Abhinav Jain Demystifying ADAM Specification Creation

8/20/2019 Abhinav Jain Demystifying ADAM Specification Creation

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Demystify ADaM Specification Creation with aCase Study Approach

Abhinav Jain

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What are we discussing today?

• Why ADaM?

• What is ADaM Implementation?

• Where to Start?

• How to review study documentation with help of a sample study?

• What is ADaM Metadata?

• How to create ADaM Metadata with help of a case-study?

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Why ADaM?

CDISC - ADaM Data Standards are guidelines for creation of analysis datasets that will beused to generate statistical analysis for submissions.

In summary, fundamental principles for ADaM are:

• Provide clear documentation of the contents, source of analysis datasets, analysisresults (statistical methods, transformations, assumptions, derivations, imputations)

•

Provide a “roadmap” of how metadata, programs and documentation translate theStatistical Analysis Plan (SAP) to the statistical results

• Analysis-ready or “one-PROC” away datasets

• Traceability between the analysis data and source data

• XML based metadata for future tools development

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What is ADaM Implementation?

To perform ADaM implementation Programming teams has to perform a set of activities.

Create ADaM Metadata/Specifications

Programming and Quality check of ADaM datasets

Program analysis tables, listings and figures

Create Define.xml

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Where to start?

To start ADaM implementation, first step is to review following documents:

γ Protocol

γ CRFs (Prefer SDTM Annotated CRF)

γ Statistical analysis plan (SAP)

γ Mock-up shells γ SDTM mapping instructions

γ SDTM datasets

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Document Review : What to look for?

ζ Study design

ζ Safety and Efficacy objectives

ζ Schedule of assessment

ζ Population definitions

ζ Analysis covariates

ζ Visit windowsζ Definition of baseline values

ζ Handling of missing values (imputation rules, missing AE data, etc.)

ζ Handling of multiple records per visit

ζ Variable computations and derivations, including categorical variables

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Protocol Example and Sample SDTM

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USUBJID EGSEQ EGTESTCD VISIT VISITNUM EGDTC EGSTAT EGSTRESN EGSTRESU

ABC-1001 1 RR Screening 100 2011-05-04 0.5 Sec

ABC-1001 2 QT Screening 100 2011-05-04 328 ms

ABC-1001 3 RR Week 1 101 2011-05-11 0.69 Sec

ABC-1001 4 QT Week 1 101 2011-05-11 366 ms

ABC-1001 5 RR Week 2 102 2011-05-17 0.6 Sec ABC-1001 6 QT Week 2 102 2011-05-17 332 ms

ABC-1001 7 RR Week 3 103 Not Done - Sec

ABC-1001 8 QT Week 3 103 Not Done - ms

ABC-1001 9 RR Week 4 104 2011-05-30 0.68 Sec

ABC-1001 10 QT Week 4 104 2011-05-30 527.03 ms


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SAP Example

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Mock-up Shell Example 1

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Mock-up Shell Example 2

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Cases from sample study

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1. Derive Baseline values taking average value

from Pre-dose readings and create Baselinerecord

AVISITN = BASELINE, DTYPE = AVERAGE,

ABLFL = Y, AVAL, BASE

2. Implement LOCF for Post-Dose records AVISITN, DTYPE = LOCF, AVAL

3. Derive two new parameters PARAMTYP = Derived, PARAM, PARAMCD,PARAMN

4. Derive Change from Baseline and Identifyrecords for By-time point analysis

CHG, ABLFL = Y, ANL01FL = Y

5. Flag abnormal category values CRITy, CRITyFL


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ADaM: Basic Data Structure (BDS)

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Variable Groups ADaM Variables

Subject Identifiers STUDYID, USUBJID, SUBJID, SITEID

ADSL variables AGE, RACE, SEX, RANDDT, TRTSDT, TRTEDT

ADaM Treatment variables TRTP, TRTPN, TRTA, TRTAN

ADaM Timing variables ADT, ADY, AVISITN, AVISIT

ADaM Parameter identifiers PARAMCD, PARAMN, PARAM, PARAMTYP, AVAL,

AVALC, BASE, CHG, PCHG, SHIFTy, SHIFTyN,

ADaM Analysis Descriptor DTYPE

ADaM Indicator variables ABLFL, ANLyFL, CRITyFL

ADaM Visit Windowing AWRANGE, AWTARGET, AWTDIFF

SDTM Traceability variables EGSEQ, VISIT, VISITNUM


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ADaM Metadata

ADaM Metadata facilitates the communication of underlying assumptions, statisticalmethods, transformations, derivations and imputations performed in the analysis of aclinical trial data.

