M4E(R2): The CTD  Efficacy  
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
July 2017 
ICH 
 
Revision 1 
  M4E(R2): The CTD  Efficacy 
 
Guidance for Industry 
 
 
 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
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Email: druginfo@fda.hhs.gov  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
or 
 
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 Food and Drug Administration 
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Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
July 2017 
ICH 
 
Revision 1
      Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
 
BACKGROUND ........................................................................................................................... 2 
Preparing and Organizing the CTD ..................................................................................................... 2 
Organization and Format of the ICH Guidances for Industry .......................................................... 6 
Numbering............................................................................................................................................... 6 
MODULE 2:  COMMON TECHNICAL DOCUMENT SUMMARIES ................................. 7 
2.5  CLINICAL OVERVIEW ...................................................................................................... 7 
Preamble .................................................................................................................................................. 7 
Table of Contents .................................................................................................................................... 8 
Detailed Discussion of Content of the Clinical Overview Sections ..................................................... 9 
2.5.1  PRODUCT DEVELOPMENT RATIONALE ................................................................. 9 
2.5.2  OVERVIEW OF BIOPHARMACEUTICS ..................................................................... 9 
2.5.3  OVERVIEW OF CLINICAL PHARMACOLOGY ....................................................... 9 
2.5.4  OVERVIEW OF EFFICACY .......................................................................................... 10 
2.5.5  OVERVIEW OF SAFETY .............................................................................................. 11 
2.5.6  BENEFITS AND RISKS CONCLUSIONS .................................................................... 13 
Preamble ................................................................................................................................................ 13 
2.5.6.1  Therapeutic Context ............................................................................................................... 14 
2.5.6.1.1  Disease or Condition .......................................................................................................... 14 
2.5.6.1.2  Current Therapies .............................................................................................................. 14 
2.5.6.2   Benefits .................................................................................................................................... 15 
2.5.6.3   Risks ......................................................................................................................................... 16 
2.5.6.4   Benefit-Risk Assessment ........................................................................................................ 18 
2.5.6.5  Appendix .................................................................................................................................. 18 
2.5.7  LITERATURE REFERENCES ...................................................................................... 19 
2.7  CLINICAL SUMMARY ..................................................................................................... 20 
Preamble ................................................................................................................................................ 20 
Table of Contents .................................................................................................................................. 20 
Detailed Guidance on Sections of the Clinical Summary.................................................................. 21 
2.7  CLINICAL SUMMARY ..................................................................................................... 21 
2.7.1  SUMMARY OF BIOPHARMACEUTIC STUDIES AND ASSOCIATED 
ANALYTICAL METHODS ...................................................................................................... 21 
2.7.1.1  Background and Overview ..................................................................................................... 21 
    i    Contains Nonbinding Recommendations 
 
 
2.7.1.2  Summary of Results of Individual Studies ............................................................................ 21 
2.7.1.3  Comparison and Analyses of Results Across Studies ........................................................... 21 
2.7.1.4 Appendix ................................................................................................................................... 22 
2.7.2  SUMMARY OF CLINICAL PHARMACOLOGY STUDIES ................................... 23 
2.7.2.1  Background and Overview ..................................................................................................... 23 
2.7.2.2  Summary of Results of Individual Studies ............................................................................ 23 
2.7.2.3  Comparison and Analyses of Results Across Studies ........................................................... 24 
2.7.2.4  Special Studies ......................................................................................................................... 25 
2.7.2.5 Appendix ................................................................................................................................... 26 
2.7.3  SUMMARY OF CLINICAL EFFICACY .................................................................... 27 
2.7.3.1  Background and Overview of Clinical Efficacy .................................................................... 27 
2.7.3.2  Summary of Results of Individual Studies ............................................................................ 27 
2.7.3.3  Comparison and Analyses of Results Across Studies ........................................................... 28 
2.7.3.3.1  Study Populations ............................................................................................................... 28 
2.7.3.3.2  Comparison of Efficacy Results of all Studies .................................................................... 29 
2.7.3.3.3  Comparison of Results in Subpopulations .......................................................................... 29 
2.7.3.4  Analysis of Clinical Information Relevant to Dosing Recommendations ........................... 30 
2.7.3.5  Persistence of Efficacy and/or Tolerance Effects .................................................................. 31 
2.7.3.6 Appendix ................................................................................................................................... 31 
2.7.4  SUMMARY OF CLINICAL SAFETY ......................................................................... 31 
2.7.4.1  Exposure to the Drug .............................................................................................................. 32 
2.7.4.1.1  Overall Safety Evaluation Plan and Narratives of Safety Studies ...................................... 32 
2.7.4.1.2  Overall Extent of Exposure ................................................................................................ 32 
2.7.4.1.3  Demographic and Other Characteristics of Study Population ........................................ 33 
2.7.4.2  Adverse Events ......................................................................................................................... 34 
2.7.4.2.1  Analysis of  Adverse Events ................................................................................................ 34 
2.7.4.2.2   Narratives .......................................................................................................................... 38 
2.7.4.3  Clinical Laboratory Evaluations ............................................................................................ 39 
2.7.4.4  Vital Signs, Physical Findings, and Other Observations Related to Safety ....................... 39 
2.7.4.5  Safety in Special Groups and Situations ................................................................................ 40 
2.7.4.5.1  Intrinsic Factors ................................................................................................................. 40 
2.7.4.5.2  Extrinsic Factors ................................................................................................................ 40 
2.7.4.5.3 Drug Interactions ................................................................................................................ 40 
2.7.4.5.4  Use in Pregnancy and Lactation ........................................................................................ 41 
2.7.4.5.5  Overdose ............................................................................................................................. 41 
2.7.4.5.6  Drug Abuse ......................................................................................................................... 41 
2.7.4.5.7  Withdrawal and Rebound ................................................................................................... 41 
2.7.4.5.8  Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability ......... 41 
2.7.4.6  Postmarketing Data ................................................................................................................. 41 
    ii    Contains Nonbinding Recommendations 
 
