Clinical Trials and Safety Data –Different View of the same

Reality

Uwe Trinks, Ph.D.PRISM Forum, San Diego

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Clinical Data Management vs. Clinical Safety

Goal: Profile Drug for Use Longitudinal Data Collection Patient and Visit driven Large Part of Analysis after

LPLV Mostly placebo-controlled,

blinded Combined with other studies

and analyzed No expedited reporting No annual reporting

Data reported at the end of product development in a CTD as CDISC SDTM dataset

Goal: Prevent Harm Situative Data Collection Event driven Immediate Follow up and Analysis Mostly unblinded data

Expedited Reporting Annual Reporting Reporting to Ethics Committees

and Investigators Reports on paper or as ICH

E2BM dataset

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Efficacy vs. Safety

Efficacy Safety

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Looking for the Outlayer

Come on! It can‘t go

wrong every time...

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Technical Hurdles

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A Study

Patient Recruitment

Randomization

Visits

FPFV LPLV

Data

Data Cleaning, QC, Data Management

Un

blin

din

gD

ata

Cle

an

ing

Re

con

ciliatio

n

DBLock

Da

ta P

oo

ling

An

alysis

Do

cum

en

tatio

n

SAE SAE SAE SAE SAE

Re

concilia

tion

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The old clinical trials paradigm

SafetyCTS

CTMS

Reconciliation

Study SitesCRF SAE

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The brave new world of EDC

EDC

SafetyCTS

EDCEDCEDCEDCEDC

CTMS

Study Sites

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Patient View vs. Event View

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SDTM Clinical Domains by Class

Interventions Events

ConMeds

Exposure AE

MedHist

Disposition

Findings

ECGPhysExam

Labs

Vitals

Demog

Other

SubjChar

Subst Use

InclExcl

RELREC

Supp Qual

Trial DesignQS

Comments

Other

Domains most relevant to safety review

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ICH ICSR DTD-XML

Message Header M.1. Message Identifier

Type, Format, Version, Number, Sender ID, Receiver ID, Date Case Admin Data

A.1. Identification of the case safety report A.2. Primary source(s) of information A.3. Information on the sender and receiver of the case

safety report Case Information

B.1. Patient Characteristics B.2. Reaction(s)/Event(s) B.3. Results of tests and procedures relevant to the

investigation B.4. Drug(s) information B.5. Narrative Case Summary and further information

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SDTM Clinical Domains by Class

Interventions Events

ConMeds

Exposure AE

MedHist

Disposition

Findings

ECGPhysExam

Labs

Vitals

Demog

Other

SubjChar

Subst Use

InclExcl

RELREC

Supp Qual

Trial DesignQS

Comments

Other

Domains most relevant to safety review

B1B2B3

B3

B4

B4 B4

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What suits one system might not suit the next...

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ArgusInterchange

SAE form

The ideal Process

Inform

Trigger

ArgusSafety

E2BPlus file

QueryDictionaries

CodelistsStudies

DiffReport

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The real Problems

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The Problem

Trigger Points EDC data collection is continuous

Study Sites update information almost daily Mostly without thinking about SAE Most prominent updates: Death Dates

Safety Collection is a “Snapshot” What fields and when should trigger a follow up Avoid having up to 40 FU reports Which labs and vital signs to transfer? Update of non-significant information?

Feedback Loop EDC System must mark transferred data as such Requires redesign of SAE form and SAE process Requires standardization of certain form design elements

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The Problem

CDISC SDTM to E2BM Conversion difficult Field inconsistencies

Need to create a mapping routine (ETL tool) Easier to create the E2B file directly

E2B Intake Incomplete E2B form

Requires separate profile and DTD Need E2B difference report Harmonize Configuration

Need to be able to automatically find Study Information in Argus

Population of Suspect Drug etc. from Safety System not from EDC System

Requires quick configuration of Studies

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Coding

Medical Semantics Vary widely Are usually not harmonized

between Safety and Clinical Coding in Safety is

Real-time Most current MedDRA version Important for Reporting

Coding in Clinical is Harmonized at the end Used only for Analysis

Two Possibilities Harmonize Coding Strategies or Only transport Verbatim

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Major Changes in Inform

Standardized SAE form Zero deviation allowed Additional fields for

Lab Data Vital Signs Event Assessments Dechallenge/Rechallenge

Selection Tables for Data that are uploaded by relevance Concomitant medications Medical History Vital Signs Patient Demographics Treatments

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Major Changes in Inform

Pop ups in other Inform Sections “Is this an SAE/Update to SAE?” Need to be “cloned” for EVERY database Death Date

Cause of Death Relatedness -> Update SAE form

Other Seriousness Criteria Change in Relatedness Change in Drug Exposure

Dechallenge/Rechallenge Pregnancy

System Down: Fax to Safety, but enter into EDC System

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Major Changes in Inform

Standardized SAE Query form Assure that answers end up in SAE form Lab Data Integration difficult

Standardized and harmonized Codelists Biggest source of errors Need full alignment of CRF writers Can probably build an E2B check into Inform

Trigger Mechanism Difficult balance between

Regulatory Requirements Operational Efficiency

Basic rule: No more than one FU per day Scheduled upload of non significant information

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Major Changes in Argus

Study Information Needs to be configured before FPFV Needs to be harmonized with Clinical

E2B Import Module Needs to be configured for partial E2B files Added non E2B fields

Sequence numbers Event Assessments

Configure for Always Accept Configure to not overwrite certain fields (e.g unblinded product

information) Configure not to upload certain events (e.g entry criteria)

No changes to Argus SAEs Except Narrative and Unblinding All Changes/Queries through EDC System

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Communication

Most difficult task Lots of Clinical and IT lingo

needs to be translated into Safety Lingo

Lots of Safety lingo needs to be translated into Clinical and IT Lingo

Very few people are bi- or tri-lingual

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E2B Transport

Non native DTD Partial E2B form

Header of non-standard format No study product information Only Study # information No Narrative Information

Added fields Sequence numbers Event Assessments/Causality Non overwrite information

No real acknowledgement Send Argus Case number back to Inform for sequencing

and FU

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The good news

It works very well at some companies GSK

Technical problems are mostly solvable It saves time and money once it works

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The bad news

It takes an effort to harmonize things SAE forms Codelists Dictionaries and Coding Conventions

It takes a while to train people Safety to use Inform for Queries and Updates Investigators to “think safety”

It requires adherence to agreed standards The “extra codelist item” will break the process Safety has to conform with not updating data in Argus

Savings will happen late in the process Once the majority of the studies is in Inform and using the

standard SAE process Can’t change studies midway

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Don’t forget