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Validation of ADaM datasets based on CDISC ADaMIG 1.1
Pinnacle 21 Community ConformanceFindings and Explanations
Jeroen Den Herder
SGS LIFE SCIENCESWednesday 26th of April 2017
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DISCLAIMER
All content included in this presentation regarding clinical data standards and compliance validation serves only as an example of the interpretation by SGS Life Sciences of the officially released documentation and how they are used.
Neither CDISC nor Pinnacle 21 were involved or have endorsed the presented items, which should not be considered official recommendations by any of these parties. The provided ‘explanations’ were introduced by the standards functional group of SGS Life Sciences and have not been approved by the FDA.
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Validation of ADaM datasets based on CDISC ADaMIG 1.1
Introduction
Purpose / Aim
Conformance Findings and Explanations
Solutions?
Summary / Conclusion
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Validation of ADaM datasets based on CDISC ADaMIG 1.1
Introduction
Purpose / Aim
Conformance Findings and Explanations
Solutions?
Summary / Conclusion
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Introduction
Clinical Data Submission to FDA• Requirement to submit data electronically and in
conformance with CDISC standards (Ref. 1)
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CDISC Documents Release DateAnalysis Data Model (ADaM), version 2.1 2009, Dec. 17ADaM Implementation Guide (ADaMIG), version 1.0 2009, Dec. 17ADaM Basic Data Structure for Time-to-Event Analyses, version 1.0 2012, May 8ADaM Data Structure for Adverse Event Analysis, version 1.0 2012, May 10ADaM Implementation Guide, version 1.1 (Ref. 2) 2016, Feb. 12ADaM Structure for Occurrence Data (OCCDS), version 1.0 (Ref. 3) 2016, Feb. 12
CDISC Documents Release DateAnalysis Data Model (ADaM), version 2.1 2009, Dec. 17ADaM Implementation Guide (ADaMIG), version 1.0 2009, Dec. 17ADaM Basic Data Structure for Time-to-Event Analyses, version 1.0 2012, May 8ADaM Data Structure for Adverse Event Analysis, version 1.0 2012, May 10
CDISC ADaM standard
SDTM as source
Analysis datasets contain the data needed for the review and re-creation of specific statistical analyses
ADaM: Documentation
Introduction
CDISC Documents Release DateAnalysis Data Model (ADaM), version 2.1 2009, Dec. 17ADaM Implementation Guide (ADaMIG), version 1.0 2009, Dec. 17
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Validation of Standards Compliance
In-house developed validation tools
Pinnacle 21 Community (Ref. 4)
• Previously called OpenCDISC• Open-source software including Validator• Latest version: 2.2.0• Standards: SDTM / SEND / ADaM / Define.xml• Controlled Terminology
Introduction
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Introduction
Validation of ADaM datasets using Pinnacle 21 Community
• Configuration file (ADaM 1.0.xml)– Rules as defined in CDISC ADaM Validation Checks v1.3 (Ref. 5)
→ ADSL, BDS, TTE, ADAE– Based on ADaMIG 1.0– Rules added by Pinnacle 21
(based on ADaMIG 1.0 but not defined in Validation Checks )– No FDA-specific rules (<> SDTM)
• See Validation Rules browser:https://www.pinnacle21.com/validation-rules/adam
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Validation of ADaM datasets based on CDISC ADaMIG 1.1
Introduction
Purpose / Aim
Conformance Findings and Explanations
Solutions?
Summary / Conclusion
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Purpose / Aim
ADaM datasets based on CDISC ADaMIG 1.1
Compliance validation using Pinnacle 21 Community 2.2.0 with ADaM 1.0.xml configuration file
Provide context of typically detected and explainable issues
Why do these issues occur and how to explain them in analysis data reviewers guide (ADRG)
Example on how to avoid these items during programming
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Validation of ADaM datasets based on CDISC ADaMIG 1.1
Introduction
Purpose / Aim
Conformance Findings and Explanations• 1) Category: Metadata/Format• 2) Category: Presence• 3) Category: Terminology• 4) Category: Consistency
Solutions?