 
2.7.4.7 Appendix ................................................................................................................................... 42 
2.7.5  LITERATURE REFERENCES .................................................................................... 42 
2.7.6  SYNOPSES OF INDIVIDUAL STUDIES.................................................................... 42 
MODULE 5:  CLINICAL STUDY REPORTS ........................................................................ 56 
Preamble ................................................................................................................................................ 56 
Detailed Organization of Clinical Study Reports and Related Information in Module 5 .............. 56 
5.2  TABULAR LISTING OF ALL CLINICAL STUDIES .............................................. 57 
5.3  CLINICAL STUDY REPORTS .................................................................................... 57 
5.3.1  Reports of Biopharmaceutic Studies ......................................................................................... 57 
5.3.1.1  Bioavailability (BA) Study Reports ....................................................................................... 57 
5.3.1.2  Comparative BA and Bioequivalence (BE) Study Reports .................................................... 58 
5.3.1.3  In Vitro  In Vivo Correlation Study Reports ........................................................................ 58 
5.3.1.4  Reports of Bioanalytical and Analytical Methods for Human Studies .................................. 58 
5.3.2  Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials ................... 58 
5.3.2.1 Plasma Protein Binding Study Reports .................................................................................. 59 
5.3.2.2  Reports of Hepatic Metabolism and Drug Interaction Studies ............................................. 59 
5.3.2.3  Reports of Studies Using Other Human Biomaterials ........................................................... 59 
5.3.3  Reports of Human Pharmacokinetic (PK) Studies .................................................................. 59 
5.3.3.1   Healthy Subject PK and Initial Tolerability Study Reports .................................................. 60 
5.3.3.2   Patient PK and Initial Tolerability Study Reports ............................................................... 60 
5.3.3.3   Intrinsic Factor PK Study Reports ....................................................................................... 60 
5.3.3.4   Extrinsic Factor PK Study Reports ...................................................................................... 60 
5.3.3.5  Population PK Study Reports ................................................................................................ 60 
5.3.4  Reports of Human Pharmacodynamic (PD) Studies ............................................................... 60 
5.3.4.1  Healthy Subject PD and PK/PD Study Reports .................................................................... 61 
5.3.4.2  Patient PD and PK/PD Study Reports .................................................................................. 61 
5.3.5  Reports of Efficacy and Safety Studies ..................................................................................... 61 
5.3.5.1  Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication .............. 62 
5.3.5.2   Study Reports of Uncontrolled Clinical Studies ................................................................. 62 
5.3.5.3   Reports of Analyses of Data from More than One Study (Including Any Formal Integrated 
Analyses, Meta-Analyses, and Bridging Analyses) ............................................................. 62 
5.3.5.4   Other Study Reports ........................................................................................................... 63 
5.3.6  Reports of Postmarketing Experience ...................................................................................... 63 
5.3.7  Case Report Forms and Individual Patient Listings ............................................................... 63 
5.4  LITERATURE REFERENCES ......................................................................................... 63 
    iii    Contains Nonbinding Recommendations 
 
 
M4E(R2):  The CTD  Efficacy 
1
Guidance for Industry  
 
 
   
This guidance represents the current thinking of the  Food and Drug Administration (FDA or Agency) 
on this topic.  It does not establish any rights for any  person and is not binding on FDA or the public.  
You can use an alternative approach if it satisfies the requirements of the applicable statutes and 
 
regulations.  To discuss an alternative approach, contact the FDA office responsible for this guidance 
 
as listed on the title page.   
 
 
 
 
 
 
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 or Agency). A common format for 
technical documentation significantly reduces the time and resources needed to compile 
applications for registration of human pharmaceuticals by eliminating the need for applicants to 
reformat data and information for submission to multiple regulatory authorities. This 
harmonization facilitates regulatory reviews, efficient communication between regulators and 
applicants, as well as the efficient exchange of information between regulatory authorities. 
 
Through the International Council for Harmonization (ICH) process, considerable harmonization 
has been achieved among the major pharmaceutical regulatory regions in the technical 
requirements for the registration of pharmaceuticals for human use. The assembly of Quality, 
Safety, and Efficacy information in the CTD format is either required or strongly recommended 
by the regulatory members of ICH (i.e., the European Commission; the Ministry of Health, 
Labor, and Welfare of Japan as represented by the Pharmaceuticals and Medical Devices 
Agency; the U.S. FDA; Health Canada; Swissmedic; Brazils Agencia Nacional de Vigilancia 
Sanitaria; and the Ministry of Food and Drug Safety in South Korea).  This guidance presents the 
agreed-upon common format that will be accepted in the ICH regulatory regions for the 
preparation of a well-structured Efficacy section of the CTD. 
   
                                                 
1 This guidance was developed within the Expert Working Group (Efficacy) of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (formerly the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use), 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 on June 15, 2016.  At Step 4 of the process, 
the final draft is recommended for adoption to the regulatory authorities represented at ICH. 
 
    1      Contains Nonbinding Recommendations 
 
 
For information on the Quality and Safety sections of the CTD, refer to 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 Agencys 
guidance for industry Submitting Marketing Applications According to the ICH/CTD Format: 
General Considerations (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. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
BACKGROUND  
 
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 Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal 
Editors (ICMJE).3 
                                                 
2 In September 2001, FDA issued a draft version of the General Considerations guidance.  When final, this guidance 
will represent FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA 
Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
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. 
    2      Contains Nonbinding Recommendations 
 
 
 
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. 
 
Module 5.  Clinical Study Reports 
The human study reports and related information should be presented in the order 
described in the guidance M4E. 
 
    3      Diagrammatic Representation of the ICH Common Technical 
 
Document
 
 
   
Not Part of 
the CTD 
Module 1 
Regional  
Administrative 
Information 
1 
1.1 Submission  
T of  C 
CTD Table of Contents 
2.1 
 
CTD Introduction 
2.2 
 
Module 2 Nonclinical  Clinical 
Overview  Overview 
2.4  2.5 
 
CTD
Quality 
Overall 
Summary  Nonclinical  Clinical 
2.3  Written and   Summary 
Tabulated   2.7 
Summaries 
2.6 
Module 3  Module 4  Module 5 
Quality  Nonclinical  Clinical 
3  Study Reports  Study Reports 
3.1 T of C  4  5 
 
4.1 T of C  5.1 T of C
    4      Contains Nonbinding Recommendations 
 
 
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 
 
 
    5      Contains Nonbinding Recommendations 
 
 
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 sections 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). 
    6      Contains Nonbinding Recommendations 
 
 
MODULE 2:  COMMON TECHNICAL DOCUMENT SUMMARIES 
 
2.5  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 necessarily 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 present the strengths and limitations of the 
development program and study results, analyze the benefits and risks of the medicinal product 
in its intended use, and describe how the study results support critical parts of the prescribing 
information. 
 
