Guidance for Industry 

 
E3 Structure and Content of 

Clinical Study Reports 

 
____________________________ 
 
Questions and Answers (R1)  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 

 
January 2013 

ICH 

   
Guidance for Industry 

 
E3 Structure and Content of 

Clinical Study Reports 

 
____________________________ 
 
Questions and Answers (R1)  

 
 
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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) 

 
January 2013 

ICH 

 
   
 
TABLE OF CONTENTS 

 
 
 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   QUESTIONS AND ANSWERS....................................................................................... 1 
 
A.   Content and Structure (1).............................................................................................................1
  
B.   Appendices (2) ................................................................................................................................3
  
C.   Terminology (3)..............................................................................................................................5
  
  Contains Nonbinding Recommendations  
1 
Guidance for Industry  
 
E3 Structure and Content of Clinical Study Reports  

Questions and Answers (R1) 

 
 
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.  	INTRODUCTION2  
 
Since the ICH E3 guidance was made final, experiences implementing the guidance in the ICH 
regions have given rise to requests for clarification.  This question and answer (Q&A) document 
is intended to facilitate implementing the ICH E3 guidance by clarifying key issues. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
 
II. 	 QUESTIONS AND ANSWERS 
 
A. 	 Content and Structure (1) 
 
Q1: 	 Some in the pharmaceutical industry have expressed concern that the ICH E3 
guidance, Structure and Content of Clinical Study Reports (ICH E3), is intended as 
a requirement (i.e., a template that must be followed).  The fact that the ICH M4 
guidance for the Common Technical Document (CTD) refers to specific structural  
elements described in ICH E3 (e.g., Clinical Study Report (CSR) section headings) may 
have contributed to this interpretation.  Interpretation of ICH E3 as a rigid template 
                                                 
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, June 2012.  At  Step 4 of  
the process, the final draft is recommended  for adoption to the regulatory bodies of  the European Union, Japan, and 
the United States. 
2 Arabic numbers reflect the organizational breakdown of the document endorsed  by the ICH Steering Committee at 
Step 4 of  the ICH process,  June 2012. 
  1
  Contains Nonbinding Recommendations  
can result in presentation of redundant and suboptimal information in CSRs.  This is a 
particular problem when ICH E3 is used for studies for which it was not designed (e.g., 
pharmacokinetic studies or studies with health economic or quality of life outcomes). 
Can ICH reaffirm that ICH E3 is a guidance and not a required template and that ICH 
E3 can be adapted to report studies that fall outside the original scope of ICH E3? 
 
A1: 	 Yes. ICH E3 is a guidance, not a set of rigid requirements or a template, and flexibility is 
inherent in its use. The [guidance] is intended to assist sponsors in the development of a 
report that is complete, free from ambiguity, well organized, and easy to review.  
Modifications and adaptations to the structure presented in the guidance that lead to 
better display and communication of information are encouraged. 
 
The introduction to ICH E3 (page 3) clearly indicates that ICH E3 is to be interpreted as a 
guidance, not a set of requirements: Each report should consider all of the topics 
described (unless clearly not relevant) although the specific sequence and grouping of 
topics may be changed if alternatives are more logical for a particular study.  Some data 
in the appendices are specific requirements of individual regulatory authorities and 
should be submitted as appropriate.  The numbering should then be adapted accordingly. 
  
To illustrate this flexibility, consider demographic baseline information.  ICH E3 
suggests presentation of this information in the efficacy evaluation, but many variations 
of this presentation are possible.  For example, if the efficacy and safety populations 
differ substantially, it would be appropriate to present demographic and baseline 
characteristics for the safety and efficacy populations in the safety and efficacy sections 
or in a new section preceding the efficacy and safety results sections. 
 
If particular types of information or topics are not addressed in ICH E3 or if their location 
is not specified, this information or topic should be placed in the section that is most 
relevant.  For example, pharmacokinetic or  quality of life results could be placed in 
appropriately identified subsections of the efficacy and safety results sections, or they  
could be placed in new, appropriately identified results sections. 
 
If a report does not address all the aspects of ICH E3 that are relevant for a given study, 
this should be clearly indicated and the rationale for doing so should be provided  for 
example, if there is no presentation of efficacy for an efficacy study.  A rationale is not 
necessary if sections presented in ICH E3 are reordered, renamed, or deleted (if 
warranted by the study design) or if new sections are added. 
 
