Guidance for Industry

Providing Regulatory Submissions to 

CBER in Electronic Format —

Investigational New Drug Applications 

(INDs)

Additional copies of this guidance document are available from:

Office of Communication, Training and Manufacturers Assistance (HFM-40)

1401 Rockville Pike, Rockville, MD 20852-1448

(Tel) 1-800-835-4709 or 301-827-1800

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

For questions on the content of this document 

contact Michael B. Fauntleroy at 301-827-5132

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Biologics Evaluation and Research (CBER)

March 2002
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Table of Contents

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

II. PURPOSE................................................................................................................... 2

III. GENERAL ISSUES................................................................................................... 3

A. HARMONIZATION WITH GUIDANCE FOR MARKETING APPLICATIONS........................ 3

B. SUBMISSIONS RELATED TO THE INITIAL IND............................................................. 3

C. ACCEPTABILITY OF ELECTRONIC SUBMISSIONS ......................................................... 3

D. ELECTRONIC SIGNATURES......................................................................................... 3

E. CROSS REFERENCES TO OTHER INDS......................................................................... 4

F. FOLDER AND FILE NAMES ........................................................................................ 4

G. BOOKMARKS AND HYPERTEXT LINKS....................................................................... 4

H. PUBLICATIONS.......................................................................................................... 5

I. SUBMISSION MANAGEMENT..................................................................................... 5

J. APPLICATION STRUCTURE ........................................................................................ 6

IV. ORGANIZING THE MAIN FOLDER .................................................................... 6

A. NAMING THE MAIN FOLDER..................................................................................... 7

B. FOLDERS................................................................................................................... 7

C. COVER LETTER ......................................................................................................... 8

D. FORM FDA 1571...................................................................................................... 8

E. IND TABLE OF CONTENTS........................................................................................ 9

F. FULL TEXT INDEX FOR THE SUBMISSION ................................................................... 9

V. ORGANIZING THE SUBMISSION ..................................................................... 10

A. ADMINISTRATIVE (ADMIN)..................................................................................... 10

B. CHEMISTRY, MANUFACTURING AND CONTROL (CMC).......................................... 11

C. NONCLINICAL PHARMACOLOGY AND TOXICOLOGY (PHARMTOX)........................... 12

D. CLINICAL................................................................................................................ 13

E. OTHER.................................................................................................................... 16

VI. APPENDICES.......................................................................................................... 17

APPENDIX A: ROADMAP FILE................................................................................... 17

APPENDIX B: IND TABLE OF CONTENTS.................................................................. 18

APPENDIX C: CBER ELECTRONIC SUBMISSION COORDINATORS.............................. 22
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GUIDANCE FOR INDUSTRY

Providing Regulatory Submissions in Electronic Format —

Investigational New Drug Applications

This guidance document represents the Agency'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 the 

Food and Drug Administration (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 guidance documents intended to assist you, sponsors, in making regulatory 

submissions in electronic format to the Center for Biologics Evaluation and Research (CBER). We, 

FDA, intend to update guidance on electronic submissions regularly to reflect the evolving nature of the 

technology and the experience of those using this technology. As FDA develops guidance on electronic 

IND submissions in the Common Technical Document (CTD) format, we intend to harmonize this 

guidance with the CTD guidance.

In this guidance, we discuss specific issues unique to the electronic submission of Investigational New 

Drug applications (INDs) and their amendments. We have described general issues such as acceptable 

file formats, media, and submission procedures that are common to all submissions in the companion 

guidance, “Providing Regulatory Submissions in Electronic Format — General Considerations,” dated 

January 1999 (January 28,1999, 64 FR 4433).

This guidance finalizes the draft guidance entitled “Guidance for Industry: Pilot Program for Electronic 

Investigational New Drug (eIND) Applications for Biological Products,” dated May 1998, that was 

announced in the Federal Register on June 1, 1998 (63 FR 104). We have incorporated into this 

guidance our experiences from the pilot program and comments received from the public, and from our 

electronic marketing applications guidance entitled, “Guidance for Industry: Providing Regulatory 

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

Biologics Marketing Applications [Biologics License Application (BLA), Product License Application 

(PLA)/Establishment License Application (ELA) and New Drug Application (NDA)],” dated 

November 1999 (November 12, 1999; 64 FR 61647).
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II. PURPOSE

This guidance is intended to facilitate the submission of INDs in electronic format as well as ensure 

quick and easy information access for the reviewer. The guidance features an IND main folder that is 

used throughout the life of the application. The IND main folder contains six subfolders, four of which 

are analogous to the review disciplines within CBER. They are described in section IV.B.

We have employed a table of contents (TOC) and bookmark driven navigational construct that is 

similar to the structure employed in CBER’s electronic marketing application. You should include at the 

top of the bookmark hierarchy the following bookmarks: Roadmap, Main TOC, and Item TOC (i.e., 

for the item currently under review). When presenting a TOC in your electronic IND submission, 

analogous bookmarks should reside in the left hand margin. 

Your submission should include individual PDF files that contain numeric prefixes. The numeric prefix 

should reflect the amendment number in which the file was submitted for review. The numeric prefix will 

facilitate the loading of new files into a pre-existing folder structure that features the IND main folder and 

it’s 6 subfolders (See IV.B.). However, the following PDF files should not contain numeric prefixes: 

roadmap.pdf (see Appendix A), protocolctoc.pdf (see V.D.1 and Appendix A, Figure VI-4), and 

adverse_eventstoc.pdf (see V.D.2 and Appendix A, Figure VI-5). These files are cumulative and will 

be replaced in subsequent submissions.

