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 Applications (NDA)] 
Additional copies are available from: 

Office of Communication, 

Training, and Manufacturers Assistance (HFM-40) 

Center for Biologics Evaluation and Research (CBER) 

1401 Rockville Pike, Rockville, MD 20852-1448 

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

(Fax) 888-CBERFAX or 301-827-3844
 
(Voice Information) 800-835-4709 or 301-827-1800 

U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
November 1999 
REVISED  TABLE OF CONTENTS 
Note: Page numbering may vary for documents distributed electronically 
I.  INTRODUCTION.............................................................................1
 
II.  GENERAL ISSUES .......................................................................... 1
 
A.  Refuse to File ........................................................................... 1
 
B.  Review and Archival Copies........................................................ 2
 
C.  Supplements and Amendments...................................................... 2
 
D.  Electronic Signatures.................................................................. 2
 
III.  ORGANIZING THE MAIN FOLDER.................................................3
 
A.  Submission Structure.................................................................. 3
 
B.  Folders.................................................................................... 6
 
C.  Cover Letter............................................................................. 7
 
D.  Form FDA 356h ....................................................................... 7
 
E.  BLA Table of Contents............................................................... 7
 
F.  Figure of Main Folder ................................................................ 8
 
G.  Submission Management ............................................................. 8
 
IV.  ORGANIZING THE ELECTRONIC SUBMISSION ............................. 9
 
A.  Item 1:  Table of Contents (Index)................................................. 9
 
B.  Item 2:  Labeling......................................................................11
 
C.  Item 3:  Summary.....................................................................15
 
D.  Item 4:  Chemistry, Manufacturing and Controls (CMC) ...................15
 
E.  Item 5:  Nonclinical Pharmacology and Toxicology..........................21
 
F.  Item 6:  Human Pharmacology and Bioavailability/Bioequivalence.......28
 
G.  Item 7:  Clinical Microbiology.....................................................32
 
H.  Item 8:  Clinical .......................................................................32
 
I.  Item 9:  Safety Update...............................................................35
 
J.  Item 10:  Statistical ...................................................................36
 
K.  Item 11:  Case Report Tabulations (CRTs).....................................36
 
L.  Item 12:  Case Report Forms ......................................................42
 
M.  Item 13:  Patent Information........................................................44
 
N.  Item 14:  Patent Certification.......................................................45
 
O.  Item 15:  Establishment Description..............................................45
 
P.  Item 16:  Debarment Certification ................................................48
 
Q.  Item 18:  User Fee Cover Sheet...................................................49
 
R.  Item 19:  Other........................................................................49
 
V.  APPENDIXES.................................................................................50
 
Appendix 1:  Example Nonclinical Pharmacology and Toxicology Datasets and 

Data Elements..........................................................................50
 
Appendix 2: Example Content of specific clinical datasets ...........................59
  Guidance for Industry1 
Providing Regulatory Submissions to the Center for Biologics 

Evaluation and Research in Electronic Format  

Biologics Marketing Applications
 
I.  INTRODUCTION 
This is one in a series of guidance documents intended to assist applicants when making 
regulatory submissions in electronic format to the Center for Biologics Evaluation and 
Research (CBER).  CBER will update guidance documents on electronic submissions 
periodically to reflect evolving technology and the experience of those using this 
technology. 
This guidance discusses issues related to the electronic submission of license applications 
[e.g., Biologics License Applications (BLAs), Product License 
Applications/Establishment License Applications (PLAs/ELAs)], new drug applications 
(NDAs), and supplements and amendments to those applications to CBER.  For a list of 
guidance documents that are under development regarding electronic submissions and 
guidance on general issues relevant to all electronic submissions refer to the companion 
guidance document, Regulatory Submissions in Electronic Format  General 
Considerations (January 1999) http://www.fda.gov/cber/guidelines.htm. 
II.  GENERAL ISSUES 
Title 21, Code of Federal Regulations, Sections 601.2 and 314.50 provide the general 
requirements for submitting marketing applications to CBER.  Currently, Form FDA 
356h (http://aosweb.psc.dhhs.gov/forms/fdaforms.htm) outlines the components required 
in the submission of a biologic or new drug application. 
 A.  Refuse to File 
CBER may refuse to file (RTF) an application or supplement as provided by 21 
CFR 601.2, and 21 CFR 314.101, including those reasons consistent with the 
published RTF policy (http://www.fda.gov/cber/regsopp/8404.htm).  Therefore, 
CBER may RTF an application or supplement if the paper or electronic portions 
are illegible, uninterpretable, or otherwise clearly inadequate, including 
incompatible formats and inadequate organization.  The absence of a complete 
                                       
1  This guidance has been prepared by the Center for Biologics Evaluation and Research (CBER) at 
the Food and Drug Administration.  This guidance document represents the Center's current thinking on 
regulatory submissions in electronic format.  It does not create or confer any rights for or on any person and 
does not operate to bind FDA or the public.  An alternative approach may be used if such approach satisfies 
the requirements of the applicable statute, regulations, or both. 
1
  electronic database in an acceptable format to permit CBER review and statistical 
analyses may be considered to be inadequate, thereby resulting in a RTF 
decision.  The intent of this guidance document is to provide information you 
need when constructing your electronic submission.  Following this guidance 
document should help ensure that your electronic submission meets the 
requirements set forth in the regulations and can be easily archived, loaded on 
network drives, and reviewed within specified time frames using CBER desktop 
standards. 
 
 B.  Review and Archival Copies 
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 those submissions it can accept in electronic format.  Once CBER has 
identified in the docket number a submission type as one that can be reviewed 
and archived in an electronic only format, you may provide all, or only a portion 
of the archival and/or review copy of the submission in electronic format.  Any 
portion of the application that is not provided in electronic format should be 
submitted in paper.  If a submission contains both electronic and paper sections, 
the index (commonly referred to as the table of contents) for the submission 
should include the location of information submitted as a paper copy, and should 
identify the location of the electronic files by file and folder name.  The location 
of information provided on paper only should be noted within the electronic 
submission through the use of a place holder.  The place holder should direct the 
reviewer to the paper based submission and provide the volume and page 
number of the submission.  Preferably, each item of the Form FDA 356h should 
be a complete electronic and/or paper document.  The paper portion of a license 
application should be submitted in accordance with other Agency guidance 
documents. 
 C.  Supplements and Amendments 
This guidance document applies equally to the original submission of an 
application, and the subsequent supplements and amendments. 
D.   Electronic Signatures 
The Agency is developing procedures to allow for the submission of electronic 
signatures.  Until those procedures are in place; documents for which regulations 
require an original signature, such as forms and certifications, should be 
accompanied by a paper copy that includes the handwritten signature.  When the 
Agency is prepared to accept electronic signatures, this will be posted in the 
above reference docket. 
2
  III.   ORGANIZING THE MAIN FOLDER
 
All electronic documents and datasets that are intended to be part of the electronic 
license application should be placed in a main folder entitled blamain.  Following the 
assignment of a reference number to a license application, the designated reference 
number should be used as the title of the main folder.  When information is submitted to 
a preexisting electronic submission, the assigned reference number should be used as the 
title of the main folder. 
 A.  Submission Structure 
The structure and content of electronic submissions to CBER should be based on 
Form FDA 356h.  Subsequent to the delivery of the original license application 
or supplement, any additional electronic and/or paper information will be added 
to the existing network base copy of the submission and distributed to 
appropriate reviewers.  The root directory of an electronic application should 
contain a roadmap.pdf file to orient the review team to the original submission 
and to any and all subsequent information added to the application. 
CBER suggests that a roadmap.pdf file be used to establish hypertext links to the 
applications main table of contents, and to the respective folders and files of the 
submission.  This roadmap should be updated and resubmitted as additional 
information is added to the application.  An example of one possible roadmap 
format is shown in the following illustrations. 
The roadmap 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.  The submissions roadmap.pdf file should be easily updated 
or modified using the Replace file command under the Document menu 
option in Adobe Exchange.  This function will automatically replace the old 
hypertext links to previously submitted sections of the application, leaving only 
the task of creating the new links corresponding to newly submitted information. 
In addition to providing a navigable guide to the application, the roadmap.pdf file 
should include the sponsors submission date in the DD-MM-YYYY format 
(e.g., 01-Jan-1999).  The contents of the original submission and of subsequent 
amendments should be briefly described in a roadmap.pdf table.  The location of 
these files and folders on the submitted CD-ROMs (Compact Disk  Read Only 
Memory) or DLT tapes (Digital Linear Tape) should be indicated in the 
roadmap.pdf.  Where portions of the submission have been submitted only in 
paper, they should be included in  the roadmap and table of contents and tagged 
as paper only. 
3
  Network Server for eSubmissions 
eBLA File and Folder Structure 
Original Submission: 99-0000 
Network Folder 
(Company Name 
or Product Name) 
Roadmap.pdf 
blamain 
blatoc.pdf 
356h.pdf 
cover.pdf 
Labeling 
Labeltoc.pdf 
pi.pdf 
carton.pdf 
contain.pdf 
diluent.pdf 
Summary 
Summary.pdf 
CM CCMC 
cmctoc.pdf 
substan 
product 
batch
4
  Network Server for eSubmissions 
eBLA File and Folder Structure 
Original Submission and Amendments
Network Folder 
(Company Name or 
Product Name) 
Roadmap.pdf 
blamain  (Original Submission Main Folder) 
blatoc.pdf 
99-0000.001  (additional info., date) 
blatoc.pdf 
356h.pdf 
cover.pdf 
Labeling 
Labeltoc.pdf 
pi.pdf 
contain.pdf 
 CMC 
cmctoccm.pcdtof c.pdf 
substan 
product 
batch
99-0000.002  (additional info., date) 
blatoc.pdf 
356h.pdf 
cover.pdf 
Clinical 
clintoc.pdf 
1234.pdf 
5  Every electronic submission delivered to CBER should contain a list of 40 key 
words describing the submission.  This list should be developed by the sponsor 
and contain a term that will identify the electronic document [e.g., sponsor name, 
reference number (if available), indication, product name, promotional name, 
USAN (United States Adopted Names) name, pivotal trial type (controlled, open 
label), types of data, etc.].  This summation should be located in the root 
directory on the CD-ROMs or DLT tape. 
The file containing the 40 key words should be an ASCII (American Standard 
Code for Information Interchange) text file entitled Summary.txt.  The ASCII test 
file will be utilized to retrieve electronic submissions from the CBERs electronic 
document room (EDR). 
B.   Folders 
Inside the main folder, all of the documents and datasets should be organized in 
accordance with the items described on page 2 of Form FDA 356h.  Each item 
should have an assigned subfolder where documents and datasets that belong to 
that item are placed.  Table 1 lists these items and folder names. 
Table 1.  Items contained within a BLA as described in Form FDA 356h. 
Items Contained Within A BLA As Described In Form FDA 356h 
Item  Description  Folder name 
1  Table of contents (Index)  Main folder 
2  Labeling  Labeling 
3  Summary  Summary 
4  Chemistry section  CMC 
5  Nonclinical pharmacology and toxicology section  Pharmtox 
6  Human pharmacology and  Hpbio 
bioavailability/bioequivalence  section 
7  Clinical microbiology section  Micro 
8  Clinical section  Clinstat 
9  Safety update report  Update 
10  Statistical section  Clinstat 
11  Case report tabulations  Crt 
12  Case report forms  Crf 
13  Patent information  Other 
14  Patent certification  Other 
15  Establishment description  Estab 
16  Debarment certification  Other 
17  Field copy certification  Other 
18  User fee cover sheet  Other 
19  Other  Other 
6
   C.  Cover Letter 
Inside the main folder, provide a cover letter as a PDF (Portable Document 
Format) file named cover.pdf.  This cover letter should also be included with any 
paper portion of the archival copy.  The cover letter should include the following 
items: 
	   A description of the submission including appropriate regulatory information. 
 
	   A listing of the sections of the submission filed as paper, only in electronic 
format, or in both paper and electronic formats. 
	   A description of the electronic submission including the type and number of 
electronic media used (e.g., two sets of three CD-ROMs), and the approximate 
size of the submission (e.g., 2 gigabytes), including the format used for DLT 
tapes 
	   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. 
 
