2018 CDISC U.S. Interchange The ADaM Universe of Mapping ... · 2018 CDISC U.S. Interchange- The ADaM Universe of Mapping Specs, Datasets, Define.xml & Beyond 10/29/2018 12 Standard

2018 CDISC U.S. InterchangeThe ADaM Universe of Mapping Specs, Datasets, Define.xml and BeyondPresented by Valerie WilliamsManager Statistical Reporting Standards, Systems and Processes, Biostatistics and Programming, ICON Clinical Research

10.10.2018

Agenda

1. Introduction

2. ADaM Content and Related Standards

3. ADaM Study Deliverables

4. Implementation Challenges

5. Solutions

The ADaM Universe

u·ni·verse /ˈyo͞onəˌvərs/

A particular sphere of activity, interest, or experience.

The ADaM universe is made up of CDISC standards content from which project/study ADaM deliverables are produced by users of those standards.

Introduction

The CDISC Analysis Data Model (ADaM), the ADaM Implementation Guide, ADaM Validation Checks, and Define.xml along with the associated TAUG standards, are the core of the ADaM universe and are surrounded by the ADaM Mapping Specifications, Data Sets, Analysis Data Reviewers Guide, and Define.xml files that are created by the implementers of the standards.

This presentation will discuss some of the challenges faced in ADaMimplementation and proposes a few solutions to improve productivity and quality metrics to utilize a standard approach across studies, facilitate code reusability and ease of code maintenance, while meeting this goal.

10/29/20182018 CDISC U.S. Interchange- The ADaM Universe of Mapping Specs, Datasets, Define.xml & Beyond 4

ADaM Content and Related Standards

Core of the Universe

ADaM Core Content


• The CDISC Analysis Data Model (ADaM),

surrounded by the ADaM Implementation Guide

(IG), Occurrence Data (OCCDS), Qualifying Rating

Scales (QRS), Therapeutic Areas (TA), and

Controlled Terminology (CT) are the core

components of the ADaM universe.

ADaM Peripheral Content

• ADaM Conformance Rules/Validation Checks

• ADaM Metadata: analysis dataset metadata, analysis variable

metadata (VLM), analysis parameter value level metadata,

and analysis results metadata (ARM.xml)

• Define.xml and XML Schema Definitions .xsd files for data

exchange. An XML schema defines the elements that an

XML file may contain. It provides a specific structure for XML

data, which is important when sharing XML files between

multiple systems. https://techterms.com/definition/schema


https://techterms.com/definition/schema

ADaM Content Status

Standard Most Current Related Documentation Notes

ADaM v2.1

ADaM Implementation Guide v1.1 Version 1.2 ready for release

ADaM Basic Data Structure (BDS) for Time-to-Event (TTE)

Analyses v1.0

ADaM OCCDS (Occurrence Datasets) v1.0 Version 1.1 in progress

Works with ADaMIG 1.1

ADaM Conformance Rules v1.3

(Validation Checks) / ADaM Integration

Version 2.0 in public review

Comments due 12-Nov-2018

Analysis Results Metadata (ARM) v1.0 for Define-XML v2.0

ADRG Completion Guidelines

ADRG Template

ADaM Geriatric Depression Scale (GDS) Short Form

Questionnaire Supplement

Resolving Public Comments.

ADaM Medical Devices Preparing for Public Review.

ADaM Oncology In Progress

ADaM PK Analysis In Progress

ADaM Traceability Examples In Progress

Analysis Results Metadata (ARM) Conformance Rules In Progress


ADaM Implementation Guide

ADaMIG v1.1 specifies ADaM standard dataset structures and variables, including naming conventions and specifies standard solutions to implementation issues.


Significant IG v1.2 updates include:

• New Permissible variable within BDS: PARQUAL

• Nomenclature for Stratification variables within

ADSL

• Recommended approach for bi-directional toxicity

grades: laboratory tests that have separate CTC

grade criteria for both ends of the normal range

(one set of grades for low values and another for

high values)

ADaM Structure for Occurrence Data

ADaM OCCDS v1.0 is based on ADaM Version 2.1 and the

ADaMIG v1.1. Occurrence analysis is the counting of

subjects with a given record or term, and often includes a

structured hierarchy of dictionary coding categories.