 

The electronic IND also features the use of the roadmap.pdf file. This is the recommended entry point 

for the electronic submission. The roadmap.pdf file should contain functional hypertext links to the 

original submission’s main TOC and to each subsequent submission’s TOC. You should include the 

submission serial number found in the prefix of each file for that submission (see Appendix A). You 

should update and resubmit this file with each amending submission. As a result, the roadmap.pdf file 

always will contain a current comprehensive submission history that will enable a reviewer easily to 

access the original IND and it’s subsequent amendments through their main TOC’s.

When amending your IND, you should utilize the same IND main folder and subfolder names (that you 

used) in your original IND submission. The amending submissions’ IND main folder should include the 

appropriate subfolders for the content of that submission (see IV.B.). The files should be identified 

through the use of the amending submissions serial number in their file name prefix (see III.F.). We will 

load the individual files of the new amendment, which reflect a new submission serial number in their 

prefix, into the preexisting content subfolders on our server. If the amendment contains a content 

subfolder not previously submitted to the IND, we will load the entire subfolder into the IND main 

folder on our server. You should submit an updated overall submission index and an updated subfolder 

specific index with every amendment to the IND. We will load these indexes into the preexisting folder 

structure.
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III. GENERAL ISSUES 

Regulations in 21 CFR part 312 provide the general requirements for submitting INDs to CBER. 

Currently, Form FDA 1571 (http://www.fda.gov/opacom/morechoices/fdaforms/cber.html) outlines the 

components required in the submission of an IND. 

A. Harmonization with Guidance for Marketing Applications

We have tried to harmonize the guidance for providing INDs and marketing applications in 

electronic format whenever possible. You should refer to the “Guidance for Industry: Providing 

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

Electronic Format — Biologics Marketing Applications [Biologics License Application (BLA), 

Product License Application (PLA)/Establishment License Application (ELA) and New Drug 

Application (NDA)],” November 1999, Revised, as a reference, 

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

B. Submissions related to the initial IND

This guidance applies equally to the original submission of an IND and to the subsequent 

submissions amending the original application. We have described IND submission types on 

the Form FDA 1571 under item 11. If you decide to provide an IND in electronic format, you 

should provide the entire submission in electronic format. You also should provide all 

amendments to the original submission in electronic format. 

C. Acceptability of Electronic Submissions

In the Federal Register of March 20, 1997 (62 FR 13467), the agency announced the 

establishment of a docket, number 92S-0251, 

(http://www.fda.gov/ohrms/dockets/dockets/92s0251/92s0251.htm) where it will publish the 

submissions it will accept in electronic format. Once a Center has identified in the docket a 

submission type as one that can be processed, reviewed and archived in an electronic only 

format, you may provide the submission utilizing electronic media without any paper copies (21 

CFR 11.1(d) and 11.2). 

D. Electronic Signatures

We are developing procedures for archiving documents with electronic signatures. Until those 

procedures are in place, you should include with the electronic document the following: 

• Documents for which the regulations require an original signature. 

• A paper copy that includes the handwritten signature of the sponsor’s authorized 

representative; and the IND number to identify the electronic document and 

attachments.
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E. Cross References to other INDs

At times, IND submissions are supported by a cross-reference to another IND [21 CFR 

312.23(b)]. The utility of the electronic IND submission will be further increased if all reference 

materials are supplied with the IND submission. You should handle these files in the same 

manner as other electronic files submitted to the IND. For example, you should generate the 

files from electronic source files rather than from scanned paper documents if at all possible. If 

the electronic source file is not available, we will accept a scanned copy. You should describe 

the file format and organization of these files as described in this guidance.

If an electronic IND or other form of documentation already exists in CBER, and the 

appropriate letters of authorization are supplied, the IND review team will be granted access to 

those documents. If the files you choose to reference have been provided in electronic format, 

you should include the main folder name in which the document resides in place of the volume 

number required under 21 CFR 312.23(b). You should provide copies of the appropriate 

letters of authorization in the admin folder of the submission.

F. Folder and File Names

We have provided specific names for the folders (see Table 1) and subfolders of the submission 

as well as the table of contents files including the roadmap file. Using these names will minimize 

confusion among the Center’s reviewers. 

For file names not specifically described, we ask that you use the following naming conventions.

• Include the submission serial number for the file in the initial 4 numbers of the file. 

• Use a descriptive name for the file up to a total of 28 characters. This is a total of 32 

characters including the 4-digit serial number. 

• Use the appropriate 3 - character extension for the file (e.g., pdf, xpt).

• Be consistent with the file names. For example, if you use the protocol number as part of 

the name of the original protocol, you should include the same name for the protocol 

revision. 

For example, protocol 1234 provided in amendment number six could be named 

0006_1234.pdf. The revised protocol submitted as part of amendment 125 would be named 

0125_1234.pdf. 

G. Bookmarks and Hypertext Links

For all documents with a table of contents, you should provide bookmarks and hypertext links 

for each item in the document’s table of contents including all tables, figures, publications, and 

appendices even if included in a separate file, to serve as part of the table of contents for the 

submission. 
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To facilitate the review, you should provide hypertext links to supporting annotations, related 

sections, references, appendices, tables, or figures that are not located on the same page 

throughout the body of the document. For a reference list at the end of a document, you should 

provide a hypertext link from the item listed to the appropriate PDF publication file. In order to 

provide reviewers maximal flexibility in using electronic documents, please avoid linking items 

across submission folders. We intend to review the information according to discipline and thus 

you should present your information in a modular fashion. For example, if you intend to use a 

reference to support a point in the CMC folder, you should not place the reference in the 

Clinical folder.

