Guidance for Industry
 
M4S:  The CTD  Safety 

U.S. Department of Health and Human Services
 
Food and Drug Administration
 
Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

August 2001 

ICH
  Guidance for Industry
 
M4S:  The CTD  Safety 

Additional copies are available from: 

Office of Training and Communications 

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Food and Drug Administration 

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or
 
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Food and Drug Administration 

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

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U.S. Department of Health and Human Services
 
Food and Drug Administration
 
Center for Drug Evaluation and Research (CDER)
 
Center for Biologics Evaluation and Research (CBER)
 
August  2001
 
ICH
  TABLE OF CONTENTS
 
INTRODUCTION......................................................................................................................... 1
 
BACKGROUND ........................................................................................................................... 2
 
The CTD .......................................................................................................................................2
 
Preparing and Organizing the CTD ..............................................................................................2
 
Module 4.  Nonclinical Study Reports ...........................................................................................4
 
Organization and Format of the ICH Guidances for Industry ......................................................7
 
Numbering....................................................................................................................................7
 
GENERAL PRINCIPLES............................................................................................................ 8
 
Guidances Referenced...................................................................................................................8
 
MODULE 2: NONCLINICAL OVERVIEW............................................................................ 8
 
General Aspects ............................................................................................................................8
 
Content and Structural Format ....................................................................................................9
 
MODULE 2:  NONCLINICAL WRITTEN AND TABULATED SUMMARIES................ 11
 
Guidance on Nonclinical Written Summaries .............................................................................11
 
Introduction................................................................................................................................11
 
General Presentation Issues........................................................................................................11
 
Guidance on Nonclinical Tabulated Summaries..........................................................................13
 
2.6. CONTENT OF NONCLINICAL WRITTEN AND TABULATED SUMMARIES...... 13
 
2.6.1 INTRODUCTION.............................................................................................................. 13
 
2.6.2 PHARMACOLOGY WRITTEN SUMMARY............................................................... 14
 
2.6.2.1 Brief Summary ................................................................................................................14
 
2.6.2.2 Primary Pharmacodynamics............................................................................................14
 
2.6.2.3 Secondary Pharmacodynamics ........................................................................................14
 
2.6.2.4 Safety Pharmacology.......................................................................................................14
 
2.6.2.5 Pharmacodynamic Drug Interactions..............................................................................14
 
2.6.2.6 Discussion and Conclusions.............................................................................................15
 
2.6.2.7 Tables and Figures...........................................................................................................15
 
2.6.3 PHARMACOLOGY TABULATED SUMMARY (SEE APPENDIX B) ..................... 15
 
2.6.4 PHARMACOKINETICS WRITTEN SUMMARY........................................................ 15
 
2.6.4.1 Brief Summary ................................................................................................................15
 
2.6.4.2 Methods of Analysis.........................................................................................................15
 
i  2.6.4.3 Absorption.......................................................................................................................16
 
2.6.4.4 Distribution......................................................................................................................16
 
2.6.4.5 Metabolism (interspecies comparison).............................................................................16
 
2.6.4.6 Excretion.........................................................................................................................16
 
2.6.4.7 Pharmacokinetic Drug Interactions.................................................................................16
 
2.6.4.8 Other Pharmacokinetic Studies........................................................................................16
 
2.6.4.9 Discussion and Conclusions.............................................................................................16
 
2.6.4.10 Tables and Figures.........................................................................................................17
 
2.6.5 PHARMACOKINETICS TABULATED SUMMARY (SEE APPENDIX B) ............. 17
 
2.6.6 TOXICOLOGY WRITTEN SUMMARY....................................................................... 17
 
2.6.6.1 Brief Summary ................................................................................................................17
 
2.6.6.2 Single-Dose Toxicity.........................................................................................................18
 
2.6.6.3 Repeat-Dose Toxicity (including supportive toxicokinetic evaluation) .............................18
 
2.6.6.4 Genotoxicity.....................................................................................................................18
 
2.6.6.5 Carcinogenicity (including supportive toxicokinetics evaluations) ...................................18
 
2.6.6.6 Reproductive and Developmental Toxicity (including range-finding studies and
 
supportive toxicokinetics evaluations).........................................................................................18
 