• Adverse Events

• Concomitant Medications

• Medical History

ADaM Conformance Rules

ADaM Conformance Rules v2.0 can be implemented with

software to test rules defined in the ADaM IG v1.0, ADaM IG v1.1,

and the ADaM OCCDS v1.0. First released on 20-Sep-2010 and

assists in traceability between SDTM and ADaM.


Updates from the previous release include:

• Change to a Wiki-formatted document

• Check table includes one row per rule per ADaMIGversion

• A revised table format, including the addition of new cited guidance column(s) and removal of legacy columns which were no longer necessary

• Addition of Message Type which contains values of “Error”, “Warning”, and “Note” (defined in Section 3)

ADaM Related Content Status


StandardMost Current Related

Documentation

Notes

Define.xml Define.xml Implementation

Guide v2.1

• Resolving public review comments

• Required by FDA and PMDA

Stylesheet In public review with PhUSE Optimizing

the Use of Data Standards Working

Group

StandardMost Current Related Documentation Notes

TAUGs Breast Cancer, COPD, Diabetes,

Diabetic Kidney Disease,

Dyslipidemia, Kidney Transplant, Major

Depressive Disorder, Prostate Cancer,

Rheumatoid Arthritis

Multiple TAUGs are in

development, including

Traditional Chinese Medicine -

Coronary Artery Disease/Angina

Therapeutic Area User Guide

v1.0 Comments Due by: 30 Oct

2018

Define.xml Documentation

Define.xml v2.1 - FDA is only supporting studies starting after Mar 15 2018 that use this. Define.xml is required standards for data submission to FDA (U.S.) and PMDA (Japan).

• The def:Class attribute on the ItemGroupDef element has been replaced by a def:Class element that includes a child element (def:SubClass)

• For Define-XML documents used for regulatory submissions, all dataset and codelist definitions where the corresponding ItemGroupDef or CodeList element represents a published CDISC standard or controlled terminology will be required to include a def:StandardOID attribute. Dataset and codelist definitions that do not follow a published CDISC standard or controlled terminology will be required to provide a def:IsNonStandard attribute.

• A new optional attribute def:HasNoData has been added to the ItemGroupDefand ItemRef elements. When the value of def:HasNoData is Yes, no data are available for the corresponding dataset or variable.


ADaM Study Deliverables

Around the Core

ADaM Deliverables


ADaM-related Study Artifacts Source Content

Documentation

SAP N/A

Specifications ADaMIG, OCCDS

Mocks for Tables, Listings, and

Figures

N/A

Analysis Data sets ADaM

Define.xml Define.xml

ARM.xml ADaM Conformance

Rules

Validation Checks (Pinnacle 21 and

supplemental programs) for .xpt or

datasets

ADaM, Define.xml

Analysis Data Reviewer’s Guide ADRG Package v1.1-

guidelines and template

SAP

A Statistical Analysis Plan (SAP) is required for each trial to

define guidelines for the analysis and presentation of data at

various stages of the trial. Statistical analysis is a clearly defined

section within the protocol and should be approved prior to the start

of the trial. https://warwick.ac.uk/fac/sci/med/research/ctu/conducting/setup/sap/


https://warwick.ac.uk/fac/sci/med/research/ctu/conducting/setup/sap/

ADaM Specifications

ADaM Specifications contain the requirements for each analysis

dataset and define.xml file, based on the analyses described in the

Statistical Analysis Plan (SAP).

• Provides traceability of a data element or metadata back to its source

SDTM (Study Data Tabulation Model) predecessor.

• Name, variable attributes, formats, and derivations required for the

analysis and reporting of clinical study data

• The specifications contain tabs for metadata, each dataset, controlled

terminology, and documentation

• The statistician reviews the draft ADaM specifications, once they have

been written by the programmer, and provides comments back to the

programmer.


Sample ADaM Specifications


ADaM details that will be included in the Define.xml are in yellow

Source information is in gray

ADSL


ADAE


ADaM Analysis Datasets

ADaM Analysis Datasets are created to support results presented in study reports, the Integrated Summary of Safety (ISS) and the Integrated Summary of Efficacy (ISE) and to support other analysis that enable a thorough regulatory review. They must facilitate unambiguous communication.

