the estimate. 
7.  Data in Line Listings and Summary Tabulations (3.7) 
 
Sections 7.1-7.3 of the DSUR should present important clinical safety information through: 
  Interval line listings of the SARs that were reported to the sponsor during the period covered 
by the DSUR; and 
  Cumulative summary tabulations of serious adverse events that have been reported to the 
sponsor since the DIBD.  
Although causality assessment is generally useful for the evaluation of individual rare adverse 
drug reactions (ADRs) and for making decisions regarding expedited reporting, individual case 
causality assessment has less value in the analysis of aggregate data, where group comparisons 
of rates are possible. Therefore, the summary tabulations in a DSUR should include all SAEs and 
not just SARs for the investigational drug and comparators.  
The line listings and tabulations should include blinded and unblinded clinical trial data. 
Unblinded data might originate from completed trials and individual cases that have been 
unblinded for safety-related reasons (e.g., expedited reporting), if applicable. Sponsors should 
not unblind data for the specific purpose of preparing the DSUR.  
At the sponsors discretion, graphical displays can be used to illustrate specific aspects of the 
data when useful to enhance understanding. 
If the Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for coding 
the adverse event/reaction terms, the Preferred Term level should be presented in the line listings 
and summary tabulations.  
In general, the tabulation(s) of SAEs should include only those terms that were used in defining 
the case as serious; they should not include nonserious events.  
  13 Contains Nonbinding Recommendations 
Certain adverse events can be excluded from the line listings and 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, and those 
that are integral to efficacy 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). 
 
7.1.  Reference Information (3.7.1) 
 
This section of the DSUR should specify the version(s) of the coding dictionary used. If 
applicable, it should also specify the document and version used as Reference Safety Information 
for determining expectedness for the tabulations, where required by national or regional laws or 
regulations. 
 
7.2.  Line Listings of Serious Adverse Reactions During the Reporting Period (3.7.2) 
 
This section of the DSUR should summarize how case reports were selected for inclusion in the 
line listings. This section should not serve to provide analyses or conclusions based on the SARs. 
The line listings should be provided in an appendix (see Appendix B, Table 5 of this guidance). 
The line listings should provide key information on all SARs (blinded and unblinded) reported 
from the sponsors clinical trials during the reporting period. The data should be organized by 
trial and then by System Organ Class (SOC). 
Where possible the line listing(s) should include each subject only once regardless of how many 
SAR terms are reported for the case. If there is more than one reaction, they should all be 
mentioned but the case should be listed under the most serious adverse reaction (sign, symptom, 
or diagnosis), as judged by the sponsor. It is possible that the same subject could experience 
different SARs on different occasions (e.g., weeks apart during a clinical trial). Under such 
circumstances, the SARs can be listed separately, and a single subject can be included in a line 
listing more than once. 
The following information should be included in the line listings: 
(a) Study identification number and EudraCT number14 as applicable 
(b) Subject clinical trial identification number 
(c) Sponsors adverse reaction case reference number 
(d) Country in which case occurred 
(e) Age and sex of trial subject 
(f) Treatment group; identified as blinded if the blind has not been broken 
(g) Dose and dosing interval of investigational drug (and, when relevant, dosage form and 
route of administration) 
(h) Date of onset and/or time to onset of the most serious adverse reaction 
(i)  Dates of treatment and/or best estimate of treatment duration 
(j)  Serious adverse reaction(s); when MedDRA is used, the Preferred Term should be 
presented 
                                                 
14 The EudraCT number is the unique identifier for trials authorized in the European Economic Area. 
  14 Contains Nonbinding Recommendations 
(k) Outcome (e.g., resolved, fatal, improved, sequelae, unknown). This field should indicate 
the consequences of the reaction(s) for the patient, using the worst of the different 
outcomes for multiple reactions. 
(l)  Comments, if relevant (e.g., causality assessment if the sponsor disagrees with the 
reporter; concomitant medications suspected to play a role in the reactions directly or by 
interaction; indication treated with suspect drug(s); dechallenge/rechallenge results if 
available) 
 
Appendix B, Table 5 of this guidance provides an example of the headings for a line listing. 
 
7.3.  Cumulative Summary Tabulations of Serious Adverse Events (3.7.3) 
 
This section should refer to an appendix that provides a cumulative summary tabulation of SAEs 
reported in the sponsors clinical trials, from the DIBD to the data lock point of the current 
DSUR. The sponsor should explain any omission of data (e.g., clinical trial data might not be 
available for products marketed for many years or for products acquired through a business 
merger). The tabulation(s) should be organized by SOC, for the investigational drug, as well as 
for the comparator arm(s) (active comparators, placebo, and treatment unknown due to blinding) 
used in the program. Data can be integrated across the program. Alternatively, when useful and 
feasible, tabulations of SAEs can be presented by protocol, 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. 
 
