Guidance for Industry

Providing Regulatory Submissions in 

Electronic Format — Human 

Pharmaceutical Product Applications 

and Related Submissions Using the 

eCTD Specifications 

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) 

June 2008 

Electronic Submissions 

Revision 2 
Guidance for Industry

Providing Regulatory Submissions in 

Electronic Format — Human 

Pharmaceutical Product Applications 

and Related Submissions Using the 

eCTD Specifications 

Additional copies are available from: 

Division of Drug Information 

Center for Drug Evaluation and Research 

Food and Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 

Silver Spring, MD 20993-0002 

(Tel) 301-796-3400 

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

and/or 

 Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

 Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

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

June 2008 

Electronic Submissions 

Revision 2 
Contains Nonbinding Recommendations

TABLE OF CONTENTS

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

II. GENERAL ISSUES.......................................................................................................... 2

A. Scope ...............................................................................................................................................2

B. Guidance on the Content of Applications and Related Submissions ........................................2

C. ICH eCTD Specification................................................................................................................3

D. Document Granularity and Table of Contents Headings...........................................................3

E. Electronic Submissions..................................................................................................................4

F. Document Information for Previous Submissions ......................................................................5

G. Referencing Previously Submitted Documents ...........................................................................5

H. Refuse to File ..................................................................................................................................5

I. Submission of Paper Copies..........................................................................................................6

J. Scanned Documents.......................................................................................................................6

K. The FDA District Office Copy ......................................................................................................6

L. Electronic Signatures.....................................................................................................................6

M. Number of Copies of Electronic Files...........................................................................................6

N. Naming Electronic Files ................................................................................................................7

O. Naming Folders ..............................................................................................................................7

P. File Formats....................................................................................................................................7

Q. PDF Bookmarks and Hypertext Links.........................................................................................8

R. Sending Electronic Submissions ...................................................................................................8

S. Technical Problems or Questions .................................................................................................8

III. ORGANIZING THE MAIN SUBMISSION FOLDER................................................. 8

A. Module 1 Administrative Information and Prescribing Information Folder...........................9

1. eCTD backbone document information files....................................................................................9

2. Cover letter (optional) .....................................................................................................................9

3. Labeling .........................................................................................................................................10

4. Advertisements and promotional material.....................................................................................10

5. Marketing annual reports ..............................................................................................................11

6. Information amendments ...............................................................................................................11

B. Module 2 Summary Folder .........................................................................................................11

C. Module 3 Quality Folder .............................................................................................................12

D. Module 4 Safety Folder ...............................................................................................................12

1. Study reports..................................................................................................................................12

2. Literature references......................................................................................................................13

3. Datasets .........................................................................................................................................13

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E. Module 5 Clinical Study Reports Folder ...................................................................................13

1. Tabular listing of all clinical studies .............................................................................................14

2. Study reports..................................................................................................................................14

3. Case report forms ..........................................................................................................................15

4. Datasets .........................................................................................................................................15

5. Periodic safety update reports .......................................................................................................16

6. Literature references......................................................................................................................16

IV. UTILITY FOLDER........................................................................................................ 16

A. Document Type Definition Folder..............................................................................................16

B. Style Folder...................................................................................................................................16

Technical specifications associated with this guidance will be provided as stand alone documents. They 

will be updated periodically. To ensure that you have the most recent versions, check the appropriate 

center's guidance Web page. For CBER, this Web site is http://www.fda.gov/cber/esub/esub.htm. For 

CDER, this Web site is http://www.fda.gov/cder/regulatory/ersr/ectd.htm. 

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Guidance for Industry1

Providing Regulatory Submissions in Electronic Format — Human 

Pharmaceutical Product Applications and Related Submissions 

Using the eCTD Specifications 

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. 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 guidance documents intended to assist applicants making regulatory 

submissions to the FDA in electronic format using the electronic common technical document 

(eCTD) specifications. This guidance discusses issues related to the electronic submission of 

applications for human pharmaceutical products2

 and related submissions, including abbreviated 

new drug applications (ANDAs), biologics license applications (BLAs), investigational new drug 

applications (INDs), new drug application (NDAs), master files (e.g., drug master files), 

advertising material, and promotional labeling.3 At this time, this does not include applications 

supporting combination products. 

This guidance revises the guidance of the same title that was issued in October 2005 and revised 

in April 2006. The first revision corrected the names of the eCTD backbone and U.S. Regional 

 

1

This guidance has been developed by the Center for Drug Evaluation and Research (CDER) and the Center for 

Biologics Evaluation and Research (CBER). 

