Guidance for Industry

M4E: The CTD — Efficacy

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 2001

ICH
Guidance for Industry

M4E: The CTD — Efficacy

Copies of this Guidance are available from:

Office of Training and Communications

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

 5600 Fishers Lane, Rockville, MD 20857

(Phone 301-827-4573)

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

or

 Office of Communication, Training and

Manufacturers Assistance, HFM-40

Center for Biologics Evaluation and Research

 Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

Internet: http://www.fda.gov/cber/guidelines.htm. 

Fax: 1-888-CBERFAX or 301-827-3844

Mail: the Voice Information System at 800-835-4709 or 301-827-1800.

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 2001

ICH
i

Table of Contents

BACKGROUND............................................................................................................................ 2

The CTD .......................................................................................................................................2

Preparing and Organizing the CTD ...............................................................................................2

Organization and Format of the ICH Guidances for Industry .......................................................7

Numbering ....................................................................................................................................7

MODULE 2: ORGANIZATION AND CONTENT OF THE CLINICAL OVERVIEW......... 8

Preamble.......................................................................................................................................8

Guidances Referenced ...................................................................................................................9

Table of Contents..........................................................................................................................9

Detailed Discussion of Content of the Clinical Overview Sections ...............................................10

2.5 CLINICAL OVERVIEW..................................................................................................... 10

2.5.1 PRODUCT DEVELOPMENT RATIONALE................................................................. 10

2.5.2 OVERVIEW OF BIOPHARMACEUTICS ..................................................................... 10

2.5.3 OVERVIEW OF CLINICAL PHARMACOLOGY........................................................ 10

2.5.4 OVERVIEW OF EFFICACY............................................................................................ 11

2.5.5 OVERVIEW OF SAFETY................................................................................................ 12

2.5.6 BENEFITS AND RISKS CONCLUSIONS...................................................................... 14

2.5.7 REFERENCES................................................................................................................... 15

MODULE 2: ORGANIZATION AND CONTENT OF THE CLINICAL SUMMARY........ 16

Preamble.....................................................................................................................................16

Table of Contents........................................................................................................................16

Detailed Guidance on Sections of the Clinical Summary .............................................................17

2.7 CLINICAL SUMMARY....................................................................................................... 17

2.7.1 SUMMARY OF BIOPHARMACEUTIC STUDIES AND ASSOCIATED

ANALYTICAL METHODS........................................................................................................ 17

2.7.1.1 Background and Overview..............................................................................................17

2.7.1.2 Summary of Results of Individual Studies.......................................................................17

2.7.1.3 Comparison and Analyses of Results Across Studies.......................................................17

2.7.1.4 Appendix .........................................................................................................................18
ii

2.7.2 SUMMARY OF CLINICAL PHARMACOLOGY STUDIES...................................... 18

2.7.2.1 Background and Overview..............................................................................................18

2.7.2.2 Summary of Results of Individual Studies.......................................................................19

2.7.2.3 Comparison and Analyses of Results Across Studies.......................................................19

2.7.2.4 Special Studies................................................................................................................20

2.7.2.5 Appendix .........................................................................................................................21

2.7.3 SUMMARY OF CLINICAL EFFICACY....................................................................... 22

2.7.3.1 Background and Overview of Clinical Efficacy................................................................22

2.7.3.2 Summary of Results of Individual Studies.......................................................................23

2.7.3.3 Comparison and Analyses of Results Across Studies.......................................................23

2.7.3.3.1 Study Populations......................................................................................................23

2.7.3.2.2 Comparison of Efficacy Results of all Studies..............................................................24

2.7.3.3.3 Comparison of Results in Subpopulations....................................................................25

2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations.........................25

2.7.3.5 Persistence of Efficacy and/or Tolerance Effects..............................................................26

2.7.3.6 Appendix .........................................................................................................................26

2.7.4 SUMMARY OF CLINICAL SAFETY............................................................................ 27

2.7.4.1 Exposure to the Drug ......................................................................................................27

2.7.4.1.1 Overall Safety Evaluation Plan and Narratives of Safety Studies...................................27

2.7.4.1.2 Overall Extent of Exposure .........................................................................................28

2.7.4.1.3 Demographic and Other Characteristics of Study Population ........................................28

2.7.4.2 Adverse Events................................................................................................................29

2.7.4.2.1 Analysis of Adverse Events........................................................................................29

2.7.4.2.2 Narratives................................................................................................................34

2.7.4.3 Clinical Laboratory Evaluations .....................................................................................34

2.7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety.......................35

2.7.4.5 Safety in Special Groups and Situations..........................................................................35

2.7.4.5.1 Intrinsic Factors........................................................................................................35

2.7.4.5.2 Extrinsic Factors.......................................................................................................35

2.7.4.5.3 Drug Interactions .......................................................................................................35

2.7.4.5.4 Use in Pregnancy and Lactation.................................................................................36

2.7.4.5.5 Overdose...................................................................................................................36

2.7.4.5.6 Drug Abuse ...............................................................................................................36

2.7.4.5.7 Withdrawal and Rebound ...........................................................................................36

2.7.4.5.8 Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability ........36

2.7.4.6 Postmarketing Data ........................................................................................................36

2.7.4.7 Appendix .........................................................................................................................37

2.7.5 REFERENCES................................................................................................................. 37

2.7.6 SYNOPSES OF INDIVIDUAL STUDIES...................................................................... 38
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MODULE 5: CLINICAL STUDY REPORTS.......................................................................... 50

Preamble.....................................................................................................................................50

Detailed Organization of Clinical Study Reports and Related Information in Module 5..............50

5.1 TABLE OF CONTENTS FOR STUDY REPORTS AND RELATED INFO.................. 50

5.2 TABULAR LISTING OF ALL CLINICAL STUDIES..................................................... 51

5.3 CLINICAL STUDY REPORTS.......................................................................................... 51

5.3.1 Reports of Biopharmaceutic Studies..................................................................................51

5.3.1.1 Bioavailability (BA) Study Reports................................................................................51

5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports................................................52

5.3.1.3 In Vitro – In Vivo Correlation Study Reports..................................................................52

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies ...............................52

5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials...................52

5.3.2.1 Plasma Protein Binding Study Reports............................................................................52

5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies..........................................53

5.3.2.3 Reports of Studies Using Other Human Biomaterials......................................................53

5.3.3 Reports of Human Pharmacokinetic (PK) Studies .............................................................53

5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports..............................................54

5.3.3.2 Patient PK and Initial Tolerability Study Reports..........................................................54

5.3.3.3 Intrinsic Factor PK Study Reports................................................................................54

5.3.3.4 Extrinsic Factor PK Study Reports ...............................................................................54

5.3.3.5 Population PK Study Reports ........................................................................................54

5.3.4 Reports of Human Pharmacodynamic (PD) Studies...........................................................54

5.3.4.1 Healthy Subject PD and PK/PD Study Reports................................................................55

5.3.4.2 Patient PD and PK/PD Study Reports............................................................................55

5.3.5 Reports of Efficacy and Safety Studies...............................................................................55

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication............55

5.3.5.2 Study Reports of Uncontrolled Clinical Studies...............................................................56

5.3.5.3 Reports of Analyses of Data from More than One Study (Including Any Formal Integrated

Analyses, Meta-Analyses, and Bridging Analyses).......................................................................56

5.3.5.4 Other Study Reports......................................................................................................56

5.3.6 Reports of Postmarketing Experience ................................................................................57

5.3.7 Case Report Forms and Individual Patient Listings...........................................................57

5.4 LITERATURE REFERENCES........................................................................................... 57
1

Guidance for Industry1

M4E: The CTD — Efficacy

INTRODUCTION

This is one in a series of guidances that provide recommendations for applicants preparing the

Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) for

submission to the U.S. Food and Drug Administration (FDA). This guidance presents the agreed

upon common format for the preparation of a well-structured Efficacy section of the CTD for

applications that will be submitted to regulatory authorities. A common format for the technical

documentation will significantly reduce the time and resources needed to compile applications for

registration of human pharmaceuticals and will ease the preparation of electronic submissions. 

Regulatory reviews and communication with the applicant will be facilitated by a standard

document of common elements. In addition, exchange of regulatory information between

regulatory authorities will be simplified.

For information on the Quality and Safety sections of the CTD, see the individual guidances for

industry that discuss those parts of the CTD. For general information about the CTD, as well as

specific information about Module 1 (regional administrative information), see the Agency's

guidance for industry, General Considerations for Submitting Applications According to the

 

1 This guidance was developed within the Expert Working Group (Efficacy) 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 was endorsed by the ICH Steering Committee at Step 4

of the ICH process, November 9, 2000. 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.

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.

 An alternative approach may be used if such approach satisfies the requirements of the applicable

statutes and regulations.
2

ICH/CTD Format (General Considerations guidance).

2

 The CTD guidances are intended to be

used together with other ICH and Agency guidances. Please refer to those guidances for detailed

information about the contents of an application.

BACKGROUND

The CTD

Through the ICH process, considerable harmonization has been achieved among the three regions

(Japan, Europe, and the United States) in the technical requirements for the registration of

pharmaceuticals for human use. However, until now, there has been no harmonization of the

organization of a submission. Each region has its own requirements for the organization of the

technical reports in the submission and for the preparation of the summaries and tables. In Japan,

the applicants must prepare the GAIYO, which organizes and presents a summary of the technical

information. In Europe, expert reports and tabulated summaries are required, and written

summaries are recommended. The U.S. FDA has guidance regarding the format and content of the

new drug application submission. To avoid the need to generate and compile different registration

dossiers, this guidance describes a format for the Efficacy section of the CTD that will be

acceptable in all three regions.

Preparing and Organizing the CTD

This guidance primarily addresses the organization of the information to be presented in the

Efficacy section of an application for new pharmaceuticals (including biotechnology-derived

products). Guidances also are available that discuss the Quality and Safety sections of the CTD.

These guidances are not intended to indicate what studies are required. The guidances merely

indicate an appropriate format for the data that have been acquired. Applicants should not modify

the overall organization of the CTD. However, in the Nonclinical and Clinical Summaries

sections of the CTD, applicants can modify individual formats, if needed, to provide the best

possible presentation of the technical information to facilitate the understanding and evaluation of

the results.

Throughout the CTD, the display of information should be unambiguous and transparent, to

facilitate the review of the basic data and to help a reviewer become quickly oriented to the

application contents. Text and tables should be prepared using margins that allow the document to

be printed on both A4 paper (E.U. and Japan) and 8.5 x 11” paper (U.S.). The left-hand margin

should be sufficiently large that information is not obscured through binding. Font sizes for text

and tables should be of a style and size that are large enough to be easily legible, even after

photocopying. Times New Roman, 12-point font is recommended for narrative text. Acronyms

and abbreviations should be defined the first time they are used in each module. References

should be cited in accordance with the current edition of the Uniform Requirements for

 

2

 A draft version of the General Considerations guidance is currently available. Once it has been finalized, it will represent the

Agency's thinking on this topic.
3

Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal

Editors (ICMJE).3

The CTD should be organized into five modules. Module 1 is region specific. Modules 2, 3, 4,

and 5 are intended to be common for all regions. Conformance with the CTD guidances should

help ensure that these four modules are provided in a format acceptable to the regulatory

authorities (see the figure and overall outline on the following pages).

Module 1. Administrative Information and Prescribing Information

This module should contain documents specific to each region; for example, application

forms or the proposed label for use in the region. The content and format of this module

can be specified by the relevant regulatory authorities. For information about this module

see the General Considerations guidance.

Module 2. Common Technical Document Summaries

Module 2 should begin with a general introduction to the pharmaceutical, including its

pharmacologic class, mode of action, and proposed clinical use. In general, the

Introduction should not exceed one page.

Module 2 should contain 7 sections in the following order:

• CTD Table of Contents

• CTD Introduction

• Quality Overall Summary

• Nonclinical Overview

• Clinical Overview

• Nonclinical Written and Tabulated Summaries

• Clinical Summary. 

The individual organization of these summaries is described in three separate documents:

• M4Q: The CTD — Quality

• M4S: The CTD — Safety

• M4E: The CTD — Efficacy.

Module 3. Quality

Information on Quality should be presented in the structured format described in the

guidance M4Q.

Module 4. Nonclinical Study Reports

The Nonclinical Study Reports should be presented in the order described in the guidance

M4S.

 

3

 The first edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals was conceived by the

Vancouver Group and was published in 1979.
4

Module 5. Clinical Study Reports

The human study reports and related information should be presented in the order

described in the guidance M4E.
5

Module 1

Regional

Administrative

Information

1

1.1 Submission

T of C

Quality

Overall

Summary

2.3

Nonclinical

Overview

2.4

Clinical

Overview

2.5

Nonclinical

Written and

Tabulated

Summaries

2.6

Clinical

Summary

2.7

Module 3

Quality

3

3.1 T of C

Module 4

Nonclinical

Study Reports

4

4.1 T of C

Module 5

Clinical

Study Reports

5

5.1 T of C

Module 2

Not Part of

the CTD

CTD

CTD Table of Contents

2.1

CTD Introduction

2.2

Diagrammatic Representation of the ICH Common Technical

Document
6

 The CTD should be organized according to the following general outline.

