# Presentation: 912344

## Study Tagging File Workshop

- February 26, 2004
- US Food and Drug Administration
- Rockville, MD

## 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 15000 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

## 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

## File System Display - Shortcomings

**File System Display - Shortcomings**

## File System Display - Shortcomings

**File System Display - Shortcomings**

## Or even - for those who prefer the icon view

**Or even - for those who prefer the icon view**

## A Better Way to Display 

**A Better Way to Display**

## 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

## 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

## 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

## 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

## Tags for Overall Study Report

- Controls used during the study
- placebo
- no-treatment-control
- dose-response-without-control
- active-control-without-placebo
- external-control

## 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

## Overall  Study Report Category Tags

- Study Report

**Synopsis file**
**Report Body file**
**Protocols file**
**Case Report Form files**
**Data Tabulation files**

## Granular Study Report File Tags

- Study Report

**Study Report**

## What is a Study Tagging File

**Mouse**

- Full Title of the Study Report

- synopsis

- study-report-body

- protocol-or-amendment

- case-report-forms
- site n

- data-tabulation-dataset

- data-tabulation-dataset

- case-report-forms
- site 1

- Document Id

## Study Report Files and Study Tagging File 

**Leaf **
**Body of Report .pdf**

**Leaf**
**Stf-study-report.xml**

**B**
**A**
**C**
**K**
**B**
**O**
**N**
**E**

**Leaf **
**dataset.XPT**

**Leaf **
**CRF.pdf**

**Leaf **
**Synopsis.pdf**

**Leaf **
**CRF.pdf**

**Leaf **
**Protocol.pdf**

**Leaf **
**dataset.XPT**

## Building a STF XML file

## Workshop Sample

- 999999/
-   0000/
-     m5/
-       53-clin-study-report/
-          535-rep-effic-safety-study/
-             Claimed indication/
- 			5351-study-report-contrib/
-                     xxx394-90-04/

## Workshop Sample

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

## 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="http://www.ich.org/ectd" xml:lang="en" dtd-version=“2.0" xmlns:xlink="http://www.w3c.org/1999/xlink">
- Note: ../../../ means to use the relative location of the STF file

## 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>

## 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>

## 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>

## 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>

## 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>

## 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>

## Displaying STF Files

## Types of Study Reports

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

## First Attempts to Display The Study File Tags 

**First Attempts to Display The Study File Tags**

## Order of Display

- The Comprehensive Table of Contents Headings and Hierarchy
- Non-clinical Study Reports
- 4.2.1.1 Primary pharmacodynamics
- Clinical Study Reports
- 5.3.1.1 Bioavailability (BA) Study reports
- http://www.fda.gov/cder/regulatory/ersr/ectd.htm

## 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** xxx394-90-04 : **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****.  **

## 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

## 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

## 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

## Concept - 5

-      Analysis Datasets
-         Analysis Datasets
-             **analysis – leaf-id**    <example for display>
- 	       **analysis – leaf-id**    <example for display>
-         Analysis Programs
-             **analysis-program – leaf-id**  <example for display>
-             **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

## Thank you for coming today!