Enables values and results to be easily replicated.

Establishes links between description of the analysis (Protocol’s data analysis section,SAP), the analysis results, the data used in the analysis, and the SDTM domains.

Components of ADaM Metadata:

• Analysis Dataset metadata

• Analysis Variable metadata

•

Analysis Parameter Value Level metadata• Analysis Results Metadata

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Analysis Dataset metadata

Dataset Name

Dataset

Description Dataset Location Dataset Structure

Key Variables of

Dataset

Class of

Dataset Documentationfilename of the

dataset.

short

summary of

contents of

the dataset

where the dataset can be

found

the level of detail in the

dataset

variable names

that parallel the

structure

general

class of the

dataset

using

controlled

terminology

links or

references to

documentation re

how the dataset

was created

ADEG

ECG analysis

data

Study ABC/Data/

ADaM/ADEG.XPT

One record per subject per

parameter per analysis

visit

USUBJID,

PARAMCD,

AVISITN,

EGSEQ BDS

SAP Section 7.8.3

ADEG.SAS

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Parameter Level Metadata – ADSL Variables

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Dataset NameParameterIdentifier

VariableName

Variable Label Variable TypeDisplayFormat

Codelist /ControlledTerms

Source / Derivation

ile name of theanalysis dataset

PARAMCD or*ALL* or*DEFAULT*

name description typedisplayinforma-tion

valid values orcodes and decodes

where the variable came from in the sourcedata or how the variable was derived

ADEG *ALL* STUDYID Study Identifier text $12 ADSL.STUDYID

ADEG *ALL* SITEID Study Site Identifier text $3 ADSL.SITEID

ADEG *ALL* USUBJIDUnique SubjectIdentifier text $11 ADSL.USUBJID

ADEG *ALL* AGE Age integer 3 ADSL.AGE

ADEG *ALL* SEX Sex text $1 SEX. ADSL.SEX

ADEG *ALL* RACE Race text $50 RACE. ADSL.RACE

ADEG*ALL* ITTFL

Intent-to-TreatPopulation Flag

text $1 Y, N ADSL.ITTFL

ADEG

*ALL* SAFFL Safety Population Flag text $1 Y., N ADSL.SAFFL

ADEG

*ALL* TRTSDTDate of First Exposure toTreatment

integer yymmdd10. ADSL.TRTSDT

ADEG

*ALL* TRTEDTDate of Last Exposure to

Treatment

integer yymmdd10. ADSL.TRTEDT

ADEG*ALL* TRTP Planned Treatment text $20

Arm A, Arm B, Arm C

ADSL.TRTP

ADEG

*ALL* TRTPN Planned Treatment (N) integer 11 = Arm A,2 = Arm B,3 = Arm C

ADSL.TRTPN


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Parameter Level Metadata – Traceability Variables

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DatasetName

ParameterIdentifier

Variable Name Variable Label VariableType

DisplayFormat

Codelist / ControlledTerms

Source / Derivation

ADEG *ALL* EGSEQ Sequence Number integer 4

EG.EGSEQ from the records in the SDTM

EG. ADEG *ALL* VISITNUM Visit Number integer 4 EG.VISITNUM

ADEG *ALL* VISIT Visit Name text $19 EG.VISIT


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Parameter Level Metadata – Timing Variables

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DatasetName

ParameterIdentifier

Variable Name Variable Label VariableType

DisplayFormat

Codelist / ControlledTerms

Source / Derivation

ADEG *ALL* ADT Analysis Date integer yymmdd10.

Convert date portion of EG.EGDTC fromcharacter to a numeric date variable andformat using yymmdd10. date format.