Module 1: Administrative Information and Prescribing Information

1.1 Table of Contents of the Submission Including Module 1

1.2 Documents Specific to Each Region (for example, application forms, prescribing

information)

Module 2: Common Technical Document Summaries

2.1 CTD Table of Contents

2.2 CTD Introduction

2.3 Quality Overall Summary

2.4 Nonclinical Overview

2.5 Clinical Overview

2.6 Nonclinical Written and Tabulated Summary

Pharmacology

Pharmacokinetics

Toxicology

2.7 Clinical Summary

Biopharmaceutics and Associated Analytical Methods

Clinical Pharmacology Studies

Clinical Efficacy

Clinical Safety

Synopses of Individual Studies

Module 3: Quality

3.1 Module 3 Table of Contents

3.2 Body of Data

3.3 Literature References

Module 4: Nonclinical Study Reports

4.1 Module 4 Table of Contents

4.2 Study Reports

4.3 Literature References

Module 5: Clinical Study Reports

5.1 Module 5 Table of Contents

5.2 Tabular Listing of All Clinical Studies

5.3 Clinical Study Reports

5.4 Literature References
7

Organization and Format of the ICH Guidances for Industry

Although the CTD is organized by modules, the guidances for industry that provide

recommendations for applicants on preparing the CTD have been organized by topic. As a result,

guidance discussing Module 2 is divided among the three guidances.

• Guidance on the Quality section of the CTD (Module 2, Quality Overall Summary (QOS),

and Module 3) can be found in the guidance for industry M4Q: The CTD — Quality.

• Guidance on the Safety section of the CTD (Module 2, the Nonclinical Overview and the

Nonclinical Written and Tabulated Summaries, and Module 4) can be found in the guidance

for industry M4S: The CTD — Safety

• Guidance on the Efficacy section of the CTD (Module 2, the Clinical Overview and the

Clinical Summary, and Module 5) can be found in the guidance for industry M4E: The

CTD — Efficacy. 

Numbering

In the guidances for industry on the Quality, Safety, and Efficacy sections of the CTD, Arabic

numbers have been assigned to designate those specific sections that should be included in the

CTD. The Arabic numbers used in the guidances also should be used when assembling the CTD

for submission. For specific information on numbering the pages and volumes of the submission,

see the guidance for industry, General Considerations for Submitting Marketing Applications

According to the ICH/CTD Format. Sections in the guidance documents that are not numbered

provide guidance on how to prepare those sections. In this guidance for industry, sections that

should be included in Module 2 and Module 5 of the CTD have been numbered using the Arabic

numbers 2 and 5, respectively.

It is possible that information for more than one indication will be submitted. In such cases, please

continue the use of Arabic numbers by repeating the specific section’s numbering, making it clear

that the data are for an additional indication. For example, if more than one indication is

submitted, repeat section 2.7.3, including the name of the indication

(e.g., 2.7.3 pneumonia, 2.7.3 URI). The same approach should be used in the Quality section of the

application for additional drug substances (2.3.S) and drug products (2.3.P).
8

MODULE 2: ORGANIZATION AND CONTENT OF THE CLINICAL OVERVIEW

Preamble

The Clinical Overview is intended to provide a critical analysis of the clinical data in the

Common Technical Document (CTD). The Clinical Overview will refer to application data

provided in the comprehensive Clinical Summary, the individual clinical study reports (ICH E3),

and other relevant reports; but it should primarily present the conclusions and implications of those

data and should not recapitulate them. Specifically, the Clinical Summary should provide a

detailed factual summarization of the clinical information in the CTD, and the Clinical Overview

should provide a succinct discussion and interpretation of these findings together with any other

relevant information (e.g., pertinent animal data or product quality issues that may have clinical

implications).

The Clinical Overview is primarily intended for use by regulatory agencies in the review of the

clinical section of a marketing application. It should also be a useful reference to the overall

clinical findings for regulatory agency staff involved in the review of other sections of the

marketing application. The Clinical Overview should (1) present the strengths and limitations of

the development program and study results, (2) analyze the benefits and risks of the medicinal

product in its intended use, and (3) describe how the study results support critical parts of the

prescribing information.

To achieve these objectives, the Clinical Overview should do the following.

• Describe and explain the overall approach to the clinical development of a medicinal product,

including critical study design decisions

• Assess the quality of the design and performance of the studies and include a statement

regarding good clinical practice (GCP) compliance

• Provide a brief overview of the clinical findings, including important limitations (e.g., lack of

comparisons with an especially relevant active comparator; absence of information on some

patient populations, on pertinent endpoints, or on use in combination therapy)

• Provide an evaluation of benefits and risks based on the conclusions of the relevant clinical

studies, including interpretation of how the efficacy and safety findings support the proposed

dose and target indication and an evaluation of how prescribing information and other

approaches will optimize benefits and manage risks

• Address particular efficacy or safety issues encountered in development and how they have

been evaluated and resolved

• Explore unresolved issues, explain why they should not be considered barriers to approval,

and describe plans to resolve them

• Explain the basis for important or unusual aspects of the prescribing information
9

The Clinical Overview should be a relatively short document (about 30 pages). The length,

however, will depend on the complexity of the application. The use of graphs and concise tables

in the body of the text is encouraged for brevity and to facilitate understanding. It is not intended

that material presented fully elsewhere be repeated in the Clinical Overview; cross-referencing to

more detailed presentations provided in the Clinical Summary or in Module 5 is encouraged.

Guidances Referenced

The following ICH guidances referenced in M4E – Efficacy are referred to by ICH topic

designation in the text.

E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for

Long-Term Treatment of Non-Life-Threatening Conditions (March 1995)

E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

(March 1995)

E3 Structure and Content of Clinical Study Reports (July 1996)

E4 Dose-Response Information to Support Drug Registration (November 1994)

E5 Ethnic Factors in the Acceptability of Foreign Clinical Data (June 1998)

E7 Studies in Support of Special Populations: Geriatrics (August 1994)

E9 Statistical Principles for Clinical Trials (September 1998)

E10 Choice of Control Group and Related Issues in Clinical Trials (May 2000)

E11 Clinical Investigation of Medicinal Products in the Pediatric Population (December

2000)

Table of Contents

We recommend that the Clinical Overview section contain a table of contents as shown here.

2.5.1 Product Development Rationale

2.5.2 Overview of Biopharmaceutics

2.5.3 Overview of Clinical Pharmacology

2.5.4 Overview of Efficacy

2.5.5 Overview of Safety

2.5.6 Benefits and Risks Conclusions

2.5.7 References
10

Detailed Discussion of Content of the Clinical Overview Sections

2.5 CLINICAL OVERVIEW

 2.5.1 PRODUCT DEVELOPMENT RATIONALE

The discussion of the rationale for the development of the medicinal product should:

• Identify the pharmacological class of the medicinal product

• Describe the particular clinical/pathophysiological condition that the medicinal product is

intended to treat, prevent, or diagnose (the targeted indication)

• Briefly summarize the scientific background that supported the investigation of the medicinal

product for the indications that were studied

• Briefly describe the clinical development program of the medicinal product, including ongoing

and planned clinical studies and the basis for the decision to submit the application at this

point in the program. Briefly describe plans for the use of foreign clinical data (ICH E5).

• Note and explain concordance or lack of concordance with current standard research

approaches regarding the design, conduct, and analysis of the studies. Pertinent published

literature should be referenced. Regulatory guidance and advice (at least from the region or

regions where the Clinical Overview is being submitted) should be identified, with discussion

of how that advice was implemented. Formal advice documents (e.g., official meeting

minutes, official guidance, letters from regulatory authorities) should be referenced, with

copies included in the references section of Module 5.

2.5.2 OVERVIEW OF BIOPHARMACEUTICS

The purpose of this section is to present a critical analysis of any important issues related to

bioavailability that might affect efficacy and/or safety of the to-be-marketed formulations (e.g.,

dosage form/strength proportionality, differences between the to-be-marketed formulation and the

formulations used in clinical trials, and influence of food on exposure).

2.5.3 OVERVIEW OF CLINICAL PHARMACOLOGY

The purpose of this section is to present a critical analysis of the pharmacokinetic (PK),

pharmacodynamic (PD), and related in vitro data in the CTD. The analysis should consider all

relevant data and explain why and how the data support the conclusions drawn. The analysis

should emphasize unusual results and known or potential problems, or note the lack thereof. This

section should address:
11

Pharmacokinetics (examples)

• Comparative PK in healthy subjects, patients, and special populations

• PK related to intrinsic factors (e.g., age, sex, race, renal and hepatic impairment) and to

extrinsic factors (e.g., smoking, concomitant drugs, diet)

• Rate and extent of absorption; distribution, including binding with plasma proteins

• Specific metabolic pathways, including effects of possible genetic polymorphism and the

formation of active and inactive metabolites

• Excretion

• Time-dependent changes in pharmacokinetics

• Stereochemistry issues

• Clinically relevant PK interactions with other medicinal products or other substances

Pharmacodynamics (examples)

• Information on mechanism of action, such as receptor binding

• Onset and/or offset of action; relationship of favorable and unfavorable pharmacodynamic

effects to dose or plasma concentration (i.e., PK/PD relationships)

• PD support for the proposed dose and dosing interval

• Clinically relevant PD interactions with other medicinal products or substances

• Possible genetic differences in response.

This section should also address interpretation of the results and implications of immunogenicity

studies, clinical microbiology studies, or other drug class specific PD studies summarized in

section 2.7.2.4 of the Clinical Summary.

2.5.4 OVERVIEW OF EFFICACY

The purpose of this section is to present a critical analysis of the clinical data pertinent to the

efficacy of the medicinal product in the intended population. The analysis should consider all

relevant data, whether positive or negative, and should explain why and how the data support the

proposed indication and prescribing information. Those studies deemed relevant for evaluation of

efficacy should be identified, and reasons that any apparently adequate and well-controlled studies

are not considered relevant should be provided. Prematurely terminated studies should be noted

and their impact considered.

The following issues should generally be considered:

• Relevant features of the patient populations, including demographic features, disease stage, any

other potentially important covariates, any important patient populations excluded from critical

studies, and participation of children and elderly (ICH E11 and E7). Differences between the

studied populations and the population that would be expected to receive the medicinal

product after marketing should be discussed.

• Implications of the study designs, including selection of patients, duration of studies and choice

of endpoints and control groups. Particular attention should be given to endpoints for which
12

there is limited experience. Use of surrogate endpoints should be justified. Validation of any

scales used should be discussed. 

• For noninferiority trials used to demonstrate efficacy, the evidence supporting a determination

that the trial had assay sensitivity and justifying the choice of noninferiority margin (ICH E10)

• Statistical methods and any issues that could affect the interpretation of the study results (e.g.,

important modifications to the study design, including endpoint assessments and planned

analyses, as they were specified in the original protocol; support for any unplanned analyses;

procedures for handling missing data; and corrections for multiple endpoints)

• Similarities and differences in results among studies, or in different patient subgroups within

studies, and their effect on the interpretation of the efficacy data

• Observed relationships between efficacy, dose, and dosage regimen for each indication in both

the overall population and in the different patient subgroups (ICH E4)

• Support for the applicability to the new region of data generated in another region, where

appropriate (ICH E5)

• For products intended for long-term use, efficacy findings pertinent to the maintenance of longterm efficacy and the establishment of long-term dosage. Development of tolerance should be

considered.

• Data suggesting that treatment results can be improved through plasma concentration

monitoring, if any, and documentation for an optimal plasma concentration range

• The clinical relevance of the magnitude of the observed effects

• If surrogate endpoints are relied on, the nature and magnitude of expected clinical benefit and

the basis for these expectations

• Efficacy in special populations. If efficacy is claimed with inadequate clinical data in the

population, support should be provided for extrapolating efficacy from effects in the general

population.

2.5.5 OVERVIEW OF SAFETY

The purpose of this section is to provide a concise critical analysis of the safety data, noting how

results support and justify proposed prescribing information. A critical analysis of safety should

consider:

• Adverse effects characteristic of the pharmacological class. Approaches taken to monitor for

similar effects should be described.
13

• Special approaches to monitoring for particular adverse events (e.g., ophthalmic, QT interval

prolongation)

• Relevant animal toxicology and product quality information. Findings that affect or could

affect the evaluation of safety in clinical use should be considered.

• The nature of the patient population and the extent of exposure, both for test drug and control

treatments. Limitations of the safety database (e.g., related to inclusion/exclusion criteria and

study subject demographics) should be considered, and the implications of such limitations

with respect to predicting the safety of the product in the marketplace should be explicitly

discussed.

• Common and nonserious adverse events, with reference to the tabular presentations of events

with the test drug and with control agents in the Clinical Summary. The discussion should be

brief, focusing on events of relatively high frequency, those with an incidence higher than

placebo, and those that are known to occur in active controls or other members of the

therapeutic class. Events that are substantially more or less common or problematic

(considering the duration and degree of the observed events) with the test drug than with active

controls are of particular interest.

• Serious adverse events (relevant tabulations should be cross-referenced from the Clinical

Summary). This section should discuss the absolute number and frequency of serious adverse

events, including deaths, and other significant adverse events (e.g., events leading to

discontinuation or dose modification) and should discuss the results obtained for test drug

versus control treatments. Any conclusions regarding causal relationship (or lack of this) to

the product should be provided. Laboratory findings reflecting actual or possible serious

medical effects should be considered.