To achieve these objectives, the Clinical Overview should: 
 
  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 
 
    7      Contains Nonbinding Recommendations 
 
 
  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 
 
The Clinical Overview should generally 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. 
 
Table of Contents 
 
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 
2.5.6.1 Therapeutic Context 
2.5.6.1.1  Disease or Condition 
2.5.6.1.2  Current Therapies 
2.5.6.2 Benefits 
2.5.6.3 Risks 
2.5.6.4 Benefit-Risk Assessment 
2.5.6.5 Appendix 
2.5.7  Literature References 
    8      Contains Nonbinding Recommendations 
 
 
Detailed Discussion of Content of the Clinical Overview Sections 
 
 
 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). 
 
  Include a brief overview of the major therapies currently used in the intended population. 
 
  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(s) 
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 formulation(s) (e.g., 
dosage form/strength proportionality, differences between the to-be-marketed formulation and 
the formulation(s) 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.  It should 
emphasize unusual results and known or potential problems, or note the lack thereof.  This 
section should address: 
    9      Contains Nonbinding Recommendations 
 
 
 
  Pharmacokinetics, e.g., comparative pharmacokinetics in healthy subjects, patients, and 
special populations; pharmacokinetics 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, e.g., information on mechanism of action, such as receptor binding; 
onset and/or offset of action; relationship of favorable and unfavorable PK 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; and possible genetic differences in response 
 
  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 population(s) and the population that would be expected to receive the 
medicinal product after marketing should be discussed.  
 
  Implications of the study design(s), including selection of patients, duration of studies, and 
choice of endpoints and control group(s).  Particular attention should be given to endpoints 
for which 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). 
    10      Contains Nonbinding Recommendations 
 
 
 
  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 
long-term 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. 
 
  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. 
    11      Contains Nonbinding Recommendations 
 
 
 
  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: 
 
 The extent of the world-wide experience 
 
 Any new or different safety issues identified 
 
    12      Contains Nonbinding Recommendations 
 
 
 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 
 
Preamble 
 
The purpose of this section is to provide a succinct, integrated, and clearly explained benefit- 
risk assessment of the medicinal product for its intended use.  The benefit-risk assessment is 
based on a weighing of the key benefits and key risks of the medicinal product.  Key benefits 
are favorable effects generally assessed by primary and other clinically important endpoints 
across the studies in a development program; key risks are unfavorable effects that are important 
from a clinical and/or public health perspective in terms of their frequency and/or severity.  The 
identification of the key benefits and key risks of a product requires a critical evaluation of the 
entirety of the efficacy and safety information regarding the medicinal product.  Not all benefits 
and risks will necessarily be considered key benefits and key risks. Subsequent benefit-risk 
assessments of approved products are the subject of the ICH E2C(R2) (Periodic Benefit-Risk 
Evaluation Report: PBRER) guidance, which similarly uses the concepts of key benefits and key 
risks. 
 
The following points should be considered when completing this section: 
 
  The aspects of the therapeutic context, benefits, and risks in the subsequent sections most 
pertinent to the benefit-risk assessment should be discussed in section 2.5.6.  References to 
more detailed information presented elsewhere in the application should be used to 
avoid unnecessary repetition in this section. 
 
  If multiple indications are proposed for the medicinal product, the applicant should consider 
whether to discuss them separately or together in the appropriate sections.  Where indications 
are discussed separately, a separate section should be provided for each indication using 
headings (e.g., 2.5.6.1 Pneumonia and 2.5.6.1 Upper Respiratory Infection). 
 
  In some cases, certain effects of the medicinal product may reasonably be described under 
either benefits or risks, but they should not be discussed as both. 
 
    Data on benefits and risks may arise from multiple sources across different populations.  
Presentations of the aggregated results may be provided, if appropriate.  The applicant 
should explain how the various data sources were handled (e.g., exclusion of particular 
studies, pooling strategy). 
 
  For situations where the intended population differs from the study population (e.g., where 
enrichment  strategies  have  been  employed),  the  benefit-risk  assessment  should  be 
presented for the intended population. 
 
    13      Contains Nonbinding Recommendations 
 
 
  Information about the patient perspective4 may be considered when describing the 
therapeutic context, benefits, risks, and the benefit-risk assessment. 
 
  Applicants may, at their discretion, use summary tables or graphical displays to 
communicate the clinical importance of the key benefits and key risks, as well as the 
resulting benefit-risk assessment. 
 
2.5.6.1  Therapeutic Context 
 
This section should briefly discuss the therapeutic context for the medicinal product.   The 
term therapeutic context describes the disease or condition to be treated, the population intended 
to be treated, and the benefits and risks of current therapies.5  Important limitations in the 
understanding of the condition and uncertainties in the benefits and risks of current therapies 
should be discussed.   If differences in relevant subpopulations are known, they should be 
discussed.  Information on the benefits and risks of the medicinal product should not be 
included here, but should be discussed in sections 2.5.6.2 and 2.5.6.3, respectively. 
 
2.5.6.1.1  Disease or Condition 
 
This section provides a description of aspects of the disease or condition that are most relevant 
to,  or  have  the  greatest  impact  on,  the  intended  population  (e.g.,  incidence,  duration, 
morbidity,  mortality,  health-related quality of life).    The discussion should focus on the 
aspects of the disease that would be covered by the proposed indication for the medicinal 
product.  Societal or public health implications of the disease (e.g., impact of poor prevention 
and control of an infectious disease) should also be addressed where relevant. 
 
2.5.6.1.2  Current Therapies 
 
This section provides a description of the major therapies in the intended population (i.e., 
those therapies used most frequently and/or recommended in clinical guidelines) and the 
medical need for a new therapy in terms of efficacy, safety, tolerability, convenience, or 
preference, if applicable.  For disease areas that are treated by different pharmacologic classes 
of therapies, this analysis may be simplified by grouping and providing commentary by drug 
class.  Other interventions used for the intended population may also be discussed when their 
use is supported by established clinical practice or clinical guidelines.   Such interventions 
could include medical and surgical procedures, drugs used off-label, and other nondrug 
interventions (e.g., diet modifications, physical therapy).  Major differences in current therapies 
between regions may be noted.  If no therapies are currently available to treat the intended 
                                                 
4 Patient perspective information describes the attitudes and preferences of patients with respect to the therapeutic 
context, benefits, and risks. Such information may be obtained directly from patients or indirectly from other 
stakeholders (e.g., parents and caregivers) using qualitative, quantitative, or descriptive methods. The detailed 
presentation of this information, if available, should be submitted in Module 5. 
 
