Guidance for Industry
Providing Regulatory Submissions in Electronic Format — Human
Pharmaceutical Product Applications and Related Submissions Using
the eCTD Specifications
(PDF
version of this document)
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
October 2005
Electronic Submissions
Additional
copies are available from:
Division of Drug Information,
HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane,
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
and/or
Office of Communication, Training
and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
October 2005
Electronic Submissions
Guidance for Industry
Providing Regulatory Submissions in Electronic Format — Human
Pharmaceutical Product Applications and Related Submissions Using
the eCTD Specifications
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or
the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach,
contact the FDA staff responsible for implementing this guidance.
If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance.
This is one in a series of guidance documents
intended to assist applicants making regulatory submissions to the
FDA in electronic format using the electronic common technical
document (eCTD) specifications. This guidance discusses issues
related to the electronic submission of applications for human
pharmaceutical products
and related submissions, including abbreviated new drug applications
(ANDAs), biologics license applications (BLAs), investigational new
drug applications (INDs), new drug application (NDAs), master files
(e.g., drug master files), advertising material, and promotional
labeling.
At this time, this does not include applications supporting
combination products.
The goals of the guidance are to enhance the
receipt, processing, and review of electronic submissions to the
FDA. Specifically, this guidance makes recommendations regarding
the use of the eCTD backbone files developed through the
International Conference on Harmonisation (ICH) to facilitate
efficient submission handling. In addition, the guidance provides
more specificity than in previous guidances for electronic
submissions with regard to the organization of individual
submissions. Finally, the guidance harmonizes the organization and
formatting of electronic submissions for multiple submission types.
This guidance
refers to a series of technical specifications associated with the
guidance. They are being provided as stand alone documents to make
them more accessible to the user. The associated specifications
will be updated periodically. To ensure that you have the most
recent versions, check the appropriate center's guidance Web page.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
This
portion of the guidance makes recommendations on general
organizational issues related to the electronic submission of
applications for human pharmaceutical products using the cCTD
specifications. The requirements for the content
of such applications are described in our regulations in chapter 21
of the Code of Federal Regulations (CFR). Additional
recommendations on the contents of applications are provided in
Agency guidances, which are available on the Agency Web page.
This guidance applies to marketing applications
(ANDAs, BLAs, NDAs), investigational applications (INDs), and
related submissions (master files, advertising material, and
promotional labeling). The guidance applies equally to original
submissions, supplements, annual reports, and amendments to these
applications and related submissions, including correspondence.
This guidance does not apply to electronic submission of prelicense
or preapproval inspection materials.
This document provides general guidance on how
to organize application information for electronic submission to the
Agency using the eCTD specifications. Guidance on the information to
be included in the technical sections of applications and
submissions is described in a series of guidance documents based on
the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH)
common technical document (CTD):
M4: Organization of the CTD,
M4Q: The CTD – Quality; M4S – The CTD Safety; and M4E: The
CTD – Efficacy.
The recommendations made here on
how to organize application information are based on the ICH CTD and
the electronic CTD (eCTD), which was developed by the ICH M2 expert
working group. Although the CTD and the eCTD were designed for
marketing applications, they could apply equally to other
submission types, including INDs, master files, advertising
material, and promotional labeling.
Details on the specification for the ICH eCTD can be found in the
guidance document M2 eCTD: Electronic Common Technical Document
Specification.
Submissions are a collection of documents. A
document is a collection of information that includes forms,
reports, and datasets. When making an electronic submission,
each document should be provided as a separate file.
The documents, whether for a marketing application, an
investigational application, or a related submission, should be
organized based on the five modules in the CTD: module 1 includes
administrative information and prescribing information, module 2
includes CTD summary documents, module 3 includes information on
quality, module 4 includes the nonclinical study reports, and module
5 includes the clinical study reports.
