Guidance for Industry: Providing Regulatory Submissions to CBER in Electronic Format -- Investigational New Drug Applications (INDs) (PDF)

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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.

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.
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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 	Protocols [§312.23(a)(6)], protocol amendments [§312.30], previous
(clinical) 	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 	Cross referenced files and other information
(other)
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 Marketin
Applications [Biologics License Application (BLA), Product License Application (PL
/ 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.
g
A)

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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 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.

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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 	CD-ROM 	Hypertext link
Content 	Destination
IND 12345.0003 	04-Jul-2001 	Cover letter
1571
3.01
3.01
amendtoc.pdf
Protocol 12-345 	3.01
Investigator
Information
3.01
IND 12345.0002 	19-Jun-2001 	Cover letter
1571
2.01
2.01
amendtoc.pdf
Lot Release 	2.01
IND 12345.0001 	10-Feb-2001 	Cover letter
1571
1.01
1.01
amendtoc.pdf
Revised Protocol 	1.01
Sponsor Name 	15-Jan-2001 	Cover letter
1571
0.01
0.01
Indtoc.pdf
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
Previous Human
Experience
Additional
Information
0.01
0.01
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 	Pharmtox\0000_Immunopath568toc.pdf
of XXX with Normal Human Tissue
3 	Immunopathology Report: Cross-Reactivity 	Pharmtox\0000_Immunopath767toc.pdf
of XXX with Limited Normal Tissue from
Rhesus and Cynomolgus Monkeys
4 	An MTD/Dose Range Finding Intravenous 	Pharmtoc\0000_Toxicitytoc.pdf
Toxicity Study in Male CD-1 Mice
5 	A Single-Intravenous Dose Pharmacokinetic 	Pharmtox\0000_SingleDosetoc.pdf
Study in Cynomolgus Monkeys

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 18
Cycle 1
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 1
Variable Regions
1.1.2 Construction of the Light and Heavy Chain Plasmids, p1933 and 1
p1937
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 10
Expression Plasmid
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 15
and Working Cell Bank
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 22
Inoculation
1.2.6.9 Detection of Viral Particles by Thin Section Electron 22
Microscopy
1.2.6.10 Assay for Murine Xenotropic Viruses by Extended S+ 23
L- Focus Assay
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
Dr. Rakesh Pandey, Ph.D.
Ms. Gale Heavner, R.N.
(301) 827-3070
Related Product Applications 	Dr. Joseph Temenak, Ph.D.
Office of Blood Research and
Review, Division of Blood
Ms. Daria Reed 	(301) 827-3524
Applications