CDISC SDTM and ADaM for survival data

Cytel Inc. - Confidential [A. Tinazzi – CDISC SDTM and ADaM for survival data – BIAS 2014 Genoa 30-31 October 2014]

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CDISC SDTM and ADaM for survival data

VI BIAS Annual Conference

Analisi della sopravvivenza ed applicazioni in Oncologia: un percorso dalle basi agli ultimiaggiornamenti

Genoa – 30-31/10/2014

Angelo TinazziCytel Inc., Wilmington Del. USA

Succursale de Meyrin – Geneva – [email protected]


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Cytel Inc. - Confidential

The information contained in this presentation is based on personal

research of the author and does not necessarily represent Cytel Inc.


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CDISC Intro

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References

CDISC is a global, open, multidisciplinary, non-profit organization that has established standards to support the acquisition, exchange, submission and archive of clinical research data and metadata.

The CDISC mission is to develop and support global, platform-independent data standards that enable information system interoperability to improve medical research and related areas of healthcare. CDISC standards are vendor-neutral, platform-independent and freely available via the CDISC website.


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CDISC IntroAvailable Standards

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC IntroStandards in Submission

Data Analysis

Data Tabulations

Data CollectionPlanning

ADaMSDTM

SEND

CDASH

LAB

Protocol

StudyDesign NCI CT

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC IntroA World of Clinical Standards

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC IntroTraceability

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References

Primary Overall Survival Analysis

ADTTE

ADaM define.xml

DM

SDTM define.xml

aCRF


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Efficacy Endpoints in OncologySolid Tumors

Clinical Trial Endpoint

Definition Source

Overall Survival (OS)

Time from randomization to death from any cause. FDA

Objective Response Rate (ORR)

Proportion of patients achieving either a partial or complete response for a minimum duration of time.

FDA

Disease-free survival (DFS)

Time from randomization until recurrence of tumor or death from any cause. DFS is typically used in clinical trials of adjuvant cancer therapy.

FDA

Progression-free survival (PFS)

Time from randomization until objective tumor progression or death.

FDA

Time to progression (TTP)

Time from randomization until objective tumor progression (does not include deaths)

FDA

Time to treatment failure (TTF)

Time from randomization to treatment discontinuation for any cause, including drug toxicity.

FDA

Progression-free survival 2 (PFS2)

Same as PFS with some indication variant. E.g. in Prostate cancer

-

Duration of Response (DOR)

Time from documentation of tumor response to disease progression

EMA

Clinical Benefit Response Rate (CBR)

Patients achieving either a complete response, partial response or absence of progression at 6 months

EMA

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References

Clinical Trial Endpoint

Definition Source

Overall Survival (OS)

Time from randomization to death from any cause. FDA

Objective Response Rate (ORR)

Proportion of patients achieving either a partial or complete response for a minimum duration of time.

FDA

Disease-free survival (DFS)

Time from randomization until recurrence of tumor or death from any cause. DFS is typically used in clinical trials of adjuvant cancer therapy.

FDA

Progression-free survival (PFS)

Time from randomization until objective tumor progression or death.

FDA

Time to progression (TTP)

Time from randomization until objective tumor progression (does not include deaths)

FDA

Time to treatment failure (TTF)

Time from randomization to treatment discontinuation for any cause, including drug toxicity.

FDA

Progression-free survival 2 (PFS2)

Same as PFS with some indication variant. E.g. in Prostate cancer

-

Duration of Response (DOR)

Time from documentation of tumor response to disease progression

EMA

Clinical Benefit Response Rate (CBR)

Patients achieving either a complete response, partial response or absence of progression at 6 months

EMA


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RAN SD SD PR CR PD

DOR

ORR

OS

PFS TTP

Death /Alive

TTF

Off TRT

Efficacy Endpoint in OncologySolid Tumors

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC SDTMSDTM Domains (as per Version 3.2)

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC SDTMDomains/Items Useful for Overall Survival

Date of Origin / Starting pointRandomization date

Treatment Start date

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References

DS

DM


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Date of deathDM

DS

Patient died (DSSCAT=REPORT OF DEATH) because of Progressive Disease (DSTERM) on 14DEC2010 (DSSTDTC)