A table of contents is defined by headings
arranged in a hierarchical fashion. See the associated
specification, Comprehensive Table of Contents Headings and
Hierarchy for the comprehensive listing of headings and hierarchy
Because this is a comprehensive listing, not all headings are
applicable to all submissions or submission types. All of the
information you need to submit is covered by these headings. If you
think other headings are needed, you should contact our electronic
submission coordinators prior to using any other headings (see
section II.S of this guidance). Reviewers will not be able
to access documents associated with headings not listed in the
“Comprehensive Table of Contents Headings and Hierarchy.”
Unless otherwise specified, documents should be
organized so that the subject matter of the document is specifically
associated with the lowest heading in the table of contents
hierarchy. For example, if you look at the associated document
“Comprehensive Table of Contents Headings and Hierarchy,” the
headings “Meeting request” and “Meeting background material” are the
lowest headings in the “Meeting” hierarchy. Therefore, the meeting
request and meeting background material would be in two separate
documents — the meeting request in one document and the meeting
background material in another document.
A document can be associated with more
than one heading. However, the actual electronic file would only be
provided once. The eCTD specifications provide details on how to
refer to an electronic file.
Under our regulations (21 CFR 11.2(b)(2)),
applicants and sponsors are expected to contact us for details on
how to proceed with electronic submissions. These details are
usually provided in guidance documents. For example, we are already
receiving marketing application submissions for human pharmaceutical
products in electronic format based on details provided in the
guidances for industry Providing Regulatory Submissions in
Electronic Format – NDAs, Providing Regulatory Submissions in
Electronic Format – ANDAs, Providing Regulatory Submissions
to the Center for Biologics Evaluation and Research (CBER) in
Electronic Format – Biologics Marketing Applications, and
Providing Regulatory Submissions in Electronic Format – General
Considerations.
However, we recommend that you begin submitting eCTD backbone
files as described in this guidance because we believe that having
the information in the eCTD backbone files will result in greater
efficiency in the future. In time, the other guidances may be
withdrawn because they may no longer be needed.
When we are ready to receive a particular
submission type in electronic format only, we usually identify it in
public docket 92S-0251. Under 21 CFR part 11, you then have the
option of providing that submission type in electronic format
according to FDA guidance so that the Agency may adequately process,
archive, and review the files.
Once you begin to submit a specific application
in electronic format based on this guidance, subsequent submissions
to the application, including amendments and supplements, should
include eCTD backbone files. Without the eCTD backbone files, we
will not be able to adequately manage, process, archive, or review
the submissions. If you choose to submit an original application
using the eCTD backbone files, you should obtain an application
number in advance by contacting the appropriate center. You may
obtain the number at any time and the numbers will not be reused.
We believe it is most beneficial to begin your
eCTD-based submissions with the initial submission of an
application. Contact the appropriate center first if you wish to
make eCTD-based submissions to pending applications. You should
avoid the submission of any paper documents when you follow the
recommendations in this document. The maximum benefit will be
derived once an application is in electronic format. This is
particularly true for the IND, where submissions are provided over a
long period of time. You should submit the electronic information
for all files in the eCTD backbone files following the
specifications associated with this guidance.
If you decide to submit a specific application
in electronic format based on this guidance, you do not have to
provide eCTD backbone files for the previous submissions to the
application. For example, if you submitted an original application
in 2001 and now submit an amendment to the application using the
eCTD backbone files, you do not have to go back and submit the
document information for the files submitted in 2001.
If a document was submitted in electronic
format with the eCTD backbone files, you should not submit
additional copies when referencing the previously submitted
document. Instead, you should include the information by reference
by providing in the text of the document (1) the application or
master file number, (2) the date of submission (e.g., letter date),
(3) the document name, and (4) the page number of the referenced
document along with a hypertext link to the location of the
information (see section II.Q of this guidance). If a document
replaces or appends a document previously submitted with an eCTD
backbone file, then you should include this information in the
appropriate eCTD backbone file. The details on how to include this
information in the eCTD backbone file are provided in the
associated specifications for eCTD backbone files.