	   The regulatory and information technology (IT) points of contact for the 

application. 

 
 D.  Form FDA 356h 
 
 Provide Form FDA 356h as a PDF file named 356h.pdf inside the main folder. 
On page 2 of the form, the applicant should note, next to each item, if the 
documents are in paper format, electronic format, or both paper and electronic 
format.  The Agency is developing procedures to allow the submission of 
electronic signatures.  Until those procedures are in place, the submission should 
be accompanied by a signed paper Form FDA 356h. 
 
 E.  BLA Table of Contents 
 
 Inside the main folder, the applicant should provide a table of contents for the 
submission named blatoc.pdf.  See Item 1 for additional information. 
7
   Figure 1: An example of the blamain folder 
 
 
 F.  Figure of Main Folder 
 
 Figure 1 is an example of the contents of the main folder for sample BLA 
123456.  Each item from Table 1 appears as a separate folder. 
 
 G.  Submission Management 
 
 Timely communications with the appropriate office prior to submitting an 
electronic document are essential to facilitate its management.  CBER should 
receive written notification of your intent to submit an electronic document at 
least six to eight months prior to the target arrival date for the submission. 
Within that timeframe, sponsors seeking to submit electronic documents to CBER 
should provide a completed copy of the computer assisted license application 
(CALA) questionnaire (http://www.fda.gov/cber/guidelines.htm).  Subsequent to 
the receipt of the CALA questionnaire [fax or email submission followed by a 
regulatory submission to the appropriate Investigational New Drug application 
(IND)], a teleconference will be scheduled with the appropriate Center staff. 
During this teleconference information relating to the proposed electronic 
submission will be discussed.  During these discussions, CBER will notify the 
sponsor of any issues specific to the submission that may not be covered in the 
current electronic submissions guidance.  CBER will also discuss administrative 
and management issues relating to the submission of electronic documents. 
8
   
 IV.  ORGANIZING THE ELECTRONIC SUBMISSION 
 
 An electronic copy of the application should contain the documents and datasets 
corresponding to the items listed on Form FDA 356h. 
 
 A.  Item 1:  Table of Contents (Index) 
 
 For every electronic submission, a comprehensive table of contents should be 
submitted containing three or four levels of detail, with the appropriate hypertext 
links and bookmarks.  The first level of detail simply lists the items in the BLA 
as shown on page 2 of Form FDA 356h (Table 2).  At this level, the 
comprehensive table of contents should be a single page and provided as a single 
PDF file.  The file containing the table of contents for an original BLA or an 
amendment to that submission should be named blatoc.pdf.  The file containing 
the table of contents for a supplement should be named suppltoc.pdf. 
 
 The second level of detail contains the table of contents for each item [e.g., 
labeling, Chemistry, Manufacturing and Controls (CMC), Case Report 
Tabulations (CRTs)].  The table of contents for a particular item should appear 
within that items folder.  Within the items table of contents, include a bookmark 
for the item and a bookmark for the submissions master table of contents. 
Provide the appropriate bookmarks and hyperlinks for each document or dataset 
listed to the appropriate file.  In general, this table of contents should consist of 
only a few pages. 
 
 The third and fourth levels of detail consist of the subheadings in the table of 
contents for each document or dataset.  For each document, provide bookmarks 
and hypertext links from each entry in the documents table of contents to the 
appropriate location in the submission.  For datasets, provide a data definition 
table as a key to the elements being used in the datasets. 
 
 In the example of the table of contents for BLA 123456 (Table 2), a portion of 
the Nonclinical Pharmacology and Toxicology sections is in paper and a 
portion is in electronic format.  The paper portion starts in Volume 5.  The 
electronic portion can be found in the pharmtox folder.  The chemistry 
section is provided in only 4 paper volumes, starting with Volume 1, and there is 
no electronic version.  The table of contents shows the entire submission 
including the paper and the electronic portions. 
 
 If an item is in paper format, the volume numbers that hold the item should be 
listed in the table of contents.  If an item is in electronic format, the folder name 
containing the files should be listed in the table of contents.  If portions of the 
item are in both paper and electronic format, both the volume number and the 
folder name should be listed in the table of contents. 
9
   
 Table 2: An example of the main table of contents 
E  xample:  Table Of Contents For BLA 123456 (n/a = not available) 
 Item   Description   Paper copy Volume   Electronic copy 
number  folder 
 1   Table of contents (Index)   1   Main folder 
 2   Labeling   n/a   Labeling 
 3   Summary   n/a   Summary 
 4   Chemistry   4.1-4.4   n/a 
 5   Nonclinical pharmacology   5.5-5.10   Pharmtox 
and toxicology section 
 6   Human pharmacokinetics and   n/a   Hpbio 
bioavailability 
 7   Clinical microbiology   n/a   Micro 
 8   Clinical   n/a   Clinstat 
 9   Safety update report   n/a   n/a 
 10   Statistical   n/a   Clinstat 
 11   Case report tabulations   n/a   Crt 
 12   Case report forms   n/a   Crf 
 13   Patent information   n/a   Other 
 14   Patent certification   n/a   Other 
 15   Establishment description   n/a   Estab 
 16   Debarment certification   n/a   Other 
 17   Field copy certification   n/a   Other 
 18   User fee cover sheet   n/a   Other 
 19   Other   n/a   Other 
 
 A hypertext link should be provided from the first level table of contents to the 
corresponding tables of contents for each item.  These links are essential for 
establishing a comprehensive table of contents for the electronic submission. 
 
 Some items in Table 2, such as items 3, 13, 14, and 16-19, are single documents 
and do not have their own table of contents.  In such cases, the hypertext link 
from the first level table of contents should go directly to the document. 
 
An index of the full text and the Document Information fields of all items in the 
application or supplement should be provided.  Name the index definition file 
blaindex.pdx.  Place all associated index files in a folder named blaindex.  Place 
the blaindex.pdx definition file and the blaindex file subfolders in the main 
folder.  Associate the blatoc.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. 
10
   B.  Item 2:  Labeling 
 
 Labeling is item 2 on page 2 of Form FDA 356h. Form FDA 2567, available at 
http://aosweb.psc.dhhs.gov/forms/fdaforms.htm, should be provided as a PDF 
file with all labeling.  This file should be named 2567.pdf.  The content and 
format of what is referred to in this section is defined in 21 CFR 201.56. 
201.57, 606.120 - .122, 610.60 - .65, and 660.28 - .55 and includes all text, 
tables, and figures proposed for use in the package insert.  The PDF text files in 
this section should be generated from electronic source documents and not from 
scanned material. 
 
 1.  Folder 
 
 All documents for this section should be placed in a single folder named 
labeling.  An example of the organization of the labeling folder is 
pictured below.  When multiple products are submitted under the same 
BLA or PLA/ELA, separate product subfolders should be created for 
each products labeling. 
 
 Figure 2. An example of the labeling folder 
 
2.   Table of contents 
 Provide a table of contents listing all labeling included in the submission 
and the history of labeling changes, if applicable, as a PDF file named 
labeltoc.pdf.  The example headings in Table 3 may be used to organize 
the files in the table of contents.  Include the location of the file by folder 
and file name, if electronic, and by volume number if paper.  As part of 
the table of contents for the submission, provide a hypertext link between 
the documents listed in the table of contents and the corresponding PDF 
file and bookmarks for the each item in the table of contents.  Place the 
labeltoc.pdf  file in the labeling folder. 
11
   
 Table 3: An example of the labeling table of contents 
 Labeling Table Of Contents 
  LOCATION* 
I .    Labeling history   
I I.   Package Insert (Circular)   
  a. Proposed labeling text   
  b. Currently used labeling text   
  c. Last approved labeling text   
I II.  Container label   
I V.  Carton label/Package label   
V  .   Diluent   
V  I.  Other   
( *Use the file name if the information is presented as an electronic document or volume 
number if the document is a paper copy.) 
 
3  .  Labeling history 
 
I n each submission containing new labeling, supply a summary of all 
labeling changes, if applicable, in a PDF file named history.pdf and place 
it in the labeling folder.  The labeling history helps CBER identify 
changes made to the labeling and should contain the following 
information: 
 
	   A complete list of the labeling changes being proposed in the 
current submission and the explanation for the changes 
	   The date of the last approved labeling. 
	   A history of all changes since the last approved labeling with 
reference to the submission that originally described the change 
and the explanation for the change. 
	   A list of supplements pending approval that may affect the review 
of the labeling in the current submission. 
 
4  .  Package Insert 
 
T  he labeling text should have the following characteristics: 
 
	   Print area should fit on an 8.5- by 11-inch sheet of paper with one inch 
margins 
	   Page orientation - (appropriate) 
	   No columns 
	   Pagination starting with page 1 
	   Text font - Times New Roman 12 point 
12
  	   Table font - Times New Roman 10 or preferably 12 point 
	   Header 1 font - Arial 12 point bold, capitalize all letters 
	   Header 2 font - Arial 12 point, bold, capitalize the initial letter for each 
word 
	   Header 3 font - Arial 12 point, regular, capitalize the initial letter for 
each word 
	   Header 4 font - Arial 12 point, italics, capitalize the initial letter for first 
word 
	   Sequential line numbers in the left margin of draft text 
 
W  hen presenting tables of information, it is critically important that the reviewer 
be able to view this information on a single computer screen. The use of 10 or 
12 point fonts may further complicate this presentation, however, in these 
instances, utilize the largest font that will allow for the presentation of the table 
on the computer screen of Centers standard desktop workstation. 
 
D  ocument information fields should contain the following information: 
 
	   Title: USAN or other established name 
	   Subject: Product name 
	   Author: applicant, applicant's label code 
	   Keywords:  BLA, PLA/ELA, NDA number (in form of 123456), 
Document name, Labeling review number, if known, Approval 
status (draft, approved, cbe for changes being effected or annual 
for annual report), Date of labeling in the form of ddmmyyyy. 
For draft, changes being effected, and annual report changes, use 
the date of submission.  For approved labeling, use the date of 
approval. 
 
  a.  Proposed labeling text 
 
T  he proposed labeling text is either the draft labeling with an initial 
application or subsequent prior approval supplements.  When labeling 
revisions or changes are submitted, provide a copy of the annotated 
version (i.e., redlined) as a pdf file.  The purpose of this file is to readily 
show the changes to the proposed labeling or currently approved 
labeling. 
 
T  he proposed labeling text should be provided as a PDF file named 
proposed.pdf.  The annotated version of the proposed labeling should be 
provided as a PDF file named redline.pdf.  Fill in the document 
information fields as described above. 
 
13
   In addition to the PDF file, provide all the draft labeling text within an 
initial application, its subsequent supplements and amendments as an MS 
Word document in a file folder named labeltext.doc for editing purposes. 
 
 b.  Current labeling text 
 
 The current labeling text is the labeling text that is being used at the 
time of the submission.  This labeling can be approved labeling as well as 
labeling that has not been approved, such as changes being effected or 
changes with the annual report.  You should provide the current labeling 
text as a PDF file named current.pdf and fill in the document information 
fields as described above. 
 
c.   Final labeling 
 The final package insert should be provided as a PDF file(s). The document 
should be captured at its actual size or to scale, with the scale visually 
represented. In addition, the PDF files should reflect the actual color of the 
text, tables and figures within the document. 
 
 5.  Container labeling 
 
 Container labeling (all panels) should be provided as a PDF file(s). Container 
labeling (all panels) should be captured at their actual size or to scale, with the 
scale visually represented. In addition, these PDF files should reflect the actual 
color of the container labeling (all panels). Fill in the document information 
fields as described with the labeling text. 
 