8.  Significant Findings from Clinical Trials During the Reporting Period (3.8) 
 
The information in this section can be provided by indication, when appropriate, and should 
address the following topics, when applicable: 
 
8.1.  Completed Clinical Trials (3.8.1) 
 
This section of the DSUR should provide a brief summary of clinically important emerging 
efficacy and safety findings obtained from clinical trials completed during the reporting period. 
This information can be presented in narrative format or as a synopsis.15 It could include 
information that supports or refutes previously identified safety issues, as well as evidence of 
new safety signals.* 
 
                                                 
15Examples of synopses are provided in ICH E3 Structure and Content of Clinical Study Reports, at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073113.pdf and 
CIOMS VII. 
  15 Contains Nonbinding Recommendations 
8.2.  Ongoing Clinical Trials (3.8.2) 
 
If the sponsor 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), this section should briefly summarize the issue(s). It could include information 
that supports or refutes previously identified safety issues, as well as evidence of new safety 
signals. 
 
8.3.  Long-Term Follow-up (3.8.3) 
 
Where applicable, this section should provide information from long-term follow-up of subjects 
from clinical trials of investigational drugs, particularly advanced therapy products (e.g., gene 
therapy, cell therapy products, and tissue engineered products). When the development program 
is completed and long-term follow-up is the only ongoing activity generating data for the DSUR, 
this could be the only section where new information is presented. 
 
8.4.  Other Therapeutic Use of Investigational Drug (3.8.4) 
 
This section of the DSUR should include clinically important safety information from other 
programs conducted by the sponsor that follow a specific protocol, with solicited reporting as per 
ICH E2D (e.g., expanded access programs, compassionate use programs, particular patient use, 
single patient INDs, and treatment INDs).  
 
8.5.  New Safety Data Related to Combination Therapies (3.8.5) 
 
If the DSUR is for an investigational drug that is also under development as a component of a 
fixed combination product or a multi-drug regimen, this section should summarize important 
safety findings from the combination therapy DSUR. 
 
Conversely, if this DSUR is for a multi-drug therapy or fixed combination product, this section 
should summarize important safety information arising from trials on the individual components. 
  
Alternatively, the information specific to the combination can be incorporated into a separate 
section(s) of the DSUR for one or all of the individual components of the combination.  
 
General Principles, section II.E (2.5), provides additional guidance on preparation of DSURs for 
combination products. 
 
9.  Safety Findings From Noninterventional Studies (3.9) 
 
This section should summarize relevant safety information from noninterventional studies* that 
became available to the sponsor during the reporting period (e.g., observational studies, 
epidemiological studies, registries,* and active surveillance programs). 
 
  16 Contains Nonbinding Recommendations 
10.  Other Clinical Trial/Study Safety Information (3.10) 
 
This section should summarize relevant safety information from any other clinical trial/study 
sources that became available to the sponsor during the reporting period (e.g., results from 
pooled analyses or meta-analyses of randomized clinical trials, safety information provided by 
co-development partners or from investigator-initiated trials).  
 
11.  Safety Findings From Marketing Experience (3.11) 
 
If the investigational drug has been approved for marketing in any country, this section should 
include a concise summary of key safety findings that have arisen from marketing experience 
and that became available to the sponsor during the reporting period, particularly if the findings 
resulted in changes to the product labeling, Investigators Brochure, or informed consent 
document or amendments to the products risk management plan. This includes not only safety 
findings relating to approved use but also off-label use, administration to special populations 
(e.g., pregnant women), medication errors, overdose and abuse. 
 
12.  Nonclinical Data (3.12) 
 
This section 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 period. Implications of these findings should be discussed in the Overall Safety 
Assessment (see section III.18 (3.18) of this guidance). 
 
13.  Literature (3.13) 
 
This section should summarize new and significant safety findings, either published in the 
scientific literature or available as unpublished manuscripts, relevant to the investigational drug 
that the sponsor became aware of during the reporting period. This section should include 
information from nonclinical and clinical studies and, if relevant and applicable, information on 
drugs of the same class. It should also summarize significant new safety information presented at 
a scientific meeting and published as an abstract; the sponsor should provide a copy of the 
abstract, if possible. 
 
14.  Other DSURs (3.14) 
 
A sponsor should prepare a single DSUR for a single investigational drug. However, if a sponsor 
prepares multiple DSURs for a single investigational drug (e.g., covering different indications, 
development programs, or formulations), this section should summarize significant findings from 
the other DSURs if they are not presented elsewhere within this report. 
 
When available, the sponsor should summarize significant findings from DSURs provided by 
other sponsors conducting clinical trials with the same investigational drug during the reporting 
period. 
   
  17 Contains Nonbinding Recommendations 
15.  Lack of Efficacy (3.15) 
 
Data indicating lack of efficacy, or lack of efficacy relative to established therapy(ies), for 
investigational drugs intended to treat 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 clinical trial subjects and should be summarized in this section.  
 
