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 Assistanc e (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 
   
   
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 CBERs 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 
its 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 submissions main TOC and to each subsequent submissions 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 its subsequent amendments through their main TOCs. 
 
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 sponsors 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 Centers 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 documents 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.  
4  
   
 
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 submissions main table of contents, 
and the folders 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, 
5  
   
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 submissions 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 
 
6  
   
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  Introductory statement, annual reports, change of address, change of 
  (admin)  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,  CMC information [312.23(a)(7)] and informational amendments 
Manufacturing  related specifically to CMC [312.31] including product 
and Controls  characterization, device information, formulation, labeling, lot release, 
  (cmc)  manufacturing information, shipment of product, source information, 
specifications, lot release data, stability, sterility and environmental 
assessment or claim for exclusion 
Nonclinical  Pharmacology and toxicology information [312.23(a)(8)] and 
Pharmacology  informational amendments related specifically to pharmtox [312.31] 
and Toxicology  including pharmacology and toxicology data, preclinical information, 
  (pharmtox)  animal models, in vitro models, pharmacokinetics, preclinical reports and 
protocols, toxicology 
7  
   
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, investigators brochures, IRB approval, new 
protocols, revised protocols, site information, investigator data, CVs, 
and 1572s 
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 sponsors authorized representative to accompany the 
1571.pdf file.  
8  
   
 
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 submissions roadmap main table of contents and the items 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 words 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. 
 
9  
   
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 investigators 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 investigators 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. 
 
10  
   
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 
authors 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 
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.  
 
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. 
 
11  
   
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 authors 
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 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.  
  
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. 
 
12  
   
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 
authors 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.  Investigators Brochure 
 
You should provide the investigators brochure as a single PDF file.  You should include 
a table of contents in the investigators 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 
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include in the citation the first authors 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 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.  
 
 
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 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.  
 
16  
   
VI.  APPENDICES 
 
Appendix A:  Roadmap file 
 
You should use the roadmap.pdf file to establish a hypertext link to the submissions 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  3.01  amendtoc.pdf 
    1571  3.01   
    Protocol 12-345  3.01   
    Investigator  3.01   
Information 
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  0.01   
Statement 
    General  0.01   
Investigational 
Plan 
    Investigator  0.01   
Brochure 
    Protocols  0.01   
    CMC  0.01   
    Pharmacology and  0.01   
Toxiology 
    Previous Human  0.01   
Experience 
    Additional  0.01   
Information 
 
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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 sponsors 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 INDs multiple TOCs.  Protocol is 
highlighted as a specific example.  These files will facilitate a reviewers 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 
 
 
 
 
18  
   
 
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 
 
19  
   
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 
20  
   
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 
 
 
 
 
 
 
 
21  
   
 
Appendix C:  CBER Electronic Submission Coordinators 
 
Office of the Director  Mr. Michael B. Fauntleroy  (301) 827-5132 
Director, Electronic Submissions 
 
Office of Therapeutic Research and  Dr. Bradley Glasscock, Pharm.D   (301) 827-5101 
Review, Division of Application  Ms. Lori Tull 
Review and Policy 
Office of Vaccines Research and  Dr. Rakesh Pandey, Ph.D.  (301) 827-3070 
Review, Division of Vaccines and  Ms. Gale Heavner, R.N. 
Related Product Applications   Dr. Joseph Temenak, Ph.D. 
Office of Blood Research and  Ms. Daria Reed  (301) 827-3524 
Review, Division of Blood 
Applications 
 
 
22