 6.  Carton labeling/Package Label 
 
 Carton labeling (all panels) should be provided as a PDF file(s). Carton labels 
(all panels) should be captured at their actual size or to scale with the scale 
visually represented. In addition, these PDF files should reflect the actual color 
of the carton labeling (all panels). Fill in the document information fields as 
described with the labeling text. 
 7.  Diluent 
 
 Diluent labeling (all panels) should be provided as a PDF file(s). ). Diluent 
labels (all panels) should be captured at their actual size or to scale with the 
scale visually represented. In addition, these PDF files should reflect the actual 
color of the diluent labeling (all panels). Fill in the document information fields 
as described with the labeling text. 
14
   
8  .  Other 
 
P  rovide any other labeling that does fall into the previous categories as a PDF 
file(s), with a view of each panel. These labels (all panels) should be captured 
at their actual size or to scale with the scale visually represented. In addition, 
these PDF files should reflect the actual color of the labeling (all panels). Fill in 
the document information fields as described for the labeling text [e.g., 
dispensing pack, patient package insert, demonstration labeling (placebo)]. 
 
C  .  Item 3:  Summary 
 
T  he summary of the submission is item 3 on page 2 of Form FDA 356h. 
 
1  .  Folder 

 
P  lace the summary document in a single folder named summary.
 
 
2  .  Table of contents 
 
T  here should be a hypertext link from the submission table of contents 
directly to the summary.pdf file. 
 
3  .  Summary document 
 
T  he information for the summary section should be provided in a single 
PDF file named summary.pdf and placed in the folder named summary. 
It should also be identified in the Document Information Title field as 
submission summary. 
 
4  .  Bookmarks and hypertext linking 
 
F  or all documents with a table of contents, provide bookmarks and 
hypertext links for each item in the documents table of contents including 
all tables, figures, publication, and appendices. 
 
D  .  Item 4:  Chemistry, Manufacturing and Controls (CMC) 
 
T  he chemistry, manufacturing and controls section is item 4 from page 2 of 
Form FDA 356h. 
 
1  .  Folders 
 
T  he information for this section should be placed into a folder named 
cmc.  CBER recommends the creation of 4 subfolders, substan, product, 
15
  batch, and pubs to organize the files in this section.  The file structure is 
pictured in Figure 3 (the file, cmcindex.pdx and additional subfolder, 
cmcindex are for the full text index). 
 
 Figure 3: An example of the cmc folder 
 
 
 2.  Table of contents 
 
 A table of contents should be provided, that lists all files provided in the 
CMC section, as a PDF file named cmctoc.pdf.  To organize the files in 
the table of contents use the example headings in Table 4.  The headings 
will vary with products and you should consult the appropriate guidance 
documents for the correct headings.  As part of the comprehensive table 
of contents for the submission, provide a hypertext 
 link between the documents listed in the table of contents and the 
corresponding PDF file and bookmarks for the each item in the table of 
contents.  Place the cmctoc.pdf file in the cmc folder. 
16
   
 Table 4: An example of the CMC Table of Contents 
 CMC Table Of Contents 
  L  ocation* 
 I.    Biological Drug Substance   
 II.   Biological Product   
 III.  Investigational Formulations   
 IV.  Environmental Assessment   
 V.   Methods Validation   
 VI.  Batch Records (list each batch record separately)   
 VII. Publications (list each publication separately)   
 (*Use the file name if the information is presented as an electronic document or volume 
number if the document is a paper copy.) 
 
3  .  Biological Substance 
 
I nformation regarding the drug substance should be divided into the 
following topics: 
 
   Description & Characterization 
   Manufacturer(s) 
   Method(s) of Manufacture 
   Process Controls 
   Reference Standard(s) 
   Specifications/Analytical Methods 
   Microbiology 
   Container/Closure System 
   Stability 
 
C  BER recommends that each of the topics listed within the biological 
substance folder be provided as a separate PDF file or that they be 
combined (all topics) into a single PDF file.  If you provide the biological 
substance information as a single PDF file, organize the table of contents 
for this document using the topics listed above. 
 
P  lace all files relating to biological substance in the substan folder in the 
CMC folder.  Identify each file in the document information Title field as 
biological substance and include the specific topic, if applicable. 
 
17
   
4  .  Biological Product 
 
I nformation regarding the biological product should be divided into the following 
topics: 
 
   Components/Composition 
   Specifications and Methods for Biological Product Ingredients 
   Manufacturer(s) 
   Methods of Manufacturing and Packaging 
   Specifications/Test Methods 
   Container/Closure System 
   Microbiology 
   Stability 
 
C  BER recommends that each one of the topics listed within the biological 
product folder be provided as a separate PDF file or that they be 
combined (all topics) into a single PDF file.  If you provide the biological 
product information as a single PDF file, organize the table of contents 
for this document using the topics listed above. 
 
I dentify each file in the Document Information Title Field as biological 
product and include the specific topic, if applicable. 
 
5  .  Investigational formulations/Comparability 
 
I nformation focusing on investigational formulations should be provided 
in a single PDF file called invest.pdf.  The table of contents for this 
document should list all investigational formulations separately with a 
bookmark and hypertext link to the appropriate formulation.  Identify this 
file in the Document Information Title Field as investigational 
formulations. 
 
6  .  Environmental assessment 
 
T  he environmental assessment or a claim for categorical exclusion should 
be provided, in a single PDF file called environ.pdf.  Identify this file in 
the Document Information Title Field as environmental assessment. 
 
7  .  Methods validation 
 
A  ll method validations should be provided in a single PDF file called 
methval.pdf.  This information should be identical to the information 
provided in the biological substance and biological product documents. 
18
  Identify this file in the Document Information Title Field as methods 
validation.  The table of contents for this document should list each 
method with a bookmark and hypertext link to the appropriate method. 
 
8  . 	 Batch records 
 
P  rovide each executed batch record in a separate PDF file.  Place all 
executed batch record PDF files into a single folder named batch.  Each 
section of a batch record should contain a bookmark.  The batch folder 
should be placed in the cmc folder.  Identify this file in the Document 
Information Title field with the batch record number.  For example, batch 
record 105 should be identified as batch record number 105. 
 
9  . 	 Publications 
 
E  ach publication should be provided as a separate PDF file.  Place all 
publications, in alphabetical order, into a single folder named pubs. 
Establish a hyperlink between the citation and the publication in the pubs 
folder.  The pubs folder should be placed 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. 
 
1  0. 	 Bookmarks and hypertext links 
 
F  or 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, publication, and appendices. 
 
H  ypertext linking provided throughout the body of the document to 
supporting annotations, related sections, publications, appendices, tables, 
or figures that are not located on the same page helps reviewers navigate 
more efficiently through a 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. 
 
C  BER have identified certain pieces of information that is frequently 
needed to know and are sometimes time consuming to locate in a 
particular submission.  The suggested hypertext links for this information 
are summarized in the following list: 
 
	   Biological substance and biological products batch numbers to 
stability data, 
19
  	   Biological substance and biological products batch numbers to 
formulation composition, 
	   Clinical protocol numbers to the appropriate biological substance 
and biological products batch numbers, 
	   Stability studies to description of container/closure systems, 
	   Impurity profile to forced degradation data, 
	   Impurity profile to source of impurity, 
	   Specifications to validation reports to test methods, 
	   Names of biological or chemical substances/degradants to their 
structures, 
	   Removal of impurities to validation studies, 
	   In process control parameters to validation studies, 
	   Letters of cross-reference to Master Files. 
11. 	 Full text index 
An index of the full text and the Document Information fields of all 
documents in this section should be provided.  Name the index definition 
file cmcindex.pdx.  Place all associated index files in a folder named cmc. 
Place the cmc.pdx definition file and the cmc index file subfolder in the 
main cmc folder.  Associate the 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. 
For license applications with blood and blood products, information should be 
organized as presented in the following guidance documents available at 
http://www.fda.gov/cber/guidelines.htm: 
Guidance for Industry For the Submission of Chemistry, Manufacturing and 
Controls and Establishment Description Information for Human and Blood and 
Blood Components Intended for Transfusion or for Further Manufacture and For 
the Completion of the FDA Form 356h "Application to Market a New Drug, 
Biologic or an Antibiotic Drug for Human Use, May 1999. 
Guidance for Industry Content and Format of Chemistry, Manufacturing and 
Controls Information and Establishment Description Information for a Biological 
In Vitro Diagnostic Product, March 1999. 
 Guidance for Industry for the Submission of Chemistry, Manufacturing and 
Controls and Establishment Description Information for Human Plasma-Derived 
Biological Products or Animal Plasma or Serum-Derived Products, February 
1999. 
 
20
  License applications for vaccines and allergenic products should be organized as 
presented in the following guidance documents: 
Guidance for Industry Content and Format of Chemistry, Manufacturing and 
Controls Information and Establishment Description Information for a Vaccine or 
Related Product, January 1999. 
 Guidance for Industry On the Content and Format of Chemistry, Manufacturing 
and Controls Information and Establishment Description Information for an 
Allergenic Extract or Allergen Patch Test (Draft), April 1999. 
 
License applications for therapeutic products should be organized as presented in 
the following guidance documents: 
Guidance for the Submission of Chemistry, Manufacturing, and Controls 
Information and Establishment Description for Autologous Somatic Cell Therapy 
Products, January 1997: 
Guidance for Industry for the Submission of Chemistry, Manufacturing, and 
Controls Information for a Therapeutic Recombinant DNA-Derived Product or a 
Monoclonal Antibody Product for In Vivo Use, August 1996. 
 
