Guidance for Industry

M4: The CTD — Efficacy 

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)

December 2004

ICH

Revision 3 
Guidance for Industry

M4: The CTD — Efficacy 

Questions and Answers

Additional copies are available from:

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Food and Drug Administration

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

Office of Communication, Training and 

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 Food and Drug Administration

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

 (Tel) Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

December 2004

ICH

Revision 3
TABLE OF CONTENTS

I. INTRODUCTION .................................................................................................................1

II. BACKGROUND....................................................................................................................2

III. QUESTIONS AND ANSWERS............................................................................................2
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Guidance for Industry1

M4: CTD — Efficacy

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. 

You can use an alternative approach if that approach satisfies the requirements of the applicable statutes 

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

I. INTRODUCTION 

This 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 efficacy. Other 

question and answer (Q &A) guidances are under development to address general questions as 

well as questions related to quality and safety. The questions and answers provided here reflect 

the consensus of the ICH parties. 

This guidance is being revised to include additional questions.

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required.

 

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This guidance was developed within the M4 CTD-Efficacy 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, June 10, 2004. 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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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) M4: The CTD — Quality, (3) M4: 

The CTD — Efficacy, and (4) M4: The CTD — Safety. Since implementation of these 

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: Clinical study reports contained in Module 5 are cited in the Clinical Overview and/or 

the Clinical Summary in Module 2. Each clinical study report may be given a unique 

short name when cited. Does the method of citing and naming have to be uniform 

throughout all modules?

A1: We recommend that each study have a unique short identifier that is used consistently 

throughout the application. The applicant can select the identifier. The full title of the 

study is provided in the Tabular Listing of All Clinical Studies (Section 5.2)

Q2: Definitions/Terminology

What is the definition of Common Adverse Events as used in the CTD?

A2: Guidance is provided by ICH E3 Guideline.

Q3: Section Numbering/Title (in Module 5)

In Module 5 of the CTD, is it necessary to have a section number for each clinical 

study report in a certain section, or is it enough just to mention the title:

5.3.5 Report of Efficacy....

5.3.5.1 Study Reports....

5.3.5.1.1 Placebo Controlled....

 Study XXX

A3: See ICH granularity document.
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Q4: How many pages should a Clinical Summary be for an application that contains 

multiple indications?

A4: The estimated size of this document is 50-400 pages, assuming one indication. 

Applications that include multiple indications will be larger, reflecting the submission of 

multiple efficacy sections.

Q5: Section “2.7.3.3” Comparisons and Analyses of Results Across Studies

The Guideline provides “This section should also cross-reference important evidence 

from Section 2, such as data that supports the dosage and administration section of the 

labeling.” However, this Guideline also provides a Section, “2.7.3.4. Analysis of 

Clinical Information Relevant to Recommended Dose.” Please specify how to 

differentiate the two sections “2.7.3.3” and “2.7.3.4”.

A5: Section 2.7.3.3 summarizes the data across all studies that characterize efficacy of the 

drug; Section 2.7.3.4 provides an integrated summary of the dose-response or blood 

concentration-response relationships of effectiveness. In both cases, supportive data from 

Section 2.7.2 can also be incorporated.

Q6: Overall Extent of Exposure

In the Guideline, a table is required to be generated to present the overall extent of 

drug exposure in all phases of the clinical development. Should the table include 

“patients alone” or “patients and healthy subjects”?

A6: That table should refer to all subjects exposed to at least one dose of the drug product. 

Appropriate subsets of subjects relevant to the proposed indications should also be 

identified and considered.

Q7: Summary of Clinical Safety

Where should information be described concerning the validity of extrapolation of 

foreign clinical safety data to a new region?

A7: Summaries 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 Section 2.7.3.2. Where appropriate, such 

information should also be described in the summarization of safety data as related to 

intrinsic and extrinsic ethnic factors (ICH E5), in Sections 2.7.4.5.1 and 2.7.4.5.2. 

Finally, some applications might include in Section 5.3.5.3 a detailed analysis of 

bridging, considering formal bridging studies, other relevant clinical studies, and other 
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appropriate information. Such information should be included in that detailed analysis of 

bridging.

Q8: Bioavailability/Bioequivalence Study Data

Where should the information on bioequivalence studies for a generic application be 

included?

A8: Bioavailability study reports should be included in Module 5 (Clinical documentation), 

under section 5.3.1 “Reports of Biopharmaceutical Studies”. More specifically, reports 

of comparative Bioavailability/Bioequivalence studies should go under section 5.3.1.2.

Q9: Tabular Listing of Clinical Studies in Paper CTD

In Module 5, 5.2 is denoted as the ‘Tabular Listing of all Clinical Studies’. Is this 

section for a summary listing of all clinical studies in the submission, or it is for the 

listing of the individual study reports? In other words, should the listings from the 

appendices of the individual study reports be included here, rather than as an appendix 

to the CSR, or are these only listings that summarize all studies?

A9: The tabular listing described in section 5.2 is a listing of all clinical studies in the 

submission.

An example of such a listing is given in Table 5.1.

