Over the past decade, CDISC Standards have been widely accepted and implemented in clinical research.   The FDA’s final “Guidance for Industry on electronic submission” mandates that submission data conform to CDISC standards such as SDTM, ADaM and SEND. This presentation will discuss how life sciences organizations can use Standards metadata to manage the regulatory compliance process. It will introduce how standards metadata management not only ensures regulatory compliance, but also supports process efficiency in clinical trial artefacts (e.g., protocol, CDASH, SDMT and ADaM) development and standards governance, and enables efficient communication between organizational units. It will also introduce metadata management system and discuss how metadata management system will create, store, govern and manage standards. It will also show how standards metadata management system interacts with ETL system and dictates standards-driven clinical artefacts development.

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Standards Metadata Management (System)
Kevin Lee, MarkLogic

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Agenda
Regulatory Requirement on Clinical Trial Standards(i.e.,
CDISC and eCTD)
Standards driven clinical artefacts development process
Standards Metadata Management
Metadata Management System
Final Thoughts

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Standards?
What do we think first about Standards?

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Standards based electronic submission of
clinical trial data

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Current Status in eSubmission in CDER FDA
Current Status in eCTD Standards Submission in CDER FDA

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Current Status in CDISC Submission in CDER FDA
In 2010,
23% of
SDTM in
NDA
In 2011,
39% of
SDTM and
32% in
ADaM in
NDA
In 2013,
55% of
SDTM in
NDA

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Section 745A(a) of the Federal Food, Drug, and Cosmetic
Act (FD&C Act)
• Enhanced by Food and Drug Administration Safety
and Innovation Act (FDASIA) on July 9, 2012.
• Requires that submissions be submitted in
electronic format.

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New FDA Guidance on CDISC eSubmission
Guidance for Industry:
Providing Regulatory Submissions in
Electronic Format – Standardized Study Data
Guidance for Industry:
Providing Regulatory Submissions in Electronic
Format – Submissions Under Section 745A (a) of
the Federal Food Drug, and Cosmetic Act
Binding rather than
recommendation

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New FDA Guidance on CDISC eSubmission - continued
Can FDA “Refuse to File / Receive” if submission data does
not follow eStudy Guidance?
YES

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What else for Standards?
• Anything else beside submission?
• What else can we do with standards?

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How does your organization want to use CDISC Standards
in the future?
• Regulatory compliance
• Reuse of Standards
• Operation Efficiency
• Faster time to submission
• Data interoperabiltiy with other Standards (e.g., HL7)
• Data compliance of external vendor
• Standards-based or driven clinical trial artefacts development

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Standards
based
submission
Standards
driven
process

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Henry Ford Assembly Line
The Model T was Ford's first automobile mass produced on moving
assembly lines with completely interchangeable STANDARDized parts.
(Dec 1st, 1913)

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Model T production and price over year
$0
$100
$200
$300
$400
$500
$600
$700
$800
$900
$1,000
0
500,000
1,000,000
1,500,000
2,000,000
2,500,000
Production
Price for
1910: $900 and 20,000 vs
1925: $260 and 2,000,000

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Can we accomplish similar production increases and cost
reduction in clinical artefacts development like Henry Ford did?

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Henry Ford Assembly line vs
Clinical artefacts development process
Henry Ford
Car
production
Model T
Interchangeable
Standardized
parts
Automated
Assembly line
Clinical
artefacts
development
SDTM datasets
SDTM &
CDASH(EDC),
CT standards
Automated ETL
system

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Standards driven clinical artefacts development
ETL system
Standards SDTM ADaM
Clinical
Artefacts
SDTM datasets ADaM datasets

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Questions
What are required for standards-driven clinical artefacts development?

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Requirements for standards-driven automated clinical
artefacts development
Standards
Metadata
Management
System
ETL
Systems

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Possibility with Standards Metadata Management(MdM)
and ETL system
Standards
Metadata
Management
System
ETL System 1 Clinical Artefacts 1
(Protocol)
ETL System 2 Clinical Artefacts 2
(CDASH/EDC)
ETL System 3 Clinical Artefacts 3
(SDTM)
ETL System 4 Clinical Artefacts 4
(ADaM)
ETL System 5 Clinical Artefacts 5
(TFL)

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Standards Metadata Management
• Definition
• Managing Standards Metadata (data about data)
• Definition of metadata
• Data about data/document
• Title: Star Wars: Episode VII - The Force
Awakens
• Release Date: Dec 18th, 2015
• Director: J.J. Abrams
• Cast: Harrison Ford, Mark Hamill, Carrie
Fisher
• Genres: Action, Adventure, Fantasy, Sci-Fi
Metadata

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Standards Metadata Management - continued
• Metadata of clinical trial data
• Dataset: DM
• Description: Demographics
• Class: Special Purpose Domains
• Structure: One record per subject
• Keys: STUDYID, USUBJID
• Versions: SDTMIG 3.2