 E.  Item 5:  Nonclinical Pharmacology and Toxicology 
The nonclinical pharmacology and toxicology section is item 5 on page 2 of 
Form FDA 356h. 
1.  Folders 
All information for this section should be placed in a folder named 
pharmtox.  CBER recommends the creation of 5 subfolders, pharm, pk, 
tox, datasets, and pubs, to organize the files in this section.  The pharm 
folder contains pharmacology studies. The pk folder contains the 
pharmacokinetics studies and the tox folder contains the toxicology 
studies. The datasets folder contains the datasets and the pubs folder 
contains the publications.  The file structure is pictured in Figure 4 (the 
file, ptindex.pdx and additional subfolder, pindex are for the full text 
index). 
21
  Figure 4: An example of the pharmtox folder 
2.  Table of contents 
A table of contents listing all study reports (including study report 
numbers), publications, and the summary should be provided in the 
pharmtox section as a PDF file named pharmtoc.pdf.  If datasets are 
provided for a study, note this in the table of contents.  To organize the 
files in the table of contents use the example headings in Table 4.  As part 
of the comprehensive table of contents for the submission, provide a 
hypertext link between the documents listed in the table of contents and 
the corresponding PDF file and bookmarks for each item in the table of 
contents.  If datasets are listed in the table of contents, provide a 
hyperlink to the appropriate data definition file (define.pdf).  This file is 
described below.  Place the pharmtoc.pdf file in the pharmtox folder. 
22
  Table 4: An example of the pharmtox table of contents 
Pharmtox Table Of Contents 
Location * 
I.   Summary 
II.  Pharmacology studies 
a. Pharmacodynamics 
b. Safety pharmacology 
c. Other pharmacology studies 
III. Pharmacokinetics 
IV. Toxicology studies 
a. Single and repeat dose toxicity studies 
b. Genotoxicity studies 
c. Carcinogenicity studies 
d. Reproduction toxicity studies 
e. Supplemental toxicity studies 
V.  Datasets 
VI. Publications 
(* Use the file name if the information is presented as an electronic document or volume 
number if the document is a paper copy.) 
3.  Summary document 
A summary of the entire nonclinical pharmacology and toxicology section 
should be provided as a single PDF file named pharmsum.pdf.  This 
document should include an overall summary of the preclinical studies as 
well as more detailed summaries of each section (i.e., pharmacology, 
pharmacokinetics and toxicology).  The summary should be identified in 
the Document Information Title field as pharmtox summary.  When 
supporting a conclusion by referring to a published article, data summary 
table or figure, a hypertext link should be provided to the corresponding 
published article, data table, or figure (whether located in a study report 
or elsewhere). 
4.  Study reports 
Study reports with all appendices should be provided as a separate PDF 
file.  The study number should be included in the name of the file.  For 
example, study 1234 can be named 1234.pdf.  Place the file in the 
appropriate subfolder of the pharmtox folder.  Files 25 MB or larger are 
technically more difficult to handle, so study reports that are larger than 
25 MB should be divided into two PDF files with the individual animal 
line listings for the study provided as a separate file.  If the animal line 
listings are provided as a separate file, include the study number in the 
23
  name of the animal line listings file and add d (for data) to the file name. 
For example, the file containing the animal line listings for study 1234 
can be named 1234d.pdf.  Place the two PDF files (e.g., full study report 
and individual animal line listings) into a folder whose name includes the 
study number.  Place these folders in the appropriate subfolder of the 
pharmtox folder. 
The title portion of the Document Information field of each study report 
should be designated as study and followed by the study report number 
and the study type.  For example, study 2001, a 12-month toxicity study 
in beagle dogs, should be identified as: study 2001, toxicity study.  For 
the file that has the animal line listing alone, the word data should be 
added to the title field.  For the above example, the animal line listings 
file would be identified as: study 2001, data, toxicity study. 
5.  Publications 
Each publication should be provided as a separate PDF file.  Place all 
publications into a single folder named pubs.  Establish a hyperlink 
between the citation and the publication in the pubs folder.  The pubs 
folder should be placed in the pharmtox folder.  The citation for the 
publication should be included 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. 
6.  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, publication, and appendices. 
Hypertext linking provided throughout the body of the document to 
supporting annotations, related sections, publications, appendices, tables, 
or figures that are not located on the same page help us navigate more 
efficiently through a 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.  Hypertext links can also be used to 
locate studies used to justify dose selection for toxicity studies such as 
carcinogenicity and reproductive toxicology studies. 
24
  7.  Full text index 
An index of the full text and the Document Information fields of all 
documents in the pharmtox section should be provided.  The index 
definition file should be named ptindex.pdx.  Place all associated index 
files in a folder named ptindex.  Place the ptindex.pdx definition file and 
the ptindex.pdx subfolder in the main pharmtox folder.  Associate the 
pharmtoc.pdf file with this index so that whenever the pharmtox table of 
contents is opened, the associated index is automatically added to the 
available index list. 
8.  Animal line listings as datasets 
Animal line listings that you would provide on paper or in PDF format 
may be provided as datasets.  Each domain should be provided as a 
single dataset. 
The decision to submit the individual line listings as electronic datasets, 
instead of on paper or in PDF format, should be made on a study-by
study basis with the prior agreement of the review division.  See 
Appendix 1 for recommended datasets and data elements. 
a.  Format of the datasets 
Provide each dataset as a SAS transport file as described in the 
companion guidance, Regulatory Submissions in Electronic Format  
General Considerations, to facilitate its use in a variety of software tools. 
Dataset files should be organized so that each file is less than 25 MB. 
The files should not be compressed.  Each dataset should be saved as an 
individual file. 
Data variable names should be no more than 8 characters.  A more 
descriptive data variable label, up to 32 characters in length, should also 
be provided. 
b.  Organization of data 
Prior to the submission, you should discuss with the review division the 
datasets to be provided and the data elements that should be included in 
each dataset.  Examples of the datasets and data elements to consider are 
provided in Appendix 1.  These examples are meant to serve as a starting 
point for discussions with the review division on the content and 
25
  organization of the datasets and, therefore, are not all inclusive. CBER 
plans on refining these data elements as we gain more experience. 
Datasets can be divided further to achieve a size smaller than 25 MB. 
For example, clinical chemistry data may be further divided by specific 
lab tests.  Dont divide a dataset type unless the size is greater than 25 
MB, and when you divide a dataset type, do so with the fewest number 
of overall datasets.  File names should include the three-character 
extension xpt to be compatible with our desktop set up. 
All datasets for an individual study should be placed in a folder identified 
by the study name and all these dataset folders placed in a single folder 
called datasets.  The datasets folder should be placed in the pharmtox 
folder. 
c.  Documentation of the datasets 
For the datasets to be usable, the data elements should be defined.  You 
should document all of the data elements in data definition tables.  There 
should be one set of data definition tables for each study. 
The first table should include a listing of all datasets provided for the 
study with a description of the dataset and the location of the dataset file. 
Provide a hypertext link from the description of the dataset to the 
appropriate data definition table.  Provide a hypertext link from the listing 
of the file to the SAS transport file.  In Table 5, the dataset for weights is 
described as body weights of the animals and the dataset file is located in 
folder 1234 in the datasets folder, which is in the pharmtox folder. 
Table 5: An Example of the Dataset Documentation 
Datasets For Study 1234 
Dataset  Description of dataset  Location 
Weights  Body weights of the animals  Pharmtox/datasets/1234/weights.xpt 
....  ...  ... 
Subsequent pages should contain a table for each dataset that includes an 
organized listing of all variable names used in the dataset, a 32 character 
descriptive variable label, data types, codes (and decodes), and 
comments.  The comments field is for further description of the variables. 
For derived variables, the method for calculating the variable should be 
included in the comments field.  Example data definition tables are 
provided in Appendix 1. 
26
  This collection of data definition tables should be provided as a single 
PDF file named define.pdf and placed in the appropriate study folder in 
the datasets folder.  The title portion of the Document Information field of 
each data definitions should be designated as the study, followed by the 
study number and the contents.  For example, the data definition file for 
study 2001 would be identified as: study 2001, data definitions. 
d. 	 Dataset table of contents 
The dataset table of contents is also part of the comprehensive table of 
contents and should list all studies that have datasets.  You should provide 
a hypertext link to the appropriate data definition table file.  The table of 
contents should be provided as a PDF file named datatoc.pdf and placed 
in the datasets folder. 
e. 	 General considerations for datasets 
The efficient use of datasets by the reviewer can be significantly 
improved if some basic principles are followed in setting up the datasets. 
	   Each animal should be identified with a single, unique number for 
all the datasets in the entire application, so that the results for each 
animal can be evaluated across studies.  This unique number 
should be provided in each dataset. 
	   For a data table, each data element should be represented as a 
single column heading.  Each row should contain a single 
observation or result for an individual animal, allowing for 
multiple rows per animal. 
 
	   The variable names and codes should be consistent across studies 
and should be unique to a particular attribute.  This is necessary 
when combining datasets and reduces the time for learning the 
datasets.  For example, if glucose is checked in a number of 
studies, use the same name to describe this variable in all of the 
studies.  Conversely, do not use the same name for different 
variables. 
 
	   Duration is frequently part of an analysis.  To facilitate the 
review, you should provide the duration of treatment based on the 
start of study treatment and express it consistently in minutes, 
hours, or days, whichever is appropriate.  When expressed in 
days, the following formula should be used to calculate study day 
((sampling date) - (date of first dose) + 1). 
27   
	   Since results are usually analyzed based on treatment group and 
sex of the animals, each dataset should include these variables. 
 
	   Data variable names should be limited to 8 characters with a more 
descriptive name, up to 32 characters, provided as a data variable 
label. 
 
	   Text should be used instead of, or in addition to, arbitrary or 
inexplicit number codes.  For example, for the variable organ, if 
there is a number code for each organ type, a separate column 
should be included that has the text name of the organ. 
 
	   For the dose data element, use numeric values rather than 
descriptors, such as control, LD (low dose), MD (mid dose), or 
HD (high dose). 
 
 F.	  Item 6:  Human Pharmacology and Bioavailability/Bioequivalence 
 
 The human pharmacology and bioavailability/bioequivalence section is item 6 on 
page 2 of Form FDA 356h. 
 
1  . 	 Folders 
 
A  ll information required in this section should be placed in the hpbio 
folder.  CBER recommends the creation of 4 folders, bio, hupharm, 
assays and pubs to organize the files in this section.  The bio folder 
contains studies related to bioavailability, bioequivalence and formulation. 
The hupharm folder contain studies using human biomaterials, 
pharmacokinetics studies and pharmacodynamics studies.  The assay 
folder contains assay descriptions and their validation reports including 
cross validation assays.  The pubs folder contains publications.  The file 
structure is pictured in Figure 5 (the additional file, bioindex.pdx and 
subfolder bioindex are for the full text index). 
28
   
F  igure 5: An example of the hpbio folder 
 
 
2  .  Table of contents 
 
A   table of contents listing all study reports (including study report 
numbers), publications, and the summaries provided for the hpbio section 
should be provided as a PDF file named hpbiotoc.pdf and placed in the 
hpbio folder.  If datasets are provided for a study, you should note this in 
the table of contents.  The example headings in Table 6 should be used to 
organize the files in the table of contents.  As part of the comprehensive 
table of contents for the submission, provide a hypertext link between the 
documents listed in the table of contents and the corresponding PDF file 
and bookmarks for each item in the table of contents.  If datasets are 
listed in the table of contents, provide a link to the appropriate data 
definition file (define.pdf).  This file is described in item 11, case report 
tabulations (crt). 
29
   
 Table 6: An example of the Hpbio Table of Contents 
  L  ocation* 
 I. Summaries   
  a. Bioavailability/Bioequivalence Summary   
 b. Human Pharmacology Summary   
 II. Reports for Bioavailability and Bioequivalence Studies   
 a. Bioavailability Study Reports   
 b. Bioequivalence Study Reports   
 c. IVIVC   
 III. Reports for Studies Using Human Biomaterials   
 a. Plasma Protein Binding Studies   
 b. Metabolism Studies Using Hepatocytes, Microsomes etc.   
 IV. Human pharmacokinetics (PK) Study Reports   
 a. Baseline PK Study Reports, Initial Safety and Tolerability   
 1.Healthy Volunteers   
 2. Patients   
 b. PK Study Reports in Population Subsets To Evaluate Effects of   
Intrinsic Factors (e.g., age, ethnic groups, organ dysfunction, 
gender, body size and weight) 
 c.  PK Study Reports in Population Subsets To Evaluate Effects   
of Extrinsic Factors (e.g., dietary factors, smoking, drug-drug 
interactions) 
 d. Population PK Study Reports   
 V. Human Pharmacodynamics (PD) Study Reports   
 a. Study Reports in Healthy Volunteers   
 b. Studies Reports in Patients   
 VI. Assays   
 VII. Publications   
 (*Use the file name if the information is presented as an electronic document or volume 
number if the document is a paper copy). 
 
3  .  Summary 
 
S  ummary documents for the human pharmacology and 
bioavailability/bioequivalence sections should be provided as PDF files 
named hpsum.pdf and biosum.pdf, respectively.  Places these files in the 
hpbio folder.  In addition, include hypertext links from each reference in 
the summary to a data summary table or figure supporting a conclusion 
and the corresponding data table or figure (whether located in a study 
report or elsewhere).  The summaries should be identified in the 
Document Information Title field as human pharmacology summary and 
bioavailability/bioequivalence summary, respectively 
30
   
4  .  Study reports 
 
A  ll study reports with appendices (except case report tabulations and case 
report forms which are described in items 11 and 12, respectively) should 
be provided as individual PDF file.  Include the study number in the 
name of the file.  For example, study 1234 can be named 1234.pdf. 
Using the table of contents as a guide, place the file in the appropriate 
subfolder in the hpbio folder. 
 
T  he Document Information Title field for the studies should include the 
type of study and the study number.  For example, the report for study 
201, a drug interaction study, should be designated as study 201, drug 
interaction. 
 
5  .  Datasets 
 
C  BER is developing specifications for data elements for human pharmacology 
and biopharmaceutics data and plan on providing detailed guidance for 
structured datasets in the future. Until this guidance is available, you should 
provide datasets as SAS transport files. Confer with the appropriate reviewers 
on the types of datasets to be provided and the data elements to be included in 
the datasets. 
 
P  lace all dataset files into folders named for the study report or type of 
data/analysis [e.g., popPK for population pharmacokinetics (PK) study data]. 
Put these folders in the datasets subfolder of the crt folder. 
 
I f datasets are included, note this with their respective study reports in the hpbio 
table of contents. Include the file location and a link to open the 
appropriate data definition file (define.pdf). 
 
6  .  Publications 
 
E  ach publication should be provided as a separate PDF file.  Place all 
publications into a single folder named pubs.  Establish a hyperlink 
between the citation and the publication in the pubs folder.  The pubs 
folder should be placed in the hpbio 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. 
 