2

 Human pharmaceutical products include those products that meet the definition of drug under the Food, Drug and 

Cosmetic Act, including those that are chemically synthesized and those derived from living sources (biologic 

products). 

3 Agency guidance documents on electronic submissions will be updated regularly to reflect the evolving nature of 

the technology and the experience of those using this technology. 

Paperwork Reduction Act of 1995: This guidance contains information collection provisions that are subject to 

review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 

3501-3520). The collections of information in this guidance have been approved under OMB Control Nos. 0910-

0014, 0910-0001, and 0910-0338. 

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backbone files referenced in section IV.A. This second revision provides updated information on 

the guidance referred to in section III.E.5. 

The goals of the guidance are to enhance the receipt, processing, and review of electronic 

submissions to the FDA. Specifically, this guidance makes recommendations regarding the use 

of the eCTD backbone files developed through the International Conference on Harmonisation 

(ICH) to facilitate efficient submission handling. In addition, the guidance provides more 

specificity than in previous guidances for electronic submissions with regard to the organization 

of individual submissions. Finally, the guidance harmonizes the organization and formatting of 

electronic submissions for multiple submission types. 

This guidance refers to a series of technical specifications associated with the guidance. They 

are being provided as stand alone documents to make them more accessible to the user. The 

associated specifications will be updated periodically. To ensure that you have the most 

recent versions, check the appropriate center's guidance Web page. 

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.

II. GENERAL ISSUES 

This portion of the guidance makes recommendations on general organizational issues related to 

the electronic submission of applications for human pharmaceutical products using the cCTD 

specifications. The requirements for the content of such applications are described in our 

regulations in chapter 21 of the Code of Federal Regulations (CFR). Additional 

recommendations on the contents of applications are provided in Agency guidances, which are 

available on the Agency Web page. 

A. Scope 

This guidance applies to marketing applications (ANDAs, BLAs, NDAs), investigational 

applications (INDs), and related submissions (master files, advertising material, and promotional 

labeling). The guidance applies equally to original submissions, supplements, annual reports, and 

amendments to these applications and related submissions, including correspondence. This 

guidance does not apply to electronic submission of prelicense or preapproval inspection 

materials. 

B. Guidance on the Content of Applications and Related Submissions 

This document provides general guidance on how to organize application information for 

electronic submission to the Agency using the eCTD specifications. Guidance on the information 

to be included in the technical sections of applications and submissions is described in a series of 

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guidance documents based on the International Conference on Harmonisation of Technical 

Requirements for Registration of Pharmaceuticals for Human Use (ICH) common technical 

document (CTD): M4: Organization of the CTD, M4Q: The CTD – Quality; M4S – The CTD 

Safety; and M4E: The CTD – Efficacy. 

C. ICH eCTD Specification 

The recommendations made here on how to organize application information are based on the 

ICH CTD and the electronic CTD (eCTD), which was developed by the ICH M2 expert working 

group. Although the CTD and the eCTD were designed for marketing applications, they could 

apply equally to other submission types, including INDs, master files, advertising material, and 

promotional labeling.4

 Details on the specification for the ICH eCTD can be found in the 

guidance document M2 eCTD: Electronic Common Technical Document Specification. 

D. Document Granularity and Table of Contents Headings 

Submissions are a collection of documents. A document is a collection of information that 

includes forms, reports, and datasets. When making an electronic submission, each document 

should be provided as a separate file.

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 The documents, whether for a marketing application, an 

investigational application, or a related submission, should be organized based on the five 

modules in the CTD: module 1 includes administrative information and prescribing information, 

module 2 includes CTD summary documents, module 3 includes information on quality, module 

4 includes the nonclinical study reports, and module 5 includes the clinical study reports. 

A table of contents is defined by headings arranged in a hierarchical fashion. See the associated 

specification, Comprehensive Table of Contents Headings and Hierarchy for the comprehensive 

listing of headings and hierarchy Because this is a comprehensive listing, not all headings are 

applicable to all submissions or submission types. All of the information you need to submit is 

covered by these headings. If you think other headings are needed, you should contact our 

electronic submission coordinators prior to using any other headings (see section II.S of this 

guidance). Reviewers will not be able to access documents associated with headings not listed 

in the “Comprehensive Table of Contents Headings and Hierarchy.” 

Unless otherwise specified, documents should be organized so that the subject matter of the 

document is specifically associated with the lowest heading in the table of contents hierarchy. 

