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: 

Office of Communications 

Division of Drug Information 

Center for Drug Evaluation and Research 

Food and Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 

Silver Spring, MD 20993-0002 

E-mail: druginfo@fda.hhs.gov 

Fax: 301-847-8714 

(Tel) 301-796-3400 

http://www.fda.gov/cder/guidance/index.htm 

or 

Office of Communication, 

Outreach, and Development, HFM-40 

Center for Biologics Evaluation and Research 

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 

Guidance for Industry1

Integrated Summaries of Effectiveness and Safety: Location 

Within the Common Technical Document 

This guidance represents the Food and Drug Administration’s (FDA’s) 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 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s 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 ClinStat 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. 

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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 

2.5.5 Overview of Safety 

N/A Not a U.S. requirement, but 

recommended by ICH M4E 

2.7 Clinical Summary (~50 – 400 pages) 

2.7.3 Summary of Clinical Efficacy 

2.7.4 Summary of Clinical Safety 

21 CFR 314.50(c)(2)(viii) U.S. requirement for a 

clinical summary 

5.3 Clinical Study Reports 

5.3.5.3 Reports of Analyses of Data 

from More than One Study (Including 

Any Formal Integrated Analyses, MetaAnalyses, and Bridging Analyses) 

21 CFR 314.50(d)(5)(v) 

21 CFR 314.50(d)(5)(vi) 

Integrated Summary of 

Effectiveness 

Integrated Summary of 

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. 

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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. 

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Contains Nonbinding Recommendations 

7

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.