31
   7.  Bookmarks and hypertext links 
 
 For all documents with a table of contents, bookmarks and hypertext links 
should be provided for each item in the documents table of contents 
including all tables, figures, publication, and appendices.  If datasets are 
provided with the study, you should include a bookmark to the 
appropriate data definition file (define.pdf). 
 
 Hypertext linking provided throughout the body of the document to 
supporting annotations, datasets, related sections, publications, 
appendices, tables, or figures that are not located on the same page will 
help the reviewer navigate more efficiently through a document.  A 
reference list at the end of a document should contain hypertext links 
from the item listed to the appropriate PDF publication file. 
 
 8.  Full text index 
 
 An index of the full text and the Document Information fields of all 
documents in this section should be provided.  The index definition file 
should be named bioindex.pdx.  Place all associated index files in a folder 
named bioindex. Place the bioindex.pdx definition file and the bio index 
file subfolder in the main hpbio folder.  Associate the hpbiotoc.pdf file 
with this index so that whenever the table of contents file is opened, the 
associated index is automatically added to the available index list.
 
  G.  Item 7:  Clinical Microbiology 
 
I tem 7 on page 2 of Form FDA 356h applies only to submissions to CDER. 
 
H  .  Item 8:  Clinical 
 
T  he clinical section is item 8 on page 2 of Form FDA 356h.  Additional 
information on the content of this section can be found in the ICH E3 document 
Structure and Content of Clinical Study Reports, July 1996, available at 
http://www.ifpma.org/ich5e.html and the Guidance for Industry Submission of 
Abbreviated Reports and Synopses in Support of Marketing Applications, 
September 21, 1999, available at http://www.fda.gov/cber/guidelines.htm 
 
1  .  Folders 
 
A  ll information in this section should be placed into a folder named 
clinstat.  CBER recommends the creation of a folder for each indication 
and for each indications integrated summary of efficacy.  In some cases, 
you may also need to create folders for individual studies and place them 
inside the appropriate indications folder.  Using the indication or study 
32
  numbers as the folder name and naming the integrated summary of safety, 
the integrated summary of efficacy, and integrated summary of risk and 
benefit, iss,  ise and riskben, respectively, will facilitate the review.  You 
should also create two folders, pubs and other, for publications and 
additional information, respectively.  An example of the file structure is 
pictured in Figure 6 (the additional file clindex.pdx and the subfolder 
clindex are for the full text index). 
 
 Figure 6: An example of the clinstat folder 
 
 
 2.  Table of Contents 
 
 Provide a table of contents which lists all of the files in this section.  The 
table of contents should be provided as a PDF file named clintoc.pdf. 
This file should be placed in the clinstat folder.  The clinstat table of 
contents should list all study reports (including study report numbers) by 
type of study (e.g., controlled clinical studies, uncontrolled studies) as 
appropriate, as well as each indications integrated summary of efficacy. 
If datasets are provided for a study or summary, you should note this in 
the table of contents.  All other documents in the clinical section, 
including publications, should also be listed.  Provide hypertext links 
between the documents listed in the table of contents and the 
corresponding PDF file and bookmarks for each item in the table of 
contents.  If datasets were listed in the table of contents, provide a link to 
the appropriate data definitions file (define.pdf).  This file is described in 
item 11, case report tabulations. 
 
 In some applications, more than one indication and/or therapeutic product 
is studied.  If this is the case, you should also organize the listing of files 
by indication and therapeutic product as appropriate.  See Table 7. 
 
 Table 7: An example of the clinstat table of contents 
33
   Clinstat Table Of Contents 
  L  ocation* 
 Indication1   
  Controlled study reports   
  Uncontrolled study reports   
 Integrated summary of efficacy   
 Integrated summary of safety   
 Integrated summary of benefits and risks   
 Other studies and information   
 Publications   
 (*Use the file name if the information is presented as an electronic document or volume 
number if the document is a paper copy). 
 1 Repeat for each indication and therapeutic product 
 
3  .  Study reports 
 
E  ach study report should be provided as a separate PDF file.  The file 
should include all appendices as defined in the ICH E3 document 
Structure and Content of Clinical Study Reports (July 1996), except for 
case report forms (CRF) and individual patient data listings [case report 
tabulations (CRT)].  Include the study number in the name of the file. 
For example, study 1234 can be named 1234.pdf. 
 
B  ecause files 25 MB or larger are technically more difficult to handle, 
study reports that are larger than 25 MB should be divided into two PDF 
files.  The first file should include the body of the study report, the 
reference list, the tables and figures that follow the study report, the 
protocol, all amendments, and a sample CRF.  This includes sections 1 to 
16.1.2 of the clinical study report as defined in ICH E3 Structure and 
Content of Clinical Study Reports (July 1996).  The second file should 
include all of the remaining appendices except for the CRFs and CRTs. 
Add the letter a to the end of the file name to distinguish the file with the 
appendices from the main file.  You should place both files in a folder 
with the study number as a name.  This folder should be placed in the 
clinstat folder. 
 
T  he title portion of the Document Information Field of each study should 
include the study number. 
 
4  .  Integrated summaries 
 
H  andle the integrated summaries in the same manner as the study reports. 
Name the integrated summary of safety, the integrated summary of 
efficacy and risk/benefit iss.pdf, ise.pdf, and, riskben.pdf, respectively. 
34
  Include integrated summary of safety, the summary of efficacy and 
risk/benefit in the title portion of the Document Information field. 
 
5  .  Publications 
 
E  ach publication should be provided as a separate PDF file.  Place all 
publications into a single folder named pubs.  Establish a hyperlink 
between the citation and the publication in the pubs folder.  The pubs 
folder should be placed in the clinstat 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. 
 
6  .  Bookmarks and hypertext links 
 
F  or all documents listed within the table of contents, you should provide 
bookmarks and hypertext links for each item in the documents table of 
contents including all tables, figures, publication, and appendices even if 
included in a separate file.  For datasets, you should include a bookmark 
to the appropriate data definition file (define.pdf). 
 
H  ypertext links provided throughout the body of the document to 
supporting annotations, related sections, references, appendices, tables or 
figures that are not located on the same page facilitate the review.  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. 
 
7  .  Full text index 
 
A  n index of the full text and the Document Information fields of all 
documents in this section should be provided.  The index definition file 
should be named clindex.pdx.  Place all associated index files in a folder 
named clindex.  Place the clindex.pdx definition file and the clindex 
subfolder in the main clinstat folder.  Associate the clintoc.pdf file with 
this index so that whenever the table of contents file is opened, the 
associated index is automatically added to the available index list. 
 
 I.  Item 9:  Safety Update 
 
 The safety update is item 9 on page 2 of Form FDA 356h.  In general, you 
should follow the guidance provided in item 8 for study reports, publications, 
and summaries. 
35
   
  1.  Folders 
 
A  ll documents for this section should be placed in a single folder named 
update and a single PDF file provided for each document. 
 
2  .  Table of contents 
 
A   table of contents for all files in this section should be provided in the 
form of a PDF file.  The organization of the table of contents should 
follow the guidance provided in item 8.  Name the PDF file updattoc.pdf 
and place it in the update folder. 
 
3  .  Full text index 
 
A  n index of the full text and the Document Information field of all 
documents in this section should be provided.  The index definition file 
should be named upindex.pdx.  Place all associated index files in a folder 
named update.  Place the upindex.pdx definition file and the update index 
file subfolder in the main update folder.  Associate updattoc.pdf 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. 
 
J  .  Item 10:  Statistical 
 
F  or electronic submissions, item 8 and item 10 are identical.  Documents 
describing statistical methods should be included in item 8.  Therefore, for this 
item, you only need to link the submission table of contents to the clintoc.pdf. 
 
K  .  Item 11:  Case Report Tabulations (CRTs) 
 
C  ase report tabulations are item 11 on page 2 of Form FDA 356h. 
 
C  RTs should be provided as either SAS datasets allowing the review divisions to 
use their own software for analysis or as a PDF printout of the SAS dataset. 
Each CRT dataset should be a single file and, in general, will include a 
combination of raw and derived data.  Prior to the submission, a sponsor should 
discuss with the review division the datasets to be provided and the data elements 
that should be included in each dataset. 
 
T  he electronic functional CRT datasets may not be adequate to eliminate the need 
for the submission of data files suitable for reproducing and confirming the study 
analyses submitted by the applicant.  Submission of these SAS datasets should be 
discussed with the appropriate review division. 
 
36
   1.  Format of the datasets 
 
 You should provide each dataset as a SAS transport file as described in 
the companion guidance, Regulatory Submissions in Electronic Format  
General Considerations. 
 
 Dataset files should be organized so that their size is generally less than 
25 MB per file.  The files should not be compressed.  Each dataset 
should be saved as an individual file. 
 
 The data variable names should be no more than 8 characters in length 
because of restrictions in our data format.  CBER recommends that you 
provide a more descriptive data variable label, up to 32 characters in 
length. 
 
 2.  Organization of data 
 
 The data organization varies from indication to indication. Prior to the 
submission, you should discuss with the review division the datasets that 
should be provided, the data elements that should be included in each 
dataset, and the organization of the data within the file.  The type of 
individual datasets that are generally provided to support each study and 
integrated summaries are as follows: 
 
   Demographics 
   Inclusion criteria 
   Exclusion criteria 
   Concomitant medication 
   Medical history 
   Drug exposure 
   Disposition 
   Efficacy results 
   Human pharmacology and bioavailability/bioequivalence data 
   Microbiology data 
   Adverse Events 
   Lab  chemistry 
   Lab  hematology 
   Lab  urinalysis 
   ECG 
   Vital signs 
   Physical examination 
 
 Examples of the variables to include in the individual datasets are 
included in Appendix 2.  These examples are intended as a starting point 
37
  for discussions with the reviewing division regarding the data elements 
that should be provided in the submission.  The data elements and 
organization may vary depending on the reviewing division and 
indication. 
 
 The layout of the data in the rows and columns in the dataset should be 
done so as to emulate the arrangement that would normally have been 
used in the printed CRTs in a paper submission.  Applicants should use 
as a conceptual model  the opening of the dataset in a reader-only 
(viewer-only) program that solely allows scrolling through a dataset file. 
Doing so should bring up screens of rows and columns of values and/or 
text information that is very similar in organization to what has been 
traditionally presented on paper. 
 
 Divide datasets that are larger than 25 MB into smaller datasets.  For 
example, clinical chemistry data may be further divided by specific lab 
tests.  A dataset type should not be divided unless the size is greater than 
25 MB and, when dividing a dataset type, it should be done with the 
fewest number of overall datasets.  Discuss the organization of the 
datasets with the appropriate review division.  File names should include 
the three character extension xpt to be compatible with our desktop 
standards and training. 
 
 All datasets for an individual study, specific data analysis (e.g., 
population PK), or integrated summary should be placed in a folder 
identified by the study name, type of data/analysis, or integrated summary 
name and placed in a single folder called datasets.  The datasets folder 
should be placed in the crt folder. 
 
 3.  Documentation of the datasets 
 
 Provide two PDF files, one should contain the data definition tables 
(define.pdf) and the other should house the annotated case report forms 
(blankcrf.pdf), to describe the datasets for each study, specific data 
analysis (e.g., population PK) and integrated summaries. 
 
 For the datasets to be useable, the definitions of the variables should be 
provided.  You should document all of the variables in the datasets in 
data definition tables.  There should be one set of data definition tables 
for each study, specific data analysis (e.g., population PK) and integrated 
summary. 
 
 The first table should include a listing of all datasets provided for the 
study with a description of the dataset and the location of the dataset file. 
Provide a hypertext link from the description of the dataset to the 
38
  appropriate data definition table.  Provide a hypertext link from the 
location listing of the file to the SAS transport file. 
 
 In Table 8, the dataset for AE is described as adverse events, and the 
dataset file is located in folder 1234 in the datasets folder, which is in the 
crt folder. 
 
T  able 8: An example of the case report tabulations dataset documentation 
D  atasets For Study 1234 
 
 Dataset  D  escription of dataset  L  ocation 
 AE  A  dverse events  C  rt/datasets/1234/ae.xpt 
 ...  ...    ...   
 