For example, if you look at the associated document “Comprehensive Table of Contents 

Headings and Hierarchy,” the headings “Meeting request” and “Meeting background material” 

are the lowest headings in the “Meeting” hierarchy. Therefore, the meeting request and meeting 

background material would be in two separate documents — the meeting request in one 

document and the meeting background material in another document. 

4

 Advertising and promotional labeling provided with marketing applications. 

5

 Some documents are provided in more than one file because a file containing everything would be too large. See 

specifications for the size limitations for a file. 

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A document can be associated with more than one heading. However, the actual electronic file 

would only be provided once. The eCTD specifications provide details on how to refer to an 

electronic file. 

E. Electronic Submissions 

Under our regulations (21 CFR 11.2(b)(2)), applicants and sponsors are expected to contact us 

for details on how to proceed with electronic submissions. These details are usually provided in 

guidance documents. For example, we are already receiving marketing application submissions 

for human pharmaceutical products in electronic format based on details provided in the 

guidances for industry Providing Regulatory Submissions in Electronic Format – NDAs, 

Providing Regulatory Submissions in Electronic Format – ANDAs, Providing Regulatory 

Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic Format 

– Biologics Marketing Applications, and Providing Regulatory Submissions in Electronic 

Format – General Considerations.6

 However, we recommend that you begin submitting eCTD 

backbone files as described in this guidance because we believe that having the information in 

the eCTD backbone files will result in greater efficiency in the future. In time, the other 

guidances may be withdrawn because they may no longer be needed. 

When we are ready to receive a particular submission type in electronic format only, we usually 

identify it in public docket 92S-0251. Under 21 CFR part 11, you then have the option of 

providing that submission type in electronic format according to FDA guidance so that the 

Agency may adequately process, archive, and review the files. 

Once you begin to submit a specific application in electronic format based on this guidance, 

subsequent submissions to the application, including amendments and supplements, should 

include eCTD backbone files. Without the eCTD backbone files, we will not be able to 

adequately manage, process, archive, or review the submissions. If you choose to submit an 

original application using the eCTD backbone files, you should obtain an application number in 

advance by contacting the appropriate center. You may obtain the number at any time and the 

numbers will not be reused. 

We believe it is most beneficial to begin your eCTD-based submissions with the initial 

submission of an application. Contact the appropriate center first if you wish to make eCTDbased submissions to pending applications. You should avoid the submission of any paper 

documents when you follow the recommendations in this document. The maximum benefit will 

be derived once an application is in electronic format. This is particularly true for the IND, 

where submissions are provided over a long period of time. You should submit the electronic 

information for all files in the eCTD backbone files following the specifications associated with 

this guidance. 

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 This includes mixed electronic and paper submissions. 

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F. Document Information for Previous Submissions 

If you decide to submit a specific application in electronic format based on this guidance, you do 

not have to provide eCTD backbone files for the previous submissions to the application. For 

example, if you submitted an original application in 2001 and now submit an amendment to the 

application using the eCTD backbone files, you do not have to go back and submit the document 

information for the files submitted in 2001. 

G. Referencing Previously Submitted Documents7

If a document was submitted in electronic format with the eCTD backbone files, you should not 

submit additional copies when referencing the previously submitted document. Instead, you 

should include the information by reference by providing in the text of the document (1) the 

application or master file number, (2) the date of submission (e.g., letter date), (3) the document 

name, and (4) the page number of the referenced document along with a hypertext link to the 

location of the information (see section II.Q of this guidance). If a document replaces or appends 

a document previously submitted with an eCTD backbone file, then you should include this 

information in the appropriate eCTD backbone file. The details on how to include this 

information in the eCTD backbone file are provided in the associated specifications for eCTD 

backbone files. 

If a document was previously submitted in either paper or electronic format without the proper 

eCTD backbone files, you should reference the document as with any paper submission. In the 

text of the document, you should include (1) the application or master file number, (2) the date of 

submission (e.g., letter date), (3) the document name, (4) the page number, and (5) the 

submission identification (e.g., submission serial number, volume number, electronic folder, and 

file name) of the referenced document. In such cases, providing an electronic copy of the 

previously submitted documents can increase the utility of the submission. These documents, 

like all documents in the submission, should be appropriately described in the eCTD backbone 

files. These files are considered new in the eCTD backbone files. 

When referring to documents that are part of other applications, please remember to include the 

appropriate letters of authorization with the submission (e.g., 21 CFR 314.420(d)). 