Patient 101001 died (DTHFL=Y) the 17JAN2013 (DTHDTC)

Patient 101006 is alive (DTHFL=NULL)

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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Date of last follow-upAny date documenting patient is still alive

Visit date, AEs, CM, Lab Samples, ECG, etc. In SDTM we have a lot of «administrative» date that should be

not considered (--DTC) Investigate for date in Supplemental Qualifiers

SUBJID SSORRES SSSTRESC

VISIT SSDTC

001001 ALIVE ALIVE FUP 1 07JAN13

001001 ALIVE ALIVE FUP 2 25MAY13

001002 DECEASED DEAD FUP 1 08JUN13

001003 ALIVE ALIVE FUP 1 01JAN12

001003 ALIVE ALIVE FUP 2 05AUG12

001003 PATIENT LOST TO FOLLOW UP

LOST FUP 3 20NOV12

Last follow-up

Date when death was reported. Date of death in DM

At this follow-up the patient was known to be lost, date of last follow-up is therefore 05AUG12 (previous visit)

Survival Status (available from version 3.2)SS

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC SDTMOncology Domains for Tumor Response TU/TR/RS

Tumor IdentificationUnique identification of tumors for that patient

Tumor ResultsQuantitative measurements and/or qualitativeassessments of the tumors identified in the TU

Disease ResponseClinical response evaluations determined from the TRdata and other SDTM domains

TU

TR

RS

Overcoming Difficulties in Implementing RECIST criteria, PhUSE 2013, G. Ruhnke

CDISC Journey on Solid Tumor Studies using RECIST 1.1., PhUSE 2013, K. Lee

SDTM Oncology Domains From Patients to Data to Narrative, PhUSE 2013, K. Stoltzfus

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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Source: Oncology Legacy Data => SDTM.

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC ADaMFoundation Models

• One record per subject• Demographics, Baseline Chars• Study Population (ITTFL, SAFFL, ..)• Study Arm, Treatment Periods

ADSL

Analysis Subject Level Dataset

• Vertical Structure• One or more record per subject/time-

point

BDS

Basic Data Structure

• Counting of subjects with a record for each term

• It often includes a structured hierarchy of dictionary

ODS

Occurrence Data Structure

• Based on BDS• Time to the Event of Interest• One or more time-to-event endpoint

per ADTTE dataset

TTE

Time to Event

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC ADaMADTTE – Analysis Dataset for Time to Event – Variables of Interest

Description of time-to-event (PARAMCD/PARAM)E.g. OS/Overall Survival

Date Origin (STARTDT)

E.g. Randomization DateCensor (CNSR) 0=EventAnalysis date of event or censoring (ADT)

E.g. Death Date / Last follow-upElapsed time to the event of interest from the origin

(AVAL)E.g. (ADT-STARTDT)+1 (days)

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC ADaMADTTE – Analysis Dataset for Time to Event – Variables of Interest

Event or Censoring Description (EVNTDESC)E.g. DEATH

Censor Date Description (CNSDTDSC)E.g. LAST FOLLOW-UP DATE

Imputation Date Flag (ADTF)E.g. D/M/Y

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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ADTTE ExamplesCase 1: Single Endpoint with Multiple Values for Censoring

Definition Time from randomization until death from any cause

Censor Last date subject was seen alive

A study with Overall Survival as Primary Endpoint

Cut-off Date Applied: 08APR2014

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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SUBJID TRTP

PARAMCD

PARAM AVAL STARTDT

ADT ADTF

CNSR

EVNTDESC

001001 PBO OS Overall Survival (Months)

16.8 15AUG11 07JAN13 0 DEATH

001002 EXP OS Overall Survival (Months)

8.4 12SEP11 25MAY12 D 1 LAST FOLLOW-UP DATE


7.2 02SEP13 08APR14 1 FINAL ANALYSIS CUT-OFF DATE

Endpoint: Overall Survival ; Cut-off Date Applied: 08APR2014

Treatment Received

Time to Event Parameter

Time part of the TTE event(ADT-STARTDT+1)/30.42*30.42 Standard for nr. of days in a month