You should also include a bookmark to the roadmap, the submission’s main table of contents, 

and the folder’s table of contents at the highest level of the bookmark hierarchy for documents 

that you supplied as part of the submission.

H. Publications

You should provide each publication as a separate PDF file. Establish a hypertext link between 

the reference to the publication in the application and the publication. You should include the 

citation for the publication in the title portion of the Document Information field for each 

publication file. 

I. Submission Management

Timely communications with the appropriate center and office staff prior to the submission of an 

electronic document are essential. You should contact us when questions arise. 

You should notify us in writing of your intent to submit an electronic IND at least three months 

prior to the target arrival date for the application. Upon receipt and review of the written 

notification, our staff will schedule a teleconference to discuss the proposed electronic dossier. 

You should submit a CD-ROM, containing mock-up text and data, conveying your 

interpretation of the guidance for review by Center staff 45 days before the submission target 

date. As individual sponsors or product teams gaain experience in utilizing this submission type, 

we may find the CD-ROM demonstration to be unnecessary.

Because the review of an initial IND submission must be completed in 30 days, it is essential 

that the electronic IND submission function smoothly. The CD-ROM demonstration is a critical 

part of ensuring that smooth function. The CD-ROM demonstration should facilitate 

discussions of the planned regulatory submission through the presentations of mock-up text, 

tables, graphics, and data to CBER from the sponsor. The CD-ROM demonstration will: (1) 

present us with an opportunity to ensure that documents are presented in a standard format 

across all electronic IND applications; (2) present an opportunity for feedback from the review 

team on the presentation of regulatory information (e.g. dataset structures, hypertext links, 
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bookmarking, and document quality); and (3) present an opportunity for our technical staff to 

provide feedback on how well the proposed submission structure is consistent with our 

guidance. Effective use of the demonstration and timely communication with our staff should 

enhance your understanding of this guidance document and its intent. We have listed the 

appropriate staff contacts for your submissions in Appendix C.

J. Application Structure

An IND is a compilation of many small submissions collected over an extended period of time. 

Frequently, during the review of an IND submission, a reviewer will need to refer to earlier 

submissions. To help reviewers navigate through the entire application, you should provide with 

each new submission a directory that includes a list of not only the files included in the current 

submission but all of the previously submitted files as well (See Appendix A – example 

roadmap.pdf file).

This list should be presented in reverse chronological order, by submission, as part of a PDF file 

called roadmap.pdf (see Appendix A). This file is linked to the submission’s main table of 

contents, which is in turn linked to the table of contents provided in each subfolder. See section 

IV.E. below for additional details on the table of contents’ files.

IV. ORGANIZING THE MAIN FOLDER

You should place in the main folder all electronic documents and datasets that you intend to be part of 

your electronic IND. The only exception is the application directory (roadmap.pdf file). This 

document should be placed in the root directory.

Figure 1; IND main folder
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A. Naming the Main Folder 

The main folder for the original submission should be named IXYZ where XYZ contains 

abbreviations for the sponsor name, product, and indication. For this submission, you do not 

know the IND number nor can you generate it before the arrival of the regulatory submission. 

All amendments to the application should use the same main folder name as the original 

submission. 

B. Folders

Inside the main folder, you should provide 5 folders, Administrative (admin), Chemistry 

Manufacturing and Controls (cmc), Pharmacology and Toxicology (pharmtox), Clinical 

(clinical), and Other (other) to organize the documents and datasets provided in the original 

submission and subsequent amendments to your IND (Figure 1). See Table 1 for the types of 

documents that would reside in each folder. In addition, the main folder should contain an 

indindex folder (see Item F)

You should name the folders as shown in Figure 1. You should not attach an extension to the 

submission subfolders. Our intent is to create one set of folders per submission and upload 

additional supporting information into these folders. This will give our review community one 

central location as a repository for information germane to their review. 

Place the types of documents/information listed below into the designated folders.

Table 1: Organization of Documents

Folder location Types of document

Administration

 (admin)

Introductory statement, annual reports, change of address, change of 

contact, change of sponsor, letters of authorization, meeting minutes, 

interim reports, final reports request for closure, fast track, inactivation, 

reactivation, rolling BLA or NDA designation, transfer of obligations, 

withdrawal, meeting request, responses to a clinical hold or information 

request correspondence

Chemistry, 

Manufacturing 

and Controls

 (cmc)

CMC information [§312.23(a)(7)] and informational amendments 

related specifically to CMC [§312.31] including product 

characterization, device information, formulation, labeling, lot release, 

manufacturing information, shipment of product, source information, 

specifications, lot release data, stability, sterility and environmental 

assessment or claim for exclusion

Nonclinical 

Pharmacology 

and Toxicology

 (pharmtox)

Pharmacology and toxicology information [312.23(a)(8)] and 

informational amendments related specifically to pharmtox [§312.31] 

including pharmacology and toxicology data, preclinical information, 

animal models, in vitro models, pharmacokinetics, preclinical reports and 

protocols, toxicology
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Clinical

 (clinical)

Protocols [§312.23(a)(6)], protocol amendments [§312.30], previous 

human experience [§312.23(a)(9)], safety reports [§312.32] and 

informational amendments related specifically to clinical [§312.31] 

including adverse reactions, consent forms, investigator information, 

general investigational plan, investigator’s brochures, IRB approval, new 

protocols, revised protocols, site information, investigator data, CV’s, 

and 1572’s

Other

 (other)

Cross referenced files and other information

C. Cover Letter

You should provide a cover letter as a PDF file named XXXX_cover.pdf inside the main 

folder, where XXXX is the submission serial number. You should include in the cover letter the 

following: 

• A description of the submission including appropriate regulatory information. 