S  ubsequent pages should contain a table for each dataset that includes an 
organized listing of all variable names (up to 8 characters) used in the 
dataset, a descriptive variable label (up to 32 characters), data types, 
codes (and decodes), and comments.  The comments field is for further 
description of the variables.  For derived variables, the method for 
calculating the variable should be included in the comments field.  For 
raw variables, the location of the variable on the annotated case report 
should be provided, along with the CRF field name if different from the 
variable name in the dataset.  Providing a hypertext link from each raw 
data variable in the data definition table to the appropriate location of the 
blankcrf.pdf also helps the review process.  An example of part of a data 
definition table for the demographics dataset for study 1234 is provided in 
Table 9. 
 
T  able 9: An example case report tabulation demographics dataset variables 
S  tudy 1234  Demographics Dataset Variables 
 
V  ariable  L  abel  T  ype  C  odes  C  omments1 
 PATID  U  nique patient ID  C  har    D  emographics page 1 
number 
 SEX  S  ex  of subject  C  har  f  = female  D  emographics page 1 
m   = male 
 BDATE  B  irth date  D  ate    D  emographics page 1 
 DUR  D  uration of Treatment  N  um    D  erived 
S  TOP DATE  START DATE 
 TRT  A  ssigned treatment  N  um  0  = placebo   
group  5  = 
5mg/day
  1 Use footnotes for longer comments. 
 
39   The data definition tables should be provided as a single PDF file named 
define.pdf and placed in the appropriate study, specific analysis type or 
integrated summary folder in the datasets folder.  The title portion of the 
Document Information field of each data definition file should include the 
appropriate study number, specific analysis type or integrated summary 
name and data definitions.  For example, the data definition file for study 
2001 would be identified as: study 2001, data definitions. 
 
 A final data definition table should be provided that lists, in a single table, 
all variables in all datasets for that study.  This table should be arranged 
in alphabetical order by variable name. This table should also include the 
name of each dataset where each of the listed variables is included. 
 
 The annotated CRF is a blank CRF including treatment assignment forms 
that map each blank on the CRF to the corresponding element in the 
database.  The annotated CRF should provide the variable names and 
coding.  Each page and each blank of the CRF should be represented. 
The sponsor should write not entered in database in all sections where 
this applies.  The annotated CRF should be provided as a PDF file. 
Name the file blankcrf.pdf and place it in the appropriate subfolder in the 
datasets folder.  The title portion of the Document Information field of 
each annotated crf file should include the appropriate study report number 
and annotated crf.  For example, the annotated crf for study 2001 would 
be identified as: study 2001, annotated crf 
 
 4.  Dataset table of contents 
 
 The dataset table of contents should list all studies and integrated 
summaries that have datasets.  A hypertext link should be provided to the 
appropriate data definition table file.  The table of contents should be 
provided as a PDF file named datatoc.pdf and placed in the datasets 
folder. 
 
 5.  Full text index 
 
 An index of the full text and the Document Information field of all 
documents in the dataset folder should be provided.  The index definition 
file should be named datindex.pdx.  Place all associated index files in a 
folder named datindex.  Place the datindex.pdx definition file and the 
datindex subfolder in the main dataset folder.  Associate datatoc.pdf 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. 
40
   
6  . 	 General considerations for datasets 
 
T  he efficient use of the datasets by the reviewer can be significantly 
improved if some basic principles are followed in setting up the datasets. 
 
	   Each subject should be identified with a single, unique number for 
the entire application.  This unique number needs to be provided 
in each dataset.  This is essential for joining different datasets. 
 
	   The variable names and codes should be consistent across studies 
and should be unique.  This is necessary when combining datasets 
and reduces the time for learning the datasets.  For example, if 
glucose is checked in a number of studies, use the same name to 
describe this variable in all of the studies.  Conversely, do not use 
the same name for different variables. 
 
	   The format of representation of variables within and across the 
datasets should be consistent for similar types of data.  For 
example, all variables that are a calendar date (e.g., birthdate, 
screening visit date, randomization date, date of death, etc.) 
should use the same format for representing the date.  Similarly, 
data indicating time within study or duration of an event within 
study should use the same format throughout (e.g., days, weeks, 
or months) unless noncomparable timescales are being addressed. 
 
	   Duration is frequently part of an analysis.  Start and stop times 
and dates should also be provided as duration of treatment based 
on the start of study treatment and expressed consistently in 
minutes, hours, or days, whichever is appropriate.  When 
expressed in days, the following formula should be used to 
calculate study day: ((test date) - (date of first dose) + 1). 
 
	   Results are frequently analyzed based on the study, center/site, 
treatment assignment, sex, age, and/or race of the subjects.  Each 
dataset should include these variables. 
 
	   For treatment assignment, all placebo subjects should be 0, and in 
fixed dose studies, the treatment assignment variable should be the 
prescribed dose. 
 
	   Data variable names should be limited to 8 characters with a more 
descriptive name, up to 32 characters, provided as a data variable 
label. 
41
   
	   Text should be used instead of or in addition to arbitrary or 
inexplicit number codes.  For example, for the variable 
concomitant medications, if there is a number code for each 
type of medication, a separate column should be included that has 
the actual name of the concomitant medication. 
 
	   Provide a file named sites.pdf.  This file should contain a 
comprehensive list of investigators and study sites (sites).  The 
reference list should contain the following four columns: name of 
investigator; investigator ID (site number); investigator's address 
(study site); and the number of subjects enrolled at the site.  If the 
site number changes, note this in the appropriate column in 
addition to providing an accurate accounting of the number of 
individuals enrolled under the specific site number(s). 
 
 L.	  Item 12:  Case Report Forms 
 
 Case report forms are item 12 on page 2 in Form FDA 356h. 
 
 If a paper CRF was used in the clinical trial, the electronically submitted CRF 
should be an exact image or series of images of the paper CRF that contains all 
original entries with all modifications, addenda, corrections, comments, 
annotations, and any extemporaneous additions.  For electronic data collection, 
CBER recommends the use of PDF generated forms.  Prior to the submission of 
CRFs captured using remote data entry, a sponsor should discuss their 
submission with the effected review division and consult the Guidance for 
Industry: Computerized Systems used in Clinical Trials, May 10, 1999, available 
at  http://www.fda.gov/cber/guidelines.htm. 
 
1  . 	 Folders 
 
A  ll information for this section should be placed in a folder named crf. 
Create a folder for each study to organize the CRFs.  In each study 
folder, there should be a folder for each study site.  Use the study 
numbers and site numbers when naming the respective folder.  An 
example of the file structure is pictured in Figure 7 (the additional file, 
crfindex.pdx and subfolder crfindex are for the full text index). 
42
   
 Figure 7: An example of the crf folders 
 
 
 2.  Table of contents 
 
 A table of contents should be supplied that lists all CRFs provided by 
their study, site and treatment assignment, as a PDF file named crftoc.pdf. 
List the patient identification numbers by study, site and treatment 
assignment and describe the location of the CRFs with the file name and 
folder(s).  A hypertext link between the documents listed in the table of 
contents and the corresponding PDF file and bookmarks for each item in 
the table of contents should be provided.  Place the crftoc.pdf file in the 
crf folder. 
 
 3.  Case report forms 
 
 Each individual patients complete case report form should be provided as 
a single PDF file.  Include the patient ID in the file name.  Place the PDF 
files in the appropriate study site folder.  For example, all CRFs for site 
003 for study 301 would be placed into a folder named 003, which then 
would be placed in a folder named 301. 
 
43
   The Document Information Title field for each file should include the 
letters crf, the study number, the site identification and the patients 
unique ID number.  The unique patient ID number should be composed 
of elements of the study number, site number, and patient number, or a 
functional equivalent.  For example, the CRF for patient 001 in study 
2001 at site 003 would have the following in the Title field: crf, study 
2001, site 003, PID 2001-003-001. 
 
 4.  Bookmarks and hypertext links 
 
 CBER recommends bookmarks for each CRF domain and study visit to 
help the reviewer navigate the CRFs.  These bookmarks can be 
considered as part of the comprehensive table of contents. 
 
 For addenda and corrections, provide a hypertext link from the amended 
item to the corrected page or addendum. 
 
 5.  Full text index 
 
 An index of the full text and the Document Information field of all 
documents in the crf folder should be provided.  Even if all of the CRFs 
are images, the text in the Document Information field should be indexed. 
The index definition file should be named crfindex.pdx.  Place all 
associated index files in a folder named crfindex.  Place the crfindex.pdx 
definition file and the crfindex subfolder in the main crf folder.  Associate 
crftoc.pdf 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. 
 
M  .  Item 13:  Patent Information 
 
T  his is item 13 on page 2 of Form FDA 356h. 
 
1  .  Folder 
 
P  lace all documents for this section in the folder named other. 
 
2  .  Table of contents 
 
T  here should be a hypertext link from the submission table of contents 
directly to the patinfo.pdf file. 
44
   
3  .  Patent information 
 
I nformation pertaining to the patent information should be provided in a 
single PDF file named patinfo.pdf. 
 
T  he Agency is developing procedures to allow for the submission of 
electronic signatures.  Until those procedures are in place, any 
certification or declaration must be accompanied by a signed paper 
certification or declaration. 
 
N  .  Item 14:  Patent Certification 
 
T  his is item 14 on page 2 of Form FDA 356h. 
 
1  .  Folder 

 
P  lace all documents for this section in the folder named other.
 
 
2  .  Table of contents 
 
T  here should be a hypertext link from the submission table of contents 
directly to the patcert.pdf file. 
 
3  .  Patent certification 
 
I nformation pertaining to the patent certification should be provided in a 
single PDF file named patcert.pdf. 
 
T  he Agency is developing procedures to allow for the submission of 
electronic signatures.  Until those procedures are in place, any 
certification or declaration must be accompanied by a signed paper 
certification or declaration. 
 
O  .  Item 15:  Establishment Description 
 
T  he establishment description section is item 15 on page 2 of Form FDA 356h. 
 
1  .  Folder 
 
T  he submission should contain a folder named estab.  Within the estab 
folder, the following individual folders should be created: water, HVAC, 
contamin, computer, diagrams and pubs.  An example of the file 
structure is pictured in Figure 8 (the file, estindex.pdx and additional 
subfolder, estabindex are for the full text index). 
45
   
 Figure 8: An example of the estab folder 
 
 
 2.  Table of contents 
 
 A table of contents should be provided that lists all files provided in the 
establishment section, as a PDF file named estabtoc.pdf.  To organize the 
files in the table of contents use the example headings in Table 10.  The 
headings may vary from product to product and you should consult the 
appropriate guidance documents for correct headings.   As part of the 
comprehensive table of contents for the submission, provide hypertext 
links between the documents listed in the table of contents and the 
corresponding PDF files, in addition to, bookmarks for each item in the 
table of contents.  Place the estabtoc.pdf file in the estab folder. 
 
 
 Table 10: An example of the estab table of contents 
 Estab Table Of Contents 
  L  ocation* 
 I.    Water system   
 II.   Heat, ventilation and air conditioning systems (HVAC)   
 III.  Contamination and cross contamination   
 IV.  Computer systems   
 V.   Lyophilization   
 VI.  Diagrams   
 VII. Publications (list each publication separately)   
 (*Use the file name if the information is presented as an electronic document or volume 
number if the document is a paper copy.) 
 
46   Consider the use of computer aided design (CAD) to produce facility 
floor plans, and/or blueprints.  These files can be embedded in adobe 
acrobat (PDF) and presented as graphics.  This will facilitate the 
presentation of establishment information. 
 
 3.  Publications 
 
 Each publication should be provided as a separate PDF file.  Place all 
publications, in alphabetical order, into a single folder named pubs. 
Establish a hyperlink between the citation and the publication in the pubs 
folder.  The pubs folder should be placed in the estab folder.  Note 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 and first name initial, the year of the publication 
and the title of the article. 
 
 4.  Bookmarks and hypertext links 
 
 For all documents within the table of contents, including all tables 
publications, and appendices, you should provide bookmarks and 
hypertext links.  Hypertext linking provided throughout the body of the 
document to supporting annotations, related sections, publications, 
appendices, tables or figures that are not located on the same page helps 
reviewers navigate more efficiently through a 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. 
 
