A Practical Implementation of ADaM - CDISCportal.cdisc.org/CDISC User Networks/Europe/English...
Transcript of A Practical Implementation of ADaM - CDISCportal.cdisc.org/CDISC User Networks/Europe/English...
11GLOBAL BIOMETRICS
BiostatisticsClinical Data Management
Epidemiology & Patient Reported OutcomesStatistical Programming and Analysis
Strategic Planning, Operations and Collaborations
A Practical Implementation of ADaM
Chris Price, Roche Products Ltd.
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Agenda
Project BackgroundADSLTraceabilityAnalysis FlagsMultiple BaselinesSafety Data and Legacy SystemsConclusions
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Project Background
Pharma / Biotech Collaboration: Roche and Genentech (pre-merger)New Rheumatoid Arthritis moleculeFour Phase III clinical studies getting startedDifferent proprietary data standards at each companyNeither company had production/filing SDTM or ADaM experienceDecision to use SDTM and ADaM taken November 2007
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Project Background - Timelines
SDTM - modelled and programmed during 2008Draft ADaM v2.1 and ADaM IG v1.0 released May 2008ADaM specifications written Q4 2008 using SDTM as the sourceADaM datasets programmed - Q1 2009Tables, Figures and Listing programmed using ADaM -Q2 2009First Study Database Lock - December 2009Final study Database Lock - May 2010Final ADaM v2.1 and ADaM IG v1.0 published December 2009
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Project Background - Key Decisions
Used draft versions ADaM v2.1 and ADaM Implementation Guide v1.0
No update to final version for subsequent studiesADaM Basic Data Structure (BDS) only implemented for efficacy data Safety data not mapped to BDS
BDS is unsuitable for occurrence/event based dataProprietary standards already in existence for reportingDecision taken to combine core and suppqual domains and add any required flagsThese were mapped to internal standards for use with the standard internal tools
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Project Background - Analysis Requirements
ACR 20/50/70/90Composite endpoint
66/68 Swollen and Tender Joint CountsHealth Assessment Questionnaire (HAQ)ESR/CRPVisual Analogue Scores (VAS)
Disease Activity Score (DAS-28)Composite Endpoint
28 Swollen and Tender Joint CountsESR/CRPVisual Analogue Scores (VAS)
Response Duration
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Project Background - Analysis Requirements
Hands and Feet X-Ray EndpointsComposite Endpoints
Erosion ScoresJoint Space Narrowing Scores
Multiple Sensitivity AnalysesDifferent missing data imputations for different parametersDifferent approach to withdrawals and use of rescue medications for different parameters
Multiple Subgroup Analyses
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Project Background - Data Flow
SDTM core and suppqual domains
combined, ISO8601 date/times
converted to numeric variables and programmable PVs written before
ADaM programming
ADaM datasets set up as a series of
dependent datasets split by endpoint
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
ADSL
Minimum requirement for a ADaM submissionContains all variables important for describing the target population
DemographicsDisease factorsTreatment GroupsOther Relevant Variables
What other relevant variables should be included in this project/study?
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
ADSL
Variables included:Demographics and DispositionTreatments and PopulationsStatistical Model covariates (e.g. IVRS stratification factors)Key study dates (e.g. Date of First Rescue Medication)
Variables excluded:Baseline measurements used in subgroups
Some complex derivation performed in later analysis datasetsUse of macros was not felt to be appropriate in this instanceMapped to ADBASE to ensure consistency between datasetsADBASE modelled using BDS
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
ADSL
ADSL
ADBASE
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Traceability
Traceability is a “cornerstone” of the ADaM modelRepresented in
Metadata between variables and their sources between analysis results and the analysis datasets
Data pointsBetween analysis observations and their predecessor observations
How practical is data point traceability in real-life?Easy to use --SEQ in simple casesHow to show traceability for second layer parameters?