• Similarities and differences in results among studies and their effect on the interpretation of the

safety data

• Any differences in rates of adverse events in population subgroups, such as those defined by

demographic factors, weight, concomitant illness, concomitant therapy, or polymorphic

metabolism

• Relation of adverse events to dose, dose regimen, and treatment duration

• Long-term safety (E1A)

• Methods to prevent, mitigate, or manage adverse events

• Reactions due to overdose; the potential for dependence, rebound phenomena, and abuse, or

lack of data on these issues

• World-wide marketing experience. The following should be briefly discussed:
14

— The extent of the world-wide experience

— Any new or different safety issues identified

— Any regulatory actions related to safety

• Support for the applicability to the new region of data generated in another region, where

appropriate (ICH E5)

2.5.6 BENEFITS AND RISKS CONCLUSIONS

The purpose of this section is to integrate all of the conclusions reached in the previous sections

about the biopharmaceutics, clinical pharmacology, efficacy, and safety of the medicinal product

and to provide an overall appraisal of the benefits and risks of its use in clinical practice. Also,

implications of any deviations from regulatory advice or guidance and any important limitations of

the available data should be discussed here. This assessment should address critical aspects of

the proposed prescribing information. This section should also (1) consider the risks and benefits

of the medicinal product as they compare to available alternative treatments or to no treatment in

illnesses where no treatment may be a medically acceptable option and (2) clarify the expected

place of the medicinal product in the armamentarium of treatments for the proposed indication. If

there are risks to individuals other than those who will receive the drug, these risks should be

discussed (e.g., risks of emergence of drug-resistant bacterial strains with widespread use of an

antibiotic for minor illnesses). The analyses provided in previous sections should not be

reiterated here. This section often can be quite abbreviated when no special concerns have arisen

and the drug is a member of a familiar pharmacological class.

This analysis of benefits and risks is generally expected to be very brief but it should identify the

most important conclusions and issues concerning each of the following points:

• The efficacy of the medicinal product for each proposed indication

• Significant safety findings and any measures that may enhance safety

• Dose-response and dose-toxicity relationships; optimal dose ranges and dosage regimens

• Efficacy and safety in subpopulations (e.g., those defined by age, sex, ethnicity, organ function,

disease severity, and genetic polymorphisms)

• Data in children in different age groups, if applicable, and any plans for a development

program in children

• Any risks to the patient of known and potential interactions, including food-drug and drug-drug

interactions, and recommendations for product use
15

• Any potential effect of the medicinal product that might affect ability to drive or operate heavy

machinery

Examples of issues and concerns that could warrant a more detailed discussion of benefits and

risks might include:

• The drug is for treatment of a nonfatal disease but has known or potential serious toxicity, such

as a strong signal of carcinogenicity, teratogenicity, pro-arrhythmic potential (effect on QT

interval), or suggestion of hepatotoxicity.

• The proposed use is based on a surrogate endpoint and there is a well-documented important

toxicity.

• Safe and/or effective use of the drug calls for potentially difficult selection or management

approaches that involve special physician expertise or patient training.

2.5.7 REFERENCES

A list of references used, stated in accordance with the International Committee of Medical

Journal Editors’ Uniform Requirements for Manuscripts Submitted to Biomedical Journals or

the system used in Chemical Abstracts, should be provided. Copies of all references cited in the

Clinical Overview should be provided in Section 5.4 of Module 5.
16

MODULE 2: ORGANIZATION AND CONTENT OF THE CLINICAL SUMMARY

Preamble

The Clinical Summary is intended to provide a detailed, factual summarization of all of the

clinical information in the CTD. This includes information provided in ICH E3 clinical study

reports; information obtained from any meta-analyses or other cross-study analyses for which full

reports have been included in Module 5; and postmarketing data for products that have been

marketed in other regions. The comparisons and analyses of results across studies provided in this

document should focus on factual observations. (In contrast, the CTD Clinical Overview

document should provide critical analysis of the clinical study program and its results, including

discussion and interpretation of the clinical findings and discussion of the place of the test drug in

the armamentarium.)

The length of the Clinical Summary will vary substantially according to the information to be

conveyed, but it is anticipated that (excluding attached tables) the length will usually range from 50

to 400 pages.

Table of Contents

We recommend that the Clinical Summary section contain a table of contents as shown here.

2.7.1 SUMMARY OF BIOPHARMACEUTIC STUDIES AND ASSOCIATED ANALYTICAL

METHODS

2.7.1.1 Background and Overview

2.7.1.2 Summary of Results of Individual Studies

2.7.1.3 Comparison and Analyses of Results Across Studies

2.7.2 SUMMARY OF CLINICAL PHARMACOLOGY STUDIES

2.7.2.1 Background and Overview

2.7.2.2 Summary of Results of Individual Studies

2.7.2.3 Comparison and Analyses of Results Across Studies

2.7.2.4 Special Studies

2.7.3 SUMMARY OF CLINICAL EFFICACY

2.7.3.1 Background and Overview

2.7.3.2 Summary of Results of Individual Studies

2.7.3.3 Comparison and Analyses of Results Across Studies

2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations

2.7.3.5 Persistence of Efficacy and/or Tolerance Effects

2.7.4 SUMMARY OF CLINICAL SAFETY

2.7.4.1 Exposure to the Drug

2.7.4.2 Adverse Events

2.7.4.3 Clinical Laboratory Evaluations

2.7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety

2.7.4.5 Safety in Special Groups and Situations

2.7.4.6 Postmarketing Data

2.7.5 REFERENCES
17

2.7.6 SYNOPSES OF INDIVIDUAL STUDIES

Detailed Guidance on Sections of the Clinical Summary

2.7 CLINICAL SUMMARY

2.7.1 SUMMARY OF BIOPHARMACEUTIC STUDIES AND ASSOCIATED

ANALYTICAL METHODS

2.7.1.1 Background and Overview

This section should provide the reviewer with an overall view of the formulation development

process, the in vitro and in vivo dosage form performance, and the general approach and rationale

used in developing the bioavailability (BA), comparative BA, bioequivalence (BE), and in vitro

dissolution profile database. Reference should be made to any guidance or literature used in

planning and conducting the studies. This section should also provide the reviewer with an

overview of the analytical methods used, with emphasis on the performance characteristics of

assay validation (e.g., linearity range, sensitivity, specificity) and quality control (e.g., accuracy

and precision). This section should not include detailed information about individual studies.

2.7.1.2 Summary of Results of Individual Studies

A tabular listing of all biopharmaceutic studies should be provided (see the Section 2.7.1

Appendix), together with narrative descriptions of relevant features and outcomes of each of the

individual studies that provided important in vitro or in vivo data and information relevant to BA

and BE. The narrative descriptions should be brief (similar to an abstract for a journal article)

and should describe critical design features and critical results. Similar studies may be described

together, noting the individual study results and any important differences among the studies. 

These narratives may be abstracted from the ICH E3 synopsis. References or electronic links to

the full report of each study should be included in the narratives.

2.7.1.3 Comparison and Analyses of Results Across Studies

This section should provide a factual summary of all in vitro dissolution, BA, and comparative BA

studies carried out with the drug substance or drug product, with particular attention to differences

in results across studies. This overview should summarize the findings in text and tables (see the

Section 2.7.1 Appendix) and should consider the following:

• Evidence of the effects of formulation and manufacturing changes on in vitro dissolution and

BA and conclusions regarding BE. When manufacturing or formulation changes are made for

products containing complex drug substances (e.g., a protein), pharmacokinetic (PK) studies

comparing the product before and after the changes can be performed to ensure that the PK

characteristics have not changed as a result of product changes. Although such studies are

sometimes referred to as BE studies, they generally do not focus on assessing release of drug

substance from drug product. Nonetheless, such studies should be reported in this section. 
18

Note also that PK studies alone may not be sufficient to ensure similarity between such drug

products. In many situations, pharmacodynamic (PD) studies or clinical trials may be

recommended. Additionally, depending on the circumstances, antigenicity data may also be

needed. Results of these other types of studies should be reported in the appropriate places in

the application.

• Evidence of the extent of food effects on BA and conclusions regarding BE with respect to

meal type or timing of the meal (where appropriate)

• Evidence of correlations between in vitro dissolution and BA, including the effects of pH on

dissolution, and conclusions regarding dissolution specifications

• Comparative bioavailability, including BE conclusions, for different dosage form strengths

• Comparative BA of the clinical study formulations (for clinical studies providing substantial

evidence of efficacy) and the formulations to be marketed

• The source and magnitude of observed inter- and intrasubject variability for each formulation

in a comparative BA study

2.7.1.4 Appendix

Tables and figures should be embedded in the text when they enhance the readability of the

document. Lengthy tables can be provided in the appendix at the end of the section. For purposes

of simplicity, the tables mentioned there are provided at the end of the section on Module 2.

Tables 2.7.1.1 and 2.7.1.2 are examples of tabular formats for reporting information and results

related to bioavailability and in vitro dissolution studies respectively. These examples display

results as well as the type and design of the study. Tables prepared for reporting the results of BE

studies can also include the mean ratios (test/reference) for Cmax and AUC and their 90 percent

confidence interval or the currently recommended metrics for BE assessments.

These tables are not intended to be templates; they illustrate the type of information that should be

considered by an applicant in designing the tables for biopharmaceutic studies. Applicants should

also decide whether information and results from these studies are best presented in tables, text, or

figures to aid clarity. If, for example, results are best presented in text and figures, tables can be

used simply to list the studies.

2.7.2 SUMMARY OF CLINICAL PHARMACOLOGY STUDIES

2.7.2.1 Background and Overview

This section should provide the reviewer with an overall view of the clinical pharmacology

studies. These studies should include clinical studies performed to evaluate human

pharmacokinetics (PK) and pharmacodynamics (PD) and in vitro studies performed with human
19

cells, tissues, or related materials (human biomaterials) that are pertinent to PK processes. For

vaccine products, this section should provide the reviewer with immune response data that support

the selection of dose, dosage schedule, and formulation of the final product. Where appropriate,

relevant data that are summarized in Sections 2.7.1, 2.7.3, and 2.7.4 can also be referenced to

provide a comprehensive view of the approach and rationale for the development of the

pharmacokinetic, pharmacodynamic, PK/PD, and human biomaterial database. This section should

not include detailed information about individual studies.

This section should begin with a brief overview of the human biomaterial studies that were

conducted and that were intended to help in the interpretation of PK or PD data. Studies of

permeability (e.g., intestinal absorption, blood brain barrier passage), protein binding, hepatic

metabolism, and metabolic-based drug-drug interactions are particularly relevant. This

information should be followed by a brief overview of the clinical studies that were carried out to

characterize PK and PD of the medicinal product, including studies of PK/PD relationships in

healthy subjects and patients and relevant effects of intrinsic and extrinsic factors on PK and

PK/PD relationships.4 Critical aspects of study design and data analysis should be noted (e.g., the

choice of the single or multiple doses used, the study population, choice of the intrinsic or extrinsic

factors that were studied, the choice of PD endpoints, and whether a traditional approach or a

population approach was used to collect and analyze data to assess PK or PD). 

2.7.2.2 Summary of Results of Individual Studies

A tabular listing of all clinical pharmacology studies should generally be provided (see the section

2 appendix), together with a narrative description of the relevant features and outcomes of each of

the critical individual studies that provided in vitro or in vivo data and information relevant to PK,

PD and PK/PD relationships. The narrative descriptions should be brief (similar to an abstract for

a journal article) and should describe critical design features and critical results. Similar studies

can be described together, noting the individual study results and any important differences among

the studies. References or electronic links to the full report of each study should be included in the

narratives.

Summaries of dose-response or concentration response (PK/PD) studies with pharmacodynamic

endpoints should generally be included in this section. In some cases, however, when wellcontrolled dose-response PD or PK/PD studies provide important evidence of efficacy or safety,

they should be placed in Section 2.7.3 or 2.7.4 as appropriate and referenced, but not summarized,

here.

2.7.2.3 Comparison and Analyses of Results Across Studies

This section should use the results of all in vitro human biomaterial studies and PK, PD, and

PK/PD studies to characterize the PK, PD, and PK/PD relationships of the drug. Results related to

the inter- and intraindividual variability in these data and the intrinsic and extrinsic factors

 

4

 In the ICH guidance E5 Ethnic Factors in the Acceptance of Foreign Data, factors that may result in different responses to a

drug in different populations are categorized as intrinsic ethnic factors or extrinsic ethnic factors. In this guidance, these

categories are referred to as intrinsic factors and extrinsic factors, respectively.
20

affecting these pharmacokinetic relationships should be discussed.

This section (typically with the use of text and tables) should provide a factual presentation of all

data across studies pertinent to the following:

• In vitro drug metabolism and in vitro drug-drug interaction studies and their clinical

implications

• Human PK studies, including the best estimates of standard parameters and sources of

variability. The focus should be on evidence supporting dose and dose individualization in the

target patient population and in special populations (e.g., pediatric or geriatric patients,

patients with renal or hepatic impairment).

• Comparison between single and repeat-dose PK

• Population PK analyses, such as results based on sparse sampling across studies that address

interindividual variations in the PK or PD of the active drug substances that may be due to

extrinsic or intrinsic factors

• Dose-response or concentration-response relationships. This discussion should highlight

evidence to support the selection of dosages and dose intervals studied in the important

clinical trials. In addition, information that supports the dosage instructions in the proposed

labeling should be discussed in Section 2.7.3.4.

• Major inconsistencies in the human biomaterial, PK, or PD database

• PK studies that were performed to determine whether foreign clinical data could be

extrapolated to the new region (see ICH E5). The result of the studies and analysis of the

similarity of the PK data between regions or races should be summarized in this section. 

Studies that use PD biomarkers (but do not evaluate clinical efficacy) can also be summarized

here. An independent subsection can be created to summarize these kinds of data.

2.7.2.4 Special Studies

This section should include studies that provide special types of data relevant to specific types of

medicinal products.5 For immunogenicity studies and other studies in which data may correlate

with PK, PD, safety, and/or efficacy data, explanations of such correlations should be summarized

here. Any observed or potential effects on PK, PD, safety and/or efficacy should be considered in

other appropriate sections of the Clinical Summary as well, with cross-referencing to this section.

Human studies that address a specific safety issue should not be reported here, but instead should

be reported in Section 2.7.4, Summary of Clinical Safety.