− Start Date Randomisation- Event/Censor Date

0=Event1..n=Censor

Event/Censor Description

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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SUBJID TRTP

PARAMCD

PARAM AVAL STARTDT

ADT ADTF

CNSR

EVNTDESC

001001 PBO OS Overall Survival (Months)

12.1 01APR13 07JAN13 0 DEATH


17.2 04APR13 25MAY12 D 1 LAST FOLLOW-UP DATE


17.5 08APR13 08APR14 1 FINAL ANALYSIS CUT-OFF DATE


A partial date (--MAY12) where the day part has been imputed. Valid values are D,M,Y

More details about censoring date. This patient either die or had a follow-up>cut-off date and therefore censored at the time of analysis cut-off date

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References

This is also traceability!!!!!!


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SUBJID

TRTP

PARAMCD

… ADT ADTF

CNSR

EVNTDESC SRCDOM

SRCVAR SRCSEQ

001001 PBO OS … 07JAN13 0 DEATH DM DTHDTC .

001002 EXP OS … 25MAY12 D 1 LAST FOLLOW-UP DATE

ADSL LASTVSDT .

001003 EXP OS … 08APR14 1 FINAL ANALYSIS CUT-OFF DATE

ADSL LASTVSDT .


SDTM.DM ADAM.ADSL

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References

This is also traceability!!!!!!


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ADTTE ExamplesCase 2: Composite Endpoint with multiple value for Event and Censoring

Definition Time from randomization until radiological tumor progression or death which ever come first

Censor Last date radiological tumor assessment

Progression Free Survival

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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ADTTE ExamplesCase 2: Composite Endpoint with multiple value for Event and Censoring

SUBJID

TRTP

PARAMCD

PARAM AVAL STARTDT

ADT CNSR

EVNTDESC CNSDTDSC

001001 PBO

PFS Progression Free Survival(Months)

16.8 15AUG11 07JAN13 0 RADIOLOGICAL PROGRESSION

001002 EXP


8.4 12SEP11 25MAY12 1 STUDY COMPLETED

LAST RADIOLOGICAL ASSESSMENT

001003 EXP


7.2 02SEP13 08APR14 2 NO BASELINE ASSESSMENT

RANDOMIZATION

001004 PBO


8.4 12SEP11 25MAY12 0 DEATH

Endpoint: Progression Free Survival

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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ADTTE ExamplesCase 3: One ADTTE with several time-to-event Endpoints

Phase III studyFirst Relapsed or Refractory Acute Myeloid

LeukemiaPrimary Endpoint: Overall SurvivalSensitivity Analysis

Overall Survival censored for Susbsequent AML TherapiesOverall Survival censored for Post Treatment

Transplantation

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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ADTTE ExamplesCase 3: One ADTTE with several time-to-event Endpoints

SUBJID

TRTP

PARAMCD

PARAM AVAL ADT CNSR

EVNTDESC CNSDTDSC

001001 PBO

AML Susbsequent AML Therapies (Months)

0.6 31AUG11 0 SUBSEQUENT AML NON PROTOCOL THERAPY

001001 PBO

TRA Post Treatment Transplantation (Months)

16.8 07JAN13 1 NO EVENT LAST VISIT DATE

001001 PBO

OS Overal Survival(Months)

16.8 07JAN13 0 DEATH

001001 PBO

OSTR

OS Censored for Transpl. (Months)

16.8 07JAN13 0 DEATH

001001 PBO

OSAML

OS Censored for Subsequent AML Therapy (Months)

0.6 31AUG11 1 NO EVENT SUBSEQUENT AML NON PROTOCOL THERAPY DATE

The Subsequent AML therapy started on 31st August 2011. The death occurred the 7th January 2013 was censored for OSAML

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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ADTTE ExamplesADaM Define.xml

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References

Variable Value Label Type Format Source/Computational Method

PARAMCD PFS Progression Free Survival (Months)

FLOAT 8.1 Analysis Date (ADT) used for Progression Free Survival will be the earliest date of radiologically documented disease progression (RS.RSDTC where RS.RSTESTCD=OVRLRESP and RSORRES=PD) or death (DM.DTHDTC)

If none of these events occurred Analysis Date (ADT) is the last post-baseline tumour assessment (Max RS.RSDTC).