ADEG *ALL* ADY Analysis Relative Day integer 3

If ADEG.TRTSDT less than or equal to ADEG.ADT then ADY=ADEG.ADT – ADEG.TRTSDT+1Else ADY=ADEG.ADT - ADEG.TRTSDT

ADEG *ALL* AVISIT Analysis Visit text $19

Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8

If ADEG.SAFFL='Y' then AVISIT is thename of the analysis visit; if

ADEG.SAFFL=blank then AVISIT=blank.Create a row for each parameter with AVISIT = 'Baseline'.Refer to Section 5.2 of the SAP for adetailed description of how Baseline will be derived and derivation of AVAL.

ADEG *ALL* AVISITN Analysis Visit (N) integer 3

1= Baseline, 2 = Week 1,3 = Week 2, 4 = Week 3,5 = Week 4, 6 = Week 5,7 = Week 6, 8 = Week 7,

9 = Week 8

if ADEG.SAFFL='Y' AVISITN=numericcode for AVISIT, blank if

ADEG.SAFFL=blank


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What is Parameter Identifier?

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For each derived variable and row in BDS dataset it is critical to understand how it was created, and

whether that derivation applies to all PARAMCD values in the dataset, or to most of them, or to a fewspecific PARAMCD values.

Value of metadata element PARAMETER IDENTIFIER provides the information on whichderivations if it is applicable on All the PARAMCD values, or few specific PARAMCD values.

Parameter Identifier Description

*ALL* The metadata for that variable is the same for all values ofPARAM/PARAMCD in the analysis dataset.

*DEFAULT* The specified metadata for that variable should be considered themetadata for all values of PARAM/PARAMCD in the analysis datasetunless otherwise specified.

Particular PARAMCD The specified metadata for that variable should be considered themetadata applicable to the particular PARAMCD, overriding thespecified *DEFAULT* metadata, if any.


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Parameter Level Metadata – Parameter Variables

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DatasetName

ParameterIdentifier

VariableName

Variable Label VariableType

DisplayFormat

Codelist /Controlled Terms

Source / Derivation

ADEG PARAMCD PARAMCD Parameter Code text $8

RR, QT, QTCF,

QTCB One-to-one correspondence with ADEG.PARAM

ADEG *ALL* PARAMNParameter CodeNumeric integer 1

RR' = 1 ,'QT' = 2,'QTCF' = 3,'QTCB' = 4 One-to-one correspondence with ADEG.PARAMCD

ADEG *DEFAULT* PARAMTYP Parameter text 1 Y Null

ADEG QTCF PARAMTYP Parameter text 1 Y ‘Derived’

ADEG QTCB PARAMTYP Parameter text 1 Y ‘Derived’

ADEG *DEFAULT* AVAL Analysis Value float 8.1

AVAL = EG.EGSTRESN or an imputed/calculated value.For AVISIT = BASELINE apply AVERAGE to all pre-dosereading to calculate the analysis value.if EG.EGSTRESN is missing, apply the LOCF algorithm, i.e.set AVAL equal to the value for the previous scheduledpost-baseline time point (AVISIT). If the previoustimepoint is baseline, leave AVAL missing

ADEG QTCF AVAL Analysis Value float 8.1

Calculate analysis value at each visit using ADEG.AVAL for ADEG.PARAMCD in ('QT', 'RR') derive AVAL =QT value/RR value**0.33Use AVAL to apply AVERAGE and LOCF.

ADEG QTCB AVAL Analysis Value float 8.1

Calculate analysis value at each visit using ADEG.AVAL for

ADEG.PARAMCD in ('QT', 'RR') derive AVAL =QT value/RR value **0.5Use AVAL to apply AVERAGE and LOCF.

ADEG *ALL* BASE Baseline Value float 8.1 BASE=ADEG.AVAL where ADEG.ABLFL=“Y”

ADEG*ALL* CHG

Change fromBaseline

float 8.1 CHG=ADEG.AVAL - ADEG.BASE for post-baseline visits


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Parameter Level Metadata – Descriptor Variables

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DatasetName

ParameterIdentifier

VariableName


DisplayFormat

Codelist /Controlled Terms

Source / Derivation

ADEG *ALL* DTYPE Derivation Type text $8LOCF, AVERAGE

DTYPE = 'AVERAGE' for AVISIT = 'BASELINE' case whenaverage of Pre-dose readings is derived.DTYPE = ‘LOCF’ if EG.EGSTRESN is missing and when the value of ADEG.AVAL is populated using Last ObservationCarried Forward method.Blank Otherwise.