2.6.6.7 Local Tolerance ...............................................................................................................19
 
2.6.6.8 Other Toxicity Studies (if available).................................................................................19
 
2.6.6.9 Discussion and Conclusions.............................................................................................19
 
2.6.6.10 Tables and Figures.........................................................................................................19
 
2.6.7 TOXICOLOGY TABULATED SUMMARY (SEE APPENDIX B) ............................. 19
 
MODULE 4: NONCLINICAL STUDY REPORTS ................................................................ 19
 
4.1 TABLE OF CONTENTS..................................................................................................... 19
 
4.2  STUDY REPORTS .............................................................................................................. 19
 
4.3  LITERATURE REFERENCES ......................................................................................... 20
 
APPENDIX A:  EXAMPLES OF TABLES AND FIGURES FOR WRITTEN 

SUMMARIES............................................................... ERROR! BOOKMARK NOT DEFINED. 

APPENDIX B:  THE NONCLINICAL TABULATED SUMMARIES TEMPLATES 

ERROR! BOOKMARK NOT DEFINED. 
APPENDIX C:  THE NONCLINICAL TABULALTED SUMMARIES  EXAMPLES 
ERROR! BOOKMARK NOT DEFINED. 
ii  1
 
Guidance for Industry
M4S:  The CTD  Safety
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  An alternative approach may be used if such approach satisfies the 
requirements of the applicable statutes and regulations. 
INTRODUCTION 
This is one in a series of guidances that provide recommendations for applicants preparing the 
Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) for 
submission to the U.S. Food and Drug Administration (FDA).  This guidance presents the agreed 
upon common format for the preparation of a well-structured Safety section of the CTD for 
applications that will be submitted to regulatory authorities.  A common format for the technical 
documentation will significantly reduce the time and resources used to compile applications for 
registration of human pharmaceuticals and will ease the preparation of electronic submissions. 
Regulatory reviews and communication with the applicant will be facilitated by a standard 
document of common elements. In addition, exchange of regulatory information among 
regulatory authorities will be simplified. 
For information on the Quality and Efficacy sections of the CTD, see the individual guidances 
for industry that discuss those parts of the CTD.  For general information about the CTD, as well 
as specific information about Module 1 (regional administrative information), see the guidance 
for industry, General Considerations for Submitting Marketing Applications According to the 
ICH/CTD Format.2 The CTD guidances are intended to be used together with other ICH and 
                                                
1 This guidance was developed within the Expert Working Group (Safety) of the International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 
subject to consultation by the regulatory parties, in accordance with the ICH process. This document was endorsed 
by the ICH Steering Committee at Step 4 of the ICH process, November 2000. At Step 4 of the process, the final 
draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. 
2 A draft version of the General Considerations guidance is currently available. Once it has been finalized, it will 
represent the Agency's thinking on this topic. 
1
  Agency guidances.  Please refer to those guidances for detailed information about the contents of 
an application. 
BACKGROUND 
The CTD 
Through the ICH process, considerable harmonization has been achieved among the three 
regions (Japan, Europe, and the United States) in the technical requirements for the registration 
of pharmaceuticals for human use.  However, until now, there has been no harmonization of the 
organization of a submission.  Each region has its own requirements for the organization of the 
technical reports in the submission and for the preparation of the summaries and tables.  In 
Japan, the applicants must prepare the GAIYO, which organizes and presents a summary of the 
technical information. In Europe, expert reports and tabulated summaries are required, and 
written summaries are recommended.  The U.S. FDA has guidance regarding the format and 
content of the new drug application submission.  To avoid generating and compiling different 
registration dossiers, this guidance describes a format for the Safety section of the CTD that will 
be acceptable in all three regions. 
Preparing and Organizing the CTD 
This guidance primarily addresses the organization of the information to be presented in the 
Safety section of an application for new pharmaceuticals (including biotechnology-derived 
products).  Guidances also are available that discuss the Quality and Efficacy 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 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 
2
  for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal 
Editors (ICMJE).3 
The CTD should be organized into five modules.  Module 1 is region specific.  Modules 2, 3, 4, 
and 5 are intended to be common for all regions.  Conformance with the CTD guidances should 
help ensure that these four modules are provided in a format acceptable to the regulatory 
authorities (see the figure and overall outline on the following pages). 
Module 1.  Administrative Information and Prescribing Information 
This module  should contain documents specific to each region; for example, application 
forms or the proposed label for use in the region.  The content and format of this module 
can be specified by the relevant regulatory authorities.  For information about this module 
see the guidance for industry, General Considerations for Submitting Marketing 
Applications According to the ICH/CTD Format. 
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 the Module 2 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. 
                                                