16.  Region-Specific Information (3.16) 
  
The information in this section can be used to comply with national or regional requirements and 
can be provided in appendices to the DSUR. Sponsors should refer to national or regional 
requirements to determine which of the following sections should be included, as well as the 
scope of clinical trials that should be covered by these sections. Examples include: 
 
  Cumulative summary tabulation of serious adverse reactions  
 
This cumulative summary tabulation of all SARs should specify the number of SARs by: 
(a) SOC, (b) adverse reaction term, and (c) treatment arm, if applicable. Unexpected 
adverse reaction terms should be identified. 
  List of subjects who died during the reporting period  
The list of subjects who died during participation in the clinical trials should include the 
following information at a minimum: case number, assigned treatment (could still be 
blinded), and cause of death of each subject. Any safety issues identified from a review of 
these deaths should be addressed in section 18 of the DSUR as appropriate. 
  List of subjects who dropped out of clinical trials in association with an adverse event 
during the reporting period  
This list should include all subjects who dropped out of clinical trials in association with 
adverse events during the reporting period, whether or not thought to be drug-related. 
Any safety issues identified from a review of these withdrawals should be addressed in 
section 18 of the DSUR as appropriate. 
  Significant Phase 1 protocol modifications  
This section should describe significant Phase 1 protocol modifications made during the 
reporting period, if not previously submitted as a protocol amendment, as described in the 
U.S. Code of Federal Regulations. 
  Significant manufacturing changes  
  18 Contains Nonbinding Recommendations 
This section should include a summary of significant manufacturing or microbiological 
changes during the reporting period and discuss potential safety issues arising from these 
changes in section 18 of the DSUR, if applicable.16 
  Description of the general investigation plan for the coming year  
This section should outline an investigational plan to replace that submitted for the 
previous year. U.S. IND holders should refer to the U.S. Code of Federal Regulations.17 
  Log of outstanding business with respect to the U.S. IND 
If desired by the sponsor, this section can provide a log of any outstanding business with 
respect to the U.S. IND for which the sponsor requests or expects a reply, comment, or 
meeting. 
17.  Late-Breaking Information (3.17) 
 
This section should summarize information on potentially important safety findings that arise 
after the data lock point but while the DSUR is in preparation. Examples include clinically 
significant new case reports, important follow-up data, clinically relevant toxicological findings, 
and any action that the sponsor, a DMC, or a regulatory authority has taken for safety reasons. 
The Overall Safety Assessment (see section III.18 (3.18)) should also take these new data into 
account. 
 
18.  Overall Safety Assessment (3.18) 
 
The overall safety assessment should be a concise, integrated evaluation of all new relevant 
clinical, nonclinical, and epidemiologic information obtained during the reporting period relative 
to previous knowledge of the investigational drug. This assessment should consider cumulative 
experience, new information collected in the period covered by the DSUR and, for 
investigational drugs with a marketing approval, clinically significant postmarketing data. It 
should not summarize or repeat information presented in previous sections of the DSUR, but 
should provide an interpretation of the information and its implications for the clinical trial 
population and the development program. If appropriate, separate assessments can be provided 
by therapeutic area, route of administration, formulation and/or indication. 
18.1.  Evaluation of the Risks (3.18.1) 
 
In evaluating the risks, particular emphasis should be placed on interpretation of data related to 
newly identified safety concerns or providing significant new information relative to previously 
identified safety concerns. Relevant points to consider include (where applicable): 
                                                 
16 In addition U.S. IND holders should refer to FDA guidance for industry, INDs for Phase 2 and Phase 3 Studies  
Chemistry, Manufacturing and Controls Information at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070567.pdf  
17 U.S. Code of Federal Regulations 21 CFR 312.23(a)(3)(iv); revised April 2009, at 
http://frwebgate.access.gpo.gov/cgi-bin/get-cfr.cgi  
  19 Contains Nonbinding Recommendations 
  newly identified safety issues (detailed description of adverse events or reactions; 
associated laboratory values; risk factors; relationship to dose, duration, time course 
of the treatment; reversibility; factors that could be useful in predicting or preventing 
reactions) 
  meaningful changes in previously identified adverse reactions (e.g., increased 
frequency or severity, outcome, specific at-risk populations) 
  symptoms, signs, and laboratory evidence of newly and previously identified 
clinically significant toxicities, for example: 
o  hepatotoxicity 
o  cardiovascular effects, including QT interval prolongation and results from 
thorough QT/QTc studies 
o  bone marrow toxicity  
o  pulmonary toxicity 
o  renal toxicity 
o  central nervous system toxicity 
o  immunogenicity and hypersensitivity 
  deaths that are an outcome of an adverse event 
  study drug discontinuations because of adverse events, including abnormal laboratory 
values or investigations 
  drugdrug and other interactions 
  important nonclinical safety findings 
  manufacturing issues that could affect risk  
  lack of efficacy where this would place trial participants at risk 
  any specific safety issues related to special populations, such as the elderly, children, 
patients with hepatic or renal impairment, or any other at-risk groups (e.g., slow or 
fast metabolizers) 
  pregnancy and lactation exposure and outcomes 
  safety findings arising from experience with long-term treatment 
  evidence of clinically significant medication errors 
  evidence of lack of patient compliance 
  experience with overdose and its treatment 
  occurrences of drug misuse and abuse 
  any safety issues resulting from procedures required by the protocol (e.g., 
bronchoscopy, biopsy, central line insertion) or associated with the conduct or design 
of a particular study (e.g., inadequate subject monitoring schedule, excessive period 
without active treatment) and 
  potential impact of significant new safety issues identified with another drug in the 
same class 
 
18.2.  Benefit-Risk Considerations (3.18.2) 
 
This section should provide a succinct statement on the perceived balance between risks that 
have been identified from cumulative safety data and anticipated efficacy/benefits* and should 
note whether there have been any changes in this balance since the previous DSUR. This section 
is not intended to be a full benefit-risk assessment of the investigational drug.  
  20 Contains Nonbinding Recommendations 
 