5 For purposes of section 2.5.6, the term therapy encompasses both pharmacologic and nonpharmacologic interventions, as 
well as preventive measures and diagnostics.  In addition, the terms therapy and treatment are used interchangeably. 
 
    14      Contains Nonbinding Recommendations 
 
 
population, this should be stated. 
 
2.5.6.2   Benefits 
 
This section provides a factual summary of the data on the key benefits that will be discussed 
in the benefit-risk assessment of the medicinal product.  Benefits are the favorable effects of the 
medicinal product.  In some cases, a benefit may be described by a combination of study 
endpoints (e.g., the benefit of improved asthma control described by the frequency of 
exacerbations and hospitalizations and the number of asthma-related deaths).  If a surrogate 
endpoint(s) is the basis of the benefit assessment, the ability of the surrogate to predict clinical 
benefit and the basis for this expectation should be explained.  Benefits may also include 
important characteristics of the medicinal product, such as convenience (e.g., a more convenient 
dosing regimen or route of administration) that may lead to improved patient compliance, or 
benefits that affect those other than the patient (e.g., population benefits of a vaccine due to herd 
immunity). 
 
When identifying the key benefits of the medicinal product, the following characteristics should 
be considered: 
 
  Clinical importance of the benefit (e.g., life-prolonging, curative, disease-modifying, 
symptomatic relief, improved patient compliance, functional or quality of life 
improvement, prevention of disease progression, prevention of infectious disease, 
diagnostic). 
 
  Magnitude of the absolute difference in frequency of the effect in the study population 
versus the comparator(s); in some cases, also expressing the difference relative to the 
comparator may be informative (e.g., if the response rate is 20% in the drug group and 
8% in the control group, the absolute difference is 12% (i.e., 20% minus 8%) and the 
relative effect is 2.5 (i.e., 20% minus 8%)). 
 
When describing each key benefit, in addition to the points above, the following considerations 
may also be discussed: 
 
  Time course of the key benefit (e.g., time to onset, continued effect of the product over 
time) 
 
  Variability of the key benefit, taking into account relevant subpopulations such as those 
defined by age, sex, ethnicity, organ function, disease severity, or genetic polymorphism 
 
This section should also include an analysis of the strengths, limitations, and uncertainties of the 
evidence related to each key benefit and the implications of this information.   The following 
points may be considered, as applicable: 
 
  Sudy design considerations (e.g., superiority or noninferiority comparison to active 
control, superiority comparison to placebo, blinding, absence of comparator) 
    15      Contains Nonbinding Recommendations 
 
 
 
  Completeness of data collection and duration of follow-up 
 
  Number of clinical studies and consistency of results across studies 
 
  Relationship between exposure (e.g., drug levels in the blood) and benefit 
 
  Generalizability of the clinical study result to clinical practice (e.g., clinically important 
differences between the study population and the intended population) 
 
  Confidence that surrogate endpoints, if used, predict that the intended population will 
benefit 
 
2.5.6.3   Risks 
 
This section provides a factual summary of the data on the key risks that will be discussed in the 
benefit-risk assessment of the medicinal product.  Risks include adverse events and other 
unfavorable effects associated with the medicinal product.  Risks that may be considered also 
include drug interactions, risks identified in the nonclinical data, risks to those other than the 
patient (e.g., fetus, those preparing and administering the medicinal product), and risks based on  
pharmacologic  class  or current  knowledge of the  product.  Factors such as potential misuse, 
abuse, or diversion of the product may also be considered. 
 
The key risks described in this section may not include all risks that are described elsewhere 
(e.g., risk management plan, prescribing information).  When identifying the key risks of the 
medicinal product, the following characteristics of risks should be considered: 
 
    Seriousness and/or severity 
    Frequency 
    Reversibility 
    Tolerability 
 
When describing each key risk, in addition to the points above, the following considerations 
may also be discussed: 
 
  Frequencies should generally be presented as the absolute difference relative to the 
comparator (e.g., placebo, active comparator), and in the context of the background 
frequency in the patient population.  In some cases, also expressing the difference 
relative to the comparator may be informative.  If the frequency is 8% in the treatment 
group and 5% in the control group, the absolute difference is 3% (i.e., 8% minus 5%) and 
the relative risk is 1.6 (i.e., 8% minus 5%). 
 
  Ability to monitor, minimize, or manage the risk. 
 
 
    16      Contains Nonbinding Recommendations 
 
 
  Variability of the key risk, taking into account relevant subpopulations such as those 
defined by age, sex, ethnicity, weight, organ function, disease severity, concomitant 
illness, concomitant therapy, or genetic polymorphism. 
 
  Time course of the adverse event in the study population (i.e., time to onset and 
resolution, whether the frequency of the event is highest when initiating the drug and 
subsequently decreases, is relatively constant with time, or increases with cumulative 
exposure). 
 
This section should also include an analysis of the strengths, limitations, and uncertainties of the 
evidence related to each key risk and the implications of this information.  The following points 
may be considered, as applicable: 
 
  Study design considerations (e.g., comparison to active control, comparison to placebo, 
blinding, absence of comparator) 
 
  Adequacy of assessment of risk (e.g., number of patients, number and design of trials, 
duration of exposure, frequency of monitoring) 
 
  Investigation(s) to address safety issues identified during development (e.g., an 
ophthalmologic investigation conducted to address a nonclinical finding) 
 
  Completeness of data collection and duration of follow-up 
 
  Number of patients in relevant subpopulations treated at the intended dose 
 
  Mechanism of action for the adverse event, if known, including nonclinical information 
or class effects 
 
  Completeness of information  on  patient  characteristics  (e.g.,  smoking history, 
concomitant medication use) that may affect risk 
 
  Consistency of results across studies 
 
  Relationship between exposure (e.g., drug levels in the blood) and risk 
 
  Generalizability of the clinical study results to clinical practice (e.g., clinically important 
differences between the study population and the intended population) 
 
The proposed approach to managing each key risk should also be discussed, including an 
explanation of why the approach provides reasonable assurance that the risk can be 
appropriately managed.  Repetition of details from the risk management plan is not necessary. 
In certain cases, a discussion of the overall approach to risk management may be sufficient 
and may be included after all key risks have been identified and described. 
 