If a document was previously submitted in
either paper or electronic format without the proper eCTD
backbone files, you should reference the document as with any
paper submission. In the text of the document, you should include
(1) the application or master file number, (2) the date of
submission (e.g., letter date), (3) the document name, (4) the page
number, and (5) the submission identification (e.g., submission
serial number, volume number, electronic folder, and file name) of
the referenced document. In such cases, providing an electronic copy
of the previously submitted documents can increase the utility of
the submission. These documents, like all documents in the
submission, should be appropriately described in the eCTD backbone
files. These files are considered new in the eCTD backbone
files.
When referring to documents that are part of
other applications, please remember to include the appropriate
letters of authorization with the submission (e.g., 21 CFR
314.420(d)).
We may
refuse to file an application or supplement under our regulations
(e.g., 21 CFR 314.101 and 601.2) if the submission is illegible,
uninterpretable, or otherwise clearly inadequate, including having
incompatible formats or inadequate organization. These regulations
apply to both paper and electronic submissions. The absence of
electronic datasets in an acceptable format to permit review and
analysis may be considered inadequate, resulting in a refuse-to-file
decision.
Following the recommendations in this guidance document will help
ensure that your electronic application meets the requirements of
FDA regulations and can be archived, processed, and reviewed within
specified time frames using our tools.
When
providing applications in electronic format using the eCTD backbone
files, paper copies of the application, including review copies and
desk copies, are not required and should not be sent.
Scanned documents
submitted electronically as images are not as useful for review as
documents that are text based. Image-based documents are more
difficult to read and cannot be electronically searched. It takes
longer to print image-based documents, and they occupy more storage
space than text-based documents. For these reasons, we strongly urge
that you provide text-based documents, rather than image files,
whenever possible. We understand that certain documents may only be
available as image files. Handwritten documents and documents that
were generated independent from the company, such as journal
publications, may be available only in paper. Documents that
may only be available in paper can be scanned and submitted in
electronic format as image-based files. However, we expect documents
such as study reports recently generated by the company or recently
generated as the result of the company's request to be available as
text-based documents. We understand that legacy study reports, those
generated years ago, may only be available in paper. For these
reports, especially those for pivotal studies, you may want to
consider converting these documents from image files to text-based
files. Optical Character Recognition that has been validated is an
option.
FDA
District offices have access to documents submitted in electronic
format. Therefore, when sending submissions in electronic format,
you need not provide any documentation to the FDA Office of
Regulatory Affairs District Office.
Documents
required by regulations to be submitted with an original signature
(e.g., FDA form 356h, FDA form 1571) should be submitted with
electronic signatures that follow the controls described under 21
CFR part 11.
You should
send a single copy of the electronic portions of a submission to the
appropriate central document room facility. Copies should not be
sent directly to the reviewer or review division. Electronic
documents that bypass the controls for electronic files described in
21 CFR 11 are not considered official documents for review.
To function properly, the eCTD backbone files
must have specific names (e.g., index.xml, us-regional.xml). For
other files without a specified name, you should provide a name that
is indicative of the contents (e.g., protocol-101). The file name
should allow a reviewer to infer some concept of the file's contents
relative to other files. The file name should be less than or equal
to 64 characters including the appropriate file extension. You
should use only letters (lower case), numbers, or hyphens in the
name. You should not use blank spaces. When naming files, it is
important to remember that — to avoid truncation — the length of the
entire path of the file should not exceed 230 characters.
The terms folder and subfolder
are used in this guidance and are intended to be synonymous with
directory and subdirectory. The main submission, regional
administrative folders, and certain subfolders should have specific
names for proper and efficient processing of the submission.
Recommendations regarding naming the main submission folders and
regional administrative folders can be found in section
III, below. Other specific folder names
can be found in the specifications associated with this guidance.
You can use only letters (lower case), numbers, or hyphens in the
name. You should not use blank spaces. The length of the folder name
should not exceed 64 characters. When naming folders, it is
important to remember that the length of the entire path should not
exceed 230 characters. You should not include empty folders in the
submission.
We
recommend that you send electronic documents in the file formats
specified in this guidance. We will not be able to manage, process,
archive, or review documents provided in other file formats.