 5.  Full text index 
 
 An index of the full text and the Document Information fields of all 
documents in this section should be provided.  Name the index definition 
file estabindex.pdx.  Place all associated index files in the folder named 
estab.  Place the estab.pdx definition file and the estab index file subfolder 
in the main estab folder.  Associate the estabtoc.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. 
 
F  or more detailed descriptions of the appropriate establishment content in item 15 
refer to the following documents available at 
http://www.fda.gov/cber/guidelines.htm: 
 
G  uidance for Industry for the Submission of Chemistry, Manufacturing and 
Controls and Establishment Description Information for Human Plasma-Derived 
Biological Products or Animal Plasma or Serum-Derived Products, February 
1999. 
47
   
 Guidance for Industry for the Submission of Chemistry, Manufacturing and 
Controls information and Establishment Description for Autologous Somatic Cell 
Therapy Products, January 1997. 
 
 Guidance for Industry Content and Format of Chemistry, Manufacturing and 
Controls Information and Establishment Description Information for a Biological 
in Vitro Diagnostic Product, March 1999. 
 
 Guidance for Industry On the Content and Format of Chemistry, Manufacturing 
and Controls Information and Establishment Description Information for an 
Allergenic Extract or Allergen Patch Test, April 1999. 
 
 Guidance for Industry For the Submission of Chemistry, Manufacturing and 
Controls and Establishment Description Information for Human and Blood and 
Blood Components Intended for Transfusion or for Further Manufacture and for 
the Completion of the FDA Form 356h "Application to Market a New Drug, 
Biologic or an Antibiotic Drug for Human Use", May 1999. 
 
 Guidance for Industry Content and Format of Chemistry, Manufacturing and 
Controls Information and Establishment Description Information for a Vaccine or 
Related Product, January 1999. 
Guidance for Industry for the Submission of Chemistry, Manufacturing, and 
Controls Information for a Therapeutic Recombinant DNA-Derived Product or a 
Monoclonal Antibody Product for In Vivo Use, August 1996. 
P.  Item 16:  Debarment Certification 
 
 This is item 16 on page 2 of Form FDA 356h. 
 
1  .  Folder 
 
P  lace the debarment certification in the folder named other. 
 
2  .  Table of contents 
 
T  here should be a hypertext link from the submission table of contents 
directly to the  debar.pdf file. 
 
3  .  Debarment certification 
 
T  he debarment statement should be provided in a single PDF file named 
debar.pdf. 
 
48
   The Agency is developing procedures to allow for the submission of 
electronic signatures.  Until those procedures are in place, any 
certification must be accompanied by a signed paper certification. 
 
 Q.  Item 18:  User Fee Cover Sheet 
 
 This is item 18 on page 2 of Form FDA 356h 
 
 1.  Folder 

 
 Place the User Fee Cover Sheet in the folder named other.
 
 
 2.  Table of contents 
 
 There should be a hypertext link from the submission table of contents 
directly to the userfee.pdf file. 
 
 3.  User fee cover sheet (FDA form 3397) 
 
 The user fee cover sheet should be provided as a single PDF file named 
userfee.pdf . 
 
 The Agency is developing procedures to allow for the submission of 
electronic signatures.  Until those procedures are in place, any 
certification must be accompanied by a signed paper certification. 
 
 R.  Item 19:  Other 
 
 This is item 19 on page 2 of Form FDA 356h.  Information that is not included 
in item 1 to 18 is included under this item.  For example, certifications for 
financial disclosure by clinical investigators are included in this item. 
 
 1.  Folder 
 
 You should place all additional information for this item in the folder 
named other. 
 
 2.  Table of contents 
 
 There should be a hypertext link from the submission table of contents 
directly to each file in this item. 
49
   
3  .  Other items 
 
Y  ou should provide each additional item as a separate PDF file.  For 
example, provide certification for financial disclosure by clinical 
investigators as a single PDF file named financial.pdf and place it in the 
other folder.  List this file in the submission table of contents and provide 
a hypertext link from the table of contents to the file. 
 
T  he Agency is developing procedures to allow the submission of 
electronic signatures.  Until those procedures are in place, any 
certification must be accompanied by a signed paper certification. 
 
V.  APPENDIXES 
 
A  ppendix 1: 	 Example Nonclinical Pharmacology and Toxicology Datasets 
and Data Elements 
 
T  he following examples of datasets and data elements are intended to serve as a 
starting point for discussion between you and the review division on the content 
and organization of the datasets and, therefore, are not all inclusive.  CBER plan 
on refining these datasets and data elements and adding more datasets as we gain 
more experience. 
 
 Data Definition Tables  (place the study subfolder name in the space with the ***) 
 
 Dataset  D  escription of dataset   Location of dataset 
 Tumor  T  umor frequency for statistical analysis   Pharmtox/datasets/*** /Tumor.xpt 
 Weights  B  ody weights   Pharmtox/datasets/*** /Weights.xpt 
 Food  F  ood consumption   Pharmtox/datasets/***/Food.xpt 
 Water  W  ater consumption   Pharmtox/datasets/***/Water.xpt 
 Signs  C  linical signs   Pharmtox/datasets/***/Signs.xpt 
 Chem  P  lasma chemistry levels   Pharmtox/datasets/***/Chem.xpt 
 Hemat  H  ematology   Pharmtox/datasets/***/Hemat.xpt 
 Urine  U  rinalysis   Pharmtox/datasets/***/Urine.xpt 
 Drug  P  lasma drug and metabolite levels   Pharmtox/datasets/***/Drug.xpt 
 Mortal  M  ortality information   Pharmtox/datasets/***/Mortal.xpt 
 Organ  O  rgan weights   Pharmtox/datasets/***/organ.xpt 
 Macro  M  acroscopic examination of tissues   Pharmtox/datasets/*** /Macro.xpt 
 Micro  M  icroscopic examination (histopathology)   Pharmtox/datasets/***/Histo.xpt 
 Other  O  ther datasets as needed   .. 
50
   Tumor Dataset For Statistical Analysis1,2 (tumor.xpt) 
 
 Variable  L  abel   Type   Codes  F  ootnotes 
S  TUDYNUM  S  tudy number  C  har    3   
A  NIMLNUM  A  nimal number  C  har     
S  PECIE  A  nimal specie  C  har  M  =mouse   
R  = rat 
S  EX  S  ex  C  har  M  =male   
F  =female 
D  OSEGP  D  ose group  C  har  U  se 0, 1, 2, 3, 4, . . .  in ascending   
order from control. Provide the dosing 
for each group. 
D  THSACTM  T  ime in days to  C  har     
death or sacrifice 
D  THSACST  D  eath or sacrifice  N  um  1   = Natural death or moribund   
status  sacrifice 
2   = Terminal sacrifice 
3   = Intermittent sacrifice 
4   = Accidental death 
A  NIMLEXM  A  nimal microscopic  N  um  1   = At least one tissue was examined   
examination code  2   = No tissues were examined 
T  UMORCOD  T  umor type code  N  um    3  ,4 
T  UMOR  T  umor name  C  har    3  ,4 
O  RGNCODE  O  rgan/tissue code  N  um    3  ,5 
O  RGAN  O  rgan/tissue name  C  har    3  ,5 
D  ETECTTM  T  ime in days of  N  um     
detection 
M  ALIGNST  M  alignancy status  N  um  1   = Malignant   
  2   = Benign 
3   = Undetermined 
D  EATHCAU  C  ause of death  N  um  1   = Tumor caused death   
2 = Tumor did not cause death 
3   = Undetermined 
O  RGANEXM  O  rgan/Tissue  N  um  1   = Organ/Tissue was examined and   
microscopic  was usable 
examination code  2   = Organ/Tissue was examined but 
was not usable (e.g. autolyzed tissue) 
3   = Organ/Tissue was not examined 
1  Each animal in the study should have at least one record even if they do not have a tumor. 

 2 Additional variables or categories of a variable, as appropriate, can be added to this dataset.
 
 3 ANIMLNUM limit to less than 12 characters; ORGANCOD and TUMORCOD limited to less than 8
 
characters; ORGAN and TUMOR should be as concise as possible.
 
 4 A missing value should be given for the variable TUMOR and TUMORCOD when the organ is unusable 

or not examined. 

51   5 Do not include a record for an organ that was useable and no tumor was found on examination. A record 
should be included for organs with a tumor, organs found unusable, and organs not examined. 
 
 
 Body Weights For Each Animal Over Time (weights.xpt) 
 
 Variable  L  abel  T  ype  C  odes  C  omments 
A  NIMLNUM  A  nimal number  N  um     
S  PECIE  A  nimal specie  C  har     
S  EX  S  ex  C  har  M  =male   
F  =female 
D  OSEGP  D  ose group  C  har  U  se 0, 1, 2, 3, 4, . . .  in   
ascending order from control. 
Provide the dosing for each 
group. 
B  ASELINE  W  eight at baseline  N  um     
D  AYS  D  ays on drug at  N  um     
observation 
W  EIGHT  B  ody weight  N  um     
C  HANGE  C  hange in weight  N  um    W  EIGHT
compared to baseline  BASELINE 
U  NIT  U  nit of weight  N  um     
measurements 
O  THER  ...    ...    ...    ...   
 
F  ood Consumption Over Time For Each Animal (food.xpt) 
 
V  ariable  L  abel  T  ype  C  odes  C  omments 
A  NIMLNUM  A  nimal number  N  um     
S  EX  S  ex  C  har  M  =male   
F  =female 
D  OSEGP  D  ose group  C  har  U  se 0, 1, 2, 3, 4, . . .  in ascending   
order from control. Provide the 
dosing for each group. 
D  AYS  D  ays on drug at  N  um     
observation 
F  OOD  F  ood consumption  N  um     
U  NIT  U  nit of measurement  N  um     
O  THER  ...    ...    ...    ...   
 
52
   
 Water Consumption Over Time For Each Animal (water.xpt) 
 
 Variable  L  abel   Type   Codes   Comments 
 ANIMLNUM  A  nimal number   Num     
 SEX   Sex   Char   M=male   
 F=female 
 DOSEGP   Dose group   Char   Use 0, 1, 2, 3, 4, . . .  in   
ascending order from control. 
Provide the dosing for each 
group. 
 DAYS   Days on drug at   Num     
observation 
 WATER   Water consumption   Num     
 UNIT   Unit of measurement   Num     
 OTHER   ...   ...   ...   ... 
 
 Clinical signs dataset (signs.xpt) 
 Variable   Label   Type   Codes   Comments 
 ANIMLNUM   Animal number   Char     
 SEX   Sex   Char   M=male   
 F=female 
 DOSEGP   Dose group   Char   Use 0, 1, 2, 3, 4, . . .  in   
ascending order from 
control. Provide the dosing 
for each group. 
 SIGN   Clinical signs   Char     1 
 START   Days on drug sign first seen   Num     
 END   Days on drug sign last seen   Num     
 DURATION   Duration of sign   Num     END
START 
 COURSE   Course of sign   Char   Intermittent or   
 Continuous 
 TERMINAL   Flag if sign present at death   Char   y= yes   2 
 n= no 
 na = not applicable 
 OTHER   ...   ...   ...   ... 
 1One clinical sign per row.  Record normal if no abnormal clinical signs were reported. 
 2Not applicable used for animals without clinical signs 
53   
 Plasma Clinical Chemistry Over Time For Each Animal (chem.xpt) 
 
 Variable  L  abel   Type   Codes   Comments 
A  NIMLNUM  A  nimal number   Char     
 SEX   Sex   Char   M=male   
 F=female 
 DOSEGP   Dose group   Char   Use 0, 1, 2, 3, 4, . . .  in   
ascending order from 
control. Provide the dosing 
for each group. 
 DAYS   Days on drug at time of test   Num     
 LABTEST   Lab test name   Char     
 BASELINE   Baseline lab value   Num     
 RESULT   Test result value   Num     
 CHANGE   Change from baseline   Num     RESULT  
BASELINE 
 UNIT   Unit of lab test   Char     
 OTHER   ...   ...   ...   ... 
 