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• Types of Standards metadata
• Protocol (e.g.,PRM)
• CDASH
• SEND
• SDTM
• ADaM
• Define.xml
• Dataset.xml
• Any company specific Standards
Standards Metadata Management - continued

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Architetcure of Standards Metadata Management System
ETL System 1 Clinical Artefacts 1
(Protocol)
ETL System 2 Clinical Artefacts 2
(CDASH/EDC)
ETL System 3 Clinical Artefacts 3
(SDTM)
ETL System 4 Clinical Artefacts 4
(ADaM)
ETL System 5 Clinical Artefacts 5
(TFL)
Standards 1
(Protocol)
Standards 2
(CDASH/EDC)
Standards 3
(SDTM)
Standards 4
(ADaM)
Standards 5
(TFL)
Standards
Metadata
Management
System

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Examples of Standards Metadata Management
• Creating new standards (e.g., variables and domains)
• Storage of Standards
• Modifying the attributes (e.g., label, type) of current standards
• Adding the new attributes to current standards
• Archiving the standards
• Assigning versions (e.g., major or minor) to standards after changes
• Maintaining multiple versions of standards (e.g., SDTMIG 3.1.2, 3.1.3)
• And many more
• Standards metadata driven process

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What does it mean by Standards metadata driven process?
• Standards metadata first
or Standards data first?
• Create metadata first or
data first?

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Why Standards metadata first?
• Easier to regulatory compliance
• Provide requirements / directions to programmers or developers
• Don’t need to create metadata(Define.xml) again
• Possible standards metadata driven process -> automated process
using ETL and MdM
• Standards driven clinical trial artefact development process
• How can we do it?
• By Metadata System

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Evolution of metadata system
Spreadsheet
or document
Database
Metadata
Management
System

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Metadata Management (MdM) System
• Definition
• Database created to store metadata
• Function
• Storages of Standards metadata in global library
• Manage Standards metadata
• Govern Standards metadata
• Create study level metadata from global library
• Receive metadata from other systems (e.g., CDISC SHARE)
• Feed metadata to other system(e.g., EDC and ETL system)

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Standards Metadata in MdM system
• Structural metadata of target data
Dataset Variable Name Variable Label Type CT Role
DM USUBJID Unique Subject Identifier Char Identifier
DM Age Age Num Identifier
• Structural metadata of source data
Dataset Variable Name Variable Label Type CT
DEMO USID Unique Subject Identifier Char

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Standards Metadata in MdM system - continued
Target
dataset
Target
variable
Machine readable derivation Source
dataset
Source
variable
DM USUBJID = DEMO USID
DM AGE %AGE(RFSTDTC – BRTHDTC)
• System readable transformation metadata from source to target data
data dm;
set demo;
usubjid = usid;
age = %age(rfstdtc – brthdtc);
…
run;

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Data flow of Standards Metadata in MdM system to
ETL and clinical artefacts
ETL
System
Source Data
Structural
metadata for
source
Structural
metadata
for target
Machine-readable
Transformation metadata
from source to target
Target Data
Standards Metadata Management System

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Semantics-driven Standards Metadata development
USID
DEMO
hasVariable
USUBJID
DM
hasVariable
AGE
hasVariable
=
Derivation
%age(rdfdtc-brthdtc)
Derivation
require
Rather than row and column structured metadata, developing with
semantic based RDF/graph-based smetadata -> PhUSE

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MdM
Protocol
Global Library
CDASH
TFL
ADaM
SDTM
Protocol
Study level (e.g., 001)
CDASH
TFL
ADaM
SDTM
Study level metadata definition development in MdM

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MdM
Protocol
Global Library
CDASH
TFL
ADaM
SDTM
Protocol
Study level (e.g., 001)
CDASH
TFL
ADaM
SDTM
Semantics-driven Study level metadata definition development
in MdM

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Semantics-driven Study level metadata definition development
in MdM : Oncology
Protocol
Cheson
2007
CDASH/
EDC
Tumor
Measurement
SDTM
TR
TFL
Progression
Free Survival
Time to Event
TFL
ADaM
ADTTEPFS
Bone Marrow
Assessment
Spleen and
Liver
Enlargement
FA
TU
LB
Response
PE
RS
• Integration from Protocol to
Analysis through semantic-linked
Standards
• End to End Standardization
• System using semantics-driven
Standards metadata could
automate oncology-specific
artifacts developments

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Why is Study Level metadata definition in MdM important?
MdM
Protocol
Study 001
CDASH
TFL
ADaM
SDTM
Protocol
EDC database
eCRF
SDTM datasets
ADaM datasets
TFL
ETL
It can dictate study
level artefacts
development.
Study 001

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Final Thought
Management
Standards
Metadata
Standards
Regulatory
Clinical Data
Submission
Standards Metadata-
driven Clinical
Artefacts Development

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Contacts and Questions Kevin Lee
Email: kevin.lee@MarkLogic.com
LinkedIn:
www.linkedin.com/in/HelloKevinLee
Slides: www.slideshare.net/KevinLee56
Tweet: @HelloKevinLee
Blogs: HiKevinLee.tumblr.com