1. Study Tagging File Workshop
February 26, 2004
US Food and Drug Administration
Rockville, MD

2. The Backdrop NDAs will have multiple submissions over their life-cycle
The 10 most active eNDAs ranged from 76 to 202 electronic submissions:
6 had 111 to 139 submissions
1 had 185 submissions
1 had 202 submissions
NDA submissions contain thousands of files in a single submission
One initial submission in FY 2003 had 5478 files
One eCTD submission in FY 2004 had over files in a supplement
Typically the majority of files are Study Report Files such as Case Report Forms (CRFs) and Case Report Tabulations (CRT) associated with multiple Study Reports

3. Problems Computer system limitations
A maximium of 256 characters can be used
This is further limited by ICH to 230 characters to permit the ICH regulatory agencies space for server and folders names to organize the submission
ICH guidance recommends that folder names not exceed 64 characters
Computer Displays can not readily display lengthy path and filenames.
In many cases some filenames could be the same up to very ending making it difficult for reviewers

4. File System Display - Shortcomings

5. File System Display - Shortcomings

6. Or even - for those who prefer the icon view

7. A Better Way to Display

8. Study Report Challenges
The ICH CTD E3 granularity document includes 25 sections for data to be submitted for each study in the application
Individual headings for each section are not included in the eCTD DTD
The E3 granularity document includes ICH recognized Type of Control, Species, and Route of Administration categories
The globally acknowledged values are not included in the eCTD DTD
The ICH CTD recommends smaller granular files instead of single large files encompassing all aspects of the study report
Changes can be made to individual sections of the study
Reviewers only need to concentrate on the changed portion
Each section can result in the creation of one or more files containing pertinent information
Multiple Case Report Forms (CRFs) from multiple sites
Multiple Case Report Datasets from multiple sites

9. Interim Fix Several proposals between July 2002 and March 2003
Including in the eCTD DTD
Separate DTD with values included as elements/attributes
Separate DTD using the values as “tags” without validation
ICH agreement in July 2003 Brussels
Use separate DTD with values as “tags” with deferred validation by a stylesheet

10. Type of Study Report Tags
Overall Study Report Document Identifier and Category Tags
Study Report Title
Study Report ID
Species
Route of Administration
Types of Control
Granular Study Report File Property Tags
E3 granularity sections

11. Tags for Overall Study Report
Species for Study
mouse
rat
rabbit
other-rodent
dog
nonhuman-primate
other-nonrodent mammal
nonmammal
Routes of Administration
oral
intravenous
intramuscular
intraperitoneal
subcutaneous
inhalation
topical

12. Tags for Overall Study Report
Controls used during the study
placebo
no-treatment-control
dose-response-without-control
active-control-without-placebo
external-control

13. Granular Study Report File Tags
E3 Granularity Section Tags
synopsis
study-report-body
protocol-or-amendment
sample-case-report-form
iec-erb-consent-form-list
list-description-investigator-site
See others defined in the Guidance

14. Overall Study Report Category Tags
oral
intravenous
topical
Study Report
placebo
no-treatment-control
dose-response-without-control
Mouse
Rat
Rabbit
Synopsis file
Report Body file
Protocols file
Case Report Form files
Data Tabulation files

15. Granular Study Report File Tags
Mouse
dose-response-without-control
intravenous
Synopsis file
Report Body file
Protocols file
CRF 1 Site 1 CRF n Site n
Data File 1 Data File 2
Study Report
synopsis
study-report-body
protocol-or-amendment
case-report-forms
site n
data-tabulation-dataset
site 1
Study Report
Study Report

16. What is a Study Tagging File
Full Title of the Study Report
Document Id
intravenous
dose-response-without-control
Mouse
study-report-body
protocol-or-amendment
synopsis
data-tabulation-dataset
case-report-forms
site 1
case-report-forms
site n
data-tabulation-dataset

17. Study Report Files and Study Tagging FileB A C K O N E
Leaf
Synopsis.pdf
Leaf
Body of Report .pdf
Leaf
Protocol.pdf
Leaf
CRF.pdf
Leaf
CRF.pdf
Leaf
dataset.XPT
Leaf
dataset.XPT
Leaf
Stf-study-report.xml

18. Building a STF XML file

19. Workshop Sample 999999/ 0000/ m5/ 53-clin-study-report/
535-rep-effic-safety-study/
Claimed indication/
5351-study-report-contrib/
xxx /

20. Workshop Sample Files in Study Report Folder XXX394-90-04synopsis.pdf
../../../../../../index.xml#ID350438
XXX body-of-report.pdf
../../../../../../index.xml#ID350438a
XXX protocol.pdf
../../../../../../index.xml#ID350438b
CRF1site01.pdf
../../../../../../index.xml#ID820214
CRFnsiten.pdf
../../../../../../index.xml#ID387525
Dataset1.xpt
../../../../../../index.xml#ID246080
Dataset2.xpt
../../../../../../index.xml#ID382213

21. Build the STF File Start with the XML headers and Root Element
<?xml version="1.0" encoding="UTF-8"?>
<?xml-stylesheet type="text/xsl"
href="../../../util/style/ich-stf-stylesheet.xsl"?>
<!DOCTYPE ectd:study SYSTEM “../../../util/dtd/ich-stf.dtd">
<ectd:study xmlns:ectd=" xml:lang="en" dtd-version=“2.0" xmlns:xlink="
Note: ../../../ means to use the relative location of the STF file