• A description of the electronic submission including the type and number of electronic 

media used (e.g., two CD-ROMs), and the approximate size of the submission (e.g., 1.2 

gigabytes). 

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

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

• Any changes from the recommendations in this guidance document should be 

documented in the cover letter.

• The regulatory and information technology (IT) points of contact for the application. 

D. Form FDA 1571 

Inside the main folder, provide a Form FDA 1571, as a PDF file named XXXX_1571.pdf, 

where XXXX is the submission serial number. The agency is developing procedures to allow 

the submission of electronic signatures. Until procedures are in place, you should attach a paper 

Form FDA 1571 that is signed by the sponsor’s authorized representative to accompany the 

1571.pdf file.
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E. IND Table of Contents

Regulations at 21 CFR 312.23(a)(2) require submission of a table of contents.

For the electronic submission, the table of contents should contain three levels of detail and the 

appropriate hypertext links and bookmarks (see Appendix B). The first level of detail, the main 

table of contents, will contain a simple listing of the items in section 12 of the Form FDA 1571. 

You should hypertext link and bookmark these items to the appropriate item table of contents 

for the IND. This single page PDF file should be named XXXX_indtoc.pdf, where XXXX is 

the submission serial number. You should place the main table of contents in the main folder. 

The second level of detail is the table of contents for each folder of the IND. You should 

provide these tables of contents as PDF files named in the following manner, e.g., 

0000_admintoc.pdf, 0000_cmctoc.pdf, 0000_pharmtoxtoc.pdf, 0000_clinicaltoc.pdf and 

0000_othertoc.pdf. You should place items in the appropriate subfolder. For each table of 

contents, you should list all of the files pertaining to that area in the specific subfolder and 

provide bookmarks and hypertext links to each document or dataset listed in the table of 

contents. In general, these tables of contents should consist of a few pages. You should 

provide bookmarks to the submission’s roadmap main table of contents and the item’s table of 

contents at the highest level of the bookmark hierarchy. This will allow a reviewer to easily 

navigate throughout the electronic submission.

The third level of detail pertains to reports and protocols. You should fully bookmark and 

hyperlink the table of contents for these documents. For datasets, you should provide a data 

definition table as a key to the elements being used in the datasets.

F. Full Text Index for the Submission 

You should provide an index of the full text and the Document Information fields of all items in 

the submission. The index is generated in PDF by using Acrobat Catalog. Name the index 

definition file indindex.pdx. You should place all associated index files in a folder named 

indindex. Place the indindex.pdx definition file and the indindex folder in the IND main 

folder. Associate the XXXX_indtoc.pdf file with the index file so that whenever the table of 

contents file is opened, the associated index is automatically added to the available index list. 

This will facilitate the use of the search function in Adobe Acrobat. The function enables a 

reviewer to enter a specific word and search the document for that word’s location throughout 

the documents covered by the indexes loaded at the time. The indindex folder and file do not 

have numerical prefixes because they are intended to be cumulative. Index information should 

be updated each time an amendment is submitted to the IND.
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V. ORGANIZING THE SUBMISSION

Guidance follows for providing files for each of the 5 content folders potentially included in an original 

submission of an IND and all of its subsequent amendments, in electronic format. 

A. Administrative (admin)

Table 1: Organization of Documents lists the types of documents that you should provide in the 

admin folder. You should place all of these files directly into the admin subfolder. Do not 

provide any subfolders within the admin folder except for the full text index and publications 

folders.

1. Letter of Authorization

When referencing information submitted to the agency by another sponsor, you must 

provide a written statement that authorizes the reference and that is signed by the person 

who submitted the information [21 CFR 312.23(b)]. You should provide this letter of 

authorization as an individual PDF file and place it in the admin folder.

2. Responses to Center Correspondence

You should include the actual comments, questions, and requests for additional 

information communicated in our letter sent to you, as well as your response to these 

items. You should bookmark each item to facilitate information access. You should 

make additional supporting information accessible through a hypertext link contained 

within your response. 

3. Annual Report

Except for the investigator’s brochure (21 CFR 312.33(d)), you should provide the 

required information for an annual report as a single PDF file. You will find the items 

required for the annual report listed in 21 CFR 312.33. As part of the annual report 

file, you should provide a table of contents listing each item detailed in 21 CFR 312.33. 

You should bookmark and hyperlink each item in the table of contents to its referenced 

information in the document. Information on providing the investigator’s brochure is 

provided below. 

4. Other Documents

You should provide other documents in this subfolder including those described in Table

1: Organization of Documents as individual PDF files.
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5. Publications

You should provide each publication as a separate PDF file. You should place all 

publications that are cited in files contained in the admin folder, in alphabetical order, 

into a single folder named pubs. You should establish a hypertext link between the 

citation and the publication in the pubs folder. Place the pubs folder in the admin

folder. You should include the citation for the publication in the Title portion of the 

Document Information field for each publication file. You should include the first 

author’s last name, the year of the publication and the title of the article in the citation.