H. Refuse to File 

We may refuse to file an application or supplement under our regulations (e.g., 21 CFR 314.101 

and 601.2) if the submission is illegible, uninterpretable, or otherwise clearly inadequate, 

including having incompatible formats or inadequate organization. These regulations apply to 

both paper and electronic submissions. The absence of electronic datasets in an acceptable 

format to permit review and analysis may be considered inadequate, resulting in a refuse-to-file 

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 Previously submitted documents include previously submitted information by reference for master files, market 

applications, and investigational applications discussed under 21 CFR 312.23(a)(11)(b), 314.50(g)(1), 314.420(b), 

and 601.51(a). 

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decision.8 Following the recommendations in this guidance document will help ensure that your 

electronic application meets the requirements of FDA regulations and can be archived, 

processed, and reviewed within specified time frames using our tools. 

I. Submission of Paper Copies 

When providing applications in electronic format using the eCTD backbone files, paper copies of 

the application, including review copies and desk copies, are not required and should not be sent. 

J. Scanned Documents 

Scanned documents submitted electronically as images are not as useful for review as documents 

that are text based. Image-based documents are more difficult to read and cannot be 

electronically searched. It takes longer to print image-based documents, and they occupy more 

storage space than text-based documents. For these reasons, we strongly urge that you provide 

text-based documents, rather than image files, whenever possible. We understand that certain 

documents may only be available as image files. Handwritten documents and documents that 

were generated independent from the company, such as journal publications, may be available 

only in paper. Documents that may only be available in paper can be scanned and submitted in 

electronic format as image-based files. However, we expect documents such as study reports 

recently generated by the company or recently generated as the result of the company's request to 

be available as text-based documents. We understand that legacy study reports, those generated 

years ago, may only be available in paper. For these reports, especially those for pivotal studies, 

you may want to consider converting these documents from image files to text-based files. 

Optical Character Recognition that has been validated is an option. 

K. The FDA District Office Copy 

FDA District offices have access to documents submitted in electronic format. Therefore, when 

sending submissions in electronic format, you need not provide any documentation to the FDA 

Office of Regulatory Affairs District Office. 

L. Electronic Signatures 

Documents required by regulations to be submitted with an original signature (e.g., FDA form 

356h, FDA form 1571) should be submitted with electronic signatures that follow the controls 

described under 21 CFR part 11. 

M. Number of Copies of Electronic Files 

You should send a single copy of the electronic portions of a submission to the appropriate 

central document room facility. Copies should not be sent directly to the reviewer or review 

division. Electronic documents that bypass the controls for electronic files described in 21 CFR 

11 are not considered official documents for review. 

8

 See more on this in CBER's SOPP 8404. 

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N. Naming Electronic Files 

To function properly, the eCTD backbone files must have specific names (e.g., index.xml, 

us-regional.xml). For other files without a specified name, you should provide a name that is 

indicative of the contents (e.g., protocol-101). The file name should allow a reviewer to infer 

some concept of the file's contents relative to other files. The file name should be less than or 

equal to 64 characters including the appropriate file extension. You should use only letters 

(lower case), numbers, or hyphens in the name. You should not use blank spaces. When naming 

files, it is important to remember that — to avoid truncation — the length of the entire path of 

the file should not exceed 230 characters. 

O. Naming Folders 

The terms folder and subfolder are used in this guidance and are intended to be synonymous with 

directory and subdirectory. The main submission, regional administrative folders, and certain 

subfolders should have specific names for proper and efficient processing of the submission. 

Recommendations regarding naming the main submission folders and regional administrative 

folders can be found in section III, below. Other specific folder names can be found in the 

specifications associated with this guidance. You can use only letters (lower case), numbers, or 

hyphens in the name. You should not use blank spaces. The length of the folder name should not 

exceed 64 characters. When naming folders, it is important to remember that the length of the 

entire path should not exceed 230 characters. You should not include empty folders in the 

submission. 

P. File Formats 

We recommend that you send electronic documents in the file formats specified in this guidance. 

We will not be able to manage, process, archive, or review documents provided in other file 

formats. 

The following file formats should be used: 

• PDF for reports and forms 

• SAS XPORT (version 5) transport files (XPT) for datasets 

• ASCII text files (e.g., SAS program files, NONMEM control files) using txt for the file 

extension 

• XML for documents, data, and document information files 

• Stylesheets (XSL) and document type definition (DTD) for the XML document 

information files 

• Microsoft Word for draft labeling (because Microsoft Word can change, check our Web 

site for the current version) 

In the future, we may consider other electronic file formats for use with electronic submissions, 

or we may consider the use of the current formats with other electronic submissions. We intend 

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to publish guidance to advise on the use of file formats for specific types of submissions for use 

in the future. 

