Guidance for Industry 
Integrated Summaries of Effectiveness 
and Safety:  Location Within the 
Common Technical Document 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
April 2009 
Procedural 
   
Guidance for Industry 
Integrated Summaries of Effectiveness 
and Safety:  Location Within the 
Common Technical Document 
 
 
 
Additional copies are available from: 
 
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Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD  20993-0002 
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(Tel) 301-796-3400 
http://www.fda.gov/cder/guidance/index.htm 
 
or 
 
Office of Communication,  
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Food and Drug Administration 
1401 Rockville Pike, Rockville, MD  20852-1448 
(Tel) 800-835-4709 or 301-827-1800 
http://www.fda.gov/cber/guidelines.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) 
 
April 2009 
Procedural 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  ISE- AND ISS-RELATED DIFFERENCES BETWEEN MODULE 2 AND 
MODULE 5 OF THE CTD AND eCTD.........................................................................2 
A.  Module 2:  Appropriate Location of Efficacy and Safety Overviews and Summaries............3 
B.  Module 5:  Appropriate Location of the ISE and ISS................................................................4 
C.  Exceptions.......................................................................................................................................4 
IV.  SPECIAL INSTRUCTIONS FOR THE eCTD FORMAT...........................................4 
V.  EXAMPLES OF NDA AND BLA SUBMISSIONS.......................................................4 
A.  Example 1:  Large ISS Placed in Module 5.................................................................................5 
B.  Example 2:  Small ISS Placed in Module 5..................................................................................5 
C.  Example 3:  Large ISS Placed in Module 2.................................................................................6 
D.  Example 4:  Small ISS Split Between Module 2 and Module 5.................................................7 
  Contains Nonbinding Recommendations 
1
Guidance for Industry  
Integrated Summaries of Effectiveness and Safety:  Location  
Within the Common Technical Document 
 
 
 
 
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  
 
This guidance is intended to clarify for industry where to include the integrated summary of 
effectiveness (ISE) and integrated summary of safety (ISS) when submitting applications in the 
common technical document (CTD) format.  The guidance applies to applicants submitting new 
drug applications (NDAs) or biologics license applications (BLAs) to the Food and Drug 
Administration (FDA) in the CTD or the electronic common technical document (eCTD) format.   
 
The word summary in the terms integrated summary of effectiveness and integrated summary of 
safety has caused confusion for companies submitting applications in the CTD format, as it 
suggests a reference to the abbreviated overview documents that are placed in Module 2 of an 
application in the CTD format.  However, the ISE and ISS are not summaries but rather detailed 
integrated analyses of all relevant data from the clinical study reports that belong in Module 5.2  
We consider the ISE and ISS critical components of the clinical efficacy and safety portions of a 
marketing or licensing application.  Therefore, the ISE and ISS are required in applications 
submitted to the FDA in accordance with the regulations for NDA submissions (21 CFR 
314.50(d)(5)(v) and 21 CFR 314.50(d)(5)(vi)(a), respectively).  Although there are no 
corresponding regulations requiring an ISE or ISS for BLA submissions, applicants are 
encouraged to provide these analyses.   
 
This guidance focuses on where to place ISE and ISS documents within the structure of the CTD 
or eCTD.  It does not outline in detail the content for the ISE and ISS.  The content will be 
addressed in separate guidances. 
                                                 
1 This guidance has been prepared by the Office of New Drugs in the Center for Drug Evaluation and Research 
(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug 
Administration.  
 
2 For more information, see http://www.fda.gov/cder/regulatory/ersr/ISS_ISE_clarification.htm. 
  1 Contains Nonbinding Recommendations 
 
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.  BACKGROUND 
 
In July 1988, the FDA published guidance on the Format and Content of the Clinical and 
Statistical Sections of an Application (Clin-Stat guidance).3  Sections II.G. and H. of the Clin-
Stat guidance describe an appropriate format for organizing the clinical and statistical sections of 
an application and presenting the clinical and statistical information and accompanying statistical 
documentation of a clinical trial.   
 
In 2001, the broad outline of the ISE and ISS, as described in the Clin-Stat guidance, was 
partially updated by the ICH guidance M4 Common Technical Document for the Registration of 
Pharmaceuticals for Human Use, which is published in four parts (i.e., general organization, 
quality, safety, and efficacy).  However, since the ISE and ISS are unique to the United States, 
their contents are not addressed in detail in M4E:  The CTD  Efficacy, which covers the 
Clinical Overview and Clinical Summary sections of Module 2 and the Clinical Study Reports in 
Module 5.  Specifically, ICH M4E does not specify the location of the full reports of the ISE and 
ISS.  Therefore, this guidance describes the appropriate location of the ISE and ISS in the CTD. 
 
 
III.  ISE- AND ISS-RELATED DIFFERENCES BETWEEN MODULE 2 AND 
MODULE 5 OF THE CTD AND eCTD 
 
The purpose of the CTD or eCTD is to provide a common organization for the contents of a 
marketing or licensing application.  In some cases, ICH guidance has led to substantial or 
complete harmonization of content areas such as the study report, but that is not the case for all 
parts of all applications.  Therefore, applications can still vary based on regional requirements or 
applicant preference, and applications using the CTD or eCTD format (Module 2 to Module 5) 
will not be identical for all ICH regions.   
 