 Hematology Results For Each Animal (hemat.xpt) 
 
 Variable   Label   Type   Codes   Comments 
 ANIMLNUM   Animal number       
 SEX   Sex   Char   M=male   
 F=female 
 DOSEGP   Dose group   Char   Use 0, 1, 2, 3, 4, . . .  in   
ascending order from 
control. Provide the 
dosing for each group. 
 DAYS   Days on drug at observation   Num     
 LABTEST   Name of lab test   Char     
 UNIT   Unit of lab test   Char     
 BASELINE   Baseline lab value   Num     
 RESULT   Test result value   Num     
 CHANGE   Change from baseline   Num     RESULT 
BASELINE 
 OTHER   ...   ...   ...   ... 
 
54
   Urinalysis Dataset (urine.xpt) 
 
 Variable  L  abel   Type   Codes   Comments 
A  NIMLNUM  A  nimal number       
S  EX  S  ex   Char   M=male   
 F=female 
 DOSEGP   Dose group   Char   Use 0, 1, 2, 3, 4, . . .   
in ascending order from 
control. Provide the 
dosing for each group. 
 DAYS   Days on drug at observation   Num     
 LABTEST   Name of lab test   Char     
 UNIT   Unit of lab test   Char     
 BASELINE   Baseline lab value   Num     
 RESULT   Test result value   Num     
 CHANGE   Change from baseline   Num     RESULT 
BASELINE 
 OTHER   ...   ...   ...   ... 
 
 Plasma Drug Levels (drug.xpt) 
 
 Variable   Label   Type   Codes   Comments 
 ANIMLNUM   Animal number       
 SEX   Sex   Char   M=male   
 F=female 
 DOSEGP   Dose group   Char   Use 0, 1, 2, 3, 4, . . .   
in ascending order from 
control. Provide the 
dosing for each group. 
 DAYS   Days on drug at observation   Num     
 DRUG   Name of drug   Char     Include 
levels for 
drug and 
metabolites 
 UNIT   Unit of measurement   Char     
 RESULT   Drug level   Num     
 OTHER   ...   ...   ...   ... 
 
55
   
 Mortality Dataset (mortal.xpt) 
 
 Variable  L  abel   Type   Codes   Comments 
A  NIMLNUM  A  nimal number   Char     
 SEX   Sex   Char   M=male   
 F=female 
 DOSEGP   Dose group   Char   Use 0, 1, 2, 3, 4, . . .  in   
ascending order from 
control. Provide the 
dosing for each group. 
 TYPE   Type of death   Char   Scheduled or   
 Unscheduled 
 DEATH   Description of death   Char   Final sacrifice,   
 Sacrificed moribund, or 
 Found dead 
 DAYS   Days on drug at time of   Num     
death 
 WEIGHT   Terminal body weight   Num     
 UNIT   Unit of measurement   Num     
 OTHER   ...   ...   ...   ... 
 
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 Organ Weight For Every Organ For Each Animal1 (organwt.xpt) 
 
 Variable  L  abel   Type   Codes   Comments 
A  NIMLNUM  A  nimal number  N  um     
S  EX  S  ex  C  har  M  =male   
F  =female 
D  OSEGP  D  ose group  C  har  U  se 0, 1, 2, 3, 4, . . .  in ascending   
order from control. Provide the 
dosing for each group. 
F  NLBDYWT  F  inal body weight  N  um     
D  AYS  D  ays on drug at  N  um     
observation 
O  RGAN  O  rgan name  C  har     
O  RGANWT  W  eight of organ in  N  um     
grams 
U  NIT  U  nit of measurement  N  um     
R  ATIO  O  rgan to body  N  um    O  RGAN 
weight ratio  WT/ 
FNLBDY 
WT 
B  ILATERL  B  ilateral organ code  N  um  1  = organ is not bilateral or weight is   
for one of the two bilateral organs 
2  = organ is bilateral and weight is 
expressed for combined weight of the 
two bilateral 
O  THER  ...    ...    ...    ...   
 1 All organs should be accounted for all animals. Each organ should be listed under ORGANAME for each 
animal.  If an organ was not weighed, the ORGANWT and BILATERL should be indicated as missing. 
57
   
 Macroscopic Findings For Each Animal (macro.xpt) 
 
 Variable  L  abel   Type   Codes   Comments 
 ANIMLNUM   Animal number   char     
 SEX   Sex   char   M=male   
 F=female 
 DOSEGP   Dose group   char   Use 0, 1, 2, 3, 4, . . .  in   
ascending order from 
control. Provide the dosing 
for each group. 
 DAYS   Days  on drug at sacrifice   num     
 DEATH   Description of death   char   Final sacrifice,   
 Sacrificed moribund, or 
 Found dead 
 ORGNAME   Name of organ   char     
 ABNORMAL   Abnormal flag   char   Abnormal or   
 Normal 
 MACRO   Macroscopic findings   char     Limit to 256 
characters1 
 MICROABN  M  icroscopic findings   char   Abnormal or   
 Normal 
 GRADE   Grade or severity of   char     
abnormality 
 TUMOR   Tumor flag   char   None,   
 Benign, 
 Malignant, or 
 Undeterminate 
 FNLBDYWT   Final body weight   num     
 OTHER   ...   ...   ...   ... 
 1 Limit to 256 characters.  Full details for abnormal findings should be described in study report 
58
   
 Microscopic Findings (histopathology) For Each Animal (micro.xpt) 
 
 Variable  L  abel   Type   Codes   Comments 
 ANIMLNUM   Animal number   char     
 SEX   Sex   char   M=male   
 F=female 
 DOSEGP   Dose group   char   Use 0, 1, 2, 3, 4, . . .  in   
ascending order from 
control. Provide the dosing 
for each group. 
 DAYS   Days  on drug at sacrifice   num     
 DEATH   Description of death   char   Final sacrifice,   
 Sacrificed moribund, or 
 Found dead 
 ORGNAME   Name of organ   char     Include blood 
 ABNORMAL   Abnormal flag   char   Abnormal or   
 Normal 
 MICRO   Microscopic findings   char    1  
 MACROABN  M  acroscopic findings   char   Abnormal or   
 Normal 
 GRADE   Grade or severity of   char     
abnormality 
 TUMOR   Tumor flag   char   None,   
 Benign, 
 Malignant, or 
 Indeterminate 
 FNLBDYWT   Final body weight   num     
 OTHER   ...   ...   ...   ... 
 1 Limit to 256 characters.  Full details for abnormal findings should be described in study report. 
 
 
 Appendix 2: Example Content of Specific Clinical Datasets 
 
 The following lists contain suggested data elements for the individual datasets. 
This listing is meant to serve as a starting point for discussion between you and 
the review division on the content and organization of the datasets and, therefore, 
is not all inclusive.  CBER plans to refine these data elements as we gain more 
experience.  The extent of the data needed for each indication varies, and more 
specific information should be obtained from the review division at the time of 
the pre-NDA meeting or earlier in the drug development process. 
 
 If you are submitting programs that you used in your statistical analysis software 
to arrive at the final analysis for principal efficacy and safety data, those 
59
  programs should be placed in the appropriate subfolder of the crt folder.  The 
programs should contain sufficient detail to allow the reviewer to follow the 
logical flow of the program. 
 
 Demographics 
   Age 
   Sex 
   Race 
   Weight 
   Height 
   Country 
   (Consult the review division regarding additional variables) 
 
 Inclusion criteria 
   Vary by protocol  consult with the review division 
 
 Exclusion criteria 
   Vary by protocol  consult with the review division 
 
 Concomitant medications 
   Drug name 
   Drug start date 
   Drug stop date 
   Drug started before study (yes/no) 
   Drug type 
   Dose 
   Reason for medication 
   (Consult the review division regarding additional variables) 
 
 Medical history 
   Medical condition 
   Past condition (yes/no) 
   Current condition (yes/no) 
   Body system 
   Date of diagnosis 
   (Consult the review division regarding additional variables) 
 
 Disposition 
   Screen (yes/no) 
   Enrolled (yes/no) 
   Randomized (yes/no) 
   Received at least one treatment (yes/no) 
   Completed study (yes/no) 
60
     Reason for discontinuation 
   Treatment at time of discontinuation 
   Cumulative dose at time of discontinuation 
   Duration of treatment at time of discontinuation 
   (Consult the review division regarding additional variables) 
 
 Drug exposure 
   Dose 
   Dose start date/time 
   Dose end date/time 
   Duration of dose 
   Treatment sequence number for cross over, titration, dose adjustments, etc. (1,2,3...) 
   Study phase (titration, maintenance, taper, washout, etc.) 
   Randomization date/time 
   Study day 
   Baseline weight 
   (Consult the review division regarding additional variables) 
 
 Efficacy results 
   Consult the appropriate reviewers 
Human pharmacology and bioavailability/bioequivalence  data 
   Consult with the appropriate reviewers 
Microbiology data 
   Consult with the appropriate reviewers 
Physical examination 
   Exam date/time 
   Study day of exam 
   Visit number 
   Exam on scheduled visit (yes/no) 
   Reason for exam 
   Timing of exam in relationship to last dose of study treatment 
   Exam parameter 
   Body system 
   Abnormal (yes/no) 
   Baseline exam (yes/no) 
   Change from baseline (improvement, worsening, no change) 
   Past condition (yes/no) 
   (additional variables) 
 
61
   Adverse events 
	   Preferred term 
	   Reported term 
	   Body system 
	   Start time of event 
	   Stop time of event 
	   Duration 
	   Course (continuous or intermittent) 
	   Severity (mild, moderate, severe) 
	   Seriousness (yes/no) 
	   Seriousness type (death, life threatening, permanently disabling, hospitalization, 
cancer, overdose, congenital anomaly) 
	   Action taken (none, decrease dose, discontinuation, etc.) 
	   Outcome (recovered, alive with sequelae, died, ongoing, persisting, unknown) 
	   Causality (possible, probable, remote, unrelated) 
	   Study day 
	   Visit number 
	   Timing of onset in relationship to last dose of study treatment 
	   Study treatment at time of event 
	   Dose of treatment in absolute amount at the time of event 
	   Drug concentration 
	   Duration of treatment 
	   Concomitant treatment 
	   (additional variables) 
 
 Vital signs 
	   Vital sign date/time 
	   Study day of vital sign 
	   Visit number 
	   Vital signs taken on scheduled visit (yes/no) 
	   Vital signs used as the baseline value (yes/no) 
	   Reason for vital signs 
	   Vital signs parameter value 
	   Baseline value of vital signs parameter 
	   Change from baseline 
	   Abnormal (yes/no) 
	   Vital sign related discontinuation (yes/no) 
	   Duration of treatment at the time of vital signs 
	   Dose of treatment at the time of vital sign 
	   Timing of vital signs in relationship to last dose of study treatment 
	   (additional variables) 
62
  ECG
 
   ECG date/time 
   Study day of ECG 
   Visit number 
   ECG taken on scheduled visit (yes/no) 
   ECG used as the baseline value (yes/no) 
   Reason for ECG 
   ECG parameter 
   ECG parameter value 
   Baseline value of ECG parameter 
   Change from baseline 
   Abnormal (yes/no) 
   ECG related discontinuation (yes/no) 
   Duration of treatment at the time of ECG 
   Dose of treatment at the time of ECG 
   Timing of ECG in relationship to last dose of study treatment 
   (additional variables) 
 
 Labs 
   Lab test name 
   Lab test upper limit of normal (ULN) 
   Lab test lower limit of normal (LLN) 
   Lab test unit of measure 
   Lab test date/time 
   Study day of test 
   Visit number 
   Sample taken on scheduled visit (yes/no) 
   Value used as the baseline value (yes/no) 
   Lab test result 
   Baseline value of lab test 
   Change from baseline 
   Lab test greater than ULN (yes/no) 
   Lab test less than LLN (yes/no) 
   Lab test value in times of ULN 
   Lab related serious adverse event (yes/no) 
   Lab related discontinuation (yes/no) 
   Duration of treatment at time of assessment 
   Dose of treatment at time of assessment 
   (additional variables) 
63