Example 1: Immunogenicity

 

5

 The reports of these studies should be filed in Module 5, Section 5.3.5.4.
21

For protein products and other products to which specific immunological reactions have been

measured, data regarding immunogenicity should be summarized in this section. For vaccines or

other products intended to induce specific immune reactions, immunogenicity data should be

described in the efficacy section, 2.7.3. Assays used should be described briefly and information

about their performance (e.g., sensitivity, specificity, reliability, validity) should be summarized;

the location of detailed information in the application should be cross-referenced.

Data regarding the incidence, titre, timing of onset, and duration of antibody responses should be

summarized for each type of antibody assay used (e.g., IgG by ELISA, neutralization). 

Relationships of antibody formation to underlying disease, concomitant medication, dose, duration,

regimen, and formulation should be explored and summarized. For drugs intended to be given as

chronic, continuous therapy, any data on the impact of interruptions of therapy on antigenicity

should be analyzed and summarized.

It is particularly important to summarize analyses of potential clinically relevant correlates of

immunogenicity (e.g., to determine the extent to which the presence of antibodies of a particular

type or titer appears to correlate with alterations of PK, changes in PD, loss of efficacy, loss of

adverse event profile, or development of adverse events). Particular attention should be paid to

events that might be immunologically mediated (e.g., serum sickness) and events that might result

from binding of cross-reactive endogenous substances by antibodies to the administered drug.

Example 2: Clinical microbiology

For antimicrobial or antiviral medicinal products, in vitro studies to characterize the spectrum of

activity are an important part of the program of studies relevant to clinical efficacy. Clinical

efficacy studies that include characterization of the susceptibility of the clinical isolates as a part

of the efficacy determination should be included in Section 2.7.3, Summary of Clinical Efficacy.

However, studies that evaluate such findings as the pattern of in vitro susceptibility of strains of

bacteria from different parts of the world (not in the context of clinical efficacy study) would be

included here.

2.7.2.5 Appendix

Tables and figures should be embedded in the text of the appropriate sections when they enhance

the readability of the document. Lengthy tables can be provided in the appendix at the end of the

section.

Table 2.7.2.1 is an example of a tabular format for reporting information and results related to

pharmacokinetic drug-drug interaction studies. Similar tables can be prepared for PK/PD studies,

dose-response studies, studies of effects on human biomaterials, and population PK studies. This

table is not intended to be a template; it illustrates the type of information that should be

considered by sponsors in designing their own tables. Applicants should also decide whether

information and results from clinical pharmacology studies are best presented in tables, text, or

figures to aid clarity. If, for example, results are best presented in text and figures, the tables can

be used simply to list the studies. 
22

In designing tables for other types of clinical pharmacology studies, such as those listed below,

applicants should consider including the following types of information. These examples are for

illustrative purposes only, and the sponsor should decide which information to present.

• Metabolism studies using human biomaterials: Biomaterials used (e.g., microsomes,

hepatocytes), probe drugs, enzymatic pathways and percentage of contribution, and

relevant kinetic parameters (e.g., Vmax, Km)

• In vitro studies of drug-drug interactions using human biomaterials:

— For studies of other drugs inhibiting the new drug, the metabolites inhibited,

enzymatic pathways affected, range of inhibitor concentrations used, IC50 and Ki

values and proposed mechanism of inhibition should be included. 

— For studies of the new drug inhibiting other drugs, the drugs and metabolites

inhibited should be included, along with the information mentioned above.

• Population PK studies: Covariates studied, number and type of subjects or patients

studied, summary statistical parameters, and final estimates of mean (± standard

deviation) PK parameters

2.7.3 SUMMARY OF CLINICAL EFFICACY

A separate Section 2.7.3 should be provided for each indication, although closely related

indications can be considered together. When more than one Section 2.7.3 is submitted, the

sections should be labeled by indication (e.g., 2.7.3 pneumonia, 2.7.3 URI).

2.7.3.1 Background and Overview of Clinical Efficacy

This section should describe the program of controlled studies and other pertinent studies in the

application that evaluated efficacy specific to the indications sought. Any results of these studies

that are pertinent to evaluation of safety should be discussed in Section 2.7.4, Summary of Clinical

Safety.

The section should begin with a brief overview of the design of the controlled studies that were

conducted to evaluate efficacy. These studies include dose-response, comparative efficacy, longterm efficacy, and efficacy studies in population subsets. Critical features of study design should

be discussed (e.g., randomization, blinding, choices of control treatment, choice of patient

population, unusual design features such as crossover or randomized withdrawal designs, use of

run-in periods, other methods of enrichment, study endpoints, study duration, and prespecified

plans for analysis of the study results). Although this section is intended to focus on clinical

investigations, nonclinical data and clinical pharmacology data can also be referenced as

appropriate to provide a comprehensive summary of human experience related to efficacy. This

section should not include detailed information about individual studies.
23

2.7.3.2 Summary of Results of Individual Studies

A tabular listing of all studies that provided (or were designed to provide) information relevant to

product efficacy should generally be included (see the Section 2.7.3 Appendix), together with

narrative descriptions for important studies. The narrative descriptions should be brief (similar to

an abstract for a journal article) and should describe critical design features and critical results. 

Similar studies can be described together, noting the individual study results and any important

differences among the studies. For studies that also contributed significantly to the safety analysis,

study narratives should include information about the extent of exposure of study subjects to the

test drug or control agent and how safety data were collected. These narratives can be abstracted

from the synopses of the clinical study reports (ICH E3). References or electronic links to the full

report of each study should be included in the narratives.

Narratives of any bridging studies using clinical endpoints (i.e., certain studies intended to

evaluate the ability to extrapolate certain types of foreign clinical data to the new region (see ICH

E5)) should be included in this section. An analysis of the results of such studies, together with

other information (e.g., PK and PD data) that addresses the ability to extrapolate the efficacy and

safety results of foreign studies, should be performed if appropriate. The conclusions of such an

analysis should be noted at the start of Section 2.7.3.3.2, Comparison of Efficacy Results of All

Studies, and the full report of the analysis should be provided in Module 5.

2.7.3.3 Comparison and Analyses of Results Across Studies

Using text, figures, and tables as appropriate (see the Section 2.7.3 Appendix), the subsections of

2.7.3.3 should summarize all available data that characterize the efficacy of the drug. This

summary should include analyses of all data, irrespective of their support for the overall

conclusion and should, therefore, discuss the extent to which the results of the relevant studies do

or do not reinforce each other. Any major inconsistencies in the data regarding efficacy should be

addressed, and any areas needing further exploration should be identified.

The section will generally use two kinds of analyses: comparison of results of individual studies

and analysis of data combined from various studies. Details of analyses that are too extensive to

be reported in a summary document should be presented in a separate report placed in Module 5,

Section 5.3.5.3.

This section should also cross-reference important evidence from Section 2.7.2, such as data that

support the dosage and administration section of the labeling. These data include dosage and dose

interval recommended, evidence pertinent to individualization of dosage and need for

modifications of dosage for specific subgroups (e.g., pediatric or geriatric subjects, subjects with

hepatic or renal impairment), and data relevant to dose-response or concentration response

(PK/PD) relationships.

2.7.3.3.1 Study Populations

The demographic and other baseline characteristics of patients across all efficacy studies should

be described. The following information should be included.
24

• The characteristics of the disease (e.g., severity, duration), prior treatment in the study

subjects, and study inclusion/exclusion criteria

• Differences in baseline characteristics of the study populations in different studies or groups of

studies 

• Any differences between populations included in critical efficacy analyses and the overall

patient population that would be expected to receive the drug when it is marketed should be

noted.

• Assessment of the number of patients who dropped out of the studies, time of withdrawal (a

defined study day or visit during treatment or follow up period), and reasons for

discontinuation 

Tabular presentations that combine and compare study populations across studies may be useful. 

2.7.3.3.2 Comparison of Efficacy Results of all Studies

The results of any bridging studies using clinical endpoints (i.e., certain studies used to evaluate

the ability to extrapolate certain types of foreign clinical data to the new region (see ICH E5))

should be summarized in this section. An analysis of the similarity of efficacy in subjects between

regions, as well as any other information that may support extrapolation of the efficacy data to the

new region, should be summarized here. An independent subsection can be created to summarize

these kinds of data.

The results from all studies designed to evaluate the drug’s efficacy should be summarized and

compared, including studies with inconclusive or negative results. Important differences in study

design (such as endpoints, control group, study duration, statistical methods, patient population,

and dose) should be identified.

Comparisons of results across studies should focus on prespecified primary endpoints. However,

when the primary endpoints involved different variables or time points in different efficacy

studies, it can be useful to provide cross-study comparisons of important data elements that were

obtained in all studies. If results over time are important, results of studies can be displayed in a

figure that illustrates the change over time in each study. 

Confidence intervals for treatment effects should be given to aid the interpretation of point

estimates. If differences are shown between placebo and test drugs in the change from baseline,

the baseline values and the magnitude of effect in all treatment groups, including placebo and

active controls (if used), should generally be presented in the table or in text accompanying a

figure. If the objective of an active control trial was to show equivalence or noninferiority, the

difference or the ratio of outcomes between treatments should be given with the confidence

interval. The results should be evaluated by using the predefined criteria for defining equivalence

or noninferiority and the rationale for the criteria, and support for the determination that the study

(studies) had assay sensitivity should be provided (see ICH E10).
25

Important differences in outcomes between studies with a similar design should be delineated and

discussed. Cross-study comparisons of factors that may have contributed to differences in

outcomes should be described.

If a meta-analysis of the clinical studies is performed, it should be clear whether this analysis is

conducted according to a predefined protocol or is a post hoc exercise. Any differences in trial

designs or populations, or in efficacy measurements between trials, should be described to allow

assessment of the relevance and validity of the results and conclusions (see ICH E9). A detailed

description of the methodology and results of the meta-analysis should generally be submitted in a

separate report (Section 5.3.5.3 of Module 5).

2.7.3.3.3 Comparison of Results in Subpopulations

The results of individual studies or overview analyses of efficacy in specific populations should

be summarized in this section. The purpose of these comparisons should be to show whether the

claimed treatment effects are observed consistently across all relevant subpopulations, especially

those where there are special reasons for concern. The comparisons can highlight apparent

variations in efficacy that call for further investigation and discussion. The limitations of such

analyses, however, should be recognized (ICH E9), and it is important to note that their purpose is

not to provide the basis for specific claims or to attempt to improve the evidence of efficacy in

situations where the overall results are disappointing.

Given the limited sample sizes in individual studies, analyses across multiple studies should be

performed to evaluate effects of major demographic factors (age, sex, and race) and of other

predefined or relevant intrinsic and extrinsic factors(e.g., disease severity, prior treatment,

concomitant illness, concomitant drugs, alcohol, tobacco, and body weight) on efficacy. Factors of

special interest may arise from general concerns (e.g., the elderly) or from specific issues that are

related to the pharmacology of the drug or that have arisen during earlier drug development.

Efficacy in the pediatric population should be routinely analyzed in applications for a proposed

indication that occurs in children. Depending on the size of the data set, if extensive, detailed

efficacy analyses are performed, they can be placed in Module 5, with the results of those analyses

reported here.

2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations

This section should provide an integrated summary and analysis of all data that pertain to the doseresponse or blood level-response relationships of effectiveness (including dose-blood level

relationships) and thus have contributed to dose selection and choice of dose interval. Relevant

data from nonclinical studies can be referenced, and relevant data from pharmacokinetic studies,

other clinical pharmacology studies, and controlled and uncontrolled clinical studies should be

summarized to illustrate these dose-response or blood level-response relationships. For

pharmacokinetic and pharmacodynamic studies from which data have been summarized in Section

2.7.2.2, it may be appropriate to draw on those data in this summary while cross-referencing the

summaries in Section 2.7.2.2, without repeating those summaries.
26

While the interpretation of how these data support specific dosing recommendations should be

supplied in the Clinical Overview, the individual study results and any cross-study analyses that

will be used to support the dosing recommendations (including the recommended starting and

maximal doses, the method of dose titration, and any other instructions regarding individualization

of dosage) should be summarized here. Any identified deviations from relatively simple doseresponse or blood level-response relationships due to nonlinearity of pharmacokinetics, delayed

effects, tolerance, or enzyme induction should be described.

Any evidence of differences in dose-response relationships that result from a patient’s age, sex,

race, disease, or other factors should be described. Any evidence of different pharmacokinetic or

pharmacodynamic responses should also be discussed, or discussions in Section 2.7.2 can be

cross-referenced. The ways in which such differences were looked for, even if no differences

were found, should be described (e.g., specific studies in subpopulations, analysis of efficacy

results by subgroup, or blood level determinations of the test drug).

2.7.3.5 Persistence of Efficacy and/or Tolerance Effects

Available information on persistence of efficacy over time should be summarized. The number of

patients for whom long-term efficacy data are available, and the length of exposure, should be

provided. Any evidence of tolerance (loss of therapeutic effects over time) should be noted. 

Examination of any apparent relationships between dose changes over time and long-term efficacy

may be useful.

The primary focus should be on controlled studies specifically designed to collect long-term

efficacy data, and such studies should be clearly differentiated from other, less rigorous studies,

such as open extension studies. This distinction also applies to specific studies designed for

evaluation of tolerance and withdrawal effects. Data concerning withdrawal or rebound effects

pertinent to product safety should be presented in the safety section (see Section 2.7.4).

In long-term efficacy trials, the effect of premature discontinuation of therapy or switching to other

therapies on the assessment of the results should be considered. These issues can also be

important for short-term trials and should be addressed when discussing the results of these trials,

if appropriate.

2.7.3.6 Appendix

Tables and figures should be embedded in the text when they enhance the readability of the

document. Lengthy tables can be provided in the appendix at the end of the section.

