The Importance of CDASH
Benjamin Vali, M.S.
Mathematical Statistician
Division of Biometrics III
CDER/OTS/OB
U.S. Food and Drug Administration
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FDA Disclaimer
This presentation reflects the views
of the authors and should not be
construed to represent FDA’s views
or policies.
Outline
• What do we do?
– NDA/BLA Statistical Review of Efficacy
• What do we need?
– All Regulatory Reviewers at FDA/CDER
• What do we get?
– Current Approaches
• CDASH
– Focusing on The Best
What do we do?
Statistical Review of Efficacy for NDA/BLA
Regulation Citation
21 CFR 314.126
....Reports of adequate and well-controlled
investigations provide the primary basis
for determining whether there is
"substantial evidence" to support the
claims of effectiveness for new drugs.
What do we do?
Statistical Review of Efficacy for NDA/BLA
• These “adequate and well-controlled
investigations” pertain to the
“Pivotal/Confirmatory” trials (i.e. Phase 3
trials) in a clinical development program
• Consequently all aspects of these protocols
and corresponding Statistical Analysis Plans
(SAPs) need to be pre-specified
– including how the clinical data are captured
What do we do?
Statistical Review of Efficacy for NDA/BLA
• Key Analysis Questions to ask during
Marketing Application Review:
– Are the key results correct?
• Programmatically validate all major results during
the filing review - IMPORTANT!
What do we do?
Statistical Review of Efficacy for NDA/BLA
• Programmatically validate all major results during the
filing review
• Reviewer needs
–
–
–
–
–
Protocol
SAP
Clinical Study Report (CSR)
Annotated case report form (aCRF)
Tabulation/clinical datasets with corresponding
metadata/data definition file (SDTM, define.xml)
– Analysis datasets with corresponding metadata/data
definition file (ADaM, define.xml)
– Reviewers’ guide (e.g., SDRG & ADRG)
What do we do?
Statistical Review of Efficacy for NDA/BLA
• Programmatically validate all major results
during the filing review
– Two-step process
• Independent quality validation of Analysis Dataset
Variables
– Primary and Key Secondary Endpoints
– Additional key subject-level analysis variables (e.g.
analysis set flags)
• Independent quality validation of Analysis Results
– Inferential and/or Descriptive
What do we do?
Statistical Review of Efficacy for NDA/BLA
• Key Analysis Questions to ask during
Marketing Application Review:
– Are the results consistent?
•
•
•
•
Similar findings from each clinical study
Not sensitive to different approaches to analysis
Similar across study subgroups
Supported by results from secondary endpoints (which are
generally related to primary endpoints)
• Conduct further analyses with support and insight from
Medical Officer
What do we need?
All Regulatory Reviewers at FDA/CDER
• Metadata
• Traceability
• Data Standards
Why Push for Traceability?
• Full transparency for each data point
throughout (end-to-end) clinical data
lifecycle (from the source “to my
computer”)
• Need to make sure that the data were
captured and analyzed in a way that is
consistent with what was pre-specified in
the protocol and SAP!
The Clinical Data Lifecycle
Source Documents
 Case Report Form (CRF)
 Clinical Database
 Analysis Database
 Tables, Listings, and Figures (TLFs)
 Clinical Study Report (CSR)
 Product Labeling
 Promotional Materials
Why Push for Data Standards?
Overall Improved Efficiency Analyzing Data
• Consistent data structure
• Consistent nomenclature
• Analysis-ready
• Standardize not only the data
– Metadata
– Representation of the relationship between data
elements
– Communication
• SDRG and ADRG
Traceability vs. Data Standards
• MY Regulatory Reviewer Perspective
– Traceability is key
– Traceability may be even more important
than Data Standards (To Me)
And I know it is important to you…
• Inherent in this principle is a need for
traceability to allow an understanding of
where an analysis value (whether an
analysis result or an analysis variable)
came from, i.e., the data’s lineage or
relationship between an analysis value
and its predecessor(s).
CDISC ADaM v2.1….
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Traceability vs. Data Standards
• What we often see submitted by
Applicants
– In the creation of standard data for
submissions, traceability is (at times),
compromised by post-data-capture mapping
Current Approaches
Approach #1
(Historical/Legacy)
… Legacy CRF  Clinical Database  Analysis Database  TLFs …
Approach #2
(Starting Out …)
SDTM
… Legacy CRF  Clinical Database  Analysis Database  TLFs …
Approach #3
(Getting Better …)
SDTM
ADaM
… Legacy CRF  Clinical Database  Analysis Database  TLFs …
Approach #4
(Better and Better …)
SDTM  ADaM
… Legacy CRF  Clinical Database  Analysis Database  TLFs …
Approach #5
(Getting There …)
… Legacy CRF  Clinical Database  SDTM  ADaM  TLFs …
Approach #6
(The Best)
… CDASH CRF  SDTM  ADaM  TLFs …
CDASH
• CDASH - Clinical Data Acquisition
Standards Harmonization
• Best facilitates mapping to SDTM and
creation of high quality CRF pages
• Closest to 1-to-1 mapping in terms of
structure, content and format
– Pages for 16 out of 25 major SDTM domains
are covered
– Best Practices for creating other domain
pages
CDASH
• Gets it right the first time
– Done at data capture stage!
– Eliminates the need for more downstream work
• Streamlines everything on the Production and
Regulatory Review sides
• Standards development instituted as early as
possible within the clinical data lifecycle
– CDASH is the best example of how effective this
can be
CDASH
• The original premise, per DIA Meeting in
January 2006, was for efficiency
• Motivated by ACRO and FDA – Critical
Path
• Current Version 1.1 – January 18, 2011
– We’ve come a long way since previous
versions/previous era
• Version 2.0 release imminent
• Will begin development of therapeutic
area specific CRFs
As We Move Forward…
• Don’t map for the sake of mapping (i.e.,
from legacy datasets to SDTM and ADaM)
– Approaches #2, #3 and #4
– Unnecessary cost (time and money) to
applicants
• Includes time and money wasted for responding
to subsequent Information Requests during the
review cycle!
• Strive for Approach #6 – no mapping
required!
As We Move Forward…
• The principle behind this approach is key
– More so than the CDASH standard itself
• Implementation is everything!
– More so than the content standards in
general themselves
– Must adhere to CDISC foundational
principles
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As We Move Forward…
• Right now we are living during a
“transitional” period (i.e., from legacy to
standardized data), hence you need to do
what you need to do
– Don’t pull the e-brake while going at 150 mph
• This doesn’t have to happen today
– Just eventually…
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Thank you for your
attention!