ADEG *ALL* ABLFLBaseline RecordFlag text $1 Y

Y if record contains the baseline value, i.e., if AVISIT='BASELINE'; blank otherwise.

ADEG *ALL* ANL01FL Analysis RecordFlag 01 text $1 Y

Populate with “Y” to identify the record selected to beanalysed for the specific value of AVISIT (Scheduled Timepoints for ECG as Schedule of events) within the specified

subject.For Pre-Dose reading flag only record with AVISIT ='Baseline'.


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Parameter Level Metadata – Indicator Variables

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DatasetName

ParameterIdentifier

VariableName


DisplayFormat

Codelist /ControlledTerms

Source / Derivation

ADEG QTCF CRIT1

Analysis

Criterion 1 text $50

Populated with ”QTcF > 450 msec” when ADEG.PARAMCD =

“QTCF” and ADEG.AVAL>450

ADEG QTCB CRIT1 AnalysisCriterion 1 text $50

Populated with ”QTcB > 450 msec” when ADEG.PARAMCD =“QTCB” and ADEG.AVAL>450

ADEG *ALL* CRIT1FLCriterion 1 EvaluationResult Flag text $1 Y Set to “Y” when ADEG.CRIT1 is populated

ADEG QTCF CRIT2 Analysis Criterion 2 text $50Populated with ”QTcF > 480 msec” when ADEG.PARAMCD =“QTCF” and ADEG.AVAL>480

ADEG QTCB CRIT2 Analysis Criterion 2 text $50Populated with ”QTcB > 480 msec” when ADEG.PARAMCD =“QTCB” and ADEG.AVAL>480

ADEG *ALL* CRIT2FL

Criterion 2 Evaluation

Result Flag text $1 Y Set to “Y” when ADEG.CRIT2 is populated

ADEG QTCF CRIT3 Analysis Criterion 3 text $50Populated with ”QTcF > 500 msec” when ADEG.PARAMCD =“QTCF” and ADEG.AVAL>500

ADEG QTCB CRIT3 Analysis Criterion 3 text $50Populated with ”QTcB > 500 msec” when ADEG.PARAMCD =“QTCB” and ADEG.AVAL>500


ADEG QTCF CRIT4 Analysis Criterion 4 text $50Populated with ”QTcF Increase from Baseline > 30 msec” when ADEG.PARAMCD = “QTCF” and ADEG.CHG>30

ADEG QTCB CRIT4 Analysis Criterion 4 text $50

Populated with ”QTcB Increase from Baseline > 30 msec” when

ADEG.PARAMCD = “QTCB” and ADEG.CHG>30


ADEG QTCF CRIT5 Analysis Criterion 5 text $50Populated with ”QTcF Increase from Baseline > 50 msec” when ADEG.PARAMCD = “QTCF” and ADEG.CHG>50

ADEG QTCB CRIT5 Analysis Criterion 5 text $50Populated with ”QTcB Increase from Baseline > 50 msec” when ADEG.PARAMCD = “QTCB” and ADEG.CHG>50



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ADEG ADaM dataset

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SUBJID AVISIT PARAM PARAMCD PARAMTYP AVAL BASE CHG DTYPE ABLFL ANL01FL CRIT1 CRIT1FL

1001 Screening RR (sec) RR 0.5 0.59 -

1001 Week 1 RR (sec) RR 0.69 0.59 -

1001 Baseline RR (sec) RR 0.59 0.59 - AVERAGE Y Y

1001 Week 2 RR (sec) RR 0.6 0.59 0.01 Y

1001 Week 3 RR (sec) RR 0.6 0.59 0.01LOCF Y

1001 Week 4 RR (sec) RR 0.68 0.59 0.09 Y

………… ………….. ………….. ………… ………….. …………. ………… …….. ………………. ………… ………….. ……………………… ……………..

1001 Screening QTcF (msec) QTCF DERIVED 413 412.5 -

1001 Week 1 QTcF (msec) QTCF DERIVED 412 412.5 -

1001 Baseline QTcF (msec) QTCF DERIVED 412.5 412.5 - AVERAGE Y Y

1001 Week 2 QTcF (msec) QTCF DERIVED 394 412.5 -18.5 Y

1001 Week 3 QTcF (msec) QTCF DERIVED 394 412.5 -18.5 LOCF Y

1001 Week 4 QTcF (msec) QTCF DERIVED 465 412.5 52.5 Y QTcF > 450 msec Y


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Have we covered all the cases?