    17      Contains Nonbinding Recommendations 
 
 
2.5.6.4   Benefit-Risk Assessment 
 
This section should provide the applicants conclusion on the benefit-risk assessment of the 
medicinal product in the proposed indication(s).  This should begin with a succinct explanation 
of the reasoning and judgment used in assessing and weighing the key benefits and key risks.   
In addition, the applicant should explain how any uncertainties affected the interpretation of 
the evidence and their impact on the benefit-risk assessment. 
 
When describing the benefit-risk assessment, the following additional aspects should be 
considered: 
 
  The  impact  of  the  therapeutic  context  on  the  assessment,  which  may  include 
information on the patient perspective if available.  This discussion should consist of 
the following: 
 
  How the severity of disease and expected benefit influence the acceptability of 
o
the risks of the therapy 
 
  How the medicinal product addresses a medical need 
o
 
  Key aspects of risk management that are important in reaching a favorable  benefit-
risk assessment, such as: 
 
  The proposed labeling 
o
 
  Whether nonresponders can be readily identified, allowing them to discontinue 
o
treatment 
 
  Other risk management activities, such as registries or restricted distribution 
o
systems 
 
There are many approaches available for conducting the benefit-risk assessment.   This guidance 
does not prescribe a specific approach.  A descriptive approach that explicitly communicates the 
interpretation of the data and the benefit-risk assessment will generally be adequate.  An 
applicant may choose to use methods that quantitatively express the underlying judgments and 
uncertainties in the assessment.  Analyses that compare and/or weigh benefits and risks using 
the submitted evidence may be presented.  However, before using any method, the applicant 
should consider its utility, complexity, the extent to which the method is established, and the 
ease of interpretation of the results.  In this situation, the written summary and explanation of 
the conclusions should be provided in this section, but the detailed presentations of the methods 
and results should be appended in section 2.5.6.5.  Tables or figures may be included in this 
section to support or provide greater clarity to key points or conclusions. 
 
2.5.6.5  Appendix 
 
    18      Contains Nonbinding Recommendations 
 
 
Detailed presentation of methods and results used in the benefit-risk assessment that are 
summarized in section 2.5.6.4 can be provided in this section. 
 
2.5.7  LITERATURE REFERENCES 
 
A list of references used, stated in accordance with the current edition of the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of 
Medical Journal Editors (ICMJE)6 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.  
                                                 
6 The first edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals was conceived 
by the Vancouver Group and was published in 1979. 
    19      Contains Nonbinding Recommendations 
 
 
2.7  CLINICAL SUMMARY 
 
Preamble 
 
The Clinical Summary is intended to provide a detailed, factual summarization of all of the 
clinical information in the Common Technical Document.  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 Clinical Summary will usually 
be in the range of 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 
2.7.1.4  Appendix 
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 
2.7.2.5  Appendix 
2.7.3  SUMMARY OF CLINICAL EFFICACY 
2.7.3.1  Background and Overview of Clinical Efficacy 
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 
2.7.3.6 Appendix 
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 
    20      Contains Nonbinding Recommendations 
 
 
2.7.4.5 Safety in Special Groups and Situations 
2.7.4.6 Postmarketing Data 
2.7.4.7 Appendix 
2.7.5  LITERATURE REFERENCES 
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, comparative bioavailability, bioequivalence, 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 generally be provided (see section 2.7.1.4 
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 
bioavailability and bioequivalence.  The narrative descriptions should be brief (e.g., 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 
 
    21      Contains Nonbinding Recommendations 
 
 
This section should provide a factual summary of all in vitro dissolution, bioavailability, and 
comparative bioavailability (BA) studies carried out with the drug substance or drug product, 
with particular attention to differences in results across studies.  This overview should typically 
summarize the findings in text and tables (see section 2.7.1.4 Appendix) and should consider the 
following: 
 
  Evidence of the effects of formulation and manufacturing changes on in vitro dissolution and 
bioavailability and conclusions regarding bioequivalence.  When manufacturing or 
formulation changes are made for products containing complex drug substances (e.g., a 
protein), PK studies comparing the product before and after the changes may 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 bioequivalence (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.  Note also that PK studies alone may not be sufficient to 
ensure similarity between such drug products.  In many situations, 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 bioavailability and conclusions regarding 
bioequivalence with respect to meal type or timing of the meal (where appropriate). 
 
  Evidence of correlations between in vitro dissolution and bioavailabiliy, including the effects 
of pH on dissolution, and conclusions regarding dissolution specifications. 
 
  Comparative bioavailability, including BE conclusions, for different dosage form strengths. 
 
  Comparative bioavailability 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 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. 
 
Tables 2.7.1.1 and 2.7.1.2 are provided as examples of tabular formats for reporting information 
and results related to bioavailability and in vitro dissolution studies respectively.  These 
examples give results as well as identify 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 maximum 
concentration (Cmax) and area under the curve (AUC) and their 90 percent confidence interval 
or the currently recommended metrics for BE assessments.  
    22      Contains Nonbinding Recommendations 
 
 
 
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 may 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 include clinical studies performed to evaluate human pharmacokinetics 
and pharmacodynamics and in vitro studies performed with human cells, tissues, or related 
materials (hereinafter referred to as 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 PK, PD, 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 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.7  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 pharmacokinetics or 
pharmacodynamics.   
 
2.7.2.2  Summary of Results of Individual Studies 
 
A tabular listing of all clinical pharmacology studies should generally be provided (see section 
2.7.2.5 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, e.g., 
                                                 
7 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. 
    23      Contains Nonbinding Recommendations 
 
 
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.  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 PD endpoints 
should generally be included in this section.  In some cases, however, when well-controlled 
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 
affecting these PK 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 repeated-dose pharmacokinetics. 
 
  Population PK analyses, such as results based on sparse sampling across studies that address 
interindividual variations in the pharmacokinetics or pharmacodynamics 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.  
    24      Contains Nonbinding Recommendations 
 
 
Such studies that use PD biomarkers (but do not evaluate clinical efficacy) may similarly 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.8  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 pharmacokinetics, pharmacodynamics, 
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 
 
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 briefly 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 (Immunoglobulin G) by ELISA 
(enzyme-linked immunosorbent assay), 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 pharmacokinetics, changes in 
pharmacodynamics, 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 
                                                 
8 The reports of these studies should be filed in Module 5, section 5.3.5.4. 
    25      Contains Nonbinding Recommendations 
 
 
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 provided as an example of a tabular format for reporting information and results 
related to PK 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 
may simply list the studies.   
  
