FDA/DCDISC
Workshop
25-Apr-2014
Welcome
› Introductions
› Housekeeping Rules
› Thanks
– Colleen Ratliffe
› What is DCDISC?
Agenda
› 9:00-9:15 – Gathering & Welcome
› 9:15-9:30 - FDA/CDER State of Data Standards
– Mary Ann Slack, Ron Fitzmartin - CDER
› 9:30-9:45 - FDA/CBER State of Data Standards
– Lise Stevens, CBER
› 9:45-10:45 –Challenges with Incoming Data
– Doug Warfield, Lisa Lin – CDER, eData Team
› 10:45-11:00 – Break
› 11:00-11:40 – “The Importance of CDASH – A Statistical
Reviewer’s Perspective”
– Ben Vali, CDER
› 11:40-12:15 –Challenges with Submission Data
– DCDISC Team
› 12:15-1:00 – Lunch/Networking
Challenges with
Submission Data
Ingeborg Holt
Jane Diefenbach
Alan Meier
Technology Provider Perspective
Ingeborg Holt
Booz Allen Hamilton
Technology Provider’s Task: Apply
Knowledge in Order to Solve a Problem
› The ideal conditions for this are:
1. The problem is clearly defined
2. The input sources are known and have stable
formats
3. The desired functionality and output are
distinctly described
• Problem: High incidence of
spilt milk
• Input: Milk
• Functionality: (1) Allow
drinking of milk from the
cup (2) Minimize spilling
when the cup isn’t
oriented properly
Technology Provider’s Task and
Submission Data
1. The problem: Can it be determined from the
submission data if the drug under review is
safe and effective?
2. The input: Submission Data
3. The functionality: The analyses that need to
be performed to determine the quality and
completeness of the data and the safety and
efficacy of the drug.
The Role of Data Standards is to
Regulate the Input
› Data standards (CDISC SDTM and ADaM)
– Organize submission data in a systematic way
– Control terminology
– Reduce the work needed to locate and understand
the data and create functionality
– Increase the potential to reuse functionality
The Problem Definition has Changed
› Success using data standards has expanded
the scope of the problem to be solved
s
c
o
p
e
Is this drug
safe and
effective?
How can
the question “Is
this drug safe
and effective”
be answered in
the more
efficiently and
effectively?
How can
data collected for
answering the
question “Is this drug
safe and effective”
be reused to inform
drug safety and
public health in
other ways?
time
How can
submission data be
better modeled for its
intended use, effective
reuse in drug safety
and public health AND
assist drug
development the precompetitive space?
Challenges to Standardized
Submission Data
› Data standards change and grow as the problem changes
and grows
– Adherence to principles of the standard
– Early communication
› Correct implementation of the standard
– Requires
› Sponsors understand which standards are accepted
› Data validation requirements are unambiguous
– Single Set of Validation Rules
› OpenCDISC rules, FDA rules, rules from other organizations
› Rules based on IG versus common sense rules
– Checks between standards (SDTM, ADaM)
› The implementation guides are as specific as possible and cover
expected scenarios
– Pharma SUG 2012 paper (Octagon)
› EX domain often implemented incorrectly
› Time and practice: implementation is improving
Well Defined Functionality and
Output
› Analyses for safety are well defined
– Therapeutic area domains may require special
analyses for safety
› Efficacy analyses, particularly those using
therapeutic area domains, may be complex and
present new challenges
› Guidance needed for derived variables
– How much support should be provided for missing
values that can be derived (eg imputing BLFL, STDY)
– Should derived SDTM variables be validated?
Technology Provider Perspective on
Submission Data
• Adherence of submission to data standards is
improving
• Many of the new challenges result from an
expanded problem space
• There are areas that need attention and work
Technology Provider’s Responsibility
› Good Technology Choices
– Designing tools to handle expected change
› Terminology changes, variable additions/deletions, validation
rule additions/changes
› Anticipating therapeutic area domains, interoperability
needs
– What is the role of the Pre-competitive Community
(FDA, CDISC and other Standard Development Organizations,
Third Party Data Providers, Technology Providers, Sponsors,…)
› Should information technology and data standards usage
decisions involve all stakeholders and open discussion about
risk/benefit issues
– Metadata Repository
– Changes to Standards
Adventures in CDISC Consulting and
eCTD Preparation
Jane Diefenbach, PharmaStat LLC
DCDISC Implementation Network at FDA
April 25, 2014
Preparing for a data submission
• 18 to 24-month lead time
• Legacy studies and Phase III may just be
starting
• Everything is changing: people, processes,
knowledge of the product, often even the
company structure
• When standards change too it can be hard to
accommodate them in this environment
Google Images for eCTD Preparation
What needs to happen
• Planning
– What studies? What data formats? What standards?
• Production – legacy studies
– Align the studies with a unified modeling plan
– Perform the conversions, verify with reanalysis
• Production – current studies
– Real time conversion and linear data flow is difficult
• Documentation, maybe most important
Planning the Submission: Company XYZ Data Flow
Studies:
101, 102,
103
10
4
CDMS
Analysis
CDMS
Item 11
SDTM
201, 202
CDMS
Analysis
SDTM
ADaM
CSR
CSR
CSR
eCTD
eCTD
20
3
301
CDMS
CDMS
SDTM
SDTM
ADaM
ADaM
CSR
CSR
eCTD
eCTD
eCTD
Integrated
Data for ISS
SDTM
ADaM
Credit John Brega 2014
eCTD
ISE
ADaM
eCTD
Experience to Date
• Work volume is astronomical, easy to
underestimate
• Clarity of purpose is sometimes absent
– Standards are overwhelming; sponsors don’t know
what is most important
– We imagine perfection at kick off; eventually just
need to get done
– Downstream changes to standards, modeling are
costly; sometimes we need to say Next time
What makes it easier?
• Use of CDASH in data collection
• Predictability of new standards, fair warning
• OpenCDISC – has done more to standardize
implementation than anything
• Electronic distribution of linked standards
(SHARe) and a data standards warehouse
• Widespread adoption
What makes it easier?
• Communication!
– The more we know about how you interact with
the data the better we’ll do
– Guesswork leads to busy work and busy work
does not advance Science or Health
Google Images for CDISC Consulting
Sponsor Company
Alan Meier
MedImmune LLC
Sponsor Company
› Implementation/Acceptance of Standards by
Agency
– Set time period for accepting submissions in new
version
› Allows sponsor time to decide when to upgrade
– Work with CDISC to implement changes rather
than publishing guidance
› Saves time searching through documents
– Set policy on use of provisional / sponsor-defined
domains
› Are sponsor-defined non-X_, Y_, Z_ domains acceptable
› Will provisional domain templates be accepted
Sponsor Company
› ADaM vs Sponsor-Formatted Analysis Data
Sets
– Will agency be requiring ADaM
› Versioning of CDISC Standards
– Some products take 10+ years to develop
– Acceptance of submission data in multiple versions
DCDISC
› Can we get an FDA representative on the
Steering Committee