Q10 Integrated Summary of Safety and Effectiveness

Does the CTD section on safety in Module 2 replace the section under 21 CFR 

314.50(d)(5)(v)-(vi) calling for integrated summary of safety and effectiveness 

(ISS/ISE)?

A10: The ISS/ISE are critical components of the safety and effectiveness submission and are 

expected to be submitted in the application in accordance with the regulation. FDA’s 

guidance Format and Content of Clinical and Statistical Sections of Application gives 

advice on how to construct these summaries. Note that, despite the name, these are 

integrated analyses of all relevant data, not summaries.

The Clinical Safety sections of the CTD follow approximately the outline of the sections 

of the ISS/ISE, although they are somewhat modified by experience with ICH E-3 

(Structure and Content of Clinical Study Reports). The CTD Clinical Overview and 

Summary in Module 2 will not usually contain the level of detail expected for an ISS. It 

may contain the level of detail needed for an ISE, but this would need to be determined 

on a case-by-case basis.
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If the requirements of 21 CFR 314.50 can be met for a particular application by what is in 

the CTD Module 2 summary, the CTD Module 2 section would fulfill the need for an 

ISS/ISE. In some cases, it will be convenient to write much of what is needed in the 

CTD Module 2 with appropriate appendices in Module 5. In other cases, the ISS/ISE 

would be summarized in Module 2, with detailed reports in Module 5.

Any questions about these matters can be raised with the reviewing division.

Q11: Microbiology Data

The microbiology data will include both in vitro and in vivo studies. Where should the 

microbiology summary, overview, and study reports be included?

A11: The microbiology data from both in vitro and in vivo studies should be included with the 

Efficacy information. The summary information should be provided in the appropriate 

section 2.7 Clinical Summary and the reports should be filed in section 5.3.5.4 Other 

Study Reports. 

In addition, the microbiology information can be described in the Nonclinical sections as 

appropriate.

Q12: Clinical Variation

For a clinical variation application, is it mandatory to submit a clinical overview and a 

clinical summary, or is it acceptable to submit either only an overview or only a 

summary? What are the parameters/conditions to be taken into account for choosing 

one or the other approach?

A12: Since variation is a term from the EU regulations, the answer should be provided by the 

EMEA.

Q13: Integrated Analysis of Efficacy (ISE) Section 2.7 – Clinical Summary – Statistical 

Listings

What approach should applicants take for the formatting and presentation of their 

integrated analyses when they have large amounts of statistical output to present 

(several thousands of pages)?

A13: As stated in section Reports of Analyses From More Than One Study 5.3.5.3, where the 

details of the analysis are too extensive to be reported in a summary document (for 

example, section Clinical Summary 2.7), they should be presented in a separate report. 

Such report should be placed in section 5.3.5.3.
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Q14: Cross References/Cross Strings (in Paper Submissions)

It is stated in the CTD that the section should be indicated in cross strings. What is 

meant here: The section number, or the section number and section name? (The 

section name is in many cases too long to indicate in a cross string.)

A14: Providing the section header in addition to the section number improves the clarity of the 

reference, particularly for the uninitiated reader. To reduce the length of the cross string 

while maintaining the ease of use, it is recommended to include only the section number 

in the cross string and write the text so the reader will also know the section content. For 

example, “...as seen in the population PK study 101 (5.3.3.5)” helps the reader to find the 

referenced study report under the Population PK Study Reports section. The text “...no 

safety problems were noted in the uncontrolled pneumonia study 101A (5.3.5.2)” helps

the reader find the referenced study report under the section Study Reports of 

Uncontrolled Clinical Studies for the Pneumonia indication.

Q15: Limitations of the Safety Database and Potential Implications

Section 2.5 Clinical Overview and section 2.5.5 Overview of Safety both refer to an 

assessment of the limitations of the safety database but give few details on how to 

describe them. How should these limitations be described? In addition, there is no 

specific reference to any postmarketing steps the applicant can take to remedy those 

limitations. Where should a discussion of any postmarketing pharmacovigilance and 

other postmarketing study plans go?

A15: A fuller discussion of how to describe in the CTD the limitations of the safety database 

and the potential implications for the safety of the drug when marketed is as follows: 

• Nonclinical toxicology and safety pharmacology concerns, such as those arising from 

reproductive / developmental toxicity, carcinogenicity, hepatic injury, central nervous 

system injury, or effects on cardiac repolarization that are not fully resolved by 

available human data, or that arise from incomplete testing. 

• Limitations of human safety database, such as: 

o Patient selection criteria that excluded people who are likely to be candidates for 

treatment in medical practice.

o Evaluations that were deficient for certain purposes (e.g., many drugs with 

sedative properties are not evaluated for effects on cognitive function in the 

elderly).

o Limited exposure of demographic or other subgroups, such as children, women, 

the elderly, or patients with abnormal hepatic or renal function.
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• Identified adverse events and potential adverse events that require further 

characterization or evaluation with respect to frequency and/or seriousness in the 

general population or in specific subgroups. 

• Important potential risks (e.g., known risks of pharmacologically related drugs) that 

require further evaluation.

• Drug-drug interactions that have not been assessed adequately.