It should be noted that ICH E3 was developed for submission of adequate and well-
controlled clinical effectiveness studies. Nevertheless, the basic principles described can 
be applied to other kinds of trials, such as clinical pharmacology studies and open-label 
safety studies, recognizing that not all sections or data presentations may be appropriate 
or important for these other types of trials.  Sponsors are encouraged to adapt the 
recommendations in the guidance as appropriate (e.g., by deleting sections that are not 
relevant or adding important sections that are not mentioned in the guidance). 
 
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  Contains Nonbinding Recommendations  
Q2: 	 The ICH E3 guidance provides limited guidance on the synopsis.  In the ICH M4E 
guidance, additional guidance on the synopsis of a CSR is given, including its use as a 
stand-alone document and its length. Although ICH E3 asks for a usual maximum 
length of 3 pages, ICH M4E extends this page limit for more complex and important  
studies (e.g., to 10 pages). How should both guidances be read together? 
 
A2: 	 The recommendations made in the ICH E3 guidance, which was developed before ICH 
M4E, should be combined with the suggestions made in the M4E guidance.  Because the 
synopsis will be used as a stand-alone document within a Common Technical Document, 
it should be written so that it can be understood and interpreted on its own (i.e., without 
the other sections of a CSR). In addition to a brief description of the study design and 
critical methodological information, the synopsis should provide efficacy and safety 
results, as well as other critical information, including data on the study population, 
disposition of subjects, important protocol deviations, and treatment compliance.  Cross-
references to other sections of the CSR should be avoided.  As explained in ICH M4E, 
complex or large and important studies may call for a synopsis longer than three pages.  
The 10-page example given in M4E is not an absolute requirement or limit but should not 
need to be exceeded greatly. The use of a tabular format for the synopsis is not 
mandatory. 
 
B.  A	 ppendices (2) 
 
Q3: 	 The CSR appendices described in the ICH E3 guidance include material now available 
in the Trial Master File (TMF) in accordance with ICH E6.  Should documents 
available in the TMF be included in the CSR appendices? 
 
A3: 	 Documentation needed to review the CSR should be included in the CSR appendices.  It 
is not sufficient for such documents to be included only in the TMF, which is not 
submitted in the marketing application. 
  
Documents that provide critical information on a study, such as the protocol (16.1.1), 
statistical methods (16.1.9), list of investigators and study sites, and sample case report 
forms, would always be needed by reviewers assessing a study and should be included in 
the trial report even if they are in a TMF.  Certain documents may be required for the 
CSR by individual countries or regions, in which case they should be included.  For 
example, according to the ICH guidance E6 Good Clinical Practice: Consolidated 
Guidance,3 an audit certificate (16.1.8) should be provided when required by applicable 
law or regulation. If there is any uncertainty about whether documents should be 
included or not, the appropriate regulatory agency can be consulted. 
  
                                                 
3  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or the FDA  
Biologics guidance page  at  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  3
  Contains Nonbinding Recommendations  
Supportive documents, such as investigator curricula vitae, ethics committee approvals, 
informed consent forms, and batch numbers per subject are in the TMF or clinical supply 
database and should generally not be included in the CSR appendices. 
   
Any documents not submitted and subsequently requested by the regulatory authority 
should be provided promptly. 
 
Q4: 	 How can I include data not mentioned in the ICH E3 text or appendices since the 
guidance predates the ICH M4 guidance associated with the CTD and Electronic 
Common Technical Document (eCTD)?  Specifically, what are the options for 
submission of data for topics such as pharmacokinetics, pharmacodynamics, 
pharmacogenomics (genomic markers), gene therapy, stem cells, biomarkers, devices, 
quality of life, assay validation, data monitoring/review committees, electrocardiogram, 
other safety reports, images, pictures/scans, diagnostic tests for individualized therapy, 
and patient-reported outcomes? 
 
A4: 	 It is appropriate to create  new headings in the CSR and new appendices for these topics.  
The guidance provides for and focuses on efficacy and safety variables known at the 
time.  Other topics should be well referenced in the CSR body and clearly identified in 
the table of contents. 
 
Current submission options include: 
 
1. 	  Stand alone reports. These can be placed in parallel with the main clinical study  
report in the eCTD. For example, a clinical pharmacology study might have the 
clinical study report, a pharmacokinetic report, and an assay validation report.  For an 
efficacy study with patient reported outcome (PRO) measures, there might be a PRO 
report. Each of these reports can be referenced under the same heading in the eCTD 
and placed alongside one another in the eCTD folder for that study.  The nature of the 
information should be clearly described in the title of the document that is provided 
through the eCTD. 
 