Q. PDF Bookmarks and Hypertext Links 

For documents with a table of contents, provide bookmarks and hypertext links for each item 

listed in the table of contents including tables, figures, publications, references, and associated 

appendices. These bookmarks and hypertext links are essential for efficient navigation through 

documents. You should make the bookmark hierarchy identical to the table of contents. 

Navigation efficiency is also improved by providing hypertext links throughout the body of the 

document to supporting annotations, related sections, references, appendices, tables, or figures 

that are not located on the same page. 

It is possible to link to other documents in a submission using relative paths when creating 

hypertext linking. Absolute links that reference specific drives and root directories are not 

functional once the submission is loaded onto the document repository. For example, the link 

path ../../../123456/0001/.. will work, but the link c:\123456\0001\... will not work. However, 

you should keep in mind that some documents may be subsequently replaced or appended, 

possibly rendering the link obsolete, so linking should be used cautiously.

When creating bookmarks and hypertext links, choose the magnification setting Inherit Zoom so 

that the destination page displays at the same magnification level that the reviewer is using for 

the rest of the document. 

R. Sending Electronic Submissions 

All submissions provided in electronic format must be sent to the appropriate central document 

room facility for processing to maintain the integrity of the submission as required under 21 CFR 

part 11. Electronic documents sent directly to division document rooms or to reviewers bypass 

the controls established for the receipt and archiving of documents and are not considered 

official documents for review. See the associated specifications for more information, including 

electronic transmission. 

S. Technical Problems or Questions 

If you have any questions on technical issues related to providing electronic submissions 

according to the recommendations in this guidance, contact the electronic submission 

coordinator at esub@cder.fda.gov. Specific technical issues related to submissions to CBER 

should be sent to esubprep@cber.fda.gov. Specific questions pertaining to content should be 

directed to the appropriate review division or office. 

III. ORGANIZING THE MAIN SUBMISSION FOLDER 

All documents in the electronic submission should be placed in a main submission folder using a 

four-digit sequence number for the application with the original submission for an application 

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designated 0000. You should assign numbers for each submission to the same application with 

consecutive numbers. For example, the folder for the 3rd submission to an application, whether it 

is an amendment, supplement, or general correspondence is numbered 0002. The 4th submission 

is numbered 0003. This also applies to applications where previous submissions were not based 

on the ICH eCTD specifications. For example, if the submission is the 25th and the previous 24 

were in paper, you would number the folder 0024. You should place the eCTD backbone file for 

modules 2 to 5 for the submission in this folder (index.xml). You should place the checksum file 

(e.g., index-md5.txt) in the same folder. Sequence numbers are used to differentiate between 

submissions for the same application and do not need to correspond to the order they are 

received by the Agency. 

We recommend that you use subfolders to organize files in a submission, including for each 

module m1, m2, m3, m4, and m5, respectively. There is a subfolder util to organize eCTD 

technical files in the submission. Place these subfolders in the sequence number folder (e.g., 

folder named 0000 for the initial submission to an application). Do not include empty subfolders. 

The following sections provide guidance for organizing the folders and files in the m1, m2, m3, 

m4, m5, and util folders. In addition, you can find instructions on preparing the submission of an 

electronic application to CBER at http://www.fda.gov/cber/esub/esub.htm. 

A. Module 1 Administrative Information and Prescribing Information Folder 

Module 1 contains administrative and labeling documents. The organization of the documents in 

module 1 is the same for all applications and related submissions. The subject matter for each 

document should be assigned to the lowest level of the hierarchy outlined in the associated 

document “Comprehensive Table of Contents Headings and Hierarchy.” Note that some 

headings apply only to specific applications or specific submissions. You should create a folder 

named us and place it in the folder named m1. The documents for module 1 should be placed in 

the us folder including the us-regional.xml file pertaining to the eCTD backbone files for module 

1. Below are some additional details on providing specific types of documents. 

1. eCTD backbone document information files 

The details on creating this file are in the associated document “eCTD Backbone Files 

Specification for Module 1.” 