Such information should be described and discussed in section 2.5.5 Overview of Safety, 

with appropriate cross references to section 2.7.4 Summary of Clinical Safety and any 

other relevant sections. 

A discussion of any planned postmarketing activity or study to address the limitations of 

the premarketing safety database should also be included in section 2.5.5 Overview of 

Safety, with any protocols for specific studies provided in section5.3.5.4 Other Clinical 

Study Reports or other sections as appropriate (e.g., module 4 if the study is a nonclinical 

study). 

An ICH guideline (E2E Pharmacovigilance Planning) is being developed to further 

address the question of how to describe the safety data and its limitations and how to 

describe planned postmarketing activities and studies.

Q16: Multiple Indications

When submitting one dossier for multiple indications, how should the applicant 

present them in the clinical part of the registration dossier, for example sections 2.5 

Clinical Overview, 2.7.3 Summary of Clinical Efficacy, and 5.3.5 Reports of Efficacy 

and Safety Studies?

A16: One section 2.5 Clinical Overview is recommended for multiple indications to be 

registered along with development rationale and cross-referencing to the corresponding 

2.7.3 and 5.3.5 sections; the “benefit/risk” conclusions should support corresponding 

claimed indications.

For section 2.7.3 Summary of Clinical Efficacy, in the case of more than one indication, 

the following organization is recommended as applicable. The current CTD numbering 

should be retained with identification of the indication, for example: 

2.7.3. UTI Summary of Clinical Efficacy

2.7.3.1. UTI Background

2.7.3.2. UTI Summary of Results of individual studies

2.7.3.3. UTI comparison and analysis

2.7.3.3.1. UTI study population

2.7.3.3.2. UTI Comparison of efficacy results

2.7.3. Pneumonia Summary of Clinical Efficacy

2.7.3.1. Pneumonia Background 

Other sections follow the same organization where applicable.
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For section 5.3.5 Reports of Efficacy and Safety Studies, in case of more than one 

indication, the following organization is recommended as applicable. The current CTD 

numbering should be retained with identification of the indications, for example:

5.3.5.UTI

5.3.5.1. UTI Controlled studies

5.3.5.2. UTI Uncontrolled studies

5.3.5. Pneumonia

5.3.5.1. Pneumonia Controlled studies

5.3.5.2. Pneumonia Uncontrolled studies

Other sections follow the same organization, where applicable.

Q17: Narrative Descriptions

The CTD guidance for Section Overall Safety Evaluation Plan and Narratives of 

Safety Studies 2.7.4.1.1 states that narrative descriptions for studies that contributed 

both efficacy and safety should be included in Section Summary of Results of 

Individual Studies 2.7.3.2 and only referenced in the safety section. Please clarify 

whether the narrative to be included in 2.7.3.2 should include the safety results as well 

as “enough detail to allow the reviewer to understand the exposure... and how safety 

data were collected” or whether the results should be included in Section 2.7.4.1.1.

A17: In general, safety results should be described in section 2.7.4.1.1, because section 

Summary of Clinical Efficacy 2.7.3 is devoted to efficacy. To avoid the need to describe 

the same study twice, section 2.7.3.2 asks for a reasonably complete description of 

studies pertinent to both safety and efficacy, including, in study narratives, information 

about the extent of exposure of study subjects to the test drug and how safety data were 

collected. This approach is confirmed in section 2.7.4.1.1, which notes that narratives for 

studies contributing both safety and efficacy data should be included in section 2.7.3.2. 

As noted in section Background and Overview of Clinical Efficacy 2.7.3.1, however, any 

results of these studies that are pertinent to evaluation of safety should be discussed in 

section Summary of Clinical Safety 2.7.4.

Q18: According to ICH E3 Structure and Content of Clinical Study Reports, the case report 

forms should be located in Appendix 16.3, the individual patient data listings in 

Appendix 16.4, and the publications and literature references in Appendices 16.1.11 

and 16.1.12 respectively. The CTD organization provides locations for case report 

forms and individual patient data listings in Module 5.3.7 and for literature references 

in Module 5.4. 

Can clarity be provided as to where these items should actually be placed in CTD and 

the eCTD submissions?

A18: For paper submissions, case report forms and individual patient data listings should be 

located in Module 5.3.7, identified by study.
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For eCTD, PDF files for case report forms and individual patient data listings should be 

organized by study in the folder for Module 5.3.7. However, in the index.xml file, the 

leaf elements for the case report forms and individual patient data listings should be 

included under the same heading as other study report files with additional information 

included with any accompanying study tagging file. In addition, a repeat of the leaf 

element can be placed under the heading 5.3.7 Case Report Forms and Individual Patient 

Data Listings. Datasets, if required by the region, should be organized according to 

regional guidance.

For paper submissions, publications and literature references should be located in Module 

5.4.

For eCTD, the files for publications and literature references should be located in the 

folder for Module 5.4. However, in the index.xml file, the leaf elements for the 

publications and literature references should be included under the same heading as other 

study report files with additional information included with any accompanying study 

tagging file. In addition, a repeat of the leaf element should be placed under the heading 

for 5.4 Literature References.