2. 	 Study tagging files.  In a region where study tagging files are used,  it is 
recommended that a file-tag option from  the valid values list be used  for 
example, safety report, antibacterial, special-pathogen (see Specifications for Study 
Tagging Files, http://www.ich.org/products/electronic-standards.html). 
  
Alternatively, if a file-tag that adequately describes the material you are planning to 
submit is not available, you can request that a new file-tag be made available.  This 
request should be submitted to your regional authority.  In the event that this change 
cannot be accommodated within your time frame, you can place the document with the 
main body of the report (i.e., the document would be tagged with the study-report-body 
file-tag). The nature of the information should be contained in the title of the document 
that is provided through the eCTD. 
   
  4
  Contains Nonbinding Recommendations  
Please refer to the most recent version of the valid values list, as it is periodically 
updated as changes are requested. 
 
C.  T	 erminology (3) 
 
Q5: 	 A subjects death could potentially be captured in two separate data listings:  
   
a. 	 The listing referenced in section 12.3.1.1, Deaths.  This section calls for sponsors to 
include a listing of all deaths during the study, including the post-treatment 
follow-up period, and deaths that resulted from a process that began during the 
study. 
b. 	 The listing referenced in section 12.3.1.2, Other Serious Adverse Events.  This 
section defines other serious adverse events as events other than death but 
including the serious adverse events temporally associated with or preceding the 
deaths. 
   
There is concern that including events with fatal outcomes in section 12.3.1.2 may lead 
to double counting or miscounting of deaths.  Can this issue be clarified? 
 
A5: 	 It is true that the structure and definitions provided in the ICH E3 guidance could result in 
deaths appearing in section 12.3.1.2 (as per E3 numbering), Other Serious Adverse 
Events, if an event terminated with, or was associated with, a subjects death. However, 
this should not result in double counting or miscounting of deaths. Although deaths may 
or may not be included in the listing for section 12.3.1.2, all deaths should be captured in 
the listing for section 12.3.1.1. That is, any subject death reported under section 12.3.1.2 
as an other serious adverse event with a fatal outcome would also have been captured 
under deaths in section 12.3.1.1. 
 
Q6: 	 Section 12.2.2 of the ICH E3 guidance states that all adverse events occurring after 
initiation of study treatments should be displayed in summary tables.  The example 
table in section 12.2.2 of ICH E3 (Adverse Events: Number Observed and Rate, with 
Subject Identification) is really a listing that will rarely be brief enough to place in the 
body of the study report. Moreover, in addition to severity, relatedness, and subject 
identifiers (shown in the example table), each adverse event should include the original 
investigators verbatim term. How is it possible to include all of this information in a 
summary table?  Can this table be modified? 
 
A6: 	 The body of the clinical study report (ICH E3 section 12.2.2) should include a summary 
table of relatively common adverse events  those occurring in at least a particular 
percentage of subjects who received the investigational drug.  This summary tabulation 
compares treatment and control groups and does not include subject identifying numbers 
or verbatim adverse event terms. 
 
Of note, the example table provided in section 12.2.2 of the guidance is not meant to be 
presented in section 12.2.2 of the report, but in section 14.3.1, which is not part of the 
text of the clinical study report. 
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  Contains Nonbinding Recommendations  
  
The ICH E3 guidance did not attempt to display all possible presentations of adverse 
event information, but rather outlined the summary table intended for section 12.2.2 and 
provided an illustration of the far more detailed display that would be placed in section  
14.3.1.  The example provided for section 14.3.1, however, does not try to illustrate all 
possibilities, but shows individuals with adverse events by body system, severity, and 
perceived drug-relatedness for treatment group X.  Listings should also display 
investigators verbatim terms for each event and could be used to show demographic or  
disease-specific information, dosage, duration of treatment, or treatment cycle (for cancer 
chemotherapy). 
  
Because it can be impractical to display all of this information in a single listing, such 
analyses can be presented in individual listings (e.g., by dose or other subgroup of 
interest). When adverse event data are presented by subgroup, however, a display of 
overall adverse events should also be included.  For example, for a drug for subjects with 
chronic kidney disease, adverse events could be tabulated separately for subjects 
receiving or not receiving dialysis, but a table that includes adverse events in all subjects 
should also be included. 
 
The listings that provide more comprehensive adverse event information, specifically 
subject identifiers and verbatim terms for each adverse event, should be provided in the 
study report, in sections 14.3.1 and 16.2.7. If each adverse event is to be characterized 
extensively (i.e., many items in the listing), electronic approaches may be appropriate. 
 