The
following file formats should be used:
·
PDF for reports
and forms
·
SAS XPORT (version
5) transport files (XPT) for datasets
·
ASCII text files
(e.g., SAS program files, NONMEM control files) using txt for
the file extension
·
XML for documents,
data, and document information files
·
Stylesheets (XSL)
and document type definition (DTD) for the XML document information
files
·
Microsoft Word for
draft labeling (because Microsoft
Word
can change, check our Web site
for the current version)
In the
future, we may consider other electronic file formats for use with
electronic submissions, or we may consider the use of the current
formats with other electronic submissions. We intend to publish
guidance to advise on the use of file formats for specific types of
submissions for use in the future.
For
documents with a table of contents, provide bookmarks and hypertext
links for each item listed in the table of contents including
tables, figures, publications, references, and associated
appendices. These bookmarks and hypertext links are essential for
efficient navigation through documents. You should make the bookmark
hierarchy identical to the table of contents. Navigation efficiency
is also improved by providing 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.
It is
possible to link to other documents in a submission using relative
paths when creating hypertext linking. Absolute links that
reference specific drives and root directories are not functional
once the submission is loaded onto the document repository. For
example, the link path ../../../123456/0001/.. will work, but the
link c:\123456\0001\… will not work. However, you should keep in
mind that some documents may be subsequently replaced or appended,
possibly rendering the link obsolete, so linking should be used
cautiously.
When
creating bookmarks and hypertext links, 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.
All submissions provided in electronic format
must be sent to the appropriate central document room facility for
processing to maintain the integrity of the submission as required
under 21 CFR part 11. Electronic documents sent directly to division
document rooms or to reviewers bypass the controls established for
the receipt and archiving of documents and are not considered
official documents for review. See the associated specifications for
more information, including electronic transmission.
If you have
any questions on technical issues related to providing electronic
submissions according to the recommendations in this guidance,
contact the electronic submission coordinator at
esub@cder.fda.gov.
Specific technical issues related to submissions to CBER should be
sent to
esubprep@cber.fda.gov.
Specific questions pertaining to content should be directed to the
appropriate review division or office.
All documents in the
electronic submission should be placed in a main submission folder
using a four-digit sequence number for the application with the
original submission for an application designated 0000. You should
assign numbers for each submission to the same application with
consecutive numbers. For example, the folder for the 3rd submission
to an application, whether it is an amendment, supplement, or
general correspondence is numbered 0002. The 4th submission is
numbered 0003. This also applies to applications where previous
submissions were not based on the ICH eCTD specifications. For
example, if the submission is the 25th and the previous 24 were in
paper, you would number the folder 0024. You should place the eCTD
backbone file for modules 2 to 5 for the submission in this folder (index.xml).
You should place the checksum file (e.g., index-md5.txt) in the same
folder. Sequence numbers are used to differentiate between
submissions for the same application and do not need to correspond
to the order they are received by the Agency.
We recommend that you use subfolders to
organize files in a submission, including for each module m1,
m2, m3, m4, and m5, respectively. There
is a subfolder util to organize eCTD technical files in the
submission. Place these subfolders in the sequence number folder
(e.g., folder named 0000 for the initial submission to an
application). Do not include empty subfolders.
The following sections provide guidance for
organizing the folders and files in the m1, m2, m3,
m4, m5, and util folders. In addition, you can
find instructions on preparing the submission of an electronic
application to CBER at
http://www.fda.gov/cber/esub/esub.htm
Module 1 contains administrative and labeling
documents. The organization of the documents in module 1 is the same
for all applications and related submissions. The subject matter
for each document should be assigned to the lowest level of the
hierarchy outlined in the associated document “Comprehensive Table
of Contents Headings and Hierarchy.” Note that some headings apply
only to specific applications or specific submissions. You should
create a folder named us and place it in the folder named
m1. The documents for module 1 should be placed in the us
folder including the us-regional.xml file pertaining to the
eCTD backbone files for module 1. Below are some additional details
on providing specific types of documents.
The details on creating this file are in the
associated document “eCTD Backbone Files Specification for Module
1.”