19.  Summary of Important Risks (3.19) 
 
This section should provide a concise, cumulative, issue-by-issue list of important identified and 
potential risks* (e.g., those that might lead to warnings, precautions, or contraindications in 
labeling). Such risks might include, for example, toxicities known to be associated with a 
particular molecular structure or drug class, or concerns based on accumulating nonclinical or 
clinical data. Each risk should be re-evaluated annually and re-summarized as appropriate, based 
on the current state of knowledge. New information should be highlighted. The appropriate level 
of detail is likely to be dependent on the stage of drug development. For example, summaries 
covering drugs in early development might include information on individual cases, whereas in 
later development, as more knowledge and perspective are gained, the information on each risk 
might be less detailed. 
The information in this section could provide the basis for the safety specification of a risk 
management plan (ICH E2E Pharmacovigilance Planning). 
Risks that have been fully addressed or resolved should remain in the summary and be briefly 
described, e.g., findings from toxicology studies or early clinical trials that were not borne out by 
later clinical data.  
The information can be provided in either narrative or tabular format (see examples of both in 
Appendix C of this guidance). 
20.  Conclusions (3.20) 
 
The conclusion should briefly describe any changes to the previous knowledge of efficacy and 
safety resulting from information gained since the last DSUR. The conclusion should outline 
actions that have been or will be taken to address emerging safety issues in the clinical 
development program. 
 
Appendices to the DSUR 
 
The DSUR should be accompanied by the following appendices, as appropriate, numbered as 
follows: 
1.  Investigators Brochure (if required by national or regional laws or requirements) 
2.  Cumulative Table of Important Regulatory Requests 
3.  Status of Ongoing and Completed Clinical Trials 
4.  Cumulative Summary Tabulations of Demographic Data 
5.  Line Listings of Serious Adverse Reactions 
6.  Cumulative Summary Tabulation of Serious Adverse Events 
7.  Scientific Abstracts (if relevant) 
The DSUR should also be accompanied by the following Regional Appendices, as appropriate 
(see section III.16 (3.16)): 
  Cumulative summary tabulation of serious adverse reactions 
  21 Contains Nonbinding Recommendations 
  List of subjects who died during the reporting period 
  List of subjects who dropped out of studies during the reporting period 
  Significant Phase 1 protocol modifications with respect to a U.S. IND 
  Significant manufacturing changes 
  Description of the general investigation plan for the coming year with respect to a 
U.S. IND 
  Log of outstanding business with respect to a U.S. IND
  22 Contains Nonbinding Recommendations 
 
IV.  APPENDICES TO THIS GUIDANCE 
 
APPENDIX A  Glossary 
 
Throughout this guidance the Working Group has used terms previously defined by ICH and 
other groups (e.g., CIOMS). Generally, the definitions of terms that were previously defined in 
ICH documents are not repeated in this glossary. However, the glossary includes several ICH 
terms of particular importance to the DSUR, as well as terms defined by CIOMS and other 
groups.  
 
Adverse event of special interest:  An adverse event of special interest (serious or nonserious) 
is one of scientific and medical concern specific to the sponsors product or program, for which 
ongoing monitoring and rapid communication by the investigator to the sponsor can be 
appropriate. Such an event might warrant further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the trial sponsor to 
other parties (e.g., regulators) might also be warranted. (Based on CIOMS VI) 
 
Anticipated efficacy/benefit:  Efficacy/benefit that has not yet been established for the 
investigational drug, but which is anticipated based on knowledge of the class of drugs or data 
from previous clinical trials or nonclinical studies. (Based on wording of CIOMS VI definition 
of anticipated risk) 
 
Clinical development program:  This refers to all clinical trials being conducted with the same 
investigational drug, regardless of indication or formulation. (ICH E2F) 
 
Completed clinical trial:  Study for which a final clinical study report is available. Note: For 
purposes of the DSUR, any clinical trial for which enrolment has begun, but for which a final 
clinical study report is not available, is considered to be ongoing (see ongoing clinical trial 
definition). (CIOMS VII) 
 
Data lock point:  The date (month and day) designated as the cut-off for data to be included in a 
DSUR. It is based on the Development International Birth Date (DIBD). (CIOMS VII) 
 
Data Monitoring Committee (synonyms: Independent Data Monitoring Committee, Data 
and Safety Monitoring Board):  An independent data monitoring committee that may be 
established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, 
and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, 
modify, or stop a trial. (ICH E6) 
 
Development International Birth Date:  Date of first approval (or authorization) for 
conducting an interventional clinical trial in any country. (CIOMS VII) 
 
Identified risk:  An untoward occurrence for which there is adequate evidence of an association 
with the medicinal product of interest.  (Volume 9A Rules Governing Medicinal Products in the 
EU) 
  23 Contains Nonbinding Recommendations 
 
Examples of identified risks include: 
  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 
 
Important identified risk; important potential risk:  An identified risk or potential risk that 
could have an impact on the risk-benefit balance of the product or have implications for public 
health. (Volume 9A Rules Governing Medicinal Products in the EU) 
 