2. Cover letter (optional) 

If you decide to include a cover letter, we recommend you include the following information: 

• Description of the submission including appropriate regulatory information 

• Description of the submission including the approximate size of the submission (e.g., 2 

gigabytes), the format used for DLT tapes, and the type and number of electronic media 

used (e.g., three CDROMs), if applicable 

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• Statement that the submission is virus free with a description of the software (name, 

version, and company) used to check the files for viruses 

• Regulatory and technical point of contact for the submission 

3. Labeling 

The following section describes how to provide specific labeling documents. 

a. Labeling history 

You can provide a history summarizing labeling changes as a single PDF file. The 

following information will help us confirm changes made to the labeling: 

• Complete list of the labeling changes being proposed in the current 

submission and the explanation for the changes 

• Date of the last approved labeling 

• History of all changes since the last approved labeling. With each change, 

you should note the submission that originally described the change and the 

explanation for the change. 

• List of supplements pending approval that may affect the review of the 

labeling in the current submission 

b. Content of labeling 

See the guidance for industry on Providing Regulatory Submissions in Electronic 

Format — Content of Labeling for details on providing the content of labeling 

files. 

c. Labeling samples 

Each labeling sample (e.g., carton labels, container labels, package inserts) should 

be provided as individual PDF files. The samples should (1) include all panels, if 

applicable; (2) be provided in their actual size; and (3) reflect the actual color 

proposed for use. 

4. Advertisements and promotional material 

Advertisements and promotional labeling include material submitted under 21 CFR 

314.81(b)(3)(i) or 601.12(f)(4) as part of the postmarketing reporting regulations for approved 

applications, submitted under the requirements of 21 CFR 314.550 and 601.45 (part of the 

accelerated approval requirements and restricted distribution for drug and biological products), 

or voluntarily submitted to INDs. You should submit promotional material to the appropriate 

application. You should not mix submissions of advertisements and promotional labeling with 

submissions containing other types of information. 

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Each promotional piece should be provided as an individual PDF file. In cases when 

promotional writing or images cover more than one page (e.g., a brochure spread), the reviewer 

should be able to view the entire layout at one time. For three-dimensional objects, you should 

provide a digital image of the object in sufficient detail to allow us to review the promotional 

material. In addition, you should provide information adequate to determine the size of the object 

(e.g., point size, dimensions). A dimensional piece shown flat, such as a flattened carton, can 

also be submitted. 

If you choose to include cover letters with your submissions of advertising and promotional 

material, they should be provided as individual PDF files and indicate for the reviewer any 

additional important information, such as which materials need priority reviews. 

If references are provided, each reference should be submitted as an individual PDF file and 

placed in the appropriate module based on subject matter. If possible, you should highlight the 

sections of the full reference that you refer to in the promotional materials. When a reference is 

used to support a claim in proposed promotional materials voluntarily submitted for advisory 

opinion or Agency comment, you should provide a hypertext link to the page of the reference or 

labeling that contains the supporting information. 

For promotional materials submitted as part of the postmarketing reporting requirements, you 

may choose to provide hypertext links to references or labeling. References improve the 

efficiency of a review. 

5. Marketing annual reports 

In the postmarketing study commitments files, you should include a bookmark for each study 

described. 

6. Information amendments 

You should include documents that are provided in information amendments in the appropriate 

module using the appropriate headings to describe the subject matter. In the unusual case when 

information amendments do not fit appropriately under any heading in the CTD, you should 

place the documents in module 1 under the heading “information amendment: Information not 

covered under modules 2 to 5.” You should provide a separate PDF file for each subject 

covered. Documents that apply to more than one module should be placed under the heading 

“Multiple module information amendments.” 

B. Module 2 Summary Folder 

You should place the documents for module 2 in the m2 folder. The subject matter for each 

document should be specific for the lowest level of the hierarchy outlined in the associated 

document “Comprehensive Table of Contents Headings and Hierarchy.” Each document should 

be provided as an individual PDF file. The subfolders described in the M2 eCTD: Electronic 

Common Technical Document Specification are not necessary for the review of the submission. 

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If you choose to use the additional subfolder, we will maintain the subfolder structure so links 

will function properly. 

C. Module 3 Quality Folder 

The organization of the module 3 folder is the same for all applications and related submissions. 

You should place the documents for module 3 in the m3 folder. The subject matter for each 

document should be specific for the lowest level of the hierarchy outlined in the associated 

document “Comprehensive Table of Contents Headings and Hierarchy.” Each document should 

be provided as an individual PDF file. The subfolders described in the M2 eCTD: Electronic 

Common Technical Document Specification are not necessary for the review of the submission. 