If you decide to include a cover letter, we
recommend you include the following information:
·
Description of the submission including appropriate
regulatory information
·
Description of the submission including the
approximate size of the submission (e.g., 2 gigabytes), the format
used for DLT tapes, and the type and number of electronic media used
(e.g., three CDROMs), if applicable
·
Statement that the submission is virus free with a
description of the software (name, version, and company) used to
check the files for viruses
·
Regulatory and technical point of contact for the
submission
The following section describes how to provide
specific labeling documents.
a. Labeling history
You can provide a history summarizing labeling changes as a single PDF
file. The following information will help us confirm changes made to
the labeling:
·
Complete list of
the labeling changes being proposed in the current submission and
the explanation for the changes
·
Date of the last
approved labeling
·
History of all
changes since the last approved labeling. With each change, you
should note the submission that originally described the change and
the explanation for the change.
·
List of
supplements pending approval that may affect the review of the
labeling in the current submission
b. Content of labeling
See the guidance for industry on Providing Regulatory Submissions in
Electronic Format — Content of Labeling for details on providing
the content of labeling files.
c. Labeling samples
Each labeling sample
(e.g., carton labels, container labels, package inserts) should be
provided as individual PDF files. The samples should (1) include all
panels, if applicable; (2) be provided in their actual size; and (3)
reflect the actual color proposed for use.
Advertisements and promotional labeling include
material submitted under 21 CFR 314.81(b)(3)(i) or 601.12(f)(4) as
part of the postmarketing reporting regulations for approved
applications, submitted under the requirements of 21 CFR 314.550 and
601.45 (part of the accelerated approval requirements and restricted
distribution for drug and biological products), or voluntarily
submitted to INDs.
You should submit promotional material to the appropriate
application. You should not mix submissions of advertisements and
promotional labeling with submissions containing other types of
information.
Each promotional
piece should be provided as an individual PDF file. In cases when
promotional writing or images cover more than one page (e.g., a
brochure spread), the reviewer should be able to view the entire
layout at one time. For three-dimensional objects, you should
provide a digital image of the object in sufficient detail to allow
us to review the promotional material. In addition, you should
provide information adequate to determine the size of the object
(e.g., point size, dimensions). A dimensional piece shown flat, such
as a flattened carton, can also be submitted.
If you choose to
include cover letters with your submissions of advertising and
promotional material, they should be provided as individual PDF
files and indicate for the reviewer any additional important
information, such as which materials need priority reviews.
If references are provided, each reference
should be submitted as an individual PDF file and placed in the
appropriate module based on subject matter. If possible, you should
highlight the sections of the full reference that you refer to in
the promotional materials. When a reference is used to support a
claim in proposed promotional materials voluntarily submitted for
advisory opinion or Agency comment, you should provide a hypertext
link to the page of the reference or labeling that contains the
supporting information.
For promotional materials submitted as part of
the postmarketing reporting requirements, you may choose to provide
hypertext links to references or labeling. References improve the
efficiency of a review.
In the
postmarketing study commitments files, you should include a bookmark
for each study described.
You should place the documents for module 2 in
the m2 folder. The subject matter for each document should be
specific for the lowest level of the hierarchy outlined in the
associated document “Comprehensive Table of Contents Headings and
Hierarchy.” Each document should be provided as an individual PDF
file. The subfolders described in the M2 eCTD:
Electronic Common Technical
Document Specification are not necessary for the review of the submission. If you choose to use
the additional subfolder, we will maintain the subfolder structure
so links will function properly.
The organization of the module 3 folder is the
same for all applications and related submissions. You should place
the documents for module 3 in the m3 folder. The subject
matter for each document should be specific for the lowest level of
the hierarchy outlined in the associated document “Comprehensive
Table of Contents Headings and Hierarchy.” Each document should be
provided as an individual PDF file. The subfolders described in the
M2 eCTD: Electronic Common Technical Document Specification
are not necessary for the review of the submission. If you choose to
use the additional subfolder, we will maintain the subfolder
structure used so links will function properly.