Interventional clinical trial:  An interventional clinical trial is any research study that 
prospectively assigns people to one or more health-related interventions (e.g., preventive care, 
drugs, surgical procedures, behavioral treatments, etc.) to evaluate their effects on health-related 
outcomes. (CIOMS VII) 
 
Investigational drug:  The term investigational drug is used in this 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. (CIOMS VII) 
 
Noninterventional clinical study:  A study where the medicinal product(s) is (are) prescribed in 
the usual manner in accordance with the terms of the marketing authorization. The assignment of 
the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but 
falls within current practice and the prescription of the medicine is clearly separated from the 
decision to include the patient in the study. No additional diagnostic or monitoring procedures 
are applied to the patients and epidemiological methods are used for the analysis of collected 
data. (EU Directive 2001/20/EC on Clinical Trials) 
 
Ongoing clinical trial:  Trial where enrolment has begun, whether a hold is in place or analysis 
is complete, but without a final clinical study report available. (CIOMS VII) 
 
Potential risk:  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.  (Volume 9A Rules Governing Medicinal Products in the EU) 
 
Examples of potential risks include: 
  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 
  A signal arising from a spontaneous adverse reaction reporting system 
  24 Contains Nonbinding Recommendations 
  An event which is known to be associated with other products of the same class or which 
could be expected to occur based on the properties of the medicinal product 
 
Registry:  A registry is a list of patients presenting with the same characteristic(s). This 
characteristic can be a disease (disease registry) or a specific exposure (drug registry). Both types 
of registries, which only differ by the type of patient data of interest, can collect a battery of 
information using standardized questionnaires in a prospective fashion. Commentary: Exposure 
(drug) registries collect information over time on populations exposed to drugs of interest and/or 
specific populations. Patients can be included in a cohort study to collect data on adverse events 
using standardized questionnaires. They can be useful for signal amplification, particularly of 
rare outcomes.  (ICH E2E) 
 
Signal:  A report or reports of an event with an unknown causal relationship to treatment that is 
recognized as worthy of further exploration and continued surveillance. (CIOMS VI) 
 
Sponsor:  An individual, company, institution, or organization which takes responsibility for the 
initiation, management, and/or financing of a clinical trial. (ICH E6 (R1)) 
 
Sponsor-investigator:  An individual who both initiates and conducts, alone or with others, a 
clinical trial, and under whose immediate direction the investigational product is administered to, 
dispensed to, or used by a subject. The term does not include any person other than an individual 
(e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator 
include both those of a sponsor and those of an investigator. (ICH E6) 
 
 
  25 Contains Nonbinding Recommendations 
 
APPENDIX B  Examples of Tables and Table Headings for Clinical Trial Listings 
 
Table 1.  Status of Ongoing and Completed Clinical Trials 
Overview of Ongoing Studies [Study Drug]  
Study ID  Phase  Country  Study Title  Study design  Dosing regimen   Study  FVFP  Planned  Subject 
    population  enrolment  exposure 
                 
 
 
  
 FVFP = first visit first patient 
 Based upon total number of patients recruited as of [date] and applied randomization schemes 
 
Overview of Studies Completed During the DSUR Period [Study Drug] 
Study ID  Phase  Country  Study Title  Study design  Dosing regimen   Study  Subject/patient patient 
  population  exposure per treatment arm 
(M/F) 
             
 
Table 2.  Estimated Cumulative Subject Exposure 
Estimates of cumulative subject exposure, based upon actual exposure data from completed clinical trials and the enrolment/randomization 
schemes for ongoing trials. 
 
Treatment  Number of subjects 
drug   
comparator   
placebo   
  26 Contains Nonbinding Recommendations 
 
Table 3.  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 4.  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] 
  27 Contains Nonbinding Recommendations 
 
Table 5.  Examples of Headings for Interval Line Listings of Serious Adverse Reactions 
Interval Line Listings of Serious Adverse Reactions 
Study ID  Case ID/  Country  Serious  Outcome  Date of onset  Suspect Drug  Daily dose  Dates of treatment  Comments 
EudraCT  Subject  Gender  adverse  Time to onset  Route  Treatment duration 
number  number  Age  drug  Formulation 
reactions 
(SARs) 
                 
 
 
  --------  --------  -------  --------  --------  --------  --------  --------  --------
 Study/center/patient 
 Primary SAR only 
 
Table 6.  Examples of Cumulative Tabulations of Serious Adverse Events 
Cumulative Summary Tabulation of Serious Adverse Events (SAEs) 
 
  System Organ Class   Total up to 31-Dec-09 
 
Preferred Term  [Study drug]  Blinded  Active  Placebo 
 
comparator 
 
  Investigations  18  4  7  2 
 
Alanine aminotransferase increased  9  2  4  1 
 
Aspartate aminotransferase increased  9  2  3  1 
 
  Nervous System Disorder  2  2  4  7 
 
  Syncope   2  2  4  7 
 
  28 Contains Nonbinding Recommendations 
 
APPENDIX C  Examples of the Summary of Important Risks 
 
This appendix depicts fictitious examples of the Summary of Important Risks, prepared in 
three consecutive years, from 2012 to 2014. The Summary of Important Risks can be 
provided in either narrative (Appendix C1) or tabular (Appendix C2) format.  
 