Tables should identify all studies pertinent to the evaluation of efficacy (including studies that

were terminated or are not yet completed, studies that failed to show effectiveness for any reason,

studies available only as publications, studies reported in full technical reports (ICH E3), and

studies described in abbreviated reports) and should provide the most important results of those

studies. Note, however, that unplanned interim analyses on ongoing studies are generally not

needed or encouraged. When more than one Section 2.7.3 is provided for an application with

more than one indication, usually each section should have its own appendix with tables.
27

Illustrative tables for an antihypertensive drug are provided, but these examples will not be

relevant to every application. In general, applications should contain tables and/or figures that are

developed specifically for the particular drug class and the studies that were carried out.

Table 2.7.3.1 Description of Clinical Efficacy and Safety Studies

Table 2.7.3.2 Results of Efficacy Studies

2.7.4 SUMMARY OF CLINICAL SAFETY

This section should be a summary of data relevant to safety in the intended patient population,

integrating the results of individual clinical study reports as well as other relevant reports (e.g., the

integrated analyses of safety that are routinely submitted in some regions).

The display of safety-related data can be considered at three levels (ICH E3):

• The extent of exposure (dose, duration, number of patients, type of patients) should be

examined to determine the degree to which safety can be assessed from the database.

• The more common adverse events and changes in laboratory tests should be identified and

classified, and their occurrence should be summarized.

• Serious adverse events (defined in ICH E2A) and other significant adverse events (defined in

ICH E3) should be identified, and their occurrence should be summarized. These events should

be examined for frequency over time, particularly for drugs that may be used chronically.

The safety profile of the drug, described on the basis of analysis of all clinical safety data, should

be outlined in a detailed, clear, and objective manner, with use of tables and figures.

2.7.4.1 Exposure to the Drug

2.7.4.1.1 Overall Safety Evaluation Plan and Narratives of Safety Studies

The overall safety evaluation plan should be described briefly, including special considerations

and observations concerning the nonclinical data, any relevant pharmacological class effects, and

the sources of the safety data (controlled trials, open studies). A tabular listing of all clinical

studies that provided safety data, grouped appropriately, should generally be provided (see the

Section 2.7.4 Appendix). In addition to studies that evaluated efficacy and safety and uncontrolled

studies that generated safety information, this section includes studies that consider special safety

issues. Examples include studies to compare particular adverse event rates for two therapies, to

assess safety in particular demographic subsets, to evaluate withdrawal or rebound phenomena, or

to evaluate particular adverse events (e.g., sedation, sexual function, effects on driving, absence of

a class adverse effect). Studies in indications for which approval is not being sought in the current

application and ongoing studies would also be included here if they contribute to the safety

analysis.
28

Narrative descriptions of these studies should be provided here, except that narrative descriptions

for studies that contributed both efficacy and safety data should be included in Section 2.7.3.2 and

cross-referenced here. The narratives should provide enough detail to allow the reviewer to

understand the exposure of study subjects to the test drug or control agent and how safety data were

collected (including the methods used and the extent of safety monitoring of the subjects enrolled in

the individual studies). If some studies are not analyzed separately but are grouped for safety

analysis, that should be noted, and a single narrative description can be provided. 

2.7.4.1.2 Overall Extent of Exposure

A table (see example provided in the Section 2.7.4 Appendix) and appropriate text should be

generated to summarize the overall extent of drug exposure from all phases of the clinical study

development program. The table should indicate the numbers of subjects exposed in studies of

different types and at various doses, routes, and durations. If a large number of different doses

and/or durations of exposure were used, these can be grouped in a manner appropriate for the

drug. Thus, for any dose or range of doses, duration of exposure can be summarized by the number

of subjects exposed for specific periods of time, such as 1 day or less, 2 days to 1 week, 1 week to

1 month, 1 month to 6 months, 6 months to 1 year, more than 1 year (ICH E3). In some

applications it may be important to identify diagnostic subgroups and/or groups receiving specific

concomitant therapies deemed particularly relevant to safety assessment in the intended use.

The dose levels used for each subject in this presentation could be the maximum dose received by

that subject, the dose with longest exposure, and/or the mean daily dose, as appropriate. In some

cases, cumulative dose can be pertinent. Dosage can be given as the actual daily dose or on a

mg/kg or mg/m2 basis, as appropriate. If available, drug concentration data (e.g., concentration at

the time of an adverse event, maximum plasma concentration, area under curve) in individual

subjects may be helpful for correlation with adverse events or changes in laboratory variables.

It is assumed that all subjects who were enrolled and received at least one dose of the treatment

are included in the safety analysis; if that is not so, an explanation should be provided.

2.7.4.1.3 Demographic and Other Characteristics of Study Population

A summary table should provide the reader with an overview of the demographic characteristics

(Table 2.7.4.2) of the population that was exposed to the therapeutic agent during its development.

 Choice of age ranges used should take into account considerations discussed in ICH E7 and E11. 

If the relative exposure of demographic groups in the controlled trials differed from overall

exposure, it may be useful to provide separate tables.

In addition, one or more tables should show the relevant characteristics of the study population and

the numbers of subjects with special characteristics. Such characteristics could include

• Severity of disease

• Hospitalization

• Impaired renal function
29

• Concomitant illnesses 

• Concomitant use of particular medications

• Geographical location

If these characteristics are distributed differently in controlled trials versus the overall database, it

is generally be useful to present tables on both groupings.

The text accompanying the tables should mention any imbalances between the drug and placebo

and/or comparator regarding any of the above demographic characteristics, particularly if the

imbalances could lead to differences in safety outcomes.

If certain subjects were excluded from studies (concomitant illness, severity of illness,

concomitant medications), this fact should be noted.

Separate demographic tables should be provided for every indication, although closely related

indications can be considered together if study subject characteristics are such that risks are

believed to be the same.

2.7.4.2 Adverse Events

2.7.4.2.1 Analysis of Adverse Events

Data on the frequency of adverse events should be described in text and tables. Text should

appear in the appropriate subsections of Section 2.7.4.2.1, and the tables that are not embedded in

the text should be placed in the Section 2.7.4 Appendix.

All adverse events occurring or worsening after treatment has begun ("treatment emergent signs

and symptoms," those adverse events not seen at baseline and those that worsened even if present

at baseline) should be summarized in tables. Tables should contain a listing of each event, the

number of subjects in whom the event occurred, and the frequency of occurrence in subjects treated

with the drug under investigation, with comparator drugs, and with placebo. Such tables could

also present results for each dose and could be modified to show adverse event rates by severity,

by time from onset of therapy, or by assessment of causality.

When most of the relevant safety data are derived from a small number of studies (e.g., one or two

studies) or when very different study subject populations were enrolled in the studies that were

performed, presentation of data by study is often appropriate. When the relevant exposure data are

not concentrated in a small number of studies, however, grouping the studies and pooling the

results to improve precision of estimates and sensitivity to differences should generally be

considered.

While often useful, pooling of safety data across studies should be approached with caution

because in some cases interpretation can be difficult, and pooling can obscure real differences. In

cases where differences are apparent, it is more appropriate to present the data by study. The

following issues should be considered:
30

• It is most appropriate to combine data from studies that are of similar design (e.g., similar in

dose, duration, methods of determining adverse events, and population).

• If the incidence for a particular adverse event differs substantially across the individual studies

in a pool, the pooled estimate is less informative.

• Any study with an unusual adverse event pattern should be presented separately.

• The appropriate extent of analysis depends on the seriousness of the adverse event and the

strength of evidence of drug causation. Differences in rates of drug-related, serious events or

events leading to discontinuation or dosage change deserve more investigation, whereas rates

of other adverse events do not merit elaborate analysis.

• Examination of which subjects experience extreme laboratory value abnormalities (outliers)

can be useful in identifying subgroups of individuals who are at particular risk for certain

adverse events.

Groups of studies that could be used in pooled safety analyses include the following.

• All controlled studies or subsets of controlled studies, such as all placebo-controlled studies,

studies with any positive control, studies with a particular positive control, or studies of

particular indications (and thus carried out in different populations). These groupings are

considered the best source of information about the more common adverse events and can

distinguish drug-related events from spontaneous events. Rates in control and treatment groups

should be compared.

• All studies, excluding short-term studies in healthy subjects. This grouping is most useful for

evaluating rarer events.

• All studies using a particular dose route or regimen, or a particular concomitant therapy

• Studies in which adverse event reports are elicited by checklist or direct questioning, or

studies in which events are volunteered

• Pools of studies by region

It is almost always useful to carry out the first two groupings; the others chosen would vary from

drug to drug and should be influenced by inspection of individual study results. Whatever methods

are used, it should be recognized that, as for results of single studies, any numerical rate is often

only a rough approximation of reality.

When a decision is made to pool data from several studies, the rationale for selecting the method

used for pooling should be described. It is common to combine the numerator events and the

denominators for the selected studies. Other methods for pooling results across studies are
31

available (e.g., weighting data from studies on the basis of study size or inversely to their

variance).

If substantial differences are seen between clinical trials in the rates of adverse events, these

differences should be noted and possible reasons for the difference should be discussed (e.g.,

relevant differences in study populations, in dose administration, or in methods of collecting

adverse event data).

Adverse events should be described as shown in the individual study report (ICH E3). In

combining data from many studies, it is important to use standardized terms to describe events and

collect synonymous terms under a single preferred term. This can be done with a standard

dictionary, and the Medical Dictionary for Regulatory Activities (MedDRA) terminology (ICH

M1) should be used. Until MedDRA can be fully implemented, other dictionaries can be used, but

should be specified. Frequencies should be presented for preferred terms and for appropriately

defined groupings. Examination of which adverse events led to change in therapy (discontinuation

of drug use, change in dose, need for added therapy) can help in assessing the clinical importance

of adverse events. These rates can be added to the adverse event rate tables or can be presented in

separate tables. Overall discontinuation rates by study can be useful, but it is also important to

specify the particular adverse events leading to discontinuation in a separate table. The preferred

terms should be grouped by body system and arranged by decreasing frequency. 

2.7.4.2.1.1 Common Adverse Events

Tabular displays of adverse event rates (see the Section 2.7.4 Appendix) should be used to

compare rates in treatment and control groups. For this analysis, it may be helpful to combine the

event severity categories and the causality categories, if they are used, leading to a simpler sideby-side comparison of treatment groups. It should be noted that while causality categories can be

reported if used, the presentation of the data should include all of the adverse events that occurred

(whether deemed related or unrelated to treatment). Evaluations of causality are inherently

subjective and may exclude unexpected adverse events that are in fact treatment related. 

Additionally, comparisons of rates of adverse events between treatment and control groups in

individual trials should be summarized here. It is often useful to tabulate rates in selected trials

(see example table 2.7.4.4, in the Section 2.7.4 Appendix).

It is usually useful to examine more closely the more common adverse events that seem to be drug

related (e.g., those that show that a dose response and/or a clear difference between drug and

placebo rates) for relationship to relevant factors, including the following.

• dosage

• mg/kg or mg/m2 dose

• dose regimen

• duration of treatment

• total dose

• demographic characteristics such as age, sex, race

• concomitant medication use

• other baseline features such as renal status

• efficacy outcomes
32

• drug concentration, where available

It may also be useful to summarize the results of examination of time of onset and duration for these

drug-related events.

Rigorous statistical evaluations of the possible relationship of specific adverse events to each of

the above factors are often unnecessary. It may be apparent from initial display and inspection of

the data that there is no evidence of a significant relationship to demographic or other baseline

features. In that case, no further analysis of these particular factors is needed. Furthermore, it is

not necessary that all such analyses be presented in this report. When the safety analyses are too

extensive to be presented in detail in this report, they may be presented in a separate report in

Module 5, Section 5.3.5.3, and summarized here.

Under certain circumstances, life table or similar analyses may be more informative than reporting

of crude adverse event rates.

2.7.4.2.1.2 Deaths

A table in the Section 2.7.4 Appendix should list all deaths occurring while on study. The list

should also include deaths that occurred shortly after treatment termination (e.g., within 30 days or

as specified in the study protocol) as well as all other deaths that occurred later but may have

resulted from a process that began during studies. Only deaths that are clearly disease related per

protocol definitions and not related to the investigational product, either in studies of conditions

with high mortality such as advanced cancer or in studies where mortality from disease is a

primary study endpoint, should be excepted from this listing. (It is assumed, however, that these

deaths would still be reported in the individual ICH E3 study reports.) Even these deaths should

be examined for any unexpected patterns between study arms and further analyzed if unexplained

differences are observed. Deaths should be examined individually and analyzed on the basis of

rates in individual trials and appropriate pools of trials, considering both total mortality and

cause-specific deaths. Potential relationships to the factors listed in Section 2.7.4.2.1.1 should

also be considered. Although cause-specific mortality can be difficult to determine, some deaths

are relatively easy to interpret. Thus deaths due to causes expected in the patient population (heart

attacks and sudden death in an angina population) are individually not considered to be

informative, but even one death due to a QT interval prolongation-associated arrhythmia, aplastic

anemia, or liver injury may be informative. Special caution is appropriate before an unusual death

is attributed to concomitant illness.

2.7.4.2.1.3 Other Serious Adverse Events

Summaries of all serious adverse events (other than death but including the serious adverse events

temporally associated with or preceding the deaths) should be displayed. Serious adverse events

that occurred after the drug use was discontinued should be included in this section. The display

should include major laboratory abnormalities, abnormal vital signs, and abnormal physical

observations that are considered serious adverse events using the ICH E2A definitions. Results of

analyses or assessments of serious adverse events across studies should be presented. Serious

events should be examined for frequency over time, particularly for drugs that may be used
33

chronically. Potential relationships to the factors listed in Section 2.7.4.2.1.1 should also be

considered.