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. 
3
  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  . 
4
  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 
5
  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 Summaries
 
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 

6
  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: Quality, 
Safety, and Efficacy.  As a result, guidance discussing Module 2 is divided among 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 4 of the CTD have been numbered 
using the Arabic numbers 2 and 4, respectively. 
7
  GENERAL PRINCIPLES 
This guidance provides recommendations for the harmonization of the Safety section of the 
CTD.  It discusses the Nonclinical Overview, Nonclinical Written Summary, and Nonclinical 
Tabulated Summaries. 
The primary purpose of the Nonclinical Written and Tabulated Summaries should be to provide a 
comprehensive, factual synopsis of the nonclinical data.  The interpretation of the data, the 
clinical relevance of the findings, cross-linking with the quality aspects of the pharmaceutical, 
and the implications of the nonclinical findings for the safe use of the pharmaceutical (i.e., as 
applicable to labeling) should be addressed in the Nonclinical Overview. 
Guidances Referenced 
The following ICH guidances are referenced in the Safety section: 
M3 	 Nonclinical Safety Studies for the Conduct of Human Cllinical Trials for 
Pharmacaeuticals (November 1997) 
S1C 	 Dose Selection for Carcinogenicity Studies of Pharmaceuticals (March 1995) 
S7 	 Safety Pharmacology Studies for Human Pharmaceuticals (August 2000) 
MODULE 2: NONCLINICAL OVERVIEW 
The Nonclinical Overview should provide an integrated, overall analysis of the information in 
the Common Technical Document.  In general, the Nonclinical Overview  should not exceed 
about 30 pages. 
General Aspects 
The Nonclinical Overview  should present an integrated and critical assessment of the 
pharmacologic, pharmacokinetic, and toxicologic evaluation of the pharmaceutical. Where 
relevant guidances on the conduct of studies exist, these should be taken into consideration, and 
any deviation from these guidances should be discussed and justified.  The nonclinical testing 
strategy should be discussed and justified.  There should be comment on the good laboratory 
practice (GLP) status of the studies submitted. Any association between nonclinical findings and 
the quality characteristics of the human pharmaceutical, the results of clinical trials, or effects 
seen with related products should be indicated, as appropriate. 
Except for biotechnology-derived products, an assessment of the impurities and degradants 
present in the drug substance and product should be included, along with what is known of their 
potential pharmacologic and toxicologic effects.  This assessment should form part of the 
justification for proposed impurity limits in the drug substance and product and be appropriately 
cross-referenced to the quality documentation.  The implications of any differences in the 
8
  chirality, chemical form, and impurity profile between the compound used in the nonclinical 
studies and the product to be marketed should be discussed.   For biotechnology-derived products, 
comparability of material used in nonclinical and clinical studies and proposed for marketing 
should be assessed.  If a drug product includes a novel excipient, an assessment of the 
information regarding the excipients safety should be provided. 
Relevant, scientific literature and the properties of related products should be taken into account. 
If detailed references to published, scientific literature are to be used in place of studies 
conducted by the applicant, this should be supported by an appropriate justification that reviews 
the design of the studies and any deviations from available guidances.  In addition, the 
availability of information on the quality of batches of drug substance used in these referenced 
studies should be discussed. 
The Nonclinical Overview  should contain appropriate reference citations to the Tabulated 
Summaries in the following format:  (Table X.X, Study/Report Number). 
Content and Structural Format 
The Nonclinical Overview  should be presented in the following sequence: 
2.4.  NONCLINICAL OVERVIEW 
2.4.1 Overview of the Nonclinical Testing Strategy 
2.4.2 Pharmacology 
2.4.3 Pharmacokinetics 
2.4.4 Toxicology 
2.4.5 Integrated Overview and Conclusions 
2.4.6 List of Literature Citations 
Studies conducted to establish the pharmacodynamic effects, the mode of action, and potential 
side effects should be evaluated, and consideration should be given to the significance of any 
issues that arise. 
The assessment of the pharmacokinetic, toxicokinetic, and metabolism data should address the 
relevance of the analytical methods used, the pharmacokinetic models, and the derived 
parameters.  It might be appropriate to cross-refer to more detailed consideration of certain issues 
within the pharmacology or toxicology studies (e.g., impact of the disease states, changes in 
physiology, antiproduct antibodies, cross-species consideration of toxicokinetic data). 
Inconsistencies in the data should be discussed.  Interspecies comparisons of metabolism and 
systemic exposure comparisons in animals and humans (AUC, Cmax, and other appropriate 
parameters) should be discussed and the limitations and utility of the nonclinical studies for 
prediction of potential adverse effects in humans highlighted. 
The onset, severity, and duration of the toxic effects, their dose dependency and degree of 
reversibility (or irreversibility), and species- or gender-related differences should be evaluated 
and important features discussed, particularly with regard to: 
9
   	  Pharmacodynamics 
 	  Toxic signs 
 	  Causes of death 
 	  Pathologic findings 
 	  Genotoxic activity  the chemical structure of the compound, its mode of action, and its 
relationship to known genotoxic compounds 
 	  Carcinogenic potential in the context of the chemical structure of the compound, its 
relationship to known carcinogens, its genotoxic potential, and the exposure data 
 	  The carcinogenic risk to humans  if epidemiologic data are available, they should be 
taken into account 
 	  Fertility, embryofetal development, pre- and postnatal toxicity 
 	  Studies in juvenile animals 
 	  The consequences of use before and during pregnancy, during lactation, and during 
pediatric development 
 	  Local tolerance 
 	  Other toxicity studies and/or studies to clarify special problems 
The evaluation of toxicology studies should be arranged in a logical order so that all relevant 
data elucidating a certain effect and/or phenomenon are brought together. Extrapolation of the 
data from animals to humans should be considered in relation to: 
 	  Animal species used 
 	  Numbers of animals used 
 	  Routes of administration employed 
 	  Dosages used 
 	  Duration of treatment or of the study 
 	  Systemic exposures in the toxicology species at no observed adverse effect levels and at 
toxic doses, in relation to the exposures in humans at the maximum recommended human 
dose.  Tables or figures summarizing this information are recommended. 
 	  The effect of the drug substance observed in nonclinical studies in relation to that 
expected or observed in humans 
If alternatives to whole animal experiments are employed, their scientific validity should be 
discussed. 
The integrated overview and conclusions should clearly define the characteristics of the human 
pharmaceutical, as demonstrated by the nonclinical studies, and arrive at logical, well-argued 
conclusions supporting the safety of the product for the intended clinical use.  Taking the 
pharmacology, pharmacokinetics, and toxicology results  into account, the implications of the 
nonclinical findings for the safe human use of the pharmaceutical should be discussed (i.e., as 
applicable to labeling). 
10
  MODULE 2:  NONCLINICAL WRITTEN AND TABULATED SUMMARIES 