22. Build the STF File -2 <document-identifier>
<title> A Parallel Group, Placebo-
Controlled, Modified Double-Blind, Dose-
Ranging Study with XXX 394 in Patients with
SLE S107</title>
<doc-id>S107</doc-id>
<category name=”type-of-control”
info-type=”ich-e3” >placebo</category>
</document-identifier>

23. Build the STF File - 3 Add the tags for the study report synopsis
<document>
<doc-content >
<property name="leaf-id" info-type=”fda”>
../../../../../../index.xml#ID350438
</property>
  <file-tag name="synopsis”
info-type=”ich-e3”/>
</doc-content>

24. Build the STF File - 4 Add the tags for the body of the study report
<doc-content >
<property name="leaf-id" info-type=”fda”>
../../../../../../index.xml#ID350438a
</property>
  <file-tag name="study-report-body“
info-type=”ich-e3”/>
</doc-content>

25. Build the STF File - 5 Add the tags for the CRF forms
<doc-content >
<property name="leaf-id" info-type=”fda”>
../../../../../../index.xml#ID820214
</property>
<property name=”site-identifier”
info-type=”fda”>1</property>
  <file-tag name="case-report-forms“
info-type=”ich-e3”/>
</doc-content>

26. Build the STF File - 5 Add the tags for the CRF forms
<doc-content >
<property name="leaf-id" info-type=”fda”>
../../../../../../index.xml#ID387525
</property>
<property name=”site-identifier”
info-type=”fda”>n</property>
  <file-tag name="case-report-forms“
info-type=”ich-e3”/>
</doc-content>

27. Build the STF File - 6
Add the tags for the analysis datasets and close the STF File
<doc-content >
<property name="leaf-id" info-type=”fda”>
../../../../../../index.xml#ID246080
</property>
<file-tag name="analysis-dataset“
info-type=”ich-e3”/>
</doc-content>
</document>
</ectd:study>

28. Displaying STF Files

29. Types of Study Reports 4.2.3.1 Single dose toxicity
grouped by species and route of administration
Repeat dose toxicity
grouped by species, route of administration, and duration
Long term [carcinogenicity] studies
grouped by species
Study reports and related information of controlled clinical studies pertinent to the claimed indication
grouped by type of control

30. First Attempts to Display The Study File Tags

31. Order of Display
The Comprehensive Table of Contents Headings and Hierarchy
Non-clinical Study Reports
Primary pharmacodynamics
Clinical Study Reports
Bioavailability (BA) Study reports

32. Concept Clinical Clinical Study Reports
Reports of Efficacy and Safety Studies
Study Reports of Controlled Clinical Studies Pertinent to Claimed
Indication
Controlled : type-of-control – placebo
doc-id xxx : title - A Parallel Group, Placebo-
Controlled, Modified Double-Blind, Dose-Ranging Study
with XXX 394 in Patients with SLE
Synopsis
synopsis – leaf-id ../../../../../../index.xml#ID350438
Note: the above is defined to mean group the study files under the heading “Controlled” based on the value “placebo” of the type-of-control tag. Show the value of the doc-id tag with the value of the title tag from the STF XML file. Create the heading “Synopsis” based on the synopsis tag. Display the title of the synopsis file as a hyper-link using the title and xlink:href values in the index.xml pointed to by the leaf-id tag value in the STF XML file.

33. Concept - 2
Study Report
study-report-body – leaf-id ../../../../../../index.xml#ID350438a
Protocol and amendments
protocol-or-amendment – leaf-id
../../../../../../index.xml#ID350438b
Documentation of Statistical Methods and Interim Analysis Plans
statistical-methods-interim-analysis-plan – leaf-id
../../../../../../index.xml#ID350438c
Demographic Data
demographic-data - leaf-id ../../../../../../index.xml#ID350438d
Adverse Event Listings
adverse-event-listings – leaf-id
../../../../../../index.xml#ID350438e

34. Concept - 3 Case Report Forms Site : site-identifier – 01
Note: Use the value provided in the STF file for “01”
Could be any meaningful value to your client such as
Hawaii, X-123, London Site 15, etc.
case-report-forms – leaf-id ../../../../../../index.xml#ID820214
case-report-forms – leaf-id ../../../../../../index.xml#ID177686
case-report-forms – leaf-id ../../../../../../index.xml#ID765021
Site : site-identifier – 02
case-report-forms – leaf-id ../../../../../../index.xml#ID387525
case-report-forms – leaf-id ../../../../../../index.xml#ID578438

35. Concept - 4 Data Tabulation Data tabulation datasets
data-tabulation – leaf-id ../../../../../../index.xml#ID246080
data-tabulation – leaf-id ../../../../../../index.xml#ID382213
data-tabulation – leaf-id ../../../../../../index.xml#ID547320
data-tabulation – leaf-id ../../../../../../index.xml#ID521586
data-tabulation – leaf-id ../../../../../../index.xml#ID49242
Data Definitions
tabulation-definition leaf-id ../../../../../../index.xml#ID861459

36. Concept - 5 Analysis Datasets
analysis – leaf-id <example for display>
Analysis Programs
analysis-program – leaf-id <example for display>
Data Definitions
analysis-definition – leaf-id <example for display>
Annotated CRF
annotated-CRF - leaf-id ../../../../../../index.xml#ID776509

37. Thank you for coming today!