6. Full Text Index 

You should provide an index of the full text and the Document Information fields of all 

documents in this folder. You should name the index definition file admin.pdx. You 

should place all associated index files in the admin index folder. You should place 

admin.pdx definition file and the admin index folder in the admin folder. You should 

associate the XXXX_admintoc.pdf file with the index file so that whenever the table of 

contents file is opened, the associated index is automatically added to the available 

index list. This will facilitate the use of the search function in Adobe Acrobat. The 

function enables a reviewer to enter a specific word and search the document for that 

word’s location throughout the documents covered by the indexes loaded at the time. 

Index files and folders do not have numerical prefixes because they are intended to be 

cumulative. They should be updated each time an amendment is submitted to the IND. 

B. Chemistry, Manufacturing and Control (CMC)

Table 1: Organization of Documents lists the types of documents that you should provide in the 

cmc folder. You should place all files directly into the cmc folder. You should not provide any 

subfolders within the cmc folder except for the full text index and the publications folder.

1. Documents and Datasets

See the “Guidance for Industry: Providing Regulatory Submissions to the Center for 

Biologics Evaluation and Research (CBER) in Electronic Format - Biologics Marketing 

Applications [Biologics License Application (BLA), Product License Application (PLA) 

/ Establishment License Application (ELA) and New Drug Application (NDA)],” 

November 1999, Revised, for guidance on the format of specific documents and 

datasets files for CMC submissions.

For documents not described in the marketing applications, you should provide 

documents as individual PDF files and place them in the cmc folder.
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2. Publications 

You should provide each publication as a separate PDF file. You should place all 

publications that are cited in files contained in the cmc folder, in alphabetical order, into 

a single into a single folder named pubs. Establish a hyperlink between the citation and 

the publication in the pubs folder. You should place the pubs folder in the cmc folder. 

You should include the citation for the publication in the Title portion of the Document 

Information field for each publication file. The citation should include the first author’s 

last name, the year of the publication and the title of the article.

3. Full Text Index 

You should provide an index of the full text and the Document Information fields of all 

documents in this folder. You should name the index definition file cmc.pdx. You 

should place all associated index files in the cmc index folder. Place the cmc.pdx

definition file and the cmc index folder in the cmc folder. You should associate the 

XXXX_cmctoc.pdf file with the index file so that whenever the table of contents file is 

opened, the associated index is automatically added to the available index list. This will 

facilitate the use of the search function in Adobe Acrobat. The function enables a 

reviewer to enter a specific word and search the document for that word’s location 

throughout the documents covered by the indexes loaded at the time. Index files and 

folders do not have numerical prefixes because they are intended to be cumulative. 

They should be updated each time an amendment is submitted to the IND.

C. Nonclinical Pharmacology and Toxicology (Pharmtox)

Table 1: Organization of Documents lists the types of documents that you should provide in the 

pharmtox folder. You should place all files directly into the pharmtox folder. You should not 

provide any subfolders within the pharmtox folder except for the full text index and the 

publications folder. 

1. Documents and Datasets

See the “Guidance for Industry: Providing Regulatory Submissions to the Center for 

Biologics Evaluation and Research (CBER) in Electronic Format - Biologics Marketing 

Applications [Biologics License Application (BLA), Product License Application (PLA) 

/ Establishment License Application (ELA) and New Drug Application (NDA)],” 

November 1999, Revised, for guidance on the format of specific documents and 

datasets files for pharmtox submissions.

For documents not described in the marketing applications, you should provide 

documents as individual PDF files and place them in the pharmtox folder.
13

2. Publications 

You should provide each publication as a separate PDF file. You should place all 

publications that are cited in files contained in the pharmtox folder, in alphabetical 

order, into a single folder named pubs. Establish a hyperlink between the 

citation and the publication in the pubs folder. You should place the pubs folder in the 

pharmtox folder. You should include the citation for the publication in the Title portion 

of the Document Information field for each publication file. You should include the first 

author’s last name, the year of the publication and the title of the article in the citation.

3. Full Text Index 

You should provide an index of the full text and the Document Information fields of all 

documents in this folder. You should name the index definition file pharmtox.pdx. 

You should place all associated index files in the pharmtox index folder. Place the 

pharmtox.pdx definition file and the pharmtox index folder in the pharmtox folder. 

You should associate the XXXX_pharmtoc.pdf file with the index file so that whenever 

the table of contents file is opened, the associated index is automatically added to the 

available index list. This will facilitate the use of the search function in Adobe Acrobat. 

The function enables a reviewer to enter a specific word and search the document for 

that words location throughout the documents covered by the indexes loaded at the 

time. Index files and folders do not have numerical prefixes because they are intended 

to be cumulative. They should be updated each time an amendment is submitted to the 

IND. 

D. Clinical 

Table 1: Organization of Documents lists the types of documents that you should provide in the 

clinical folder. You should place all files directly into the clinical folder. You should not 

provide any subfolders within the clinical folder except for the full text index, publications, 

protocol and adverse events folders.