Guidance on Nonclinical Written Summaries 
Introduction 
This guidance is intended to assist authors in the preparation of nonclinical pharmacology, 
pharmacokinetics, and toxicology written summaries in an appropriate format.  This guidance is 
not intended to indicate what studies are required.  It merely indicates an appropriate format for 
the nonclinical data that have been acquired. 
The sequence and content of the Nonclinical Written Summary sections are described below.  It 
should be emphasized that no guidance can cover all eventualities, and common sense and a 
clear focus on the needs of the regulatory authority assessor are the best guides to constructing a 
document. Therefore, applicants can modify the format, if needed, to provide the best possible 
presentation of the information and to facilitate the understanding and evaluation of the results. 
Whenever appropriate, age- and gender-related effects should be discussed.   Relevant findings 
with stereoisomers and/or metabolites should be included, as appropriate.  Consistent use of units 
throughout the Nonclinical Written Summaries will facilitate their review.  A table for 
converting units might also be useful. 
In the Discussion and Conclusion sections, information should be integrated across studies and 
across species, and exposure in the test animals should be related to exposure in humans given 
the maximum intended doses. 
General Presentation Issues 
Order of Presentation of Information Within Sections 
When available, in vitro studies should precede in vivo studies. Where multiple studies of the 
same type are summarized within the Pharmacokinetics and Toxicology sections, studies should 
be ordered by species, by route, and then by duration (shortest duration first). 
Species should be ordered as follows: 
   Mouse 
   Rat 
   Hamster 
   Other rodent 
   Rabbit 
   Dog 
   Nonhuman primate 
   Other nonrodent mammal 
   Nonmammals 
11
  Routes of administration should be ordered as follows: 
   The intended route for human use 
   Oral 
   Intravenous 
   Intramuscular 
   Intraperitoneal 
   Subcutaneous 
   Inhalation 
   Topical 
   Other 
Use of Tables and Figures 
Although the Nonclinical Written Summaries are envisaged to be composed mainly of text, some 
information contained within them might be more effectively and/or concisely communicated 
through the use of appropriate tables or figures.  Examples of formats that might be included in 
the Written Summaries are shown in Appendix A. 
To allow authors flexibility in defining the optimal structure for the written summaries, tables 
and figures should preferably be included within the text.  Alternatively, they could be grouped 
together at the end of each of the Nonclinical Written Summaries. 
Throughout the text, reference citations to the Tabulated Summaries should be included in the 
following format:  (Table X.X, Study/Report Number). 
Length of Nonclinical Written Summaries 
Although there is no formal limit to the length of the Nonclinical Written Summaries, it is 
recommended that the total length of the three Nonclinical Written Summaries in general not 
exceed 100-150 pages. 
Sequence of Written Summaries and Tabulated Summaries 
The following order is recommended: 
   Introduction 
   Pharmacology written summary 
   Pharmacology tabulated summary 
   Pharmacokinetics written summary 
   Pharmacokinetics tabulated summary 
   Toxicology written summary 
   Toxicology tabulated summary 
12
  Guidance on Nonclinical Tabulated Summaries 
It is recommended that summary tables for the nonclinical information in the Common Technical 
Document be provided in the format outlined in this guidance.  Applicants can modify the 
format, if warranted, to provide the best possible presentation of the information and to facilitate 
the understanding and evaluation of the results. 
This guidance is not intended to indicate what studies are requested, but solely to advise how to 
tabulate study results if a study is performed.  Applicants can add some items to or delete some 
items from the cited format, where appropriate.  One tabular format can contain results from 
several studies. Alternatively, it may be appropriate to cite the data resulting from one study in 
several tabular formats. 
The recommended formats for the tables in the Nonclinical Tabulated Summaries are provided in 
Appendices B and C, which follow.  Appendix B contains templates for use in preparation of the 
tables. The templates are annotated (in italics) to provide guidance on their preparation. (The 
italicized information should be deleted when the tables are prepared.)  Appendix C provides 
examples of the summary tables.  The purpose of the examples is to provide additional guidance 
on the suggested content and format of the Tabulated Summaries.  However, it is the 
responsibility of the applicant to decide on the best possible presentation of the data for each 
product.  Authors should keep in mind that, in some regions, a review of the Tabulated 
Summaries (in conjunction with the Written Summaries) represents the primary review of the 
nonclinical information.  Presentation of the data in the formats provided as templates and 
examples should ensure that a sufficient level of detail is available to the reviewer and should 
provide concise overviews of related information. 
When a juvenile animal study has been conducted, it should be tabulated using the template 
appropriate for the type of study. 
The order of presentation given for the Nonclinical Written Summaries should be followed for 
the preparation of the tables for the Nonclinical Tabulated Summaries. 
2.6. CONTENT OF NONCLINICAL WRITTEN AND TABULATED SUMMARIES 
2.6.1 INTRODUCTION 
The aim of this section should be to introduce the reviewer to the pharmaceutical and to its 
proposed clinical use.  The following key elements should be covered: 
 	  Brief information concerning the pharmaceuticals structure (preferably, a structure 
diagram should be provided) and pharmacologic properties 
 	  Information concerning the pharmaceuticals proposed clinical indication, dose, and 
duration of use 
13
  2.6.2 PHARMACOLOGY WRITTEN SUMMARY 