You should provide the files pertaining to Key
Literature References (CTD section 3.3) as individual PDF files.
The filenames should be short and meaningful.
The organization of the module 4 folder is the
same for all applications and related submissions. You should place
the documents for module 4 in the m4 folder. The subject
matter for each document should be specific for the lowest level of
the hierarchy outlined in the associated document “Comprehensive
Table of Contents Headings and Hierarchy.” The headings for study
reports should also be specific for the lowest level of the
hierarchy. Each document should be provided as an individual PDF
file. The subfolders described in the M2 eCTD:
Electronic Common Technical
Document Specification
are not necessary for the review of the submission. If you choose to
use the additional subfolder, we will maintain the subfolder
structure so links will function properly.
Typically, a single document should be provided
for each study report included in this module. However, if you
provide the study reports as multiple documents, you should confine
the subject matter of each document to a single item in the
following list.
·
Synopsis
·
Study report body
·
Protocol and
amendments
·
Signatures of
principal or coordinating investigator(s)
·
Audit certificates
and reports
·
Documentation of
statistical methods and interim analysis plans
·
Documentation of
interlaboratory standardization methods of quality assurance
procedures if used
·
Publications based
on the study
·
Important
publications referenced in the report
·
Compliance and/or
drug concentration data
·
Individual subject
data listings
— Data tabulations
- Data tabulations datasets
- Data definitions
— Data listing
- Data listing datasets
- Data definitions
— Analysis datasets
- Analysis datasets
- Analysis programs
- Data definitions
— IND safety reports
In the following examples, you should provide
the study reports as separate documents
·
Documents previously submitted. If you have provided a
document in a previous submission (e.g., protocol), you should
provide a reference to the protocol, not resubmit the protocol.
·
Additional information added. If you think you will
want to add information to the study report over time (e.g., audit
information, publication based on the study), you should provide the
study reports as separate documents and then the new information can
be provided as a separate file, rather than replacing the entire
study report.
·
Different file formats. If you submit the individual
animal data listings as datasets (e.g., SAS transport files), you
should provide these as separate files from the study reports (e.g.,
submitted as PDF files).
You should provide each literature reference as
an individual PDF file. The filenames should be short and
meaningful.
See the associated document “Study Data
Specifications” for details on providing datasets and related files
(e.g., data definition file, program files)
The organization of the module 5 folder is the
same for all applications and related submissions. You should place
the documents for module 5 in the m5 folder. The subject
matter for each document should be specific for the lowest level of
the hierarchy outlined in the associated document “Comprehensive
Table of Contents Headings and Hierarchy.” One exception is that
legacy study reports can be provided as a single document. Each
document should be provided as an individual PDF file. The
subfolders described in the guidance M2 eCTD:
Electronic Common Technical
Document Specification
are not necessary for the review of the submission. If you choose to
use the additional subfolder, we will maintain the subfolder
structure so links will function properly.
You should provide the tabular listing of all
clinical studies as a single PDF file.
Typically, clinical study reports are provided
as more than one document based on the ICH E3 guidance document when
providing a study.