2.7.4.2.1.4 Other Significant Adverse Events

Marked hematologic and other laboratory abnormalities (other than those meeting the definition of

serious) and any events that led to a substantial intervention (premature discontinuation of study

drug, dose reduction, or substantial additional concomitant therapy), other than those reported as

serious adverse events, should be displayed.

Events that led to premature discontinuation of study drug represent an important safety concern

and deserve particular attention in the analysis of drug safety for two reasons. First, even for

expected events (based on pharmacologic activity), the discontinuation or alteration of treatment

reflects the severity and perceived importance of the event to patient and physician. Second,

discontinuation may represent a drug-related event not yet recognized as drug related. Adverse

events leading to treatment discontinuation should be considered possibly drug-related even if this

was not recognized initially and even if the event was thought to represent intercurrent illness. 

Reasons for premature treatment discontinuations should be discussed and rates of

discontinuations should be compared across studies and compared with rates of discontinuations

for placebo and/or active control treatment. In addition, the study data should be examined for any

potential relationships to the factors listed in Section 2.7.4.2.1.1.

2.7.4.2.1.5 Analysis of Adverse Events by Organ System or Syndrome

Assessment of the causality of, and risk factors for, deaths, other serious events, and other

significant events is often complicated by the fact that these events are uncommon. As a result,

consideration of related events as a group, including less important events of potentially related

pathophysiology, can be of critical value in understanding the safety profile. For example, the

relationship to treatment of an isolated sudden death can become much clearer when considered in

the context of cases of syncope, palpitations, and asymptomatic arrhythmias.

Thus it is generally useful to summarize adverse events by organ system so that they can be

considered in the context of potentially related events including laboratory abnormalities. Such

presentations of adverse events by organ system should be placed in subsections of Section

2.7.4.2.1.5, labeled 2.7.4.2.1.5.1, 2.7.4.2.1.5.2, and titled by the organ system under

consideration. The list of organ systems to be addressed and the approach to grouping certain

events should be selected as appropriate to best present the adverse event data for the medicinal

product. If some adverse events tend to occur in syndromes (e.g., influenza-like syndrome,

cytokine release syndrome), the sponsor may choose to create some subsections of 2.7.4.2.1.5 for

syndromes rather than organ systems.

The same data and summarizations should generally not be repeated in more than one subsection of

Section 2.7.4.2.1. Instead, a summary presentation can be placed in one subsection and crossreferenced as appropriate in others.
34

2.7.4.2.2 Narratives

The locations in the application of individual narratives of patient deaths, other serious adverse

events, and other significant adverse events deemed to be of special interest because of clinical

importance (as described in ICH E3 individual study reports) should be referenced here for the

convenience of the reviewer. The narratives themselves should be a part of the individual study

reports, if there is such a report. In cases where there is no individual study report (e.g., if many

open studies are pooled as part of a safety analysis and are not individually described), narratives

can be placed in Module 5, Section 5.3.5.3. Narratives should not be included here unless an

abbreviated narrative of particular events is considered critical to the summary assessment of the

drug.

2.7.4.3 Clinical Laboratory Evaluations

This section should describe changes in patterns of laboratory tests with drug use. Marked

laboratory abnormalities and those that led to a substantial intervention should be reported in

Section 2.7.4.2.1.3 or 2.7.4.2.1.4. If these data are also presented in this section, this duplicate

reporting should be made clear for the reviewer. The appropriate evaluations of laboratory values

will in part be determined by the results seen, but, in general, the analyses described below should

be provided. For each analysis, comparison of the treatment and control groups should be carried

out as appropriate and should be compatible with study sizes. In addition, normal laboratory

ranges should be given for each analysis (ICH E3). Where possible, laboratory values should be

provided in standard international units.

A brief overview of the major changes in laboratory values across clinical studies should be

provided. Laboratory data should include hematology, clinical chemistry, urinalysis, and other

data as appropriate. Each parameter at each time over the course of the study (e.g., at each visit)

should be described at the following three levels:

• The central tendency (i.e., the group mean and median values)

• The range of values and the number of subjects with abnormal values or with abnormal values

of a certain size (e.g., twice the upper limit of normal, five times the upper limit; choices

should be explained). When data are pooled from centers with differences in normal

laboratory ranges, the methodology used in pooling should be described. The analysis of

individual subject changes by treatment group can be shown with a variety of approaches (e.g.,

shift tables, see ICH E3 for examples). 

• Individual clinically important abnormalities, including those leading to discontinuations. The

significance of laboratory changes and the likely relation to the treatment should be assessed

(e.g., by analysis of such features as relationship to dose, relationship to drug concentration,

disappearance on continued therapy, positive dechallenge, positive rechallenge, and the nature

of concomitant therapy). Potential relationships to other factors listed in Section 2.7.4.2.1.1

should also be considered.
35

2.7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety

The manner of presenting cross-study observations and comparisons of vital signs (e.g., heart rate,

blood pressure, temperature, respiratory rate), weight, and other data (e.g., electrocardiograms, Xrays) related to safety should be similar to that for laboratory variables. If there is evidence of a

drug effect, any dose-response or drug concentration-response relationship or relationship to

individual variables (e.g., disease, demographics, concomitant therapy) should be identified and

the clinical relevance of the observation described. Particular attention should be given to

changes not evaluated as efficacy variables and to those considered to be adverse events. 

Particular attention should be given to studies that were designed to evaluate specific safety issues

(e.g., studies of QT interval prolongation).

2.7.4.5 Safety in Special Groups and Situations

2.7.4.5.1 Intrinsic Factors

This section should summarize safety data pertinent to individualizing therapy or patient

management on the basis of demographic and other factors defined as intrinsic ethnic factors in

ICH E5. These factors include age, sex, height, weight, lean body mass, genetic polymorphism,

body composition, other illness, and organ dysfunction. Safety in the pediatric population should

be routinely analyzed in applications for a proposed indication that occurs in children. Analysis of

the impact of such factors on safety outcomes should have been presented in other sections but

should be summarized here, together with pertinent PK or other information (e.g., in patients with

renal or hepatic disease). If a sufficiently large number of subjects with a given co-morbid

condition (such as hypertension, heart disease, or diabetes) was enrolled, analyses should be

carried out to assess whether the co-morbid condition affected the safety of the drug under study.

Cross-reference should be made to the tables or description of adverse events when analyses of

such subgroups have been carried out.

2.7.4.5.2 Extrinsic Factors

This section should summarize safety data pertinent to individualizing therapy or patient

management on the basis of factors defined as extrinsic ethnic factors in ICH E5. These are

factors associated with the patient environment. Examples are the medical environment, use of

other drugs (see Section 2.7.4.5.3, Drug Interactions), use of tobacco, use of alcohol, and food

habits.

For example, if a potential interaction with alcohol is suggested by the metabolic profile, by the

results of studies, by postmarketing experience, or by information on similar drugs, information

should be provided here.

2.7.4.5.3 Drug Interactions

Studies on potential drug-drug or drug-food interactions should be summarized in the Summary of

Clinical Pharmacology Studies section of the CTD (Section 2.7.2). The potential impact on safety

of such interactions should be summarized here, based on PK, PD, or clinical observations. Any
36

observed changes in the adverse event profile, changes in blood levels thought to be associated

with risk, or changes in drug effects associated with other therapy should be presented here.

2.7.4.5.4 Use in Pregnancy and Lactation

Any information on safety of use during pregnancy or breast-feeding that becomes available during

clinical development or from other sources should be summarized here.

2.7.4.5.5 Overdose

All available clinical information relevant to overdose, including signs and/or symptoms,

laboratory findings, and therapeutic measures and/or treatments and antidotes (if available), should

be summarized and discussed. Information on the efficacy of specific antidotes and dialysis

should be provided if available.

2.7.4.5.6 Drug Abuse

Any relevant studies and information regarding the investigation of the dependence potential of a

new therapeutic agent in animals and in humans should be summarized and cross-referenced to the

nonclinical summary. Particularly susceptible patient populations should be identified.

2.7.4.5.7 Withdrawal and Rebound

Any information or study results pertinent to rebound effects should be summarized. Events that

occur, or increase in severity, after discontinuation of double-blind or active study medication

should be examined to see if they are the result of withdrawal of the study medication. Particular

emphasis should be given to studies designed to evaluate withdrawal and/or rebound.

Data concerning tolerance should be summarized under Section 2.7.3.5 in the Summary of Clinical

Efficacy.

2.7.4.5.8 Effects on Ability to Drive or Operate Machinery or Impairment of Mental

Ability

Safety data related to any impairment in the senses or coordination or any other factor that would

result in diminished ability to drive a vehicle or operate machinery or that would impair mental

ability should be summarized. This includes relevant adverse effects reported in safety monitoring

(e.g., drowsiness) and specific studies concerning effects on ability to drive or operate machinery

or impairment of mental ability.

2.7.4.6 Postmarketing Data

If the drug has already been marketed, all relevant postmarketing data available to the applicant

(published and unpublished, including periodic safety update reports if available) should be

summarized. The periodic safety update reports can be included in Module 5. Details of the
37

number of subjects estimated to have been exposed should be provided and categorized, as

appropriate, by indication, dosage, route, treatment duration, and geographic location. The

methodology used to estimate the number of subjects exposed should be described. If estimates of

the demographic details are available from any source, these should be provided.

A tabulation of serious events reported after the drug is marketed should be provided, including

any potentially serious drug interactions.

Any postmarketing findings in subgroups should be described.

2.7.4.7 Appendix

Tabular presentations should be provided that summarize the important results from all studies

pertinent to the evaluation of safety and particularly from those to support product labeling.

Tables and figures should be embedded in the text when they enhance the readability of the

document. Lengthy tables can be provided in the appendix at the end of the section.

A few illustrative tables are provided, but a clinical summary will routinely need tables and

figures that have been developed for the particular drug, drug class, and clinical indications.

See Sections 2.7.4.2.1, 2.7.4.2.2.3, and 2.7.4.3 of this guidance for additional discussion regarding

the content of section 4 tables.

Table 2.7.4.1 Study Subject Drug Exposure by Mean Daily Dose and Duration of Exposure

Table 2.7.4.2 Demographic Profile of Patients in Controlled Trials

Table 2.7.4.3 Incidence of Adverse Events in Pooled Placebo and Active Controlled Trials

Table 2.7.4.4 Incidence of Adverse Events in the Largest Trials

Table 2.7.4.5 Patient Withdrawals by Study: Controlled Trials

Table 2.7.4.6 Listing of Deaths

2.7.5 REFERENCES

A list of references cited in the Clinical Summary should be provided. Copies of all important

references should be provided in Module 5, Section 5.4. The reference list should indicate which

references are available in Module 5, Section 5.4. All references that have not been provided

should be available on request. 
38

2.7.6 SYNOPSES OF INDIVIDUAL STUDIES

ICH E3 suggests inclusion of a study synopsis with each clinical study report and provides one

example of a format for such synopses.

This section should include the table entitled Listing of Clinical Studies, described in guidance for

Module 5, followed by all individual study synopses organized in the same sequence as the study

reports in Module 5.

It is expected that one synopsis will be prepared per study for use in all regions and that the same

synopsis will be included in this section and as part of the clinical study report in Module 5. The

length of a synopsis will usually be up to 3 pages, but a synopsis for a more complex and important

study may be longer (e.g., 10 pages). Within the individual synopsis, tables and figures should be

used as appropriate to aid clarity.
39

Table 2.7.1.1 Summary of Bioavailability Studies

Study

Ref.

No.

Study Objective Study Design Treatments

(Dose,

Dosage Form,

Route)

[Product ID]

Subjects

(No.(M/F)

type

Age: mean

(range)

Mean Parameters (+/- SD) Study

Report

Location

Cmax

(mg/L)

Tmax

(hr)

AUC*

(mg/L x

hr)

Cmin**

(mg/L)

T1/2

(hr)

Other

192

(Japan)

Pilot relative BA study

comparing the absorption

from a 200 mg tablet batch to

a 200mg reference batch.

Open, randomized,

cross-over, single

200 mg dose

200mg Tab., p.o.

[17762]

200mg Tab.. p.o.

[19426]

20 (10/10)

Healthy volunteer

27 y (20-35)

83 ± 21

80 ± 32

1

0.5

217 ±

20

223 ±

19

3.1

2.9

195

(Japan)

Comparative BA study of xx

under fasted and fed

conditions

Open, randomized,

cross-over, single

dose

200mg Tab, p.o.

[19426]

30 (15/15)

Healthy volunteer

32 y (26-50)

83 ± 21

120 ± 30

1

2

217 ±

20

350 ±

40

AUC*: AUCTAU or AUCinf

Cmin**: For multiple dose studies
40

Table 2.7.1.2. Summary of In Vitro Dissolution Studies

Study

Ref.

No.