Summary / Conclusion
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1) Category: Metadata/Format
Change of variable label (BDS)
• Label of ANLzzFL updated from ‘Analysis Record Flag zz’ in ADaMIG 1.0 to ‘Analysis Flag zz’ in ADaMIG 1.1
• P21 Validator expects variable label from IG 1.0• Similar issue for other variables
Issue SummarySource Pinnacle 21 ID Publisher ID Message SeverityBDS AD0018 18 Variable label mismatch between dataset and ADaM standard Error
Variables Values Pinnacle 21 IDVARIABLE, LABEL ANL01FL, Analysis Flag 01 AD0018
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See also P21 Forum topic: https://www.pinnacle21.net/forum/adam-labels-placeholders-inclusion-adsl-trtxxpn-and-trtxxan-bds-210
Change of variable label (BDS)
• ADSL treatment variables copied to BDS• Not explicitly defined in P21 config file
1) Category: Metadata/Format
Issue SummarySource Pinnacle 21 ID Publisher ID Message SeverityBDS AD0018 18 Variable label mismatch between dataset and ADaM standard Error
Variables Values Pinnacle 21 IDVARIABLE, LABEL ANL01FL, Analysis Flag 01 AD0018VARIABLE, LABEL TRTSEQP, Planned Sequence of Treatments AD0018VARIABLE, LABEL TRTSEQPN, Planned Sequence of Treatments (N) AD0018
→ P21 validator expects label of TRT*P(N)
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1) Category: Metadata/Format
Issue SummarySource Pinnacle 21 ID Publisher ID Message SeverityADSL AD0018 18 Variable label mismatch between dataset and ADaM standard Error
Variables Values Pinnacle 21 IDVARIABLE, LABEL TRCMPG1, Treatment Compliance (%) Group 1 AD0018VARIABLE, LABEL TRCMPG1N, Treatment Compliance (%) Group 1 (N) AD0018
Change of variable label (ADSL)
• New variable in ADaMIG 1.1
• Recognized by P21 validator as pooled treatment variable TRxxPGy and expecting that label
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Illegal variable name
• New variable in ADaMIG 1.1
• Recognized by P21 validator as pooled treatment variable TRxxPGy and expecting xx from 01 to 99 corresponding to a treatment period
• Rule AD0065 not applicable for this variable
1) Category: Metadata/Format
Issue SummarySource Pinnacle 21 ID Publisher ID Message SeverityADSL AD0065 65,217 Illegal variable name: xx is not in [01-99] and y is not in [1-9] for
TRxxPGy(N)Error
Variables Values Pinnacle 21 IDVARIABLE TRCMPG1 AD0065VARIABLE TRCMPG1N AD0065
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APHASE/APERIOD concept
• Rule AD1015 was added by P21 based on definition of APHASE in ADaMIG 1.0: ‘a higher-level categorization of APERIOD’
• ADaMIG 1.1: definition APHASE broadened to ‘a categorization of timing within a study’; Core= ‘Permissible’.
• Dataset OK for study with single treatment / subject (only ADSL.TRT01P present)
Variables Values Pinnacle 21 IDVARIABLE APERIOD AD1015
2) Category: Presence
Issue SummarySource Pinnacle 21 ID Publisher ID Message SeverityBDS AD1015 + APHASE is present but APERIOD is not present Warning
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2) Category: Presence
Required variables
• ADaMIG 1.0: Core= ‘Required’ADaMIG 1.1: Core= ‘Conditional’
• TRTP only conditionally required in BDS dataset if no other subject-level or record-level treatment variables are present
• Dataset OK if any other treatment variable is included, eg, TRT01P from ADSL
Issue SummarySource Pinnacle 21 ID Publisher ID Message SeverityBDS/OCCDS AD0047
47,49,50,51,52,55,71,72,88,89,90,194,195,257,260,261,262,278 Required variable is not present Error
Variables Values Pinnacle 21 IDVARIABLE APERIOD AD1015VARIABLE TRTP AD0047
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2) Category: Presence
Missing Variable in Variable pair
• Rule AD1012 added by P21:If AVALCA1N is present on the dataset; P21 expects the corresponding primary variable AVALCA1.
• ADaMIG 1.1: secondary variable for AVALCAT1 = AVALCA1N (truncated due to variable length restrictions).
• Dataset OK if variable pair is present on dataset
Issue SummarySource Pinnacle 21 ID Publisher ID Message SeverityBDS AD1012 + Secondary variable is present but its primary variable is not present Error
Variables Values Pinnacle 21 IDVARIABLE APERIOD AD1015VARIABLE TRTP AD0047VARIABLE AVALCA1 AD1012
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Extensible codelists: unallowed SDTM value
• Values ‘MULTIPLE’, ‘NOT REPORTED’, ‘UNKNOWN’, and ‘OTHER’ are not defined for the CDISC codelist{RACE} (C74457)
• Variable RACE: Required in ADSL• copy of DM.RACE without any (content) changes• Non-alignment CT with SDTMIG: to be resolved at SDTM level
Variables Values Pinnacle 21 IDRACE MULTIPLE CT2002RACE NOT REPORTED CT2002RACE OTHER CT2002RACE UNKNOWN CT2002
3) Category: Terminology
Issue SummarySource Pinnacle 21 ID Publisher ID Message SeverityADSL CT2002 RACE value not found in 'Race' extensible codelist Warning
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Calculation issue
• Can occur in rare cases (limited number of errors) for parameters with results below 1 and >10 decimals.
