Guidance for Industry
 
M4:  The CTD  Safety
 
Questions and Answers
  
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) 

February 2003 

ICH
  Guidance for Industry
 
M4: The CTD  Safety
 
Questions and Answers 

Additional copies are available from: 

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Food and Drug Administration 

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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) 

February 2003 

ICH
  TABLE OF CONTENTS 
I.  INTRODUCTION................................................................................................................. 1
 
II.  BACKGROUND ................................................................................................................... 1
 
III.  QUESTIONS AND ANSWERS........................................................................................... 2
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Guidance for Industry
M4: The CTD  Safety 
Questions and Answers 
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. 
I.  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 provides answers 
to questions that have arisen since the finalization of the harmonized CTD guidance documents 
in November 2000. This guidance specifically addresses questions related to safety. Other 
question and answer (Q &A) guidances are under development to address general questions as 
well as questions related to quality and efficacy. The questions and answers provided here 
reflect the consensus of the ICH parties. 
II.  BACKGROUND 
The guidance for industry issued in November 2000 on preparing the CTD was divided into four 
separate documents:  (1) M4:  Organization of the CTD, (2) M4Q: The CTD  Quality, (3) 
M4E: The CTD  Efficacy, and (4) M4S: The CTD  Safety. Since implementation of these 
                                                
1  This guidance was developed within the M4 CTD-Safety Implementation Working Group 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 
has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, September 12, 2002. 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. 
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  guidances, a number of questions regarding the various CTD documents have been submitted to 
the various ICH regions.  The ICH has developed a process for responding to questions 
submitted to the ICH Web site. 
III. 	 QUESTIONS AND ANSWERS 
Q1: 	 Kinetics in Pregnant Animals and Neonates 
Kinetics in pregnant animals and neonates are included in the pharmacokenetics (PK) 
section. Is it expected that these data will come from PK studies, or can they be from 
kinetics in the Segment 2 studies? 
A1:	  The CTD  Safety guidance is not intended to indicate what studies are required.  It 
merely indicates an appropriate format for the nonclinical data that have been acquired. 
Q2: 	 Conduct/Nonconduct of Specific Studies 
If a particular category of toxicology studies (e.g., carcinogenicity) is not conducted for 
a drug because of the nature of the drug (e.g., oncology agent), should the section 
heading be maintained in the CTD document with an explanation provided as to why 
these studies were not conducted, or should the heading section be deleted and 
subsequent sections renumbered? 
A2:	  Section headings should be maintained in the CTD and a brief explanation provided as to 
why these studies were not conducted. 
Q3: 	 Pivotal Studies 
Would a 3-month toxicity study that was needed to support clinical studies of 3
months duration, which was later replaced with a 9-month toxicity study, be 
considered pivotal and tabulated as in Table 2.6.7.7? 
A3:	  Yes.  There should be one table for each of the repeat-dose toxicity studies specified by 
the ICH guidance M3, as well as any other repeat dose toxicity studies that could be 
considered pivotal. 
Q4: 	 Tabulated Summary 
Are only toxicologically significant changes, as considered by applicants, to be 
tabulated in CTD? 
A4:	  Only noteworthy findings should be tabulated in the CTD.  These might include 
statistically significant differences from controls, as well as noteworthy findings that are 
not statistically significant. 
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  Q5: 	 Impurity Data Table in CTD-Safety-1 
Generally speaking, it is unlikely to have the finalized specification for related 
substances and their analytical method throughout drug development. Therefore, 
direct comparison of related-substance data between different stages of development 
would be very difficult, because of analytical method changes. 
A5:	  One purpose of the Drug Substance table is to facilitate a review of the qualification of 
the specified impurities.  If the analytical methods have changed, information on early 
batches might not be applicable for qualification of impurities.  In this case, it is 
recommended that you use footnotes in the Drug Substance table to identify the 
batches that are relevant to qualification of impurities. 
Q6: 	 Impurity Data Table in CTD-Safety-2 
Should impurity-specification test results of test articles used in early-stage toxicology 
studies be included in CTD tables? Do test articles of non-GLP (good laboratory 
practice) studies in the CTD need to have specification test data? 
A6:	  You need not analyze the drug substance used in non-GLP studies.  However, if such 
analyses have been conducted, the results should be included in the Drug Substance 
table. 
Q7: 	 Nonclinical Tabulated Summaries Templates 
Are the templates for the nonclinical tabulated summaries (Module 2.6) a suggested or 
a required format? 
A7:	  It is recommended that summary tables for the nonclinical information in the Common 
Technical Document be provided in the format outlined.  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. 
Q8: 	 Granularity/Nonclinical Tabulated Summaries 
Is it right that we need to correct the Nonclinical Tabulated Summaries  Word 
Templates (in Appendix B) lines Location in the CTD with volume and section 
instead of volume and page? 
A8:	  Yes. Applicants should put volume and section number in the column of Location in 
the CTD within the Nonclinical Tabulated Summaries. 
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  Q9: 	 List of References 
A section for list of references of the nonclinical summary (2.6.8 or 2.6.2.8 plus 
2.6.4.11 plus 2.6.6.11) is not covered in the guidance, unlike for the clinical summary 
and both nonclinical and clinical overview. Could you please provide clarity where in 
these summaries lists of references should be included? 
A9:	  Applicants can place the list of references in the most appropriate location and create new 
subsection numbers as far as it facilitates the best possible understanding by the 
regulatory reviewers. 
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