• Support traceability relationships between the analysis results and source data relationships across data types relationships within data types

• Be linked to machine-readable metadata (define.xml)

• Be analysis-ready allow for analysis with minimal additional processing

• Be usable with currently available tools SAS, Pinnacle21

Standard tools to create define.xml or check compliance


ADaM Datasets

Analysis datasets must:

• include subject-level analysis dataset “ADSL”.

• comprise the optimum number of analysis datasets needed to allow analysis and review with little or no additional programming or data processing.

• be named using the convention “ADxxxxxx.”

• follow naming conventions for datasets and variables that are applied consistently across a given submission or multiple submissions for a product.


ADaM Dataset Structures

• The Subject-Level Analysis Dataset (ADSL) Structureo One record per subject

o (Required for all CDISC based submissions)

• The ADaM Basic Data Structure (BDS) • One or more records per subject

o Per analysis parameter Per analysis timepoint (Conditional)

• ADLB, ADEG, ADVS, ADQS

• ADTTE

• The ADaM Structure for Occurrence Data (OCCDS)• Supports occurrence analysis, counting number of subjects with

given records or terms

• Often is there one record per record in SDTM domain

• ADAE, ADCM, ADMH

• ADaM Other (does not fit in the above data structures but adheres to ADaM basic guidelines)


ADaM Dataset Usage

• ADaM Dataset Validation Checks

• Input= .xpt or ADaM data set shells

• Output= .xls files

Pinnacle 21

Supplemental ADaM Dataset Validation Checks for

compliance not covered in Pinnacle 21 ADaM v1.3 Data

Validation Checks

• Report Generation

• Generate Define.xml with ARM

Input= validated ADaM datasets

Output= define.xml


ADaM Variables

• Any SDTM variable name in ADaM:

“same name, same meaning, same values”

• When ADaM column has an SDTM name, values must be copied and not altered

• If a standard ADaM variable exists, then one must use the ADaM variable name for that concept

• Obey SAS V5 transport file naming and labeling conventions

• Core Definitions are in the ADaM Mapping Specification

• Req- Required

• Cond- Required if applicable; conditionally required

• Perm- Permissible


ADaM Variable Name Fragments

*N – a numeric version of a variable named *

*GRP – a grouping of a variable named *

*GRPN – a numeric version of a grouping of a variable named *

RACE, RACEN, RACEGRP, RACEGRPN

*FL – character flag

*FN – numeric version of character flag

TRT* – a treatment variable

*DY – a relative day (no day 0)

*DT, *TM, *DTM – numeric date, time, datetime

*DTF – date imputation flag (Y, M, D, null)

*TMF – time imputation flag (H, M, S, null)


ADaM Variables

# Variable Type Len Format Label

1STUDYID Char 15 Study Identifier

2USUBJID Char 25 Unique Subject Identifier

3SUBJID Char 25 Subject Identifier for the Study

4SITEID Char 25 Study Site Identifier

5AGE Num 8 Age

6SEX Char 2 Sex

7SEXN Num 8 Sex (N)

8RACE Char 41 Race

9RACEN Num 8 Race (N)

10RACEOTH Char 100 Race Other

11ENRLFL Char 1 Enrolled Population Flag

12RANDFL Char 1 Randomized Population Flag

13SAFFL Char 1 Safety Population Flag

14 ITTFL Char 1 Intent-To-Treat Population Flag

15TRT01PN Num 8 Planned Treatment for Period 01 (N)

16TRT01P Char 100 Planned Treatment for Period 01

17TRT01AN Num 8 Actual Treatment for Period 01 (N)

18TRT01A Char 100 Actual Treatment for Period 01

19TRTSDT Num 8 DATE9. Date of First Exposure to Treatment

20TRTEDT Num 8 DATE9. Date of Last Exposure to Treatment

21RANDDT Num 8 DATE9. Date of Randomization

22TRTP Char 100 Planned Treatment

23TRTPN Num 8 Planned Treatment (N)

24TRTA Char 100 Actual Treatment

25TRTAN Num 8 Actual Treatment (N)