Product ID/Batch No. Dosage Form Conditions No. of

Dosage Units

Collection times

Mean % Dissolved (range)

Study

Report

Location

1821 979-03 25 mg Cap. Dissolution: Apparatus 2 (USP)

Speed of Rotation: 50 rpm

Medium/Temperature: Water 37°

12 10 20 30 (min)

 42 (32-49) 71 (58-85) 99 (96-100) (%)
41

Table 2.7.2.1 Summary of Drug-Drug Interaction PK Studies

Study/

Protocol #

(Country)

Product

ID/Batch #

(NME)

Study

Objective

Study Design # Subjects

Entered/Comp

leted (M/F)

HV/P1

(Age:

Mean,

range)

Treatments Mean Pharmacokinetic Parameters (%CV) Substrate Drug Mean ratio2

Confidence interval

Location

Substrate Interacting

Drug

Cmax Tmax AUC T1/2 CL/kg Cmax AUC

001

(USA)

19B

Batch 0034

Effect of

warfarin on

Drug X

Randomized,

Crossover

(8M/4F)/

(7M/4F)

HV (34,

20-41)

Drug X 100

mg bid x 7d

Placebo 45 (18)

Fg/mL

2.0

(30) hr

456 (24)

Fg*hr/

mL

4.25 (30)

hr

0.05 (20)

mL/min/k

g

1.16

1.01-1.30

1.16

1.03-1.34

Drug X 100

mg bid x 7d

Warfarin 10

mg qd x 7d

52 (20)

Fg/mL

2.1 

(35) hr

530 (27)

Fg*hr/

mL

4.75 (35)

hr

0.04 (22)

mL/min/k

g

001

(USA)

19B

batch 0034

Effect of

drug X on

warfarin

Randomized,

Crossover

(8M/4F)/

(7M/4F)

HV (34,

20-41)

Warfarin 10

mg qd x 7d

placebo 12 (25)

Fg/mL

1.5

(30) hr

60 (37)

Fg*hr/

mL

40

(35) hr

0.04 (30)

mL/min/k

g

1.08

0.92-1.24

1.07

0.92-1.18

Warfarin 10

mg qd x 7d

drug X 100

mg bid x 7d

13 (20)

Fg/mL

1.45

(27) hr

64 (39)

Fg*hr/

mL

42

(37) hr

0.39 (34)

mL/min/k

g

002 (UK) 19B2

Batch 0035

Effect of

Cimetidine

on Drug X

Crossover,

Single

sequence

(4M/8F)

(4M/8F)

HV (30,

19-45)

Drug X 50

mg bid x 5d

Placebo 49 (18)

F/mL

2.1

(30) hr

470 (24)

Fg*hr/

mL

4.4

(30) hr

0.05 (20)

mL/min/k

g

1.22

1.03-1.40

1.36

1.11-1.53

drug X 50

mg bid x 5d

Cimetidine

200 mg bid x

5d

60 (10)

Fg//mL

2.2

(30) hr

640 (24)

Fg*hr/

mL

5.2

(30)

hr

0.03 (20)

mL/min/k

g

1HV=Healthy Volunteers, P=Patients

2Value for substrate with interacting drug / value with placebo
42

Table 2.7.3.1 Description of Clinical Efficacy and Safety Studies

Study ID Number of

Study Centers

Study start Design Study & Ctrl

Drugs

Study

Objective

# subjs by

arm

Duration Gender M/F Diagnosis Primary Endpoint(s)

Location(s) Enrollment

status, date

Control type Dose,Route entered/

compl.

Median Age

(Range)

Inclusion Criteria

Total

enrollment /

Enrollment

goal

& Regimen

PG- 2476 1 Aug-94 Randomized,

double blind,

parallel

TP: 30 mg

po bid

Efficacy

and Safety

27/24 4 weeks 27/23 Mild hypertension Change from baseline systolic

and diastolic pressure at 4

weeks.

U. Antarctica Completed Apr

98

50 / 50

Placebo Pbo 23/21 38 (20-64) Diastolic 90-100

Systolic 150-170

PG- 2666 4 May-98 Randomized,

open label,

parallel

TP: 100 mg

po bid

Efficacy

and Safety,

34/30 4 weeks,

followed by

12 weeks

open-label

 66/60 Mild hypertension

Systolic 150-170

Change from baseline systolic

and diastolic pressure at 4

weeks and at 12 weeks.

 Affiliated

Physicians of

Florida, 

Ongoing as of

May 2001

126/

400

Placebo and

Dose-response

TP: 50 mg

po bid

Long-term

efficacy and

safety

30/28 55 (24-68) Diastolic 90-100

Smith & Jones

CRO

TP: 25 mg

po bid

34/32

Placebo 28/26
43

Table 2.7.3.2 Results of Efficacy Studies

 Study Treatment Arm # Enrolled/

Completed

Mean systolic and diastolic BP Primary

Endpoint

Statistical test /

 P value

Secondary

Endpoints

Other Comments

Baseline 20 wks 40 wks Placebosubtracted

change in DBP

at 40 weeks

% normalized**

(ITT analysis)

PG- TP: 100 mg po bid 34/30 162/96 140/85 138/84 6 88

2678 TP: 50 mg po bid 30/28 165/97 146/87 146/87 4 78

TP: 25 mg po bid 34/32 167/96 148/88 148/88 2 50

TP: 10 mg po bid

Placebo

26/20

28/26

162/95

166/97

153/93

160/92

153/93

159/91

-4 20

30

**Provide definition
44

Table 2.7.4.1 Study Subject Drug Exposure by Mean Daily Dose and Duration of Exposure

Intravenous formulation N= Cutoff Date:

Duration

Mean Daily Dose (mg)

(Weeks)

0 < Dose

£ 5mg

5 < Dose

£ 10mg

10 < Dose

£ 20mg

20 < Dose

£ 30mg

30 < Dose

£ 50mg 50mg < Dose

Total

(Any Dose) Percent

0 < Dur £ 1

1 < Dur £ 2

2 < Dur £ 4

4 < Dur £ 12

12 < Dur £ 24

24 < Dur £ 48

48 < Dur £ 96

Dur >96

Total

(Any Duration)

Percent

Similar tables can be generated for median, for modal, and for maximum dose, or for dose of longest exposure. The same table can be generated for

any pool of studies and any subgroup of interest (e.g., on the basis of age groupings, sex, ethnic factors, comorbid conditions, concomitant

medications, or any combination of these factors).

Dose can also be expressed as mg/kg, mg/m2, or in terms of plasma concentration if such data are available.
45

Table 2.7.4.2 Demographic Profile of Patients in Controlled Trials Cutoff Date:

 Treatment Groups

Test Product

N =

Placebo

N =

Active Control

N =

 Age (years)

 Mean ± SD

 Range

 Groups

<18

18 - 40

40 - 64

65 - 75

>75

50 ± 15

20-85

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

Sex

 Female

 Male

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

Race

Asian

Black

 Caucasian

Other

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

Other Factors
46

Table 2.7.4.3 Incidence of Adverse Events in Pooled Placebo and Active Controlled Trial Database

Body System / Adverse Event Test Drug Placebo Active

Control 1

Active Control 2

All doses

n = 1685

10 mg

n = 968

20 mg

n = 717 n = 425

20 mg

n = 653

50 mg

n = 334

100 mg

n = 546

Body as a whole

 Dizziness 19 (1%) 7 (1%) 12 (2%) 6 (1%) 23 (4%) 1 (<1%) 3 (1%)

 Etc.

Cardiovascular

 Postural Hypotension 15 (1%) 10 (1%) 5 (1%) 2 (<1%) 7 (1%) 6 (2%) 12 (2%)

 Etc.

Gastrointestinal

 Constipation
47

Table 2.7.4.4 Incidence of Adverse Events in Individual Studies

 Reported Incidence by Treatment Groups

Body System / Adverse Event Study 95-0403 Study 96-0011 Study 97-0007 Study

98-

0102s

Drug x

60 mg

bid

N =104

Drug x

30 mg bid

N =102

Placebo

N = 100

Drug x

60 mg bid

N = 500

Placebo

N=495

Drug x

60 mg bid

N=200

Drug y

100 mg qd

N=200

Drug x

60 mg

bid

N=800

Body as a whole

 Dizziness N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%)

 Etc. N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%)

Cardiovascular

 Postural

 Hypotension

 Etc.

Gastrointestinal

 Constipation
48

Table 2.7.4.5 Patient Withdrawals4 by Study: Controlled Trials Cutoff Date:

Studies Total Withdrawal Reason for Withdrawal

Number Without

Postwithdrawal

Efficacy Data

Total

Male/

Female

Age

 > 65

Race

(identify

groupings)

/ / /

Adverse

Events

N (%)

Lack of

Efficacy

N (%)

Other

N (%)

N (%)

Study

Drug X N (%) N (%) / N

(%)

N (%) N (%) / N (%) /

N (%)

XXX Placebo

Study

Drug X

AAA Comparator A

Study

Drug X

BBB Comparator B

Study

Drug X

CCC Comparator C

Note: withdrawal data can be subdivided by dose level, if that appears to be useful.

4

 Withdrawals are all subjects who were enrolled but did not complete the planned course of treatment (includes subjects who

discontinued treatment or changed to a different treatment prematurely and/or were lost to follow up).
49

Table 2.7.4.6 Listing of Deaths Treatment: Test Product: Cutoff Date:

Trial /

Source1

Center Patient

ID

Age

(yrs)

Sex Dose

(mg)

Duration of

Exposure

(Days)

Diagnosis Cause

of

Death

Other

Medications

Other

Medical

Conditions

Location of Narrative

Description

1

PM = deaths from postmarketing experience

This listing should include all deaths meeting the inclusion rule, whether arising from a clinical trial or from any secondary source (e.g.,

postmarketing experience). In electronic applications, a link to the narrative or other documentation regarding the event should be

provided.

A footnote should describe the rule for including deaths in the table (e.g., all deaths that occurred during a period of drug exposure or

within a period of up to 30 days following discontinuation from drug and also those occurring later but resulting from adverse events that

had an onset during exposure or during the 30-day follow up period). Other rules may be equally appropriate.

Similar lists should be provided for patients exposed to placebo and active control drugs.
50

MODULE 5: CLINICAL STUDY REPORTS

Preamble

Through the ICH process, a guidance has been published on the structure and content of clinical

study reports (ICH E3). The Clinical Study Reports Section of M4E provides guidance on the

organization of these study reports, other clinical data, and references within a Common Technical

Document (CTD) for registration of a pharmaceutical product for human use. These elements

should facilitate the preparation and review of a marketing application.

This guidance is not intended to indicate what studies are required for successful registration. It

indicates an appropriate organization for the clinical study reports that are in the application.

Detailed Organization of Clinical Study Reports and Related Information in Module 5

This guidance recommends a specific organization for the placement of clinical study reports and

related information in Module 5 of the CTD to simplify preparation and review of applications

and to ensure completeness. The placement of a report should be determined by the primary

objective of the study. Each study report should appear in only one section. Where there are

multiple objectives, the study should be cross-referenced in the various sections. An explanation

such as “not applicable” or “no study conducted” should be provided when no report or

information is available for a section or subsection.

5.1 TABLE OF CONTENTS FOR STUDY REPORTS AND RELATED INFORMATION

A table of contents for the study reports should be provided as follows.

5.1 TABLE OF CONTENTS FOR CLINICAL STUDY REPORTS AND RELATED

INFORMATION

5.2 TABULAR LISTING OF ALL CLINICAL STUDIES

5.3 CLINICAL STUDY REPORTS AND RELATED INFORMATION

5.3.1 Reports of Biopharmaceutic Studies

5.3.1.1 Bioavailability (BA) Study Reports

5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports

5.3.1.3 In Vitro-In Vivo Correlation Study Reports

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies

5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials

5.3.2.1 Plasma Protein Binding Study Reports

5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies

5.2.2.3 Reports of Studies Using Other Human Biomaterials

5.3.3 Reports of Human Pharmacokinetic (PK) Studies

5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports

5.3.3.2 Patient PK and Initial Tolerability Study Reports

5.3.3.3 Intrinsic Factor PK Study Reports

5.3.3.4 Extrinsic Factor PK Study Reports

5.3.3.5 Population PK Study Reports
51

5.3.4 Reports of Human Pharmacodynamic (PD) Studies

5.3.4.1 Healthy Subject PD and PK/PD Study Reports

5.3.4.2 Patient PD and PK/PD Study Reports

5.3.5 Reports of Efficacy and Safety Studies

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed

Indication

5.3.5.2 Study Reports of Uncontrolled Clinical Studies

5.3.5.3 Reports of Analyses of Data from More Than One Study (Including Any

Formal Integrated Analyses, Meta-analyses, and Bridging Analyses)

5.3.5.4 Other Study Reports

5.3.6 Reports of Postmarketing Experience

5.3.7 Case Report Forms and Individual Patient Listings

5.4 LITERATURE REFERENCES

5.2 TABULAR LISTING OF ALL CLINICAL STUDIES

A tabular listing of all clinical studies and related information should be provided. For each

study, this tabular listing generally should include the type of information identified in Table 5.1 of

this guidance. Other information can be included in this table if the applicant considers the

information useful. The sequence in which the studies are listed should follow the sequence

described in Section 5.3 below. Use of a different sequence should be noted and explained in an

introduction to the tabular listing.

5.3 CLINICAL STUDY REPORTS

5.3.1 Reports of Biopharmaceutic Studies

BA studies evaluate the rate and extent of release of the active substance from the medicinal

product. Comparative BA or BE studies may use PK, PD, clinical, or in vitro dissolution

endpoints, and may be either single dose or multiple dose. When the primary purpose of a study is

to assess the PK of a drug, but also includes BA information, the study report should be submitted

in Section 5.3.1, and referenced in Sections 5.3.1.1 and/or 5.3.1.2.

5.3.1.1 Bioavailability (BA) Study Reports

This section should include the following BA studies.

• Studies comparing the release and systemic availability of a drug substance from a solid oral

dosage form to the systemic availability of the drug substance given intravenously or as an oral

liquid dosage form

• Dosage form proportionality studies

• Food-effect studies
52

5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports

Studies in this section compare the rate and extent of release of the drug substance from similar

drug products (e.g., tablet to tablet, tablet to capsule). Comparative BA or BE studies can include

comparisons between:

• The drug product used in clinical studies supporting effectiveness and the to-be-marketed drug

product

• The drug product used in clinical studies supporting effectiveness and the drug product used in

stability batches

• Similar drug products from different manufacturers

5.3.1.3 In Vitro – In Vivo Correlation Study Reports

In vitro dissolution studies that provide BA information, including studies used in seeking to

correlate in vitro data with in vivo correlations, should be placed in Section 5.3.1.3. Reports of in

vitro dissolution tests used for batch quality control and/or batch release should be placed in the

Quality Section of the CTD.