In designing tables, if any, for various types of other 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 (maximal velocity), Km 
(Michaelis Constant) 
 
  In vitro studies of drug-drug interactions using human biomaterials:  
 For studies of other drugs inhibiting the new drug, the metabolite(s) inhibited, 
enzymatic pathways affected, range of inhibitor concentrations used, IC  and K 
50 i
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 
 
    26      Contains Nonbinding Recommendations 
 
 
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, long-
term 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 may 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. 
 
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 provided (see section 2.7.3.6 Appendix), together with 
narrative descriptions for important studies.  The narrative descriptions should be brief, e.g., 
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.  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 necessary.  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. 
 
    27      Contains Nonbinding Recommendations 
 
 
2.7.3.3  Comparison and Analyses of Results Across Studies 
 
Using text, figures, and tables as appropriate (see section 2.7.3.6 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 to be 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: 
 
  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.   
 
    28      Contains Nonbinding Recommendations 
 
 
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 drugs 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 may 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 may 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). 
 
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 
    29      Contains Nonbinding Recommendations 
 
 
those where there are special reasons for concern.  The comparisons may highlight apparent 
variations in efficacy that require 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 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 
dose-response 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 may 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 PK and 
PD 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. 
 
While the interpretation of how these data support specific dosing recommendations should be 
supplied in the Clinical Overview document, 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 dose-response 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 patients age, sex, 
race, disease, or other factors should be described.  Any evidence of different PK or PD 
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). 
 
    30      Contains Nonbinding Recommendations 
 
 
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 may 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. 
 
Illustrative tables for an antihypertensive drug are provided, but these examples will not be 
relevant to every application.  In general, applications will require 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).  
 
    31      Contains Nonbinding Recommendations 
 
 
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 (e.g., 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 generate 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.  
 
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 section 2.7.4.7 Appendix) and appropriate text should be 
generated to summarize the overall extent of drug exposure from all phases of the clinical study 
    32      Contains Nonbinding Recommendations 
 
 
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 may be pertinent.  Dosage may be given as the actual daily dose or 
on a milligram (mg)/kilogram (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 
the ICH guidances for industry E7 Studies in Support of Special Populations: Geriatrics and E11 
Clinical Investigation of Medicinal Products in the Paediatric Population.  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 
  Concomitant illnesses   
  Concomitant use of particular medications 
  Geographical location 
 
If these characteristics are distributed differently in controlled trials versus the overall database, 
it will generally be useful to present tables on both groupings. 
 
    33      Contains Nonbinding Recommendations 
 
 
The text accompanying the tables should mention any imbalance(s) between the drug and 
placebo and/or comparator regarding any of the above demographic characteristics, particularly 
if the imbalance(s) 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 2.7.4.7 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 listing 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 will often be 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 it 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: 
 
  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. 
 
    34      Contains Nonbinding Recommendations 
 
 
  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) 
may 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 
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 should be discussed (e.g., relevant differences 
in study populations, in dose administration, or in methods of collecting adverse event data). 
 
    35      Contains Nonbinding Recommendations 
 
 
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 guidance) 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 may 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 section 2.7.4.7 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 side-by-side 
comparison of treatment groups.  It should be noted that while causality categories may be 
reported if used, the presentation of the data should include total 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 section 2.7.4.7 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: 
  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 
  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. 
 
    36      Contains Nonbinding Recommendations 
 
 
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 section 2.7.4.7 Appendix should list all deaths occurring while on study (including 
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 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  
 
    37      Contains Nonbinding Recommendations 
 
 
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, may be of critical value in understanding the safety profile.  For example, the 
relationship to treatment of an isolated sudden death may 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 may 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 may be placed in one subsection and cross-
referenced as appropriate in others.  
 
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 
    38      Contains Nonbinding Recommendations 
 
 
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. 
 
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, X-rays) related to safety should be similar to that for laboratory variables.  If 
    39      Contains Nonbinding Recommendations 
 
 
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 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. 
 
    40      Contains Nonbinding Recommendations 
 
 
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, 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 
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 
    41      Contains Nonbinding Recommendations 
 
 
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 to support product labeling.  
 
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. 
 
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 2.7.4 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  LITERATURE 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.   
 
 
2.7.6  SYNOPSES OF INDIVIDUAL STUDIES 
 
    42      Contains Nonbinding Recommendations 
 
 
ICH guidance for industry E3 Structure and Content of Clinical Study Reports 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. 
    43      Contains Nonbinding Recommendations 
 
 
Table 2.7.1.1  Summary of Bioavailability Studies 
 
Study  Study Objective  Study Design  Treatments  Subjects  Mean Parameters (+/- SD)  Study 
Ref.  (Dose,  (No.(M/F)  Report 
No.  Dosage Form,  type  Location 
Route)  Age: mean 
[Product ID]  (range) 
          Cmax  Tmax  AUC*  Cmin**  T1/2  Other   
(mg/L)   (hr)  (mg/L  (mg/L)  (hr) 
x hr) 
192  Pilot relative BA study  Open, randomized,  200mg Tab., p.o.  20 (10/10)  83  21  1  217     3.1     
(Japan)  comparing the absorption  cross-over, single  [17762]  Healthy volunteer      20   
from a 200 mg tablet batch  200 mg dose    27 y (20-35)         
to a 200mg reference batch.  200mg Tab.. p.o.    80  32  0.5  223   2.9 
[19426]  19 
195  Comparative BA study of xx  Open, randomized,  200mg Tab, p.o.  30 (15/15)  83  21  1  217          
(Japan)  under fasted and fed  cross-over, single  [19426]  Healthy volunteer      20 
conditions  dose  32 y (26-50)  120  30     
2  350  
40 
AUC*:  AUCTAU or AUCinf 
Cmin**:  For multiple dose studies 
    44      Contains Nonbinding Recommendations 
 
 
Table 2.7.1.2.  Summary of In Vitro Dissolution Studies 
 
Study  Product ID/Batch  Dosage Form  Conditions  No. of  Collection times  Study 
Ref.  No.  Dosage Units  Mean % Dissolved (range)  Report 
No.  Location 
1821  979-03  25 mg Cap.  Dissolution: Apparatus 2 (USP)  12       10                 20                 30     (min)   
Speed of Rotation: 50 rpm        42 (32-49)    71 (58-85)    99 (96-100) (%) 
Medium/Temperature: Water 37  
             