26AESEQ Num 8 Sequence Number

27AESTDTC Char 19 Start Date/Time of Adverse Event

28AEENDTC Char 19 End Date/Time of Adverse Event

29ASTDT Num 8 DATE9. Analysis Start Date

# Variable Type Len Format Label

30 ASTDTF Char 1 Analysis Start Date Imputation Flag

31 ASTDY Num 8 Analysis Start Relative Day

32 AENDT Num 8DATE9. Analysis End Date

33 AENDY Num 8 Analysis End Relative Day

34 AENDTF Char 1 Analysis End Date Imputation Flag

35 ADURN Num 8 Analysis Duration (N)

36 ADURU Char 20 Analysis Duration Units

37 AETERM Char 200 Reported Term for the Adverse Event

38 AEDECOD Char 200 Dictionary-Derived Term

39 AEBODSYS Char 67 Body System or Organ Class

40 AELLT Char 200 Lowest Level Term

41 AEHLGT Char 200 High Level Group Term

42 AEREL Char 20 Causality

43 AERELN Num 8 Causality (N)

44 AERELNST Char 200 Relationship to Non-Study Treatment

45 AESCONG Char 2 Congenital Anomaly or Birth Defect

46 AESDISAB Char 2 Persist or Signif Disability/Incapacity

47 AEACN Char 16 Action Taken with Study Treatment

48 AEOUT Char 32 Outcome of Adverse Event

49 AESDTH Char 2 Results in Death

50 AEDDTC Char 19 Date and Time of Death

51 AESHOSP Char 2 Requires or Prolongs Hospitalization

52 AESLIFE Char 2 Is Life Threatening

53 AEDIS Char 1 Study Discontinuation Due to AE

54 AESMIE Char 2 Other Medically Important Serious Event

55 AESEV Char 8 Severity/Intensity

56 AESEVN Num 8 Severity/Intensity (N)

57 AETOXGR Char 1 Standard Toxicity Grade

58 AETOXGRN Num 8 Standard Toxicity Grade (N)

59 AESER Char 2 Serious Event

60 TRTEMFL Char 1 Treatment Emergent Analysis Flag


Define.xml and Schema


ARM.xml


ADaM Validation Checks

• Pinnacle 21

• Supplemental Checks


Analysis Data Reviewer’s Guide

The ADRG provides context for the analysis datasets and

terminology that benefit from additional explanation beyond the

Data Definition document (define.xml). In addition, this document

provides a summary of ADaM conformance findings.

https://www.phusewiki.org/wiki/index.php?title=Analysis_Data_Reviewer%27s_Guide


https://www.phusewiki.org/wiki/index.php?title=Analysis_Data_Reviewer's_Guide

ADRG_Completion_Guidelines_2015-01-26.pdf

1. Introduction

1.1. Purpose

1.2. Acronyms

1.3. Study Data Standards and Dictionary Inventory

1.4. Source Data Used for Analysis Dataset Creation

2. Protocol Description

2.1. Protocol Number and Title

2.2. Protocol Design in Relation to ADaM Concepts

3. Analysis Considerations Related to Multiple Analysis Datasets

3.1. Comparison of SDTM and ADaM Content

3.2. Core Variables

3.3. Treatment Variables

3.4. Subject Issues that Require Special Analysis Rules

3.5. Use of Visit Windowing, Unscheduled Visits, and Record Selection

3.6. Imputation/Derivation Methods

4. Analysis Data Creation and Processing Issues

4.1. Split Datasets

4.2. Data Dependencies

4.3. Intermediate Datasets

4.4. Variable Conventions

5. Analysis Dataset Descriptions

5.1. Overview

5.2. Analysis Datasets

5.2.1 ADSL – Subject Level Analysis Dataset

5.2.x Dataset – Dataset Label

6. Data Conformance Summary

6.1. Conformance Inputs

6.2. Issues Summary

7. Submission of Programs

8. Appendix


Implementation Challenges

Traceability

The main challenges are maintaining traceability of each data element

and correctly following the ADaM documentation:

Statistical Outputs (TFLs) => Analysis Data sets ADaM => ARM.xml =>

ADaM Define.xml => ADaM Mapping Specifications => SDTM Define.xml

=> CRF (see https://www.lexjansen.com/phuse/2014/dh/DH01.pdf)

Pinnacle 21 does not include the most current version of the ADaM

Validation Checks.

Over 1.2 million non-critical errors/warnings

Issues related to:

o Updating dataset code lists

o Study Design

o Propcase vs upcase for character variable values as per ADaM

Standards


https://www.lexjansen.com/phuse/2014/dh/DH01.pdf

ADaM Specifications

• ADAE specification tab in not in desired format

• Metadata tab is not in desired format

• Metadata and spec tab column names are not in desired format

• ADSL, ADDS and ADEG specification tabs not in desired format

• Specification file extension is not in desired format


Non-Compliant Analysis Datasets


illegal variable name: y is not in

[1-9] for PARCATy(N)

Define.xml


• Links for attached documents not working.