APPENDIX C1: Narrative Format 
 
DSUR 2012 
 
19  Summary of Important Risks 
 
New or updated risks are denoted with an asterisk. 
 
1.   Nephrotoxicity 
 
Drug Z is a para-aminoglycolate that bears structural similarities to aminoglycosides, 
currently under development for amelioration of angina pectoris in patients with stable 
coronary artery disease. Other members of this class are known to be nephrotoxic, and there 
was evidence of nephrotoxicity in both rats and rabbits at doses of 20 and 60 mg/kg/d, 
respectively. 
 
In Phase 1 trials in healthy volunteers, 2 of 30 subjects (6.7%) who received the highest dose 
of drug Z (100 mg po qd for 7 days) exhibited transient increases in serum creatinine 
associated with proteinuria: subject 0127 had an increase in creatinine from 0.9 mg/dL at 
baseline to 1.8 mg/dL at Day 7; subject 0139 had an increase from 1.0 mg/dL at baseline to 
1.9 mg/dL at Day 7. Both subjects had mild proteinuria (2+ by dipstick, 24-hour urinary 
protein not quantified). Urinalyses of both subjects were unremarkable (minimal cells; no 
casts). By Day 21, serum creatinine had returned to baseline in both subjects, and proteinuria 
had resolved (see sections 8.2 and 18.1 for details). None of the other 28 healthy subjects who 
received drug Z 100 mg qd, and none of the 119 subjects who received drug Z at lower doses 
(50 mg or less, including 72 subjects with coronary artery disease), experienced proteinuria or 
significant increases in creatinine. 
 
The increases in creatinine in the healthy volunteers who received the highest dose of drug Z 
(100 mg QD) were thought likely to be drug-related, in part because of the known 
nephrotoxicity of the drug class. It was decided, therefore, to reduce the maximum dose of 
drug Z in the Phase 2 trials to 50 mg. In addition, subject monitoring was intensified: serum 
creatinine, eGFR, albumin/creatinine ratios, blood urea nitrogen, and urinalysis are now 
performed at baseline, Weeks 1, 2, 4, 8, 16, and 24. Twenty-four-hour urinary protein 
excretion will be determined for any subject who develops proteinuria by dipstick. Study drug 
will be discontinued in subjects with creatinine increases of 0.5 mg/dL, a 30% rise in 
creatinine, or a 25% decrease in eGFR (repeated 2 times over a 3-day period). The protocol, 
informed consent document, and Investigators Brochure have been revised accordingly. 
 
  29 Contains Nonbinding Recommendations 
2.   Hepatotoxicity 
 
In rat study KR-102, 2 of 8 rats in the highest dose group (60 mg/kg/d) developed hepatic 
injury, with centrilobular necrosis. None of the rats that received lower doses had evidence of 
hepatotoxicity, and no hepatotoxicity was evident in rabbits at doses at high as 60 mg/kg/d.  
 
One (1) subject (102-037) with coronary artery disease in study 102 who received 50 mg po 
qd drug Z developed moderate elevation of alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) on Day 14 (2.7 and 2.3 x the upper limits of normal, respectively), 
without increases in alkaline phosphatase or bilirubin (see sections 8.2 and 18.1 for details). 
Drug Z was discontinued on Day 16, and transaminases returned to normal by Day 28. The 
subject denied alcohol consumption, and all serology was negative. The subject had been 
receiving drugs X and Y concomitantly on a chronic basis for >2 years prior to enrolment. 
Neither drug was suspected of causing the elevation in transaminases. Both were continued 
during the adverse event, making it very unlikely that they were the cause of the transaminase 
elevations. Of note, subject 102-037 was found to have concentrations of drug Z (Cmax) 
approximately 8-fold higher than the mean of the 50 mg cohort, suggesting an inability to 
metabolize drug Z. This possibility remains under investigation. An additional 148 subjects 
were exposed to drug Z in the Phase 1 program, and none exhibited transaminase elevations.  
 
In light of the rat findings and the transaminase elevations in subject 102-037, more frequent 
monitoring has been implemented for the Phase 2 study. Assessments at Weeks 4 and 16 have 
been added, so that subjects now undergo assessment of ALT, AST, bilirubin, and alkaline 
phosphatase at baseline, Weeks 1, 2, 4, 8, 16, and 24. The protocol, informed consent 
document, and Investigators Brochure have been revised accordingly. 
 
 
DSUR 2013 
 
19  Summary of Important Risks 
 
New or updated risks are denoted with an asterisk. 
 