Within the Pharmacology Written Summary, the data should be presented in the following 
sequence: 
   Brief summary 
   Primary pharmacodynamics 
   Secondary pharmacodynamics 
   Safety pharmacology 
   Pharmacodynamic drug interactions 
   Discussion and conclusions 
   Tables and figures (either here or included in text) 
2.6.2.1 Brief Summary 
The principal findings from the pharmacology studies should be briefly summarized in 
approximately two to three pages.  This section should begin with a brief description of the 
content of the pharmacologic data package, pointing out any notable aspects such as the 
inclusion and/or exclusion of particular data (e.g., lack of an animal model). 
2.6.2.2 Primary Pharmacodynamics 
Studies on primary pharmacodynamicsa should be summarized and evaluated. Where possible, it 
would be helpful to relate the pharmacology of the drug to available data (e.g., selectivity, safety, 
potency) on other drugs in the class. 
2.6.2.3 Secondary Pharmacodynamics 
Studies on secondary pharmacodynamicsa should be summarized by organ system, where 
appropriate, and evaluated in this section. 
2.6.2.4 Safety Pharmacology 
Safety pharmacology studiesa  should be summarized and evaluated in this section.   In some 
cases, secondary pharmacodynamic studies can contribute to the safety evaluation when they 
predict or assess potential adverse effects in humans.  In such cases, these secondary 
pharmacodynamic studies should be considered, along with safety pharmacology studies. 
2.6.2.5 Pharmacodynamic Drug Interactions 
If they have been performed, pharmacodynamic drug interaction studies should be briefly 
summarized in this section. 
                                                