             
 
 
             
 
 
             
 
 
 
    45      Contains Nonbinding Recommendations 
 
 
Table 2.7.2.1  Summary of Drug-Drug Interaction PK Studies 
 
Study/  Product  Study  Study  # Subjects  HV/P1  Treatments  Mean Pharmacokinetic Parameters (%CV) Substrate  Mean ratio2   Location 
Protocol #  ID/Batch #  Objective  Design  Entered/Com (Age:  Drug  Confidence interval 
(Country)  (NME)  pleted (M/F)  Mean, 
range) 
            Substrate  Interacting  Cmax  Tmax  AUC  T1/2  CL/kg  Cmax  AUC   
Drug 
001  19B  Effect of  Randomized,  (8M/4F)/  HV (34,  Drug X 100  Placebo  45 (18)  2.0   456 (24)  4.25  0.05 (20)  1.16  1.16   
(USA)  Batch 0034  warfarin on  Crossover  (7M/4F)  20-41)  mg bid x 7d  g/mL  (30) hr  g*hr/  (30) hr  mL/min/ 1.01-1.30  1.03-1.34 
Drug X  mL  kg 
            Drug X 100  Warfarin 10  52 (20)  2.1    530 (27)  4.75  0.04 (22)       
mg bid x 7d  mg qd x 7d  g/mL  (35) hr  g*hr/  (35) hr  mL/min/
mL  kg 
001  19B  Effect of  Randomized,  (8M/4F)/  HV (34,  Warfarin  placebo  12 (25)  1.5   60 (37)  40   0.04 (30)  1.08  1.07   
(USA)  batch 0034  drug X on  Crossover  (7M/4F)  20-41)  10 mg qd x  g/mL  (30) hr  g*hr/  (35) hr  mL/min/ 0.92-1.24  0.92-1.18 
warfarin  7d  mL  kg 
            Warfarin  drug X 100  13 (20)  1.45   64 (39)  42   0.39 (34)       
10 mg qd x  mg bid x 7d  g/mL  (27) hr  g*hr/  (37) hr  mL/min/
7d  mL  kg 
002 (UK)  19B2  Effect of  Crossover,  (4M/8F)  HV (30,  Drug X 50  Placebo  49 (18)  2.1   470 (24)  4.4   0.05 (20)  1.22  1.36   
Batch 0035  Cimetidine  Single  (4M/8F)  19-45)  mg bid x 5d  /mL  (30) hr  g*hr/  (30) hr  mL/min/ 1.03-1.40  1.11-1.53 
on Drug X  sequence  mL  kg 
            drug X 50  Cimetidine  60 (10)  2.2   640 (24)  5.2  0.03 (20)       
mg bid x 5d  200 mg bid x  g//mL  (30) hr  g*hr/  (30)  mL/min/
5d  mL  hr  kg 
 
1HV=Healthy Volunteers, P=Patients 
 
2Value for substrate with interacting drug / value with placebo 
 
    46      Contains Nonbinding Recommendations 
 
 
 
Table 2.7.3.1  Description of Clinical Efficacy and Safety Studies 
 
Study ID  Number of  Study start  Design  Study & Ctrl  Study  # subjs by  Duration  Gender M/F  Diagnosis          Primary Endpoint(s) 
Study Centers  Drugs  Objective  arm 
  Location(s)  Enrollment  Control type  Dose,Route    entered/    Median Age  Inclusion Criteria   
status, date  compl.  (Range) 
    Total    & Regimen             
enrollment / 
Enrollment 
goal 
PG-  1  Aug-94  Randomized,  TP:  30 mg  Efficacy  27/24  4 weeks  27/23  Mild hypertension  Change from baseline systolic 
2476  double blind,  po bid  and Safety  and diastolic pressure at 4 
parallel  weeks. 
  U. Antarctica  Completed Apr  Placebo  Pbo    23/21    38 (20-64)  Diastolic 90-100   
98  Systolic 150-170 
 
50 / 50 
PG-  4  May-98  Randomized,  TP:  100 mg  Efficacy  34/30  4 weeks,   66/60  Mild hypertension  Change from baseline systolic 
2666  open label,  po bid  and Safety,  followed by  Systolic 150-170  and diastolic pressure at 4 
parallel  12 weeks  weeks and at 12 weeks. 
open-label 
   Affiliated  Ongoing as of  Placebo and  TP:  50 mg  Long-term  30/28    55 (24-68)  Diastolic 90-100   
Physicians of  May 2001  Dose-response  po bid  efficacy 
Florida,        and safety 
126/ 
400 
  Smith & Jones      TP:  25 mg    34/32         
CRO  po bid 
                     
        Placebo    28/26         
 
 
   
    47      Contains Nonbinding Recommendations 
 
 
Table 2.7.3.2  Results of Efficacy Studies 
 
 Study     Treatment Arm  # Enrolled/  Mean systolic and diastolic BP  Primary  Statistical test /  Secondary  Other Comments 
Completed  Endpoint   P value  Endpoints 
      Baseline  20 wks  40 wks  Placebo-   % normalized**   
subtracted  (ITT analysis) 
change in DBP 
at 40 weeks 
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  26/20  162/95  153/93  153/93  -4    20   
Placebo  28/26  166/97  160/92  159/91  30 
 
**Provide definition  
    48      Contains Nonbinding Recommendations 
 
 
 
Table 2.7.4.1  Study Subject Drug Exposure by Mean Daily Dose and Duration of Exposure 
Intravenous formulation                              N=                             Cutoff Date: 
   
  Mean Daily Dose (mg) 
Duration 
(Weeks)                 
0 < Dose  5 < Dose  10 < Dose  20 < Dose  30 < Dose    Total   
 5mg   10mg   20mg   30mg   50mg  50mg < Dose  (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). 
    49      Contains Nonbinding Recommendations 
 
 
Dose can also be expressed as mg/kg, mg/m2, or in terms of plasma concentration if such data are available. 
    50      Contains Nonbinding Recommendations 
 
 
 
Table 2.7.4.2  Demographic Profile of Patients in Controlled Trials Cutoff Date: 
  