1.   Nephrotoxicity* 
 
Drug Z is a para-aminoglycolate, one of a class of drugs bearing structural similarities to 
aminoglycosides, and known to be nephrotoxic. Two of 30 healthy volunteers (6.7%) in the 
Phase 1 program who had received drug Z 100 mg PO qd developed transient increases in 
serum creatinine associated with mild proteinuria (by dipstick), and the 100 mg dose was 
dropped from further development. In the completed Phase 2 trial of drug Z in patients with 
coronary artery disease and stable angina pectoris (Study 201), increases in creatinine >1.25 
but <1.5 times baseline were observed in 5 of 60 subjects (8.3%) in the 50 mg group, 5 of 62 
subjects (8.1%) in the 25 mg group, and 3 of 59 subjects (5.1%) in the 10 mg group, versus 6 
of 61 subjects (10%) in the placebo group. For all of these subjects, the study drug was 
continued (per protocol), and serum creatinine returned to baseline within 2 weeks. Increases 
in creatinine >1.5 times baseline were observed in 1 of 60 subjects (1.7%) in the 50 mg group, 
  30 Contains Nonbinding Recommendations 
0 of 62 subjects in the 25 mg group, and 1 of 59 subjects (1.7%) in the 10 mg group, versus 2 
of 61 subjects (3.3%) in the placebo group. The study drug was discontinued in all of these 
subjects (per protocol), and serum creatinine returned to baseline within 2 weeks. As 
explained in sections 8.2 and 18.1, the recovery of creatinine to normal (i.e., the slope of the 
creatinine vs. time relationship) was the same in subjects who continued and discontinued the 
study drug, suggesting that this was not a specific drug effect. Of note, 3 of the 4 drug Z-
treated subjects who developed creatinine elevations were taking concomitant diuretics. In 
ongoing studies 202 and 204, serum creatinine, eGFR, blood urea nitrogen, and urinalysis 
continue to be monitored at baseline, Weeks 1, 2, 4, 12, 24, and 48. Twenty-four-hour urinary 
protein excretion is determined in any subject who develops proteinuria by dipstick.  
 
2.  Hepatotoxicity* 
 
Drug Z caused centrilobular necrosis at the highest dose tested (60 mg/kg/d) in rats (although 
there was no evidence of liver damage at this dose in rabbits). One (1) of 149 subjects (0.7%) 
in the Phase 1 program developed unexplained elevations of ALT and AST approximately 2.5 
x the upper limit of normal on Day 14; which resolved on discontinuation of the drug. Two 
drug Z-treated subjects in the completed Phase 2 study #201 (2/181, 1.1%) had transaminase 
elevations (see section 8.2), but these were mild and transient, and one subject in the placebo 
group (1/61, 1.6%) had more severe elevations. Based on this information, the present 
monitoring plan seems appropriate, and no changes have been made to the protocol, 
Investigators Brochure, or informed consent document. Of note, one subject with elevated 
transaminases (102-037) had been thought to have had an unusually high Cmax; however, this 
was subsequently determined to be a laboratory error. 
 
3.  Syncope* 
 
Drug Z is thought to be a mild nitric oxide (NO)-dependent vasodilator, which could be partly 
responsible for its anti-anginal effect. During this period there were 2 reports of syncope 
(2/81, 1.1%) from study #201 that were considered by investigators to be causally-related to 
drug Z (subjects 201-119 and 201-212). The subjects had been receiving 10 and 25 mg of 
drug Z, respectively. Although both subjects were predisposed to syncope (one was 
apparently very dehydrated; the other had a long history of syncope), there is mechanistic 
plausibility and we will continue to focus on syncope as a possible drug-related side effect. 
No specific changes have been were made to the monitoring plan as a result of these adverse 
events. 
 
 
DSUR 2014 
 
19  Summary of Important Risks 
 
New or updated risks are denoted with an asterisk. 
 
1.   Nephrotoxicity* 
 
  31 Contains Nonbinding Recommendations 
Drug Z is a para-aminoglycolate, one of a class of drugs bearing structural similarities to 
aminoglycosides, and known to be nephrotoxic. A 100 mg dose, studied in Phase 1, was 
dropped from further development because of increases in creatinine and proteinuria in 
normal volunteers. In the Phase 2 program, increases in creatinine >1.25 but <1.5 times 
baseline were observed in 7.8%, 6.8%, and 5.8% of subjects in the 50, 25, and 10 mg 
treatment groups, respectively, versus 6.3% in the placebo group. Increases in creatinine >1.5 
times baseline were observed in 1.5%, 0.5%, and 1.9% of subjects in the 50, 25, and 10 mg 
treatment groups, respectively, versus 2.7% in the placebo group. As noted in sections 8.2 and 
18.1, increases in creatinine seem to be associated with dehydration and diuretic use. In 
addition, a number of the subjects with increases in creatinine of more than 50% from 
baseline have had unusually low baseline values (i.e., <0.6 mg/dL). The clinical meaning of 
this is unclear.  
 
In the ongoing Phase 3 trial (301), serum creatinine, eGFR, blood urea nitrogen, and 
urinalysis are monitored at baseline, Weeks 1, 4, 12, and 48. Twenty-four-hour urinary 
protein excretion is determined in any subject who develops 3+ or greater proteinuria by 
dipstick.  
 
2.  Hepatotoxicity* 
 
Drug Z caused centrilobular necrosis at the highest dose tested in rats. There was frequent 
monitoring of ALT, AST, alkaline phosphatase, and bilirubin in the Phase 1 and 2 trials, and 
no consistent pattern of laboratory abnormalities has emerged suggestive of liver injury. 
 
In the ongoing Phase 3 study (301), the above laboratory tests of liver injury are monitored at 
baseline, Weeks 1, 4, 12, and 48. 
  