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1. Derive Baseline values taking average value from Pre-dose

readings and create Baseline record. Variables: AVISIT = BASELINE,DTYPE = AVERAGE, ABLFL = Y, AVAL, BASE

√

2. Implement LOCF for Post-Dose records Variables: AVISITN, DTYPE = LOCF, AVAL √

3. Derive two new parameters Variables: PARAMTYP = Derived, PARAM, PARAMCD,PARAMN

√

4. Derive Change from Baseline and Identify records for By-time point analysis Variables: CHG, ABLFL = Y, ANL01FL = Y

√

5. Flag abnormal category values Variables: CRITy, CRITyFL

√


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Analysis Result Metadata

Table 14.3.4.1 - Post-baseline and Change from Baseline of ECG (Safety population)

Metadata Field Metadata

DISPLAY IDENTIFIER Table 14.3.4.1

DISPLAY NAME Post-baseline and Change from Baseline of ECG (Safety population)

RESULT IDENTIFIER Visit wise Analysis of all ECG parameters

PARAM RR (sec), QT (msec), QTcF (msec), QTcB (msec)

PARAMCD RR, QT, QTCF, QTCB

ANALYSIS VARIABLE AVAL, CHG

REASON Safety Analysis as specified in SAP section 7 (7.8.3) DATASET ADEG

SELECTION CRITERIA SAFFL=“Y” and PARAMCD in (“RR”, “QT”, “QTCF”, “QTCB”) and ANL01FL=’Y’

DOCUMENTATION Analysis description specified in SAP section 5.2, 5.4 and 7.8.3

PROGRAMMING

STATEMENTS

For each TRTAN compute the statistics using ;

PROC UNIVARIATE DATA=ADEG;

BY AVISITN AVISIT PARAMCD; VAR AVAL CHG;

RUN;

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Analysis Result Metadata

Table 14.3.4.2- Summary of Post-baseline Abnormal QTc (Safety population)

Metadata Field Metadata

DISPLAY IDENTIFIER Table 14.3.4.2

DISPLAY NAME Summary of Post-baseline Abnormal QTc (Safety population)

RESULT IDENTIFIER Summary analysis of Abnormal ECG parameters (QTCB and QTCF)

PARAM QTcF (msec), QTcB (msec)

PARAMCD QTCF, QTCB

ANALYSIS VARIABLE CRIT1FL, CRIT2FL, CRIT3FL, CRIT4FL, CRIT5FL

REASON Safety Analysis as specified in SAP 7.8 (7.8.3)DATASET ADEG

SELECTION CRITERIA SAFFL=“Y” and PARAMCD in (“QTCF”, “QTCB”) and CRIT1FL=’Y’

SAFFL=“Y” and PARAMCD in (“QTCF”, “QTCB”) and CRIT2FL=’Y’



SAFFL=“Y” and PARAMCD in (“QTCF”, “QTCB”) and CRIT5FL=’Y’ DOCUMENTATION Analysis description specified in SAP section 5.2, 5.4 and 7.8.3

PROGRAMMING

STATEMENTS

Compute the following for CRIT1FL to CRIT5FL;

PROC FREQ DATA=ADEG;

TABLES CRIT1FL * TRTAN;

BY PARAMCD;

RUN;

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Take away

£ What is ADaM Metadata?

£ How to document ADaM Metadata?

£ What are ADaM BDS Variable groups?

£ How to review the study documentation to create ADaM specification?

£ How ADaM standards are a “roadmap” of how metadata, programs and

documentation translate the Statistical Analysis Plan (SAP) to the statistical results

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Food for thought - Cases I have not covered?

? How to handle Visit Windowing

? How to deal with analysis results when the domain has both character only results

? How to implement SDTM Traceability with –SRC variables

? How to deal with cases when there are multiple reading at same visit or havingmultiple time point readings within single visit.

? How to create ADaM variables for shift tables

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References

ADaM version 2.1 and the ADaMig 1.0 can be downloaded from http://www.cdisc.org.

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THANK YOU

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Abhinav Jain Demystifying ADAM Specification Creation

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