aA draft ICH guidance S7 Safety Pharmacology Studies for Human Pharmaceuticals discusses this term in more 
detail. This draft guidance published in August 2000 and is currently under revision. Once finalized, it will 
represent the Agencys current thinking on this topic. 
14
  2.6.2.6 Discussion and Conclusions 
This section provides an opportunity to discuss the pharmacologic evaluation and to consider the 
significance of any issues that arise. 
2.6.2.7 Tables and Figures 
Text tables and figures can be included at appropriate points throughout the summary within the 
text.  Alternatively, tables and figures can be included at the end of the summary. 
2.6.3 PHARMACOLOGY TABULATED SUMMARY (SEE APPENDIX B) 
2.6.4 PHARMACOKINETICS WRITTEN SUMMARY 
The sequence of the Pharmacokinetics Written Summary should be as follows: 
   Brief summary 
   Methods of analysis 
   Absorption 
   Distribution 
   Metabolism 
   Excretion 
   Pharmacokinetic drug interactions 
   Other pharmacokinetic studies 
   Discussion and conclusions 
   Tables and figures (either here or included in text) 
2.6.4.1 Brief Summary 
The principal findings from the pharmacokinetics studies should be briefly summarized in 
approximately two to three pages.  This section should begin with a description of the scope of 
the pharmacokinetic evaluation, emphasizing, for example, whether the species and strains 
examined were those used in the pharmacology and toxicology evaluations, and whether the 
formulations used were similar or identical. 
2.6.4.2 Methods of Analysis 
This section should contain a brief summary of the methods of analysis for biological samples, 
including the detection and quantification limits of an analytical procedure. If possible, 
validation data for the analytical method and stability of biological samples should be discussed 
in this section.  The potential impact of different methods of analysis on the interpretation of the 
results should be discussed in the following relevant sections. 
15
  2.6.4.3 Absorption 
The following data should be summarized in this section: 
 	  Absorption (extent and rate of absorption, in vivo and in situ  studies) 
 	  Kinetic parameters, bioequivalence and/or bioavailability (serum/plasma/blood PK 
studies) 
2.6.4.4 Distribution 
The following data should be summarized in this section: 
 	  Tissue distribution studies 
 	  Protein binding and distribution in blood cells 
 	  Placental transfer studies 
2.6.4.5 Metabolism (interspecies comparison) 
The following data should be summarized in this section: 
 	  Chemical structures and quantities of metabolites in biological samples 
 	  Possible metabolic pathways 
 	  Presystemic metabolism (GI/hepatic first-pass effects) 
 	  In vitro metabolism including P450 studies 
 	  Enzyme induction and inhibition 
2.6.4.6 Excretion 
The following data should be summarized in this section: 
  	 Routes and extent of excretion 
 	  Excretion in milk 
2.6.4.7 Pharmacokinetic Drug Interactions 
If they have been performed, nonclinical pharmacokinetic drug interaction studies (in vitro 
and/or in vivo) should be briefly summarized in this section. 
2.6.4.8 Other Pharmacokinetic Studies 
If studies have been performed in nonclinical models of disease (e.g., renally impaired animals), 
they should be summarized in this section. 
2.6.4.9 Discussion and Conclusions 
This section provides an opportunity to discuss the pharmacokinetic evaluation and to consider 
the significance of any issues that arise. 
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  2.6.4.10 Tables and Figures 
Text tables and figures can be included at appropriate points throughout the summary within the 
text.  Alternatively, there is the option of including tables and figures at the end of the summary. 
2.6.5 PHARMACOKINETICS TABULATED SUMMARY (SEE APPENDIX B) 
2.6.6 TOXICOLOGY WRITTEN SUMMARY 
The sequence of the Toxicology Written Summary should be as follows: 
   Brief summary 
   Single-dose toxicity 
   Repeat-dose toxicity 
   Genotoxicity 
   Carcinogenicity 
   Reproductive and developmental toxicity 
   Studies in juvenile animals 
   Local tolerance 
   Other toxicity studies 
   Discussion and conclusions 
   Tables and figures (either here or included in text) 
2.6.6.1 Brief Summary 
The principal findings from the toxicology studies should be briefly summarized in a few pages 
(generally not more than six).  In this section, the extent of the toxicologic evaluation can be 
indicated by the use of a table listing the principal toxicologic studies (results should not be 