The CTD/eCTD Module 2 contains several clinical sections that are summaries.  These sections 
include section 2.7.3, Summary of Clinical Efficacy, and section 2.7.4, Summary of Clinical 
Safety.  Generally, the Module 2 clinical summary sections (hereafter clinical summary sections) 
follow the outline of the ISE and ISS described in ICH M4E; however, they do not describe the 
needed level of detail for an ISE or an ISS.  In addition, these clinical summary sections are 
subject to space limitations in the eCTD of about 400 pages, whereas a typical ISS alone often 
can be substantially larger.   
 
                                                 
3 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the CDER 
guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 
  2 Contains Nonbinding Recommendations 
A common problem with the CTD-formatted applications is that applicants incorrectly assume 
that the clinical summary sections satisfy the regulatory requirement for the ISE and ISS.  This 
assumption can result in a determination by the FDA that an application is incomplete and may 
result in a refusal-to-file action for the application.4  Although the clinical summary sections 
should be considered the appropriate locations for the clinical summary portions of a marketing 
application submitted to the United States (as required under 21 CFR 314.50(c)(2)(viii)), as 
discussed in section III.A, the clinical summary sections should not be considered the 
appropriate location for the ISE or ISS, with rare exceptions.  The recommended appropriate 
location for the ISE or ISS is Module 5, as discussed in section III.B. 
 
Table 1 lists the CTD sections that contain summary and integrated discussions of efficacy and 
safety.  The listed sections are mapped to the corresponding U.S. regulations that apply to the 
content of those sections, where applicable.  Any questions about these matters should be 
discussed with the appropriate review division. 
 
Table 1:  ISE- and ISS-Related Sections with Corresponding Regulations 
CTD Section  U.S. Regulation  Comment 
2.5 Clinical Overview (~30 pages)     
2.5.4 Overview of Efficacy  N/A  Not a U.S. requirement, but 
2.5.5 Overview of Safety  recommended by ICH M4E 
2.7 Clinical Summary (~50  400 pages)     
2.7.3 Summary of Clinical Efficacy  21 CFR 314.50(c)(2)(viii)  U.S. requirement for a 
2.7.4 Summary of Clinical Safety  clinical summary 
5.3 Clinical Study Reports     
5.3.5.3 Reports of Analyses of Data  21 CFR 314.50(d)(5)(v)  Integrated Summary of 
from More than One Study (Including    Effectiveness 
Any Formal Integrated Analyses, Meta- 21 CFR 314.50(d)(5)(vi)  Integrated Summary of 
Analyses, and Bridging Analyses)  Safety 
 
A.  Module 2:  Appropriate Location of Efficacy and Safety Overviews and 
Summaries 
 
An overview of efficacy and safety results can be included in Module 2, sections 2.5.4, 
Overview of Efficacy, and 2.5.5, Overview of Safety.  Usually, these overviews should be brief 
but thorough discussions of the study design, effectiveness, and general safety results.  These 
overviews should contain mostly text with some tables and figures incorporated.   
 
More detailed summaries of efficacy and safety should be provided in Module 2, sections 2.7.3, 
Summary of Clinical Efficacy, and 2.7.4, Summary of Clinical Safety.  These summary 
documents should consist mostly of text, but with tables and figures incorporated as needed.  The 
clear intent of sections 2.7.3 and 2.7.4 is to provide data summaries, not a complete exposition.  
It is not necessary, or desirable, to provide all of the details appropriate to an ISE or ISS in these 
sections, as this would defeat the purpose of a summary.  Rather, sections 2.7.3 and 2.7.4 should 
contain summarized information derived from the full ISE and ISS (i.e., the highlights of the 
                                                 
4 For more information, refer to the CDER guidance for industry Refusal to File 
(http://www.fda.gov/cder/guidance.index.htm) and the CBER Standard Operating Procedure and Policy 8404 
Refusal to File Procedures for Biologic License Applications (http://www.fda.gov/cber/regsopp/regsopp.htm). 
  3 Contains Nonbinding Recommendations 
appropriate sections of each document as outlined in ICH M4E).  Only in unusual cases should 
the narrative parts of the full ISE or ISS and the summaries in sections 2.7.3 and 2.7.4 be the 
same (see section III.C.).  The ISE and ISS will be more extensive than the summaries and 
should include not only text and incorporated tables and figures, but additional appendices of 
tables, figures, and datasets as well.  
 
B.  Module 5:  Appropriate Location of the ISE and ISS 
 
In general, Module 5, specifically section 5.3.5.3, Reports of Analyses of Data from More than 
One Study (Including Any Formal Integrated Analyses, Meta-Analyses, and Bridging Analyses), 
is the appropriate location for the ISE and ISS.  This module is designed to contain more detailed 
in-depth analyses, and unlike Module 2, Module 5 has no space limitation.  Module 5 is the 
appropriate CTD section for analyses containing large appendices of tables, figures, and datasets 
typically found in an ISE and ISS. 
 