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies

Bioanalytical and/or analytical methods for biopharmaceutic studies or in vitro dissolution studies

should ordinarily be provided in individual study reports. Where a method is used in multiple

studies, the method and its validation should be included once in Section 5.3.1.4 and referenced in

the appropriate individual study reports.

5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials

Human biomaterials is a term used to refer to proteins, cells, tissues and related materials

derived from human sources that are used in vitro or ex vivo to assess PK properties of drug

substances. Examples include cultured human colonic cells that are used to assess permeability

through biological membranes and transport processes and human albumin that is used to assess

plasma protein binding. Of particular importance is the use of human biomaterials such as

hepatocytes and/or hepatic microsomes to study metabolic pathways and to assess drug-drug

interactions with these pathways. Studies using biomaterials to address other properties (e.g.,

sterility or pharmacodynamics) should not be placed in the Clinical Study Reports Section, but in

the Nonclinical Study Section (Module 4).

5.3.2.1 Plasma Protein Binding Study Reports

Ex vivo protein binding study reports should be provided here. Protein binding data from PK

blood and/or plasma studies should be provided in Section 5.3.3.
53

5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies

Reports of hepatic metabolism and metabolic drug interaction studies with hepatic tissue should be

placed here.

5.3.2.3 Reports of Studies Using Other Human Biomaterials

Reports of studies with other biomaterials should be placed in this section.

5.3.3 Reports of Human Pharmacokinetic (PK) Studies

Assessment of the PK of a drug in healthy subjects and/or patients is considered critical to

designing dosing strategies and titration steps, to anticipating the effects of concomitant drug use,

and to interpreting observed pharmacodynamic differences. These assessments should provide a

description of the body’s handling of a drug over time, focusing on maximum plasma

concentrations (peak exposure), area-under-curve (total exposure), clearance, and accumulation of

the parent drug and its metabolites, in particular those that have pharmacological activity.

The PK studies whose reports should be included in Sections 5.3.3.1 and 5.3.3.2 are generally

designed to (1) measure plasma drug and metabolite concentrations over time, (2) measure drug

and metabolite concentrations in urine or feces when useful or critical, and/or (3) measure drug

and metabolite binding to protein or red blood cells. On occasion, PK studies may include

measurement of drug distribution into other body tissues, body organs, or fluids (e.g., synovial

fluid or cerebrospinal fluid), and the results of these tissue distribution studies should be included

in Section 5.3.3.1 or 5.3.3.2, as appropriate. These studies should characterize the drug’s PK and

provide information about the absorption, distribution, metabolism, and excretion of the drug and

any active metabolites in healthy subjects and/or patients. Studies of mass balance and changes in

PK related to dose (e.g., determination of dose proportionality) or time (e.g., due to enzyme

induction or formation of antibodies) are of particular interest and should be included in Sections

5.3.3.1 and/or 5.3.3.2. Apart from describing mean PK in normal and patient volunteers, PK

studies should also describe the range of individual variability. In the ICH guidance on ethnic

factors in the acceptance of foreign data (ICH E5), factors that may result in different responses to

a drug in different populations are categorized as intrinsic ethnic factors or extrinsic ethnic

factors. In this M4E guidance, these categories are referred to as intrinsic factors and extrinsic

factors, respectively. Additional studies can also assess differences in systemic exposure as a

result of changes in PK due to intrinsic (e.g., age, gender, racial, weight, height, disease, genetic

polymorphism, and organ dysfunction) and extrinsic (e.g., drug-drug interactions, diet, smoking,

and alcohol use) factors. Reports of PK studies examining the influence of intrinsic and extrinsic

factors on exposure should be organized in Sections 5.3.3.3 and 5.3.3.4, respectively.

In addition to standard multiple-sample PK studies, population PK analyses based on sparse

sampling during clinical studies can also address questions about the contributions of intrinsic and

extrinsic factors to the variability in the dose-PK-response relationship. Because the methods used

in population PK studies are substantially different from those used in standard PK studies,

population PK studies should be placed in Section 5.3.3.5.
54

5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports

Reports of PK and initial tolerability studies in healthy subjects should be placed in this section.

5.3.3.2 Patient PK and Initial Tolerability Study Reports

Reports of PK and initial tolerability studies in patients should be placed in this section.

5.3.3.3 Intrinsic Factor PK Study Reports

Reports of PK studies to assess effects of intrinsic factors should be placed in this section.

5.3.3.4 Extrinsic Factor PK Study Reports

Reports of PK studies to assess effects of extrinsic factors should be placed in this section.

5.3.3.5 Population PK Study Reports

Reports of population PK studies based on sparse samples obtained in clinical trials including

efficacy and safety trials should be placed in this section.

5.3.4 Reports of Human Pharmacodynamic (PD) Studies

Reports of studies with a primary objective of determining the PD effects of a drug product in

humans should be placed in this section. Reports of studies whose primary objective is to

establish efficacy or to accumulate safety data should be placed in Section 5.3.5. 

This section should include reports of (1) studies of pharmacologic properties known or thought to

be related to the desired clinical effects (biomarkers), (2) short-term studies of the main clinical

effect, and (3) PD studies of other properties not related to the desired clinical effect. Because a

quantitative relationship of these pharmacological effects to dose and/or plasma drug and

metabolite concentrations is usually of interest, PD information is frequently collected in doseresponse studies or together with drug concentration information in PK studies (concentrationresponse or PK/PD studies). Relationships between PK and PD effects that are not obtained in

well-controlled studies are often evaluated using an appropriate model and used as a basis for

designing further dose-response studies or, in some cases, for interpreting effects of concentration

differences in population subsets.

Dose-finding, PD, and/or PK-PD studies can be conducted in healthy subjects and/or patients and

can also be incorporated into the studies that evaluate safety and efficacy in a clinical indication. 

Reports of dose-finding, PD, and/or PK/PD studies conducted in healthy subjects should be placed

in Section 5.3.4.1, and the reports for those studies conducted in patients should be placed in

Section 5.3.4.2. 

In some cases, the short-term PD, dose-finding, and/or PK-PD information found in

pharmacodynamic studies conducted in patients will provide data that contribute to assessment of
55

efficacy because they show an effect on either an acceptable surrogate marker (e.g., blood

pressure) or a clinical benefit endpoint (e.g., pain relief). Similarly, a PD study can contain

important clinical safety information. When these studies are part of the efficacy or safety

demonstration, they are considered clinical efficacy and safety studies that should be included in

Section 5.3.5, not in Section 5.3.4.

5.3.4.1 Healthy Subject PD and PK/PD Study Reports

PD and/or PK/PD studies having nontherapeutic objectives in healthy subjects should be placed in

this section.

5.3.4.2 Patient PD and PK/PD Study Reports

PD and/or PK/PD studies in patients should be submitted in this section.

5.3.5 Reports of Efficacy and Safety Studies

This section should include reports of all clinical studies of efficacy and/or safety carried out with

the drug, conducted by the sponsor or otherwise available, including all completed and all ongoing

studies of the drug in proposed and nonproposed indications. The study reports should provide the

level of detail appropriate to the study and its role in the application. ICH E3 describes the

contents of a full report for a study contributing evidence pertinent to both safety and efficacy. 

Abbreviated reports can be provided for some studies (see ICH E3 and individual guidance by

region).

Within Section 5.3.5, studies should be organized by design (controlled, uncontrolled) and, within

controlled studies, by type of control. Within each section, studies should be categorized further,

ordered by whether the study report is complete or abbreviated (ICH E3), with completely

reported studies presented first. Published reports with limited or no further data available to the

sponsor should be placed last in this section. 

In cases where the application includes multiple therapeutic indications, the reports should be

organized in a separate Section 5.3.5 for each indication. In such cases, if a clinical efficacy study

is relevant to only one of the indications included in the application, the study should be included

in the appropriate Section 5.3.5; if a clinical efficacy study is relevant to multiple indications, the

study report should be included in the most appropriate Section 5 and referenced as appropriate in

other Sections 5.3.5 (e.g., Section 5.3.5A, Section 5.3.5B).

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed

Indication

The controlled clinical study reports should be sequenced by type of control:

• Placebo control (could include other control groups, such as an active\comparator or other

doses)

• No-treatment control
56

• Dose-response (without placebo)

• Active control (without placebo)

• External (historical) control, regardless of the control treatment

Within each control type, where relevant to assessment of drug effect, studies should be organized

by treatment duration. Studies of indications other than the one proposed in the application, but

that provide support for efficacy in the proposed use, should be included in Section 5.3.5.1.

Where a pharmacodynamic study contributes to evidence of efficacy, it should be included in

Section 5.3.5.1. The sequence in which studies were conducted is not considered pertinent to their

presentation. Thus, placebo-controlled trials, whether early or late, should be placed in Section

5.3.5.1. Controlled safety studies, including studies in conditions that are not the subject of the

application, should also be reported in Section 5.3.5.1.

5.3.5.2 Study Reports of Uncontrolled Clinical Studies

Study reports of uncontrolled clinical studies (e.g., reports of open label safety studies) should be

included in Section 5.3.5.2. This includes studies in conditions that are not the subject of the

marketing application.

5.3.5.3 Reports of Analyses of Data from More than One Study (Including Any Formal

Integrated Analyses, Meta-Analyses, and Bridging Analyses)

Many clinical issues in an application can be addressed by an analysis considering data from more

than one study. The results of such an analysis should generally be summarized in the clinical

summary documents, but a detailed description and presentation of the results of such analyses are

considered critical to their interpretation. Where the details of the analysis are too extensive to be

reported in a summary document, they should be presented in a separate report. Such reports

should be placed in Section 5.3.5.3. Examples of reports that would be placed in this section

include (1) a report of a formal meta-analysis or extensive exploratory analysis of efficacy to

determine an overall estimate of effect size in all patients and/or in specific subpopulations and

(2) a report of an integrated analysis of safety that assesses such factors as the adequacy of the

safety database, estimates of event rates, and safety with respect to variables such as dose,

demographics, and concomitant medications. A report of a detailed analysis of bridging,

considering formal bridging studies, other relevant clinical studies, and other appropriate

information (e.g., PK and PD information), should be placed in this section if the analysis is too

lengthy for inclusion in the Clinical Summary.

5.3.5.4 Other Study Reports6

This section can include:

• Reports of interim analyses of studies pertinent to the claimed indications

 

6

 This section also includes reports of any studies not included in other sections of Module 5 (e.g., reports that were summarized

in Section 2.7.2.4).
57

• Reports of controlled safety studies not reported elsewhere

• Reports of controlled or uncontrolled studies not related to the claimed indication

• Published reports of clinical experiences with the medicinal product that are not included in

Section 5.3.5.1. However, when literature is important to the demonstration or substantiation

of efficacy, it should be included in Section 5.3.5.1.

• Reports of ongoing studies

5.3.6 Reports of Postmarketing Experience

For products that are currently marketed, reports that summarize marketing experience (including

all significant safety observations) should be included in Section 5.3.6.

5.3.7 Case Report Forms and Individual Patient Listings

Case report forms and individual patient data listings that are described as appendices 16.3 and

16.4 in the ICH clinical study report guidance (E3) should be placed in this section when

submitted, in the same order as the clinical study reports and indexed by study.

5.4 LITERATURE REFERENCES

Copies of referenced documents, including important published articles, official meeting minutes,

or other regulatory guidance or advice should be provided here. This includes copies of all

references cited in the Clinical Overview and copies of important references cited in the Clinical

Summary or in the individual technical reports that were provided in Module 5, section 5.3. Only

one copy of each reference should be provided. Copies of references that are not included here

should be available immediately on request.
58

Table 5.1. Listing of Clinical Studies

Type of

Study

Study

Identifier

Location

of Study

Report

Objective(s) of

the Study

Study Design

and Type of

Control

Test Product(s);

Dosage

Regimen;

Route of

Administration

Number of

Subjects

Healthy

Subjects or

Diagnosis of

Patients

Duration of

Treatment

Study

Status;

Type of

Report

BA 001 Vol 3, Sec.

1.1, p. 183

Absolute BA IV

vs Tablet

Cross-over Tablet, 50 mg

single dose, oral,

10 mg IV

20 Healthy

Subjects

Single dose Complete;

Abbreviated

BE 002 Vol 4, Sec.

1.2, p. 254

Compare clinical

study and to-bemarketed

formulation

Cross-over Two tablet

formulations, 50

mg, oral

32 Healthy

Subjects

Single dose Complete;

Abbreviated

PK 1010 Vol 6, Sec.

3.3, p. 29

Define PK Cross-over Tablet, 50 mg

single dose, oral

50 Renal

Insufficiency

Single dose Complete;

Full

PD 020 Vol 6, Sec.

4.2, p. 147

Bridging study

between regions

Randomized

placebocontrolled

Tablet, 50 mg,

multiple dose,

oral, every 8 hrs

24 (12 drug,

12 placebo)

Patients with

primary

hypertension

2 weeks Ongoing;

Interim

Efficacy 035 Vol 10,

Sec. 5.1, p.

1286

Long-term;

Efficacy and

Safety;

Population PK

analysis

Randomized

activecontrolled

Tablet, 50 mg,

oral, every 8 hrs

300 (152 test

drug, 148

active

control)

Patients with

primary

hypertension

48 weeks Complete;

Full