• False error due to rounding used by validator
• Recalculate manually to see if the error can be ignored (values in details sheet: fewer decimals than dataset values)
Variables Values Pinnacle 21 IDCHG, AVAL, BASE 0.00008442, 0.11747573, 0.1173913 AD0223PCHG, AVAL, BASE -0.02192988, 0.04947368, 0.04948454 AD0225
4) Category: Consistency
See also P21 Forum topic: https://www.pinnacle21.net/forum/ad0225-calculation-issue-pchg-aval-basebase-100
Issue SummarySource Pinnacle 21 ID Publisher ID Message SeverityBDS AD0223 223 Calculation issue: CHG != AVAL - BASE ErrorBDS AD0225 225 Calculation issue: PCHG != (AVAL - BASE)/BASE * 100 Error
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Validation of ADaM datasets based on CDISC ADaMIG 1.1
Introduction
Purpose / Aim
Conformance Findings and Explanations
Solutions?
Summary / Conclusion
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Solutions?
How to avoid detection of these explainable issues?
Await CDISC ADaM Validation Checks v1.4 and ADaMIG 1.1-based configuration file from Pinnacle 21
Meanwhile: In-house development of ADAM 1.1.xml configfile by modifying the source ADAM 1.0.xml file • Adjust/correct variable labels• Inactivate rules no longer applicable• Set existing rules to active for other domain• Add exception variables to some existing rules • Addition of new rules
Avoids investigation of repeatedly detected explainable issues during programming
For submission: use ADaM 1.0.xml file and explain in ADRG
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Solutions?
Modifying the configuration file• Adjust the label eg, ANLzzFL
(Refer to: https://www.pinnacle21.com/projects/validator/opencdisc-validation-framework)
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Solutions?
Modifying the configuration file• Adjust the label eg, ANLzzFL• Inactivate rule eg, AD0148 for BDS
(Refer to: https://www.pinnacle21.com/projects/validator/opencdisc-validation-framework)
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Solutions?
Modifying the configuration file• Adjust the label eg, ANLzzFL• Inactivate rule eg, AD0148 for BDS• Rule modification: add exception variables
(Refer to: https://www.pinnacle21.com/projects/validator/opencdisc-validation-framework)
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Solutions?
Modifying the configuration file• Adjust the label eg, ANLzzFL• Inactivate rule eg, AD0148 for BDS• Rule modification: add exception variables• New rule: presence of any treatment variable (BDS/OCCDS)
(Refer to: https://www.pinnacle21.com/projects/validator/opencdisc-validation-framework)
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ADaM Compliance Validation• Used internally during programming: ADAM 1.1_SGS.xml
• Official conformance validation (for ADRG): ADAM 1.0.xml
Solutions?
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Validation of ADaM datasets based on CDISC ADaMIG 1.1
Introduction
Purpose / Aim
Conformance Findings and Explanations
Solutions?
Summary / Conclusion
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Summary / Conclusion
Explainable issues for ADaMIG 1.1-based ADaM datasets
Software for validation lags behind development of CDISC standard
Multiple sources for ‘issue’ detection• Errors in CDISC ADaMIG 1.0• Incomplete rules in CDISC ADaM Validation Checks v1.3
(used as base for Pinnacle 21 configuration file)• Bugs in Pinnacle 21 Validation software / config file• Updates in CDISC ADaMIG 1.1
Solution• Workaround: adapt ADaM 1.0.xml configuration file• Explain in ADRG for ADaM datasets (Conformance Findings)
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Reference List
1. FDA Center for Drug Evaluation and Research (CDER). (2016). Study Data Standards in eCTD: What You Need to Know About the New Technical Rejection Criteria [Powerpoint slides]. Retrieved from: http://sbiaevents.com/past-sbia-events/
2. CDISC Analysis Data Model Team. (2016-02-12). Analysis Data Model Implementation Guide, Version 1.1 [PDF file]. Retrieved from: https://www.cdisc.org/system/files/members/standard/foundational/adam/ADaMIG_v1.1.pdf
3. CDISC Analysis Data Model Team. (2016-02-12). ADaM Structure for Occurrence Data (OCCDS), Version 1.0 [PDF file]. Retrieved from: https://www.cdisc.org/system/files/members/standard/foundational/adam/ADaM_OCCDS_v1.0.pdf
4. Pinnacle 21 LLC. (2017). Pinnacle 21 Community, version 2.2.0 [Computer software]. Available at: https://www.pinnacle21.com/downloads
5. CDISC ADaM Compliance Sub-Team. (2015-03-17). CDISC ADaM Validation Checks, Version 1.3 [PDF file]. Retrieved from: https://www.cdisc.org/system/files/members/standard/foundational/adam/ADaMv1_3ValChecks.zip
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Questions?
WHERE EXPERIENCEMEETS SPEED
Jeroen Den Herder, Ph.D.Life SciencesBiostatistical Analyst
SGS Belgium NVGeneraal De Wittelaan 19A bus 5BE - 2800 MechelenPhone: +32 15 299 341 Email: [email protected]
