- INTRODUCTION
This is one in a series of guidance documents intended to assist
you when making regulatory submissions in electronic format to the
Center for Drug Evaluation and Research (CDER) and the Center for
Biologics Evaluation and Research (CBER), Food and Drug
Administration (FDA). This guidance discusses general issues
common to all types of electronic regulatory submissions. In some
cases, the guidance for one center differs from that for the other
center because of differences in procedures and in the computer
infrastructures in the centers. We will work to minimize these
differences wherever possible.
Agency guidance documents on electronic regulatory submissions
will be updated regularly to reflect the evolving nature of the
technology involved and the experience of those using this
technology.
Table of Contents
- BACKGROUND
In the Federal Register of March 20, 1997 (62 FR 13430), the FDA
published the Electronic Records; Electronic Signatures regulations
(21 CFR Part 11). This regulation provided for the voluntary
submission of parts or all of regulatory records in electronic
format without an accompanying paper copy. Publication of this
regulation resulted in a series of related actions:
March 1997:
The Agency established public docket number 92S-0251 to provide
a permanent location for a list of the Agency units that are
prepared to receive electronic submissions and the specific types
of regulatory records that can be accepted in electronic format
(62 FR 13467, March 20, 1997). This docket can be accessed
on the Internet at
http://www.fda.gov/ohrms/dockets/dockets/92s0251/92s0251.htm.
September 1997:
CDER published a guidance for industry entitled Archiving
Submissions in Electronic Format - NDAs (62 FR 49695,
September 23, 1997) to assist applicants wanting to make electronic
submissions of case report forms (CRFs) and case report tabulations
(CRTs) as part of the NDA archival submission.
April 1998:
CDER issued a draft guidance for industry, Providing Regulatory
Submissions in Electronic Format - NDAs, which expanded on the
September 1997 guidance by providing information on submitting a
complete archival copy of the NDA in electronic format
(63 FR 17185; April 8, 1998).
June 1998:
CBER published the following draft guidances to assist applicants
in their efforts to submit electronic documents to the Center for
review and archive as part of their BLA or PLA/ELA submissions:
Electronic Submissions of a Biologics License Application (BLA),
Product License Application (PLA) /Establishment License Application
(ELA) to the Center for Biologics Evaluation and Research
(63 FR 29741, 6/1/98).
Electronic Submissions of Case Report Forms (CRFs), Case Report
Tabulations(CRTs) and Data to the Center for Biologics Evaluation
and Research (63 FR 29739; 6/1/98).
Pilot Program for Electronic Investigational New Drug (eIND)
Applications for Biological Products (63 FR 29740; 6/1/98).
Instructions for Submitting Electronic Lot Release Protocols to
the Center for Biologics Evaluation and Research (63 FR 29742;
6/98).
January 1999:
CDER and CBER finalized this joint guidance on general
considerations for electronic submissions. Subsequent guidances
will focus on specific submission types.
The Agency envisions the series of guidance documents on electronic
regulatory submissions to provide guidance on the following:
- General considerations for all electronic submissions (e.g.,
file formats)
- NDAs to CDER (including supplements and amendments)
- Marketing Applications to CBER (e.g., BLAs, PLAs, ELAs, NDAs)
- Abbreviated New Drug Applications (ANDAs)
- Postmarketing Safety Reports
- Investigational New Drug Applications (INDs)
- Annual Reports
- Drug Master Files (DMFs)
- Launch Material
- Advertising
- Other
As individual documents are completed, they will be issued first
in draft for comment, then finalized and added to the series.
The guidances will be updated regularly to reflect the continuously
evolving nature of the technology and experience of those using
this technology.
Table of Contents
- WHAT FILE FORMATS SHOULD I USE FOR ELECTRONIC DOCUMENTS?
Regulations in 21 CFR Part 11 require that the Agency be able to
generate from any document provided in electronic format an accurate
and complete paper copy that is both legible ("human readable")
and suitable for inspection, review, and copying. Therefore,
documents submitted in electronic format should:
- Enable the user to easily view a clear and legible copy of the
information
- Enable the user to print each document page by page, as it would
have been provided in paper, maintaining fonts, special
orientations, table formats, and page numbers
- Include a well-structured table of contents and allow the user
to navigate easily through the submission
- Allow the user to copy text and images electronically into common
word processing documents
To achieve the above goals, you should submit all electronic
documents in Portable Document Format (PDF). CDER and CBER are
prepared to archive documents provided as PDF files. PDF is an open,
published format created by Adobe Systems Incorporated
(http://www.adobe.com). You do not need to use a product from Adobe
or from any specific company to produce your PDF documents. PDF
has been accepted as a standard for providing documents in
electronic format by the International Conference on Harmonisation
(ICH).