Q7: 	 Section 10.2 of the ICH E3 guidance requests an accounting of important protocol 
deviations. However, the flowchart in Annex IVa of ICH E3 (Disposition of Patients) 
recommends that data be provided on the number of subjects withdrawn from the study 
because of protocol violations.  Neither the term protocol deviations nor protocol 
violations has been previously defined by ICH.  What is the distinction between a 
protocol deviation, important protocol deviation, and a protocol violation?  Can these 
terms be clarified?  In addition, does the guidance provide for sponsors flexibility in 
defining what constitutes an important protocol deviation for a trial? 
 
A7:  A	  protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. 
  
Important protocol deviations are a subset of protocol deviations that might significantly 
affect the completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a subject's rights, safety, or well-being.  For example, important 
protocol deviations might include enrolling subjects in violation of key eligibility criteria 
designed to ensure a specific subject population or failing to collect data necessary to 
interpret primary endpoints, as this may compromise the scientific value of the trial. 
 
Protocol violation and important protocol deviation are sometimes used interchangeably 
to refer to a significant departure from protocol requirements.  The word violation can 
also have other meanings in a regulatory context.  However, in Annex IVa of the ICH E3 
  6
  Contains Nonbinding Recommendations  
guidance (Disposition of Patients), the term  protocol violation was intended to mean only 
a change, divergence, or departure from the study requirements, whether by the subject or 
investigator, that resulted in a subjects withdrawal from study participation. (Whether 
such subjects should be included in the study analysis is a separate question.) 
 
To avoid confusion over terminology, sponsors are encouraged to replace the phrase 
protocol violation in Annex IVa with protocol deviation, as shown in the example 
flowchart below. Sponsors can also choose to use another descriptor, provided that the 
information presented is generally consistent with  the definition of protocol violation  
provided above. 
 
The ICH E3 guidance provides examples of the types of deviations that are generally 
considered important protocol deviations and that should be described in section 10.2 and 
included in the listing in Appendix 16.2.2.  The definition of important  protocol 
deviations for a particular trial is determined in part by study design, the critical 
procedures, study data, subject protections described in the protocol, and the planned 
analyses of study data. In keeping with the flexibility of the guidance, sponsors can 
amend or add to the examples of important deviations provided in ICH E3 in 
consideration of a trials requirements.  Substantial additions or changes should be clearly 
described for the reviewer. 
 
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  Contains Nonbinding Recommendations  
EXAMPLE FLOWCHART 
 
DISPOSITION OF  PATIENTS
  
      N=1,724       
PATIENTS RECEIVING 
DOUBLE-BLINDED 
MEDICATION 
                           
                           
                 
N = 340  N =  N =  N =  N = 
REGIMEN A  REGIMEN B  REGIMEN C  REGIMEN D  REGIMEN E 
         
                           
                                                         
N  =  281    N =  59     N =    N =      N =     N =      N =     N =      N =     N =   
COMPLETED  WITHDRAWN  COMPLETED  WITHDRAWN COMPLETED  WITHDRAWN COMPLETED  WITHDRAWN COMPLETED  WITHDRAWN  
STUDY  STUDY  STUDY  STUDY  STUDY 
                                                         
ADVERSE EVENT  (20)    ADVERSE EVENT  (19)    ADVERSE EVENT  (26)    ADVERSE EVENT  (24)    ADVERSE EVENT  (42) 
UNSAT. RESPONSE   UNSAT. RESPONSE   UNSAT. RESPONSE   UNSAT. RESPONSE   UNSAT. RESPONSE  
EFFICACY (1)  EFFICACY (2)  EFFICACY (1)  EFFICACY (1)  EFFICACY (0) 
FAILURE TO RETURN (6)  FAILURE TO RETURN (8)  FAILURE TO RETURN (7)  FAILURE TO RETURN (6)  FAILURE TO RETURN (6) 
OTHER MED. EVENT (5)  OTHER MED. EVENT (8)  OTHER MED. EVENT (4)  OTHER MED. EVENT (8)  OTHER MED. EVENT (14)  
OTHER NONMED. EVENT (5)  OTHER NONMED. EVENT (4)  OTHER NONMED. EVENT (6)  OTHER NONMED. EVENT (7)  OTHER NONMED. EVENT (1) 
PROTOCOL DEVIATION (10)  PROTOCOL DEVIATION (10)  PROTOCOL DEVIATION (10)  PROTOCOL DEVIATION (6)  PROTOCOL DEVIATION (14) 
PATIENT REQUEST  (12)  PATIENT REQUEST  (10)  PATIENT REQUEST  (25)  PATIENT REQUEST  (27)  PATIENT REQUEST  (15) 
 
 
  8