C.  Exceptions 
 
There may be situations in which sections 2.7.3, Summary of Clinical Efficacy, and 2.7.4, 
Summary of Clinical Safety, would be sufficiently detailed to serve as the narrative portion of 
the ISE and ISS, respectively, while still concise enough to meet the suggested size limitations 
for Module 2.  This situation is rare but can occur if the application is small and consists of a 
single study or a number of small studies.  In our experience, the narrative portion of the ISE 
often is more amenable for inclusion in Module 2 than is the ISS.  In such situations, the ISE and 
ISS can be split across Module 2 and Module 5, with the narrative portion located in section 
2.7.3 or 2.7.4 and the appendices of tables, figures, and datasets located in section 5.3.5.3.  If the 
ISE or ISS is split across modules in this way, it is critical to include a clear explanation of where 
the parts are located.  This explanation should be placed both in Module 2 (section 2.7.3 or 2.7.4) 
and in Module 5 (section 5.3.5.3). 
 
 
IV.  SPECIAL INSTRUCTIONS FOR THE eCTD FORMAT 
 
Because an increasing number of applications are being submitted electronically, it is important 
for review purposes that the location of information in an eCTD be consistent across 
applications.  Therefore, the ISE and ISS should be placed in Module 5, section 5.3.5.3, except 
as described above.  If the narrative portion of the ISE or ISS is suitable for use in section 2.7.3 
or 2.7.4, the narrative portion should be submitted only once and referenced in both Module 2 
(section 2.7.3 or 2.7.4) and Module 5, section 5.3.5.3 (i.e., provide leaf elements in both 
locations).  
 
 
V.  EXAMPLES OF NDA AND BLA SUBMISSIONS 
 
The following examples describe real-life scenarios of NDA and BLA submissions and where 
the ISE and ISS information should be located appropriately in the CTD. 
 
  4 Contains Nonbinding Recommendations 
A.  Example 1:  Large ISS Placed in Module 5 
 
An applicant submits a BLA or BLA supplement with an ISS consisting of 1,000 pages of text 
(with incorporated tables and figures), 3,000 pages of appendices of supporting tables and 
figures, and 4 gigabytes (GB) of datasets used in the integrated safety analyses.  The full ISS is 
placed in Module 5 (section 5.3.5.3).  The text portion is summarized in a smaller 100-page 
document and placed in Module 2 (section 2.7.4) as the Summary of Clinical Safety.  Figure 1 
illustrates this example. 
 
Figure 1 
 
 
This submission is acceptable.  The ISS is appropriately located in section 5.3.5.3.  The text 
portion is too large for Module 2 and is appropriately summarized for section 2.7.4.  
 
B.  Example 2:  Small ISS Placed in Module 5 
 
An applicant submits an NDA for an orphan drug.  The ISS contains 100 pages of text (with 
incorporated tables and figures), 1,000 pages of appendices of supporting tables and figures, and 
1 GB of datasets used in the integrated safety analyses.  The full ISS is placed in Module 5 
(section 5.3.5.3).  The text portion of the ISS is repeated in Module 2 (section 2.7.4) as the 
Summary of Clinical Safety.  Figure 2 illustrates this example. 
 
  5 Contains Nonbinding Recommendations 
Figure 2 
 
 
This submission is acceptable.  The ISS is small so the text portion can also serve as the 
Summary of Clinical Safety in Module 2.   
 
C.  Example 3:  Large ISS Placed in Module 2 
 
An applicant submits an NDA for a new molecular entity.  The ISS contains 1,000 pages of text 
(with incorporated tables and figures), 3,000 pages of appendices of supporting tables and 
figures, and 4 GB of datasets.  All are placed in Module 2, section 2.7.4.  Nothing is placed in 
Module 5 (section 5.3.5.3).  Figure 3 illustrates this example. 
 
Figure 3 
 
 
This submission is unacceptable.  Although the application contains an ISS, it is inappropriately 
placed in Module 2 and exceeds the suggested size limitation for section 2.7.4.  The application 
does not contain a true clinical summary, which could result in a refusal-to-file action.  
 
  6 Contains Nonbinding Recommendations 
D.  Example 4:  Small ISS Split Between Module 2 and Module 5 
 
An applicant submits an NDA supplement.  The ISS contains 100 pages of text (with 
incorporated tables and figures), 1,000 pages of appendices of supporting tables and figures, and 
1 GB of datasets used in the integrated safety analyses.  The ISS is split: the text portion is 
placed in Module 2 (section 2.7.4), and the appendices and datasets are placed in Module 5 
(section 5.3.5.3).  Section 2.7.4 refers the reader to section 5.3.5.3 for the appendices and 
datasets.  Section 5.3.5.3 refers the reader to section 2.7.4 for the text portion of the ISS.  Figure 
4 illustrates this example. 
 
Figure 4 
 
 
This submission is acceptable.  The ISS is small, allowing the text portion of the ISS to also 
function as the Summary of Clinical Safety in Module 2.  Each section of the split ISS refers the 
reader to the appropriate section where the remainder of the ISS is located.  
 
  7