The following recommendations will help you create PDF files that
we can review and archive.
- Version
We should be able to read all PDF files with version 3.0 of the
Acrobat Reader with the search plug in. We should not need any
additional software to read and navigate the PDF files.
- Fonts
PDF viewing software automatically substitutes a font to display
text if the font used to create the text is unavailable on the
reviewer's computer. Font substitution can affect a document's
appearance and structure, and in some cases it can affect the
information conveyed by a document. We cannot guarantee the
availability of any one font. Therefore, you should embed all
fonts you are using in the PDF files to ensure that those fonts
will always be available to the reviewer. When embedding fonts,
all characters for the font should be embedded, not just a subset
of the fonts being used in the document.
One problem associated with embedding fonts is that embedding
requires additional computer storage space. Three techniques to
help limit the storage space taken by embedding fonts include:
- Limiting the number of fonts used in each document
- Using only True Type or Adobe Type 1 fonts
- Avoiding customized fonts
Resizing a document because the contents are too small to read is
inefficient. We believe that Times New Roman, 12-point font, the
font used for this document, is adequate in size for reading
narrative text. Although sometimes tempting for use in tables and
charts, fonts smaller than 12 points should be avoided whenever
possible.
We recommend the use of a black font color. Blue font may be used
for hypertext links (preferred for submissions to CBER). If a font
color other than black is used, avoid light colors that do not
print well on grayscale printers. You can test the color
reproduction prior to submission by printing sample pages from
the document using a grayscale printer.
- Page Orientation
Pages should be properly oriented. For example, you should set
the page orientation of landscape pages to landscape prior to
saving the PDF document in final form to ensure correct page
presentation.
- Page Size and Margins
The print area for pages should fit on a sheet of paper that is
8.5 inches by 11 inches. You should allow a margin of at least
1 inch on all sides to avoid obscuring information if the pages
are subsequently printed and bound.
- Source of Electronic Document
PDF documents produced by scanning paper documents are usually
inferior to those produced from an electronic source document.
Scanned documents are more difficult to read and do not allow us
to search or copy and paste text for editing. They should be
avoided if at all possible. If you use optical character
recognition software, you should verify that all imaged text
converted by the software is accurate.
- Methods for Creating PDF Documents and Images
Choose a method for creating PDF documents that produces the best
replication of a paper document. You can ensure that the paper
and PDF version of the document are the same by printing the
document from the PDF version.
Documents that are available only in paper should be scanned at
resolutions that will ensure the pages are legible both on the
computer screen and when printed. At the same time, you should
also limit the file size. We recommend scanning at a resolution
of 300 dots per inch (dpi) to balance legibility and file size.
We discourage the use of grayscale or color because of file size.
After scanning, avoid resampling to a lower resolution.
When creating PDF files containing images, you should not
resample images. Resampling does not preserve all of the pixels
in the original. For PDF images, you can use one of the following
lossless compression techniques (with the exception that, when
submitting to CBER, standard radiographic images, PET, and SPECT
images should not be compressed).
- For lossless compression of color and grayscale images, use
Zip/Flate (one technique with two names). This is specified in
Internet RFC 1950 and RFC 1951
(http://info.internet.isi.edu/in-notes/rfc/files/rfc1950.txt).
- For lossless compression of black and white images, use the
CCITT Group 4 Fax compression technique. It is specified as
CCITT recommendations T.6 (1988) - Facsimile coding schemes and
coding control functions for Group 4 facsimile apparatus.
Paper documents containing handwritten notes should be scanned at
300 dpi. Handwritten notes should be done in black ink for clarity.
For photographs, the image should be obtained with a resolution of
600 dpi. If black and white photos are submitted, consider 8-bit
gray scale images. If color photos are submitted, consider 24-bit
RGB images. A captured image should not be subjected to nonuniform
scaling (i.e., sizing).
Gels and karyotypes should be scanned directly, rather than from
photographs. Scanning should be at 600 dpi and 8-bit grayscale
depth.
Plotter output graphics should be scanned or captured digitally
at 300 dpi.
High-pressure liquid chromatography or similar images should be
scanned at 300 dpi.