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Traceability
First layer datasetsIndividual observations used in the derivation of a new parameter included in dataset and traced using --SEQ
E.g. Individual Joint Results included in ADJNT for use in calculating total joint counts
Missing data rules implemented using derivation type to flag LOCF observations
E.g. DTYPE used to flag LOCF observations at the individual joint level
Analysis flags to used to flag different types of calculating total scores for use in both analysis and other derivationsFunctional specifications written to be included in define.xmldescribing the derivation
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Traceability
ADJNT
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Traceability
Second/Third layer datasetsImmediate predecessor observations included
E.g. Total 66/68 joint counts included from ADJNT in ADACR to derive ACR score
Functional specifications used to facilitate traceability for composite endpoints based on derived parameters
Analysis flags used to identify selected observations based on imputation and rescue rulesNew analysis flags derived for the composite endpoints based on the imputation rules used in the individual parametersParameter Invariance rule interpreted in a way to support clarity
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Traceability
ADACR
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Analysis Flags
Analysis flags are conditionally required to identify observations used in one or more analyses
Can be sole identifierOr more usefully in conjunction with other variables
Generic naming convention can cause problems with consistency between studiesCan in some cases form part of the primary key
Missing values are expected as controlled terminology is Y/nullDoes this matter? - Is a primary key necessary in an analysis dataset?Additional sponsor defined variables were added to avoid this issue
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Analysis Flags
An observation was created for each analysis flag required
Not necessary as per IG rulesIncreases the size of the datasetSimpler to specify and programSimpler visual review of data and developer checking of programmingClearer metadataAllows for an additional variable so a valid primary key is created
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Analysis Flags
Potential pooling issues minimized by using project levels specificationsFlags were set up so have the same meaning across all datasets and the submission
23 different analysis flags needed across all ADaM datasetsANL01FL = LOCF excluding rescue and withdrawal…ANL18FL = Linear Extrapolation…
Cross tabulations included in specifications to show which Analysis flags were created for which parameters
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Analysis Flags
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Multiple Baselines
Rule 6 from IG“When there is more than one definition of baseline, each additional definition of baseline requires the creation of its own set of rows”BASETYPE is used to identify the baseline definition
Logical approach from a standard design perspectiveMakes building standard reporting tools easierCan massively increase the size of datasets if required for lots of parameters compared to adding new variables
But… If only one parameter required in a large dataset - less data points are added
Adds to the complexity of the dataset
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Multiple Baselines
For some Pharmacodynamic Parameters Change from Screening was analysed as well as Change from Baseline
Data was duplicatedObservations for Change from BaselineObservations for Change from ScreeningFor matching parameters and visits AVAL did not change
BASETYPE was additionally required to identify observations for analysis
Analysis flags were used to differentiate between observations within each type of baseline
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Multiple Baselines
ADACR
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Safety Data and Legacy Systems
BDS is unsuitable for Occurrence based dataE.g. Adverse Events, Concomitant Medications
ADAE is expected to be released by the ADaM teamExisting internal standard safety reporting tools did not support ADaM structure (or SDTM)Collection and tabulation models are currently being updated internallyConsequently tools are also being updated to work with SDTM and ADaM
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Safety Data and Legacy Systems
Flags were added to SDTM datasets where necessary to create Safety Analysis Datasets (SADs)An interim step of converting SDTM to the internal standard was performedStandard Safety Reporting
Programmed using standard toolsNon-standard safety reporting
Additional ADaM datasets created from SADsE.g. Patient Years Exposure
Analyses programmed from SADs
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GLOBAL BIOMETRICS Biostatistics
Clinical Data ManagementEpidemiology & Patient Reported Outcomes
Statistical Programming and Analysis Strategic Planning, Operations and Collaborations
Conclusions
Implementation of ADaM is challenging but possibleBut is legacy mapping any easier?
ADaM is currently an immature standardADaM datasets can become increasingly complex very quicklyThere are currently too many grey areas
Current documentation is insufficient for full scale implementationHopefully the implementation examples of ADAE and ADTTE will help when released
A sponsor introducing a wide scale implementation would be taking a big risk