3.  Syncope* 
 
Drug Z is thought to be a nitric oxide (NO)-dependent vasodilator, which could be partly 
responsible for its anti-anginal effect. There have been 21 reports of syncope in drug Z-treated 
subjects thus far in the development program (21/632, 3.3%), versus 3 (1.4%) in placebo. 
Most of the cases were orthostatic, and/or associated with coadministration of nitrates or 
vasodilators. In the Phase 3 program, subjects are advised against concurrent administration 
of vasodilators (e.g., nitrates, dihydropyridine calcium channel blockers), and given general 
precautions regarding orthostatic dizziness. The protocol, informed consent document, and 
Investigators Brochure have been revised to include this risk. 
 
4.  Pancreatitis* 
 
Three case reports of pancreatitis have been reported from subjects in the completed Phase 2 
and ongoing Phase 3 trials (see sections 8.1 and 8.2, respectively). Although there were 
plausible alternative explanations for each case, evidence of pancreatitis will be carefully 
sought thorough laboratory monitoring: all subjects enrolled in the Phase 3 trial (301) undergo 
screening evaluations of lipase and amylase, with repeat evaluations at Weeks 1 and 4. 
  32 Contains Nonbinding Recommendations 
APPENDIX C2: Tabular Format 
 
19  Summary of Important Risks 
 
This section summarizes the important identified or potential risks that have been recognized 
during the conduct of the Drug Z clinical development program. At present, all are considered 
as potential risks, with none characterized as identified risks associated with the 
administration of drug Z. 
 
The following have been recognized as important potential risks during the reporting period: 
  Nephrotoxicity 
  Hepatotoxicity  
  Syncope 
  Pancreatitis 
 
Additional details are provided in Table X, below: 
  33 Contains Nonbinding Recommendations 
 
Table X  Summary of Important Risks 
 
New or updated risks are denoted with an asterisk. 
 
Risk  Nonclinical data  Clinical data  Actions 
Nephrotoxicity*  Nephrotoxicity in rats and  Drug Z is a para- In Phase 3 trial (301), 
rabbits at doses of 20 and  aminoglycolate, in drug class  serum creatinine, eGFR, 
60 mg/kg/d, respectively  structurally similar to  blood urea nitrogen, and 
aminoglycosides.  urinalysis monitored at 
Nephrotoxicity well known.  baseline, Weeks 1, 4, 12, 
  and 48.  
Phase1: A 100 mg dose was   
dropped from further  24-hour urinary protein 
development because of  excretion is determined in 
increases in creatinine and  subjects who develop >2+ 
proteinuria in normal  or proteinuria by dipstick.  
volunteers.    
 
Phase 2: Increases in 
creatinine >1.25 but <1.5 
times baseline were observed 
in 7.8%, 6.8%, and 5.8% of 
subjects in the 50, 25, and 10 
mg treatment groups, 
respectively, versus 6.3% in 
the placebo group.  
 
Increases in creatinine >1.5 
times baseline were observed 
in 1.5%, 0.5%, and 1.9% of 
subjects in the 50, 25, and 10 
mg treatment groups, 
respectively, versus 2.7% in 
the placebo group. 
 
Increases in creatinine seem 
to be associated with 
dehydration and diuretic use. 
In addition, a number of the 
subjects with increases in 
creatinine of more than 50% 
from baseline have had 
unusually low baseline values 
(i.e., <0.6 mg/dL). The 
  34 Contains Nonbinding Recommendations 
Risk  Nonclinical data  Clinical data  Actions 
clinical meaning of this is 
unclear.  
See sections 8.2 and 18.1, i  
Hepatotoxicity*  Rat study KR-102: 2 of 8  With frequent monitoring of  Routine monitoring in 
rats in the highest dose  ALT, AST, alkaline  ongoing Phase 3 study 
group (60 mg/kg/d)  phosphatase, and bilirubin in  (301): ALT, AST, alkaline 
developed centrilobular  the Phase 1 and 2 trials, no  phosphatase, and bilirubin 
necrosis. At lower doses,  consistent pattern of  monitored at baseline, 
no rats had evidence of  laboratory abnormalities  Weeks 1, 4, 12, and 48. 
hepatotoxicity.   emerged suggestive of liver   
  injury. 
No hepatotoxicity seen in 
rabbits at doses < 60 
mg/kg/d.  
Syncope*  Published studies: drug Z  21 reports of syncope in drug  In Phase 3 program, 
is a nitric oxide (NO)- Z-treated subjects to date in  subjects advised against 
dependent vasodilator in  the development program  concurrent administration 
canine models.  (21/632, 3.3%), versus 3  of vasodilators; given 
(1.4%) in placebo. Most cases  precautions regarding 
orthostatic, and/or associated  orthostatic dizziness. 
with coadministration of  Protocol, informed consent, 
nitrates or vasodilators.   and Investigators 
Brochure revised to include 
this risk. 
 
Pancreatitis*  No findings.  3 cases of pancreatitis  Subjects in the Phase 3 trial 
  reported from subjects in the  (301) undergo screening 
completed Phase 2 and  evaluations of lipase and 
ongoing Phase 3 trials.  amylase, with repeat 
Causal relationship with drug  evaluations at Weeks 1 and 
Z not determined - plausible  4. 
alternative explanations for 
each case. 
 
 
  35