- Hypertext Linking and Bookmarks
Hypertext links and bookmarks are techniques used to improve
navigation through PDF documents. Hypertext links can be
designated by rectangles using thin lines or by blue text (the
latter is preferred by CBER). In CDER, you can use invisible
rectangles for hypertext links in a table of contents to avoid
obscuring text. Recommendations for hypertext linking and bookmarks
are provided in the guidance for the specific submission type.
In general, for documents with a table of contents, provide
bookmarks and hypertext links for each item listed in the table of
contents including all tables, figures, publications, other
references, and appendices. These bookmarks and hypertext links
are essential for the efficient navigation through documents. In
general, including a bookmark to the main table of contents for a
submission or item is helpful. Make the bookmark hierarchy identical
to the table of contents. Avoid using bookmark levels in addition
to those present in the table of contents. Each additional level
increases the need for space to read the bookmarks. We recommend
using no more than 4 levels in the hierarchy.
Hypertext links throughout the body of the document to supporting
annotations, related sections, references, appendices, tables, or
figures that are not located on the same page are helpful and
improve navigation efficiency. Use relative paths when creating
hypertext linking to minimize the loss of hyperlink functionality
when folders are moved between disk drives. Absolute links that
reference specific drives and root directories will no longer work
once the submission is loaded onto our network servers.
When creating bookmarks and hyperlinks, choose the magnification
setting Inherit Zoom so that the destination page displays at the
same magnification level that the reviewer is using for the rest
of the document.
- Page Numbering
If a submission includes more than one document, you need not
provide pagination for the entire submission. Include page numbers
only for individual documents.
It is easier to navigate though an electronic document if the page
numbers for the document and the PDF file are the same. To
accomplish this, the initial page of the paper document should be
numbered page 1.
- Document Information Fields
Document information fields are used to search for individual
documents and to identify the document when found. Recommendations
for the document information fields will be provided in the guidance
for the specific submission type.
- Open Dialog Box
The open dialog box sets the document view when the file is
opened. The initial view of the PDF files should be set as
Bookmarks and Page. If there are no bookmarks, set the initial
view as Page only. Set the Magnification and Page Layout to
default.
- Naming PDF Files
We are recommending names for folders and selected files in
individual guidances for specific submission types. For
uniformity, we hope that you use our specific naming conventions
when they are provided. Reviewers are trained to look for these
folders and files, and using the recommended names should help
avoid misunderstandings, improve communication, and speed the
review of a submission.
When we do not specify a file name, you can use file names up to
32 characters in length with a 3-character extension. Avoid using
punctuation, spaces, or other nonalphanumeric symbols in file
names.
- Security
You should not include any security settings or password protection
for PDF files. Allow printing, changes to the document, selecting
text and graphics, and adding or changing notes and form fields.
Our internal security and archival processes will maintain the
integrity of the submitted files. A read-only copy of the files,
generated from the submitted files, will be provided to the
reviewer.
- Indexing PDF Documents
We use full text indexes to help find specific documents and/or
search for text within documents. When a document or group of
documents is indexed, all words and numbers in the file and all
information stored in the Document Information fields are stored
in special index files that are functionally accessible using the
search tools available in Acrobat. Portions of a document that
are imaged are not indexed. Even if the document only contains
images, the text in the Document Information fields of the file
will be indexed.
These full text indexes should not be confused with a table of
contents. Adobe Acrobat Catalog is one example of a tool that
can be used to index PDF documents. Indexes should not require
extensions or additions to off-the-shelf Acrobat programs.
With many submissions, we ask that you associate the table of
contents file for a section with the corresponding full text index
file. By associate, we mean that when the table of contents file
is opened, the index file is automatically added to the available
index list and is ready to be used.
Further recommendations for full text indexes will be provided in
guidance for the specific submission types.
- Plug Ins
We are developing procedures for archiving documents with
electronic signatures. Until those procedures are in place,
documents for which regulations require an original signature,
such as certifications, must be accompanied by a paper copy
that includes the handwritten signature and the submission
identifier (e.g., NDA number).
- Electronic Signatures
We are developing procedures for archiving documents with
electronic signatures. Until those procedures are in place,
documents for which regulations require an original signature,
such as certifications, must be accompanied by a paper copy
that includes the handwritten signature and the submission
identifier (e.g., NDA number).
Table of Contents
- WHAT FILE FORMATS SHOULD I USE FOR ELECTRONIC DATASETS ?
