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

Or even - for those who prefer the icon view

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 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

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

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

Study Report Files and Study Tagging File B 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

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

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 – 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

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