presented in this table), for example: 
Toxicology Program 
Study type and  Route of  Species  Compound 
duration  administration  administered* 
Single-dose toxicity  po and iv  Rat and mouse  Parent drug 
Single-dose toxicity  po and iv  Rat and mouse  Metabolite X 
Repeat-dose toxicity 
1 month  po  Rat and dog  Parent drug
6 months  po  Rat               
9 months  po  Dog                
* This column should be included only if metabolites are investigated. 
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  The scope of the toxicologic evaluation should be described in relation to the proposed clinical 
use.  A comment on the GLP status of the studies should be included. 
2.6.6.2 Single-Dose Toxicity 
The single-dose data should be very briefly summarized, in order by species and by route. In 
some instances, it may be helpful to provide the data in the form of a table. 
2.6.6.3 Repeat-Dose Toxicity (including supportive toxicokinetic evaluation) 
Studies should be summarized in order by species, by route, and by duration, giving brief details 
of the methodology and highlighting important findings (e.g., nature and severity of target organ 
toxicity, dose (exposure) and/or response relationships, no observed adverse effect levels). 
Nonpivotal studies can be summarized in less detail (pivotal studies are the definitive GLP 
studies specified by ICH guidance M3). 
2.6.6.4 Genotoxicity 
Studies should be briefly summarized in the following order: 
 	  In vitro nonmammalian cell system 
 	  In vitro mammalian cell system 
 	  In vivo  mammalian system (including supportive toxicokinetics evaluation) 
 	  Other systems 
2.6.6.5 Carcinogenicity (including supportive toxicokinetics evaluations) 
A brief rationale should explain why the studies were chosen and the basis for high-dose 
selection.  Individual studies should be summarized in the following order: 
 	  Long-term studies (in order by species), including range-finding studies that cannot 
appropriately be included under repeat-dose toxicity or pharmacokinetics) 
 	  Short- or medium-term studies (including range-finding studies that cannot appropriately 
be included under repeat-dose toxicity or pharmacokinetics) 
 	  Other studies 
2.6.6.6 Reproductive  and Developmental Toxicity (including range-finding studies 
and supportive toxicokinetics evaluations) 
Studies should be summarized in the following order, giving brief details of the methodology 
and highlighting important findings: 
 	  Fertility and early embryonic development 
 	  Embryofetal development 
 	  Prenatal and postnatal development, including maternal function 
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   	  Studies in which the offspring (juvenile animals) are dosed and/or further evaluated if 
such studies have been conducted 
If modified study designs are used, the subheadings should be modified accordingly. 
2.6.6.7 Local Tolerance 
If local tolerance studies have been performed, they should be summarized in order by species, 
by route, and by duration, giving brief details of the methodology and highlighting important 
findings. 
2.6.6.8 Other Toxicity Studies (if available) 
If other studies have been performed, they should be summarized.  When appropriate, the 
rationale for conducting the studies should be provided. 
 	  Antigenicity 
 	  Immunotoxicity 
 	  Mechanistic studies (if not reported elsewhere) 
 	  Dependence 
 	  Studies on metabolites 
 	  Studies on impurities 
 	  Other studies 
2.6.6.9 Discussion and Conclusions 
This section should provide an opportunity to discuss the toxicologic evaluation and the 
significance of any issues that arise.  Tables or figures summarizing this information are 
recommended. 
2.6.6.10 Tables and Figures 
Text tables and figures can be included at appropriate points throughout the summary within the 
text.  Alternatively, tables and figures can be included at the end of the summary. 
2.6.7 TOXICOLOGY TABULATED SUMMARY (SEE APPENDIX B) 
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  MODULE 4: NONCLINICAL STUDY REPORTS 
This guidance presents an agreed upon format for the organization of the nonclinical reports in 
the Common Technical Document for applications that will be submitted to regulatory 
authorities.  This guidance is not intended to indicate what studies are required.  It merely 
indicates an appropriate format for the nonclinical data that have been acquired. 
The appropriate location for individual animal data is in the study report or as an appendix to the 
study report. 
4.1 TABLE OF CONTENTS
 