If you choose to use the additional subfolder, we will maintain the subfolder structure used so 

links will function properly. 

You should provide the files pertaining to Key Literature References (CTD section 3.3) as 

individual PDF files. The filenames should be short and meaningful. 

D. Module 4 Safety Folder 

The organization of the module 4 folder is the same for all applications and related submissions. 

You should place the documents for module 4 in the m4 folder. The subject matter for each 

document should be specific for the lowest level of the hierarchy outlined in the associated 

document “Comprehensive Table of Contents Headings and Hierarchy.” The headings for study 

reports should also be specific for the lowest level of the hierarchy. Each document should be 

provided as an individual PDF file. The subfolders described in the M2 eCTD: Electronic 

Common Technical Document Specification are not necessary for the review of the submission. 

If you choose to use the additional subfolder, we will maintain the subfolder structure so links 

will function properly. 

1. Study reports 

Typically, a single document should be provided for each study report included in this module. 

However, if you provide the study reports as multiple documents, you should confine the subject 

matter of each document to a single item in the following list. 

• Synopsis 

• Study report body 

• Protocol and amendments 

• Signatures of principal or coordinating investigator(s) 

• Audit certificates and reports 

• Documentation of statistical methods and interim analysis plans 

• Documentation of interlaboratory standardization methods of quality assurance 

procedures if used 

• Publications based on the study 

• Important publications referenced in the report 

• Compliance and/or drug concentration data 

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• Individual subject data listings 

— Data tabulations 

- Data tabulations datasets 

- Data definitions 

— Data listing 

- Data listing datasets 

- Data definitions 

— Analysis datasets 

- Analysis datasets 

- Analysis programs 

- Data definitions 

— IND safety reports 

In the following examples, you should provide the study reports as separate documents 

• Documents previously submitted. If you have provided a document in a previous 

submission (e.g., protocol), you should provide a reference to the protocol, not resubmit 

the protocol. 

• Additional information added. If you think you will want to add information to the 

study report over time (e.g., audit information, publication based on the study), you 

should provide the study reports as separate documents and then the new information 

can be provided as a separate file, rather than replacing the entire study report. 

• Different file formats. If you submit the individual animal data listings as datasets (e.g., 

SAS transport files), you should provide these as separate files from the study reports 

(e.g., submitted as PDF files). 

When providing a study report, you should include the study tagging file (STF) described in the 

associated document “The eCTD Backbone File Specifcation for Study Tagging Files.” 

2. Literature references 

You should provide each literature reference as an individual PDF file. The filenames should be 

short and meaningful. 

3. Datasets 

See the associated document “Study Data Specifications” for details on providing datasets and 

related files (e.g., data definition file, program files) 

E. Module 5 Clinical Study Reports Folder 

The organization of the module 5 folder is the same for all applications and related submissions. 

You should place the documents for module 5 in the m5 folder. The subject matter for each 

document should be specific for the lowest level of the hierarchy outlined in the associated 

document “Comprehensive Table of Contents Headings and Hierarchy.” One exception is that 

legacy study reports can be provided as a single document. Each document should be provided as 

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an individual PDF file. The subfolders described in the guidance M2 eCTD: Electronic Common 

Technical Document Specification are not necessary for the review of the submission. If you 

choose to use the additional subfolder, we will maintain the subfolder structure so links will 

function properly. 

 

1. Tabular listing of all clinical studies 

You should provide the tabular listing of all clinical studies as a single PDF file. 

2. Study reports 

Typically, clinical study reports are provided as more than one document based on the ICH E3 

guidance document when providing a study.9

 In addition, if you have provided a document in a 

previous submission (e.g., protocol), you should provide a reference to the protocol rather than 

resubmitting the protocol. In cases when a legacy report has already been prepared as a single 

electronic document, you can provide the entire study report, other than the case report forms 

(CRFs) and individual data listings, as a single document. The individual documents that should 

be included in a study report are listed below: 

• Synopsis10 (E3 2) 

• Study report (E3 1, 3 to 15) 

• Protocol and amendments (E3 16.1.1) 

• Sample case report forms (E3 16.1.2) 

• List of IECs or IRBs (E3 16.1.3) and consent forms 

• List and description of investigators (E3 16.1.4) and sites 

• Signatures of principal or coordinating investigator(s) or sponsor’s responsible 

medical officer (E3 16.1.5) 

• Listing of patients receiving test drug(s) from specified batch (E3 16.1.6) 