Regulations in 21 CFR Part 11 require all datasets provided in
electronic format to provide an accurate and complete copy of the
data suitable for inspection, review, and copying. Currently,
we are able to accept and archive datasets in SAS System XPORT
transport format (Version 5 SAS transport file). We plan on
providing guidance for additional file format types for datasets.
See Section B, below. See also recommendations provided in
guidance for the specific submission types.
- SAS System XPORT Transport Format (Version 5 SAS Transport
Format)
SAS XPORT transport format, also called Version 5 SAS transport
format, is an open format published by the SAS Institute. The
description of this SAS transport file format is in the public
domain. Data can be translated to and from this SAS transport
format to other commonly used formats without the use of programs
from SAS Institute or any specific vendor.
You should follow the recommendations in this section to create
SAS transport files that we can review and archive.
- Version
In SAS, SAS XPORT transport files are created by PROC XCOPY in
Version 5 of SAS software and by the XPORT engine in Version 6 and
higher of SAS Software. We are unable to archive SAS Transport
files processed by the CPORT engine.
You can find the record layout for SAS XPORT transport files in
SAS technical support TS-140. This document and additional
information about the SAS Transport file layout can be found on
the SAS world wide web page at http://www.sas.com/fda-esub.
- Transformation of Datasets
We use a variety of software tools to analyze the datasets.
Stat/Transfer from Circle Systems and DBMS/copy from Conceptual
Software Inc., are two programs used to transfer data to various
formats used for analysis. SAS Viewer version 7 is used to open
SAS transport files directly.
- Naming SAS Transport Files
All SAS transport files should use xpt as the file extension.
- Compression Of SAS Transport Files
The SAS transport files should not be compressed.
- Content Of Datasets And Organization
You should provide a single transport file for each dataset. Many
of the software tools used by the reviewers require datasets to be
loaded into random access memory (RAM) prior to opening the file.
Therefore, dataset files should be organized so that their size is
generally less than 25 MB per file. The datasets should be
accompanied by data definition tables that include the variable
name, a description of the variable, the type of variable (e.g.,
number, character, date), and codes used in the dataset. For
derived variables, the method of deriving the variable should
also be included in this table. Variable names are limited to
8 characters. You should include a descriptive name up to 32
characters in the label header. Further recommendations for
content of SAS Transport files are provided in guidance for each
specific submission type.
We recommend that you discuss the content of the datasets with the
review division prior to submission.
- Other Dataset Formats
Although we are not prepared to archive other dataset file formats
at this time, additional file formats are being considered, such as
structured ASCII for ANDA and postmarketing safety data. Structured
ASCII is also being explored for use with the chemistry,
biopharmaceutic, and clinical pharmacology data for NDAs. As these
projects mature, we will provide additional guidance.
Table of Contents
- WHAT ARE THE PROCEDURES FOR SENDING ELECTRONIC SUBMISSIONS FOR ARCHIVE ?
Submissions should be sent directly to the appropriate center
involved. The procedure for handling paper submissions is
unchanged from the past.
- CDER
Send one copy of the electronic regulatory submission for archive
to the CDER Central Document Room (CDR) as follows:
Central Document Room
Center for Drug Evaluation and Research
Food and Drug Administration
12229 Wilkins Avenue
Rockville, MD 20852
CDER uses this copy to make other copies as needed (see section
VIII, below, on processing electronic submissions).
- CBER
Send two copies of the electronic regulatory submission as described
in this guidance to CBER's Document Control Center (DCC) as
follows:
Center for Biologics Evaluation and Research
Attn: (Insert "Responsible Office")
HFM-99, Room 200N
1401 Rockville Pike
Rockville, MD 20852-1448
It is essential to communicate with the appropriate CBER office
prior to submitting an electronic document, notifying us of your
intention to submit an electronic document at least six to eight
months in advance of the target date for the submission. At that
time, the sponsor should forward a completed copy of the appropriate
application specific questionnaire
http://www.fda.gov/cber/guidelines.htm.
Subsequent to the receipt of the questionnaire, a teleconference
will be scheduled with the appropriate CBER staff. The objective
of the teleconference is to convey information relating to the
proposed electronic submission's management paradigm, content,
format, and structure. Moreover, we will discuss any issues
specific to your submission that may not have been fully addressed
in the general considerations guidance.
Table of Contents
- WHAT TYPE OF MEDIA SHOULD I USE?