1. Protocol and Protocol Revisions (amendments)

You should provide each protocol in a separate PDF file in a subfolder labeled 

Protocols. To help us easily identify the file, use the protocol number as part of the 

filename. Each protocol should have a table of contents. You should hypertext link and 

bookmark the table of contents. For protocol revisions or amendments, you should use 

the same protocol number that identifies the original protocol. You should submit to the 

file a complete copy of any revised protocol. This will facilitate the use of the “text 

compare” function in Adobe Acrobat by our clinical reviewers.
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You should create a PDF file named protocolctoc.pdf (i.e., protocol cumulative table 

of contents) within the Protocols subfolder. The protocolctoc.pdf is a cumulative list of

the protocols and revisions with the date of submission presented as a PDF file. The 

cumulative list should be in inverse chronological order with the most recent protocol 

submission at the top of the list. Because this file is cumulative, it does not have a 

numerical prefix. The protocolctoc.pdf should not affect the submission content in any 

fashion. You should hypertext link the protocols and revisions listed in this file to the 

documents they reference. You should update this file with the submission of any 

protocol or protocol revision. The document should function in a manner similar to the 

roadmap.pdf file (see Appendix A and Appendix B, Figure VI-4) 

2. Adverse Events

You should provide each adverse event report as a separate PDF file in a subfolder 

labeled “Adverse Events”. To aid Center staff in identifying each PDF file, please use a 

combination of the protocol number, patient number and event date in each file name 

(e.g., RIT-02-004_010-023_07132001). Within the Adverse Events subfolder you 

should provide a PDF file named adverse_eventsctoc.pdf (i.e., adverse events 

cumulative table of contents). The adverse_eventsctoc.pdf is a cumulative list of all 

adverse events that occurred during the clinical investigation. The cumulative list should 

be in inverse chronological order with the most recent submission at the top of the list. 

Because this file is cumulative, it does not have a numerical prefix. The 

adverse_eventsctoc.pdf should not affect the submission content in any fashion. You 

should hypertext link the adverse event reports listed in this file to the documents they 

reference. You should update this file with the submission of any adverse event report. 

The document should function in a manner similar to the roadmap.pdf file (see 

Appendix A and Appendix, B Figure VI-5).

3. Investigator’s Brochure

You should provide the investigator’s brochure as a single PDF file. You should include 

a table of contents in the investigator’s brochure. You should name the file 

XXXX_investbrochuretoc.pdf. You should bookmark and hypertext link the table of 

contents for this file.

4. General Investigational Plan

You should provide the general investigational plan as a single PDF file. You should 

include a table of contents in the general investigational plan. You should name the file 

XXXX_geninvestplantoc.pdf. You should bookmark and hypertext link the table of 

contents for this file.
15

5. Clinical Trials Data Bank

We have established a clinical trials data bank to collect information on your clinical 

trials protocols. Please list your protocols for serious and life-threatening conditions 

(Food and Drug Administration Modernization Act of 1997 (FDAMA) section 113). 

When finalized, you should list your protocols in accordance with our “Draft Guidance 

for Industry – Information Program on Clinical Trials for Serious or Life-Threatening 

Diseases: Implementation Plan,” June 2001.

6. Investigator Information

You should provide the investigator information as a single PDF file. If more than one 

investigator is included in the file, you should provide a bookmark to each investigator.

7. Previous Human Experience

You should provide previous human experience in a separate PDF file that is reserved 

for summary information. You should include a table of contents in the previous human 

experience file. You should name the file XXXX_prevhumexptoc.pdf. You should 

bookmark and hypertext link the table of contents for this file. If you are providing 

study reports, you should provide them as described in the appropriate marketing 

guidance document.

8. Other Files

See the “Guidance for Industry: Providing Regulatory Submissions to the Center for 

Biologics Evaluation and Research (CBER) in Electronic Format - Biologics Marketing 

Applications [Biologics License Application (BLA), Product License Application (PLA) 

/ Establishment License Application (ELA) and New Drug Application (NDA)],” 

November 1999, Revised, for guidance on the format of specific documents and 

datasets files for clinical submissions.

For documents not described in the marketing applications, provide documents as 

individual PDF files and place them in the clinical folder.

9. Publications 

You should provide each publication as a separate PDF file. You should place all 

publications that are cited in files contained in the clinical folder, in alphabetical order, 

into a single folder named pubs. You should establish a hypertext link 

between the citation and the publication in the pubs folder. You should place the pubs 

folder in the clinical folder. You should include the citation for the publication in the 

Title portion of the Document Information field for each publication file. You should 
16

include in the citation the first author’s last name, the year of the publication, and the title 

of the article.

10. Full Text Index 

You should provide an index of the full text and the Document Information fields of all 

documents in this section. You should name the index definition file clinical.pdx. You 

should place all associated index files in the clinical folder. Place the clinical.pdx

definition file and the clinical index folder in the clinical folder. You should associate 

the XXXX_clinicaltoc.pdf file with the index file so that whenever the table of contents 

file is opened, the associated index is automatically added to the available index list. 

This will facilitate the use of the search function in Adobe Acrobat. The function 

enables a reviewer to enter a specific word and search the document for that word’s 

location throughout the documents covered by the indexes loaded at the time. Index 

files and folders do not have numerical prefixes because they are intended to be 

cumulative. They should be updated each time an amendment is submitted to the IND. 

E. Other 

Table 1: Organization of Documents lists the types of documents that you should provide in the 

subfolder. You should place all files directly into the other folder. You should not provide any 

subfolders within the other folder except for the full text index.

1. Documents

You should provide an individual PDF file for each document. 