• Randomizations scheme (E3 16.1.7) 

• Audit certificates (E3 16.1.8) and reports 

• Documentation of statistical methods (E3 16.1.9) and interim analysis plans 

• Documentation of interlaboratory standardization methods of quality assurance 

procedures if used (E3 16.1.10) 

• Publications based on the study (E3 16.1.11) 

• Important publications referenced in the report (E3 16.1.12) 

• Discontinued patients (E3 16.2.1) 

• Protocol deviations (E3 16.2.2) 

• Patients excluded from the efficacy studies (E3 16.2.3) 

• Demographic data (E3 16.2.4) 

• Compliance and/or drug concentration data (E3 16.2.5) 

• Individual efficacy response data (E3 16.2.6) 

9 When providing a study report, you should include the study tagging file (STF) described in the associated 

document “The eCTD Backbone File Specification for Study Tagging Files.” 

10 The synopsis should be provided as a document separate from the study report. 

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• Adverse event listings (E3 16.2.7) 

• Listing of individual laboratory measurements by patient (E3 16.2.8) 

• Case report forms (E3 16.3) 

• Individual patient data listings (CRTs) (E3 16.4) 

— Data tabulations 

- Data tabulations datasets 

- Data definitions 

- Annotated case report form 

— Data listing 

- Data listing datasets 

- Data definitions 

- Annotated case report form 

— Analysis datasets 

- Analysis datasets 

- Analysis programs 

- Data definitions 

- Annotated case report form 

— Subject profiles 

— IND safety reports 

3. Case report forms 

You should provide an individual subject’s complete CRF as a single PDF file. If a paper CRF 

was used in the clinical trial, the electronic CRF should be a scanned image of the paper CRF 

including all original entries with all modifications, addenda, corrections, comments, 

annotations, and any extemporaneous additions. If electronic data capture was used in the 

clinical trial, you should submit a PDF-generated form or other PDF representation of the 

information (e.g., subject profile). 

You should use the subject’s unique identifier as the title of the document and the file name. 

These names are used to assist reviewers in finding the CRF for an individual subject. Each CRF 

must have bookmarks as part of the comprehensive table of contents required under 

21 CFR 314.50(b). We recommend bookmarks for each CRF domain and study visit to help the 

reviewer navigate the CRFs. For addenda and corrections, making a hypertext link from the 

amended item to the corrected page or addendum is a useful way to avoid confusion. Bookmarks 

for these items should be displayed at the bottom of the hierarchy. 

4. Datasets 

See the associated document “Study Data Specifications” for details on providing datasets and 

related files (e.g., data definition files, program files). For subject profiles, you should use the 

subject’s unique identifier in the title of the document and the file name. 

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5. Periodic safety update reports 

To facilitate electronic submissions, we have divided the postmarketing periodic adverse drug 

experience report into three parts: (1) individual case safety reports (ICSRs), (2) ICSR 

attachments, if applicable, and (3) descriptive information. The descriptive information includes 

the narrative summary and analysis of the information in the report (i.e., periodic ICSRs and 

ICSR attachments), an analysis of the 15-day alert reports submitted during the reporting interval 

(i.e., expedited ICSRs and ICSR attachments), and the history of actions taken since the last 

report because of adverse drug experiences (e.g., labeling changes, studies initiated) as described 

in 21 CFR 314.80(c)(2)(ii)(a) and (c) and 600.80(c)(2)(ii)(A) and (C)). You should supply the 

descriptive information as an individual PDF file. You should provide bookmarks for each of the 

sections and subsections of this report. ICSR and ICSR attachments should be provided as 

described in FDA’s guidance for industry on electronic submission of postmarketing ICSRs 

(Available under the topic “Electronic Submission” on CDER and CBER’s guidance Web 

pages). 

6. Literature references 

You should provide each literature reference as an individual PDF file. The filenames should be 

short and meaningful. 

IV. UTILITY FOLDER 

You should create two folders, dtd and style and place them in the util folder. 

A. Document Type Definition Folder 

You should place the document type definition (DTD) that you used to create the eCTD 

backbone file (index.xml), the DTD you used to create the FDA Regional eCTD backbone file 

(us-regional.xml), and the DTD used for the STF in the folder named dtd. You should use the 

most recent DTD.11 

B. Style Folder 

You should use the most recent stylesheet. See the guidance for industry M2 eCTD: Electronic 

Common Technical Document Specification. 

11 See the FDA Web site at http://www.fda.gov/cder/regulatory/ersr/. 

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