In addition, if you have provided a document in a previous
submission (e.g., protocol), you should provide a reference to the
protocol rather than resubmitting the protocol. In cases when a
legacy report has already been prepared as a single electronic
document, you can provide the entire study report, other than the
case report forms (CRFs) and individual data listings, as a single
document. The individual documents that should be included in a
study report are listed below:
·
Synopsis
(E3 2)
·
Study report (E3
1, 3 to 15)
·
Protocol and
amendments (E3 16.1.1)
·
Sample case report
forms (E3 16.1.2)
·
List of IECs or
IRBs (E3 16.1.3) and consent forms
·
List and
description of investigators (E3 16.1.4) and sites
·
Signatures of
principal or coordinating investigator(s) or sponsor’s responsible
medical officer (E3 16.1.5)
·
Listing of
patients receiving test drug(s) from specified batch (E3 16.1.6)
·
Randomizations
scheme (E3 16.1.7)
·
Audit certificates
(E3 16.1.8) and reports
·
Documentation of
statistical methods (E3 16.1.9) and interim analysis plans
·
Documentation of
interlaboratory standardization methods of quality assurance
procedures if used (E3 16.1.10)
·
Publications based
on the study (E3 16.1.11)
·
Important
publications referenced in the report (E3 16.1.12)
·
Discontinued
patients (E3 16.2.1)
·
Protocol
deviations (E3 16.2.2)
·
Patients excluded
from the efficacy studies (E3 16.2.3)
·
Demographic data
(E3 16.2.4)
·
Compliance and/or
drug concentration data (E3 16.2.5)
·
Individual
efficacy response data (E3 16.2.6)
·
Adverse event
listings (E3 16.2.7)
·
Listing of
individual laboratory measurements by patient (E3 16.2.8)
·
Case report forms
(E3 16.3)
·
Individual patient
data listings (CRTs) (E3 16.4)
— Data tabulations
- Data tabulations datasets
- Data definitions
- Annotated case report form
— Data listing
- Data listing datasets
- Data definitions
- Annotated case report form
— Analysis datasets
- Analysis datasets
- Analysis programs
- Data definitions
- Annotated case report form
— Subject profiles
— IND safety reports
You should
provide an individual subject’s complete CRF as a single PDF file.
If a paper CRF was used in the clinical trial, the electronic CRF
should be a scanned image of the paper CRF including all original
entries with all modifications, addenda, corrections, comments,
annotations, and any extemporaneous additions. If electronic data
capture was used in the clinical trial, you should submit a
PDF-generated form or other PDF representation of the information
(e.g., subject profile).
You should
use the subject’s unique identifier as the title of the document and
the file name. These names are used to assist reviewers in finding
the CRF for an individual subject. Each CRF must have bookmarks as
part of the comprehensive table of contents required under 21 CFR 314.50(b).
We recommend bookmarks for each CRF domain and study visit to help
the reviewer navigate the CRFs. For addenda and corrections, making
a hypertext link from the amended item to the corrected page or
addendum is a useful way to avoid confusion. Bookmarks for
these items should be displayed at the bottom of the hierarchy.
See the associated document “Study Data
Specifications” for details on providing datasets and related files
(e.g., data definition files, program files). For subject profiles,
you should use the subject’s unique identifier in the title of the
document and the file name.
To facilitate electronic submissions,
we have divided the postmarketing
periodic adverse drug experience
report into three parts: (1) individual case safety reports (ICSRs),
(2) ICSR attachments, if applicable, and (3) descriptive
information. The descriptive information includes the narrative
summary and analysis of the information in the report (i.e.,
periodic ICSRs and ICSR attachments), an analysis of the 15-day
alert reports submitted during the reporting interval (i.e.,
expedited ICSRs and ICSR attachments), and the history of actions
taken since the last report because of adverse drug experiences
(e.g., labeling changes, studies initiated) as described in 21 CFR
314.80(c)(2)(ii)(a) and (c) and 600.80(c)(2)(ii)(A) and (C)). You
should supply the descriptive information as an individual PDF file.
You should provide bookmarks for each of the sections and
subsections of this report. ICSR and ICSR attachments should be
provided as described in the guidance for industry Providing
Regulatory Submissions in Electronic Format — Postmarketing Periodic
Adverse Drug Experience Reports.
You should provide each literature reference as
an individual PDF file. The filenames should be short and
meaningful.
You should create two folders, dtd and
style and place them in the util folder.
You should place the document type definition (DTD)
that you used to create the eCTD backbone file (regional.xml), the
DTD you used to create the FDA Regional eCTD backbone file (us-index.xml),
and the DTD used for the STF in the folder named dtd. You
should use the most recent DTD.
You should use the most recent stylesheet. See
the guidance for industry M2 eCTD: Electronic Common Technical
Document Specification.
This
guidance has been developed by the Center for Drug Evaluation
and Research (CDER) and the Center for Biologics Evaluation and
Research (CBER).
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Date created: October 18, 2005 |