2. Full Text Index 

You should provide an index of the full text and the Document Information fields of all 

documents in the other section. You should name the index definition file 

otherindex.pdx. You should place all associated index files in a folder named 

otherindex. Place the otherindex.pdx definition file and the otherindex folder in the 

main other folder. You should associate the XXXX_othertoc.pdf file with this index 

so that whenever the other table of contents is opened, the associated index is 

automatically added to the available index list. This will facilitate the use of the search 

function in Adobe Acrobat. The function enables a reviewer to enter a specific word 

and search the document for that word’s location throughout the documents covered by 

the indexes loaded at the time. Index files and folders do not have numerical prefixes 

because they are intended to be cumulative. They should be updated each time an 

amendment is submitted to the IND. 
17

VI. APPENDICES

Appendix A: Roadmap file

You should use the roadmap.pdf file to establish a hypertext link to the submission’s table of 

contents. You should locate the roadmap.pdf file in the root directory of the submission. You 

should update and resubmit the file when you submit amendments to the application. An 

example of the roadmap.pdf file format is shown in Figure VI-1.

Figure VI-1: Example of a roadmap file

Electronic Roadmap

IND Submission Submission Date Submission 

Content

CD-ROM Hypertext link 

Destination

IND 12345.0003 04-Jul-2001 Cover letter 3.01 amendtoc.pdf

1571 3.01

Protocol 12-345 3.01

Investigator 

Information

3.01

IND 12345.0002 19-Jun-2001 Cover letter 2.01 amendtoc.pdf

1571 2.01

Lot Release 2.01

IND 12345.0001 10-Feb-2001 Cover letter 1.01 amendtoc.pdf

1571 1.01

Revised Protocol 1.01

Sponsor Name 15-Jan-2001 Cover letter 0.01 Indtoc.pdf

1571 0.01

Table of Contents 0.01

Introductory 

Statement

0.01

General 

Investigational 

Plan

0.01

Investigator 

Brochure

0.01

Protocols 0.01

CMC 0.01

Pharmacology and 

Toxiology

0.01

Previous Human 

Experience

0.01

Additional 

Information

0.01
18

The roadmap.pdf file should not contribute in any way to the content of what is under review. 

It is a map, intended to facilitate navigation through the contents of the submission. You should 

replace the roadmap.pdf file with each new submission of regulatory information. 

In addition to providing a navigable guide to the application (i.e., a correspondence history), the 

roadmap.pdf file should include the sponsor’s submission date in the DD-MM-YYYY format 

(e.g., 15-01-2000). You should describe briefly the contents of the original submission and of 

subsequent amendments in a roadmap.pdf table. You should indicate in the roadmap.pdf file 

the location of these files and folders on the submitted CD-ROMs (Compact Disk – Read Only 

Memory).

Appendix B: IND Table of Contents

The IND table of contents should facilitate access to the submission text and data. Examples of 

the first, second, and third levels for the IND table of contents are shown in Figures VI- 2 

through 7. These examples portray the intent of the IND’s multiple TOC’s. Protocol is 

highlighted as a specific example. These files will facilitate a reviewer’s ability to navigate 

throughout an electronic dossier. Bookmarks should mirror the contents of each table of 

contents. At the top of the bookmark hierarchy, three bookmarks (Roadmap, Main TOC, 

Section/Item TOC) should always reside.

Figure VI-2: IND Main Table of Contents for Original Submission 12345. This is the 

first level TOC. 

Main IND Table of Contents

Section Description Electronic folder/filename

 - Coverletter 0000_coverletter.pdf

 1 Form FDA 1571 0000_1571.pdf

 2 Table of Contents 0000_indtoc.pdf

 3 Introductory Statement 0000_intro.pdf

 4 General Investigational Plan Clinical\0000_clintoc.pdf

 5 Investigator Brochure Clinical\0000_clintoc.pdf

 6 Protocols Clinical\0000_clintoc.pdf

 7 Chemistry, Manufacturing and Controls Cmc\0000_cmctoc.pdf

 8 Pharmacology and Toxicology Data Pharmtox\0000_pharmtoxtoc.pdf

 9 Previous Human Experience Clinical\0000_clintoc.pdf

 10 Additional Information/Pre-IND Information Admin\0000_admintoc.pdf

 11 Other Other
19

Figure VI-3: Section Based Table of Contents. This is the second level TOC.