Progression Free Survival (months)=(ADT - STARTDT+1)/30.42


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ADTTE ExamplesAnalysis Results Metadata

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References

Analysis Results Metadata Fields

Description

Display Identifier Tables 14.2.1

Display Name Overall Survival (months) by Treatment

Result Identifier Overall Survival (months)

PARAM Overall Survival (months)

PARAMCD OS

Analysis Variables AVAL, CNSR

Reason Primary Efficacy Endpoint as per Protocol

Dataset ADTTE

Selection Criteria ITTFL=‘Y’ and PARAMCD=‘OS’

Documentation SAP Section 10.1.1

Programming Statements PROC LIFETEST DATA=ADTTE; TIME AVAL*CNSR(1); STRATA TRTP; WHERE PARAMCD=‘OS’;RUN;


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ADTTE ExamplesThe Analysis Reviewer Guide: The ideal place where to clarify

potential source of misinterpretation not enough explained in the SAPCDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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RECIST and OTHER NON SOLID TUMOR REFERENCES P Therasse et al, "New response evaluation criteria in solid tumors: Revised

RECIST guideline (version 1.1)," European Journal of Clinical Oncology, pp. 45: 228-247, 2009.

Overcoming Difficulties in Implementing RECIST criteria, PhUSE 2013, G. Ruhnke

CDISC Journey on Solid Tumor Studies using RECIST 1.1., PhUSE 2013, K. Lee

SDTM Oncology Domains From Patients to Data to Narrative, PhUSE 2013, K. Stoltzfus

D Cheson et al, "Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia," Journal of Clinical Oncology, pp. Vol 21, No 24: pp 4642-4649, 2003

References

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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ONCOLOGY RELATED REGULATORY GUIDANCE Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Cancer

Drugs and Biologics, FDA, 2011

Cancer Drug Approval Endpoints http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/CancerDrugs/ucm094586.htm

References

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC SDTM CDISC Standards

CDISC Study Data Tabulation Model (SDTM) v1.4

Study Data Tabulation Model Implementation Guide (SDTMIG) v3.2

Associated Persons Implementation Guide (SDTMIG-AP) v1.0

Released Therapeutic Area Standards: Diabetes, Alzheimer, Asthma, Multiple Sclerosis, Pain, Parkinson Disease, Polycystic Kidney

Disease, Tuberculosis and Virology

Oncology for Tumor Response domains (integrated into SDTMIG 3.1.3)

CDISC/NCI-EVE Standard Controlled Terminology

FDA Guidance and Technical Documents: CDER and CBER: Guidance for Industry - Providing Regulatory Submissions in Electronic Format -

Standardized Study Data (Draft)

Study Data Specifications (soon replaced by Study Data Technical Conformance Guide)

CDER Common Data Standards Issues

C Holland J Shostak - Implementing CDISC Using SAS, SAS 2012

F Wood - Creating SDTM Datasets from Legacy Data - PharmaSUG - 2011

A Tinazzi - Looking for SDTM Migration Specialist – PhUSE - London 2014

References

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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CDISC ADaM Analysis Data Model (ADaM) Implementation Guide v1.0

The ADaM Basic Data Structure for Time-to-Event Analyses v1.0

Analysis Data Model (ADaM) Data Structure for Adverse Event Analysis

G Cappellini - ADaM and traceability: Chiesi experience. BIAS Seminar «Data handling and reporting in clinical trials with SAS» - Milan 2013

A Tinazzi - Interpreting CDISC ADaM IG through Users Interpretation. PhUSE - Bruxelles 2013

References

CDISC Intro

Efficacy Endp. Onco

CDISC SDTM

CDSIC ADaM

ADTTE Examples

References


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Thank you for your time!

Angelo Tinazzi – Associate Director – Statistical Programming

[email protected]


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Data & Analytics

CDISC SDTM and ADaM for survival data