CDER and CBER are prepared to accept electronic submissions provided
on the media listed in the table below. To optimize processing
efficiency, we recommend choosing media with a capacity most
appropriate to the size of the submission. Whenever possible,
applicants should choose media capable of holding the submission
on the fewest number of units.
Recommendations for Media |
Size of Submission |
Media and format |
Units |
Less than 10MB |
3.5 inch DOS Formatted Floppy Disks |
1 to 10 |
Less than 3.25GB |
CD-ROM ISO 9660 |
1 to 5 CDs |
Greater than 3.25GB |
Digital Tape - Digital Equipment Corp. DLT 20/40 and 10/20 GB format using OPENVMS with VMS backup or NT server 4.0 with NT backup or backup exec. |
No limit |
Table of Contents
- HOW SHOULD I PREPARE THE MEDIA FOR ELECTRONIC SUBMISSIONS
FOR ARCHIVE ?
Send all electronic media adequately secured in a standard binder
marked clearly on the outside ELECTRONIC REGULATORY SUBMISSION FOR
ARCHIVE. CDs should be packaged carefully to ensure that they
arrive in a usable condition. Particularly vulnerable are diskettes
and CD jewel cases shipped in envelopes without bubble-type
protective material or stiff backing. The use of a jiffy-type bag
by itself to ship media will not provide adequate protection for
shipping electronic media.
The first binder with electronic media should include only a paper
copy of the cover letter for the submission, a paper copy of the
appropriate FDA form for the submission (e.g., for an NDA/BLA
include FDA form 356h), and the electronic media for archiving.
Please attach labels to the media including the CD jewel cases.
Label the media with the following:
- Submission identifier (e.g., NDA, BLA number)
- Proprietary and generic name.
- Company name
- Submission serial number, if applicable.
- Submission date: in the format of DD-MMM-YYYY (for example,
01-Jan-1997).
- Disk/CD-ROM/tape number (the number should include the total
number submitted such as Disk # of #)
When sending CD ROMS to CBER, number them from 0.001 through
0.XXX for the original submission, and 1.001 through 1.XXX for
subsequent submissions with additional information.
Table of Contents
- HOW DO THE CENTERS PROCESS ELECTRONIC SUBMISSIONS FOR
ARCHIVE?
- CDER
When an electronic submission arrives in CDER, we copy the
electronic files to tape to create an archival copy of the
submission. We also copy the files to a network server to create
a read-only copy for the reviewer. We use internal procedures to
track submissions (do not send roadmap files described below with
submissions to CDER).
- CBER
When an electronic submission arrives in CBER, one copy of the
media is archived; the second copy of the submission's media is
copied to a network server to create a read-only copy for the
reviewer.
The structure and content of electronic submissions to CBER
should be based upon the application (e.g., BLAs, PLA/ELAs).
Subsequent to the delivery of the electronic application, any
additional electronic and/or paper information will be added to
the existing network 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 application 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 application's main table of contents, and
to the applications folders and files. This roadmap or home page
should be updated and resubmitted as additional information to the
application.
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 an application. The
application's roadmap.pdf file should be easily updated or modified,
for example, 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 sponsor's submission date in
the DD-MMM-YYYY format (e.g., 01-Jan-1999). The contents of the
original application and any subsequent amendments to that
application should be briefly described in a roadmap.pdf table.
The location of these files and folders on the submitted media
should be indicated in the roadmap.pdf. Where portions of an
application have been submitted only as a paper documents, they
should be included in the roadmap and table of contents and tagged
as paper only.
A summation of the electronic document, using at least 40 key
words from the main document should be included with all
electronic applications delivered to CBER. This summation should
be located in the root directory on the CDROM or DLT tape. The
file containing the key words should be an ASCII text file entitled
Summary.txt.
Table of Contents
- WHAT IF I HAVE A QUESTION ?
- CDER
You may direct questions regarding the preparation of submissions
in electronic format in CDER to the Electronic Submissions
Coordinator, email ESUB@CDER.fda.gov.
- CBER
You may direct questions regarding the preparation of submissions
in electronic format in CBER to the Electronic Submissions
Coordinator email ESUBPREP@CBER.fda.gov.
1 This guidance has been prepared by the Center for Drug Evaluation
and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
On June 1, 1998, the President instructed all Federal agencies
to ensure the use of plain language in all new documents. This
guidance reflects Agency efforts to comply with the President's
plain language initiative.
Table of Contents