Clinical Table of Contents – Items contained within the Clinical Folder

Item Description Folder/File

 1 General Investigational Plan Clinical\0000_geninvestplantoc.pdf

 2 Investigator Brochure Clinical\0000_investbrochuretoc.pdf

 3 Protocol – XOXOXO Clinical\protocols\protocolctoc.pdf

 4 Sample Informed Consent Clinical\0000_consent.pdf

 5 Previous Human Experience Clinical\0000_prevhumexptoc.pdf

 6 Adverse Events Clinical\adverse 

events\adverse_eventsctoc.pdf

Pharmtox Table of Contents – Items contained within the Pharmtox 

Folder 

Item Description Folder/File

 1 Pharmacology and Toxicology Summary Pharmtox\0000_summarytoc.pdf

 2 Immunopathology Report: Cross-Reactivity 

of XXX with Normal Human Tissue

Pharmtox\0000_Immunopath568toc.pdf

 3 Immunopathology Report: Cross-Reactivity 

of XXX with Limited Normal Tissue from 

Rhesus and Cynomolgus Monkeys

Pharmtox\0000_Immunopath767toc.pdf

 4 An MTD/Dose Range Finding Intravenous 

Toxicity Study in Male CD-1 Mice

Pharmtoc\0000_Toxicitytoc.pdf

 5 A Single-Intravenous Dose Pharmacokinetic 

Study in Cynomolgus Monkeys

Pharmtox\0000_SingleDosetoc.pdf
20

Figure VI-4: Protocol Cumulative Table of Contents 

Submission Date Protocol Title Hyperlink Destination

15-Jan-2001 The Real Deal 0005_Pnca101.01.pdf

25-Dec-2000 Pure Profit 0003_Shazam100.pdf

30-May-2000 Home Cooking 0002_Tcencore50.01.pdf

22-Nov-1999 The Real Deal 0000_Pnca101.pdf

22-Nov-1999 Home Cooking 0000_TCencore50.pdf

Figure VI-5: Adverse Event Cumulative Table of Contents

Submission Date Adverse Event Hyperlink Destination

13-Jul-2001 Thrombocytopenia 0015_RIT-02-004_01023_07132001.pdf

04-Jul-2001 Leukocytopenia 0012_RIT-02-004_711_07042001.pdf

01-Apr-2000 Alopecia 0007_SUC-01-001_061968_04012000.pdf

Figure VI-6: Part of a Protocol Table of Contents – Pure Profit. This is the third level 

TOC.

TABLE OF CONTENTS

SYNOPSIS ii

LIST OF ABBREVIATIONS vii

1.0 OVERVIEW 1

2.0 BACKGROUND 2

2.1 Overview 2

2.2 Toxicology 3

2.3 Pharmacokinetics 4

2.4 Human Clinical Trials 5

2.5 Rationale for Study Design 6

3.0 OBJECTIVES 7

4.0 INCLUSION AND EXCLUSION CRITERIA 8

4.1 Inclusion Criteria 8

4.2 Exclusion Criteria 9

5.0 INVESTIGATIONAL PLAN 10

5.1 Study Design 10

5.2 Dose-Limiting Toxicity and Maximum Tolerated Dose 11

5.3 Sample Size 12

5.4 Treatment 12

5.4.1 Clinical Trial Material 12

5.4.2 Drug Administration 17

5.4.3 Dosage Modification 17

5.4.4 Criteria for Continuation of Treatment Beyond 

Cycle 1

18

5.4.5 Retreatment Eligibility Criteria 19

5.4.6 Concomitant Therapy 20

5.5 Outcome Measures 21
21

5.5.1 Safety Outcome Measures 21

Figure VI-7: Part of a CMC Table of Contents. This is the third level TOC.

TABLE OF CONTENTS

LIST OF ABBREVIATIONS vii

1.0 CHEMISTRY 1

1.1 Development of the Expression Construct 1

1.1.1 Construction of Genes Encoding the Light and Heavy Chain 

Variable Regions

1

1.1.2 Construction of the Light and Heavy Chain Plasmids, p1933 and 

p1937

1

1.1.3 Construction of the Expression Plasmid, p1937 2

1.1.4 Cloning and Expression of Soluble 10

1.1.4.1 Expression Plasmid for Soluble 10

1.1.4.2 Cloning of the cDNA Encoding and Development of 

Expression Plasmid

10

1.1.4.3 Development of Cell Line for Production of 10

1.1.4.4 Production and Purification of 11

1.2 Development of the Production Cell Line for 15

1.2.1 History of Cell Line 15

1.2.2 Development of the Producing Cell Line 15

1.2.3 Preparation and Characterization of the Clone Master Cell Bank 

and Working Cell Bank

15

1.2.4 Preparation and Storage of MCB 15

1.2.5 Preparation and Storage of MWCB 16

1.2.6 Characterization of MCB and MWCB 16

1.2.6.1 Growth and ING-1 Productivity of MCB and MWCB 17

1.2.6.2 Sterility Testing 19

1.2.6.3 Mycoplasma Testing 19

1.2.6.4 Isoenzyme Analysis 19

1.2.6.5 Karyotyping 20

1.2.6.6 Hamster Antibody Production (HAP) Assay 21

1.2.6.7 In Vitro Assay for the Presence of Viral Contaminants 21

1.2.6.8 Detection of Inapparent Viruses by In Vitro 

Inoculation

22

1.2.6.9 Detection of Viral Particles by Thin Section Electron 

Microscopy

22

1.2.6.10 Assay for Murine Xenotropic Viruses by Extended S+ 

L- Focus Assay

23

1.2.6.11 Assay for Bovine Adventitious Agents 23

1.2.6.12 Reverse Transcriptase Testing 24

1.2.6.13 Summary of Characterization of MCB abd MWCB 25
22

Appendix C: CBER Electronic Submission Coordinators

Office of the Director Mr. Michael B. Fauntleroy

Director, Electronic Submissions

(301) 827-5132

Office of Therapeutic Research and 

Review, Division of Application 

Review and Policy

Dr. Bradley Glasscock, Pharm.D 

Ms. Lori Tull

(301) 827-5101

Office of Vaccines Research and 

Review, Division of Vaccines and 

Related Product Applications 

Dr. Rakesh Pandey, Ph.D.

Ms. Gale Heavner, R.N.

Dr. Joseph Temenak, Ph.D.

(301) 827-3070

Office of Blood Research and 

Review, Division of Blood 

Applications

Ms. Daria Reed (301) 827-3524