Integrated Summaries of Effectiveness and Safety: Location Within the Common Technical Document

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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
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Outreach, and Development, HFM-40
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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
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.
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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 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.
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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, Meta-
Analyses, 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).
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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.
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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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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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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.