   
                                          Treatment Groups 
 
  Test Product  Placebo  Active Control 
N =   N =  N = 
            Age (years)       
            Mean  SD  50  15     
    Range  20-85     
  Groups       
<18  N (%)  N (%)  N (%) 
18 - 40  N (%)  N (%)  N (%) 
40 - 64  N (%)  N (%)  N (%) 
65 - 75  N (%)  N (%)  N (%) 
>75  N (%)  N (%)  N (%) 
Sex       
         Female  N (%)  N (%)  N (%) 
      Male  N (%)  N (%)  N (%) 
Race       
Asian  N (%)  N (%)  N (%) 
Black  N (%)  N (%)  N (%) 
       Caucasian  N (%)  N (%)  N (%) 
Other  N (%)  N (%)  N (%) 
Other Factors       
 
 
 
 
   
    51      Contains Nonbinding Recommendations 
 
 
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  Active Control 2 
Control 1 
  All doses  10 mg  20 mg    20 mg  50 mg  100 mg 
  n = 1685  n = 968  n = 717  n = 425  n = 653  n = 334  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               
               
 
 
 
   
    52      Contains Nonbinding Recommendations 
 
 
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  Drug x  Placebo  Drug x  Placebo  Drug x  Drug y  Drug x 
60 mg  30 mg bid    60 mg bid    60 mg bid  100 mg qd  60 mg 
bid  N =102  N = 100  N = 500  N=495  N=200  N=200  bid 
N =104  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                 
                 
 
 
 
   
    53      Contains Nonbinding Recommendations 
 
 
Table 2.7.4.5  Patient Withdrawals4 by Study: Controlled Trials                          Cutoff Date: 
      Number Without 
Studies  Total Withdrawal  Reason for Withdrawal  Postwithdrawal 
  Efficacy Data 
       Male/  Age  Race  Adverse  Lack of  Other  N           (%) 
Total  Female   > 65  (identify  Events  Efficacy  N           (%) 
groupings)  N           (%)  N           (%) 
/ / / 
  Drug X  N (%)  N (%) / N  N (%)  N (%) / N (%)         
Study    (%)  / N (%) 
XXX  Placebo                 
 
  Drug X                 
Study   
AAA  Comparator A                 
 
  Drug X                 
   
Study 
BBB  Comparator B                 
 
  Drug X                 
Study   
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). 
 
    54      Contains Nonbinding Recommendations 
 
 
 
Table 2.7.4.6  Listing of Deaths                                Treatment:              Test Product:                 Cutoff Date: 
Trial /  Center  Patient  Age  Sex  Dose  Duration of  Diagnosis  Cause  Other  Other  Location of 
Source1  ID  (yrs)  (mg)  Exposure  of  Medications  Medical  Narrative 
(Days)  Death  Conditions  Description 
                       
 
                       
 
                       
 
 
1PM = 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. 
 
 
 
    55      Contains Nonbinding Recommendations 
 
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).  This document 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 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 of Module 5 
 
5.2  Tabular Listing of All Clinical Studies 
 
5.3  Clinical Study Reports 
 
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 
 
5.3.2.3  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 
 
  56  Contains Nonbinding Recommendations 
 
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 
 
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 
 
5.3.5.4  Other Clinical Study Reports 
 
5.3.6  Reports of Post-Marketing 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 
 
  57  Contains Nonbinding Recommendations 
 
BA studies in this section should include: 
 
  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  
 
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 may 
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 
  58  Contains Nonbinding Recommendations 
 
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. 
 
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 pharmacokinetics 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 PD differences.  These assessments should 
provide a description of the bodys 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 drugs PK and 
provide information about the absorption, distribution, metabolism, and excretion of a 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 for industry 
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 document, 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 pharmacokinetics due to intrinsic (e.g., age, gender, racial, 
weight, height, disease, genetic polymorphism, and organ dysfunction) and extrinsic (e.g., drug-
  59  Contains Nonbinding Recommendations 
 
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 these studies are substantially different from those used in standard PK studies, 
population PK studies should be placed in section 5.3.3.5. 
 
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, however, 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 
dose-response studies or together with drug concentration information in PK studies 
(concentration-response 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 
  60  Contains Nonbinding Recommendations 
 
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 PD studies 
conducted in patients will provide data that contribute to assessment of efficacy, because they 
show an effect either on an acceptable surrogate marker (e.g., blood pressure) or on a clinical 
benefit endpoint (e.g., pain relief).  Similarly, a PD study may 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 
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indications, the study report should be included in the most appropriate section 5 and referenced 
as necessary 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 
  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 found 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 
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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 Reports 
 
This section can include: 
 
  Reports of interim analyses of studies pertinent to the claimed indications. 
 
  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, which 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.  
  63  Contains Nonbinding Recommendations 
 
 
Table 5.1.  Listing of Clinical Studies 
 
Type of  Study  Location  Objective(s) of  Study  Test  Number of  Healthy  Duration of  Study 
Study  Identifier  of Study  the Study  Design and  Product(s);  Subjects  Subjects or  Treatment  Status; 
Report  Type of  Dosage  Diagnosis of  Type of 
Control  Regimen;  Patients  Report 
Route of 
Administration 
BA  001  Vol 3, Sec.  Absolute BA IV  Cross-over  Tablet, 50 mg  20  Healthy  Single dose  Complete; 
1.1, p. 183  vs Tablet  single dose, oral,  Subjects  Abbreviated 
10 mg IV 
BE  002  Vol 4, Sec.  Compare  Cross-over  Two tablet  32  Healthy  Single dose  Complete; 
1.2, p. 254  clinical study  formulations, 50  Subjects  Abbreviated 
and to-be- mg, oral 
marketed 
formulation 
PK  1010  Vol 6, Sec.  Define PK  Cross-over  Tablet, 50 mg  50  Renal  Single dose  Complete; 
3.3, p. 29  single dose, oral  Insufficiency  Full 
PD  020  Vol 6, Sec.  Bridging study  Randomized  Tablet, 50 mg,  24 (12 drug,  Patients with  2 weeks  Ongoing; 
4.2, p. 147  between regions  placebo- multiple dose,  12 placebo)  primary  Interim 
controlled  oral, every 8 hrs  hypertension 
Efficacy  035  Vol 10,  Long-term;  Randomized  Tablet, 50 mg,  300 (152 test  Patients with  48 weeks  Complete; 
Sec. 5.1, p.  Efficacy and  active- oral, every 8 hrs  drug, 148  primary  Full 
1286  Safety;  controlled  active  hypertension 
Population PK  control) 
analysis 
 
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