A Table of Contents should be provided that lists all of the Nonclinical Study Reports and gives 
the location of each study report in the Common Technical Document. 
4.2  STUDY REPORTS 

The study reports should be presented in the following order: 
4.2.1 Pharmacology 

4.2.1.1 Primary Pharmacodynamics 

4.2.1.2 Secondary Pharmacodynamics 

4.2.1.3 Safety Pharmacology
 
4.2.1.4 Pharmacodynamic Drug Interactions 

4.2.2 Pharmacokinetics 

4.2.2.1 Analytical Methods and Validation Reports (if separate reports are 

available)
 
4.2.2.2 Absorption
 
4.2.2.3 Distribution
 
4.2.2.4 Metabolism
 
4.2.2.5 Excretion
 
4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical) 

4.2.2.7 Other Pharmacokinetic Studies
 
4.2.3 Toxicology 

4.2.3.1 Single-Dose Toxicity (in order by species, by route) 

4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by duration, 

including supportive toxicokinetics evaluations) 

4.2.3.3 Genotoxicity 

4.2.3.3.1 In vitro 

4.2.3.3.2 In vivo (including supportive toxicokinetics evaluations) 

4.2.3.4 Carcinogenicity (including supportive toxicokinetics evaluations) 

4.2.3.4.1 Long-term studies (in order by species, including range-finding 

studies that cannot appropriately be included under repeat-dose toxicity or 

pharmacokinetics)
 
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  4.2.3.4.2 Short- or medium-term studies (including range-finding studies 

that cannot appropriately be included under repeat-dose toxicity or 

pharmacokinetics)
 
4.2.3.4.3 Other studies 

4.2.3.5 Reproductive  and Developmental Toxicity (including range-finding
 
studies and supportive toxicokinetics evaluations) (If modified study 

designs are used, the following subheadings should be modified 

accordingly.) 

4.2.3.5.1 Fertility and early embryonic development 

4.2.3.5.2 Embryofetal development 

4.2.3.5.3 Prenatal and postnatal development, including maternal function 

4.2.3.5.4  Studies in which the offspring (juvenile animals) are dosed 

and/or further evaluated 

4.2.3.6. Local Tolerance 

4.2.3.7. Other Toxicity Studies (if available)
 
4.2.3.7.1 Antigenicity
 
4.2.3.7.2 Immunotoxicity
 
4.2.3.7.3 Mechanistic studies (if not included elsewhere)
 
4.2.3.7.4 Dependence 

4.2.3.7.5 Metabolites 

4.2.3.7.6 Impurities 

4.2.3.7.7 Other 

4.3  LITERATURE REFERENCES 

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