• Keys column for datasets needed updates (added AVISITNM

and QSGRPID to USUBJID, PARAMCD, ADT, ATM)

• Unwanted notes in derivation of variables

• Code list with parameters not up-to-date

ADRG


• Incorrect study number

• Typos or grammatical errors

• Number of subject screened vs enrolled

• Site name vs center name

• Correct number of sites

• Inconsistent fonts

• Insufficient information; i.e., which ADaM domains have screen failure

subjects; imputations/derivations - specifying which analyses were

used for unscheduled visits

• Renaming datasets mentioned in ADRG but not updating the TLF

programs to output those dataset names.

Solutions

10/29/20182018 CDISC U.S. Interchange- The ADaM Universe of Mapping Specs, Datasets, Define.xml & Beyond39

Ways to Address ADaM Implementation Challenges

Develop Standard Tools and Processes:

• Specifications

• TLF Mocks

• Validation Checks

• ADaM Template Code

• Define.xml

• ARM.xml Code

• ADRG QC

• Compliance Metrics


Solutions

• Develop/utilize the following items:

• Standard ADaM Specifications template and process

• Standard TLF Mocks

• Pinnacle 21 and supplemental user-written validation checked, based on ADaM Validation Checks 1.3.

• Validation checks to supplement P21

• ADaM Template Code, based on standard safety TFL mocks

• Standard Define.xml- use ADaM Specifications, ADaM Datasets and TFL annotation, Pinnacle 21, SHARE API, or develop a custom generic program to generate define.xml version and ARM.xml

• Standard ARM.xml code

• ADRG review process for accuracy and consistency

• Compliance metrics to track use and effectiveness


Standard Code to Produce ADaM Datasets, Define.xml, and ARM.xml

• Develop ADaM Template Code that would need <20% modification

from study to study for creation of “analysis-ready” datasets, to

improve efficiency.

• Allows programmers to meet aggressive timelines and robust coding

with clear logical program flow and follow ADaM standards for all

studies for regulatory authority submissions.

• In the future, ADaM datasets may be generated from SDTM data sets

via machine learning.

• Improves Productivity & Quality metrics; Utilize a standard approach

across studies

• Code reusability; easy maintenance; represent high standards for

coding structure, defensive coding, commenting and cleanup of work

library.


ADaM Template Code

• Base on ADaM V2.1, ADaM IG V1.1 and ADaM OCCDS V1.0.

• Include Safety datasets: ADSL, ADAE, ADCM, ADMH, ADEG, ADLB, ADVS, ADPE, etc.; include additional domains such as Oncology datasets.

• Include all ADaM required variables and standard TLF mock variables at minimum

• Assume a parallel study design

• Add study specific variables, drop extraneous variables, update existing derivation as per study need, etc.), in the respective study folder by the Study team, per study requirements

• Simple derived variables, e.g., TRTSDTM derived with Datetime of first exposure to treatment for a subject in a study

• Is not source code but a TEMPLATE so will not work without modification in studies.

• In lieu of validation, perform code review and User Acceptance Testing

• Helps to avoid code redundancy and unforeseeable issues


Validate Define.xml

• Run Pinnacle 21• All the issues/errors/warnings identified should be resolved prior

to final package or a valid explanation should be provided explaining why these errors can’t be resolved.

• Check define.xml Source/Derivation/Comment section

• Check ALL the external documentation hyper-links

• Perform all the checks given in ADaM Electronic Submission

• Material Checklist


Compliance Metrics


Conclusion- Balance the ADaM Universe

• Establishing a team of ADaM subject matter experts to use standard tools and processes around ADaM standards and project deliverables improves quality and efficiency

• Next step for users of the standards- align project/study deliverables with ADAMIG v1.2

Acknowledgements

Thanks to ICON Programming


Thank You!

Valerie [email protected]

mailto:[email protected]

Documents

2018 CDISC U.S. Interchange The ADaM Universe of Mapping ... · 2018 CDISC U.S. Interchange- The ADaM Universe of Mapping Specs, Datasets, Define.xml & Beyond 10/29/2018 12 Standard