NCICB JamboreeFebruary 25, 2005

NCICB Clinical Trials Modeling Activities

Part 1- CDISC Modeling Activities

Part 2- Clinical Trials Modeling (caBIO extension)

CDISC Modeling Effort - Background

Clinical Data Interchange Standards Consortium (CDISC) is a non-profit organization committed to development of industry standards to support electronic exchange of clinical trials data and metadata.

HL7 provides standards for data exchange to allow interoperability between healthcare information systems. The Clinical Trials technical committee of HL7 (RCRIM) has it’s own models for clinical trials

To achieve true semantic interoperability between these 2 major standards in Clinical Trials domain – CDISC and HL7 have partnered to develop ONE common representation of the Clinical Trials domain across the industry

Shared Objectives – CDISC, HL7 & FDA

To improve the quality of public health

To have ONE overarching standard model for data interchange for healthcare information and clinical trial/clinical research data

Ensure interoperability among the various CDISC standards

Develop interoperability between CDISC standards and the HL7 Reference Information Model (RIM)

CDISC – Domain Analysis Model

Being developed as a UML class diagram and documented in Rational Rose XDE

Main subject areas (packages) are as follows:– Entities and Roles– Interventions and Observations– Structured Protocol– Meta-data (ODM)– Statistics

Modeling team represents various stakeholders:– Pharmaceutical companies– Federal Agencies (FDA, NCICB)– Cancer Centers and Academic Institutions (caBIG CTMS developers)– CDISC and HL7

Modeling effort lead by Dr. Charlie Mead

CDSIC Domain Analysis Model – Entities and Roles

FunctionalRole (HL7 Participation)

+ name+ responsibilities+ GPSAddress+ electronicCommunicationAddress

ProtocolAuthor

IRB

RegulatoryAgency

StudyAnalyst

LivingSubject

+ dateofBirth+ sex+ deceasedIndicator(Y/N)+ dateTimeOfDeath

Person

+ geographicAddress+ electronicCommAddr+ race+ ethnicity

Investigator

+ type+ id

DataManager

ProjectManager

Laboratory

SafetyMonitor

Organization

+ geographicAddress+ electronicCommAddr+ standardIndustryClassCode

CRO

BioPharmaceuticalCompany

Entities and Roles View of Problem Space Model

Entity

+ name+ dateCreated+ status

Non-personLivingSubject

+ strain

Place

+ gpsCoordinatesMaterial

+ formCode

Role

+ status+ effectiveStartDate+ effectiveEndDate+ name+ geographicAddress+ electronicCommAddr+ id+ certificate/licenseText

plays/is played by

0..*1..1

plays/is played by

0..*

1..1

PopulationMember

InvestigativeSite

+ id

StudySponsor

HealthCareFacility

+ type

Subject

+ status+ id+ type

RegulatedProduct

Specimen

FundingOrganization

RegulatoryOverseer

StudyDirector

Patient

+ confidentialityCode

Signatory

See Subject State Diagram

Explain role link in Raleigh-Durham

HealthcareProvider

OVERVIEW: In the clinical trial space, the concept "Study" flows through a business process roughly described as "Propose, Plan, Execute, Report." These phases of a given Study (the more general term for Clinical Trial) can be at least approximately mapped to HL7 mood codes (INTENT, REQUEST, EVENT, ???). The overall goal of the Problem Space Model is to present a logcial view of the concept "Study" at each of the four identified business process stages with a realization that such a construct will result in a certain amount of redundancy beetween views, as well as pointing out structures that are unique to a particular phase and/or play a critical 'hand-off' role. Note that in the real world, not all structures defined for a given phase may be in place when the next stage begins.

Document

+ version+ author : SET+ ID : SET PSMID+ documentID+ type : ENUMERATED = formal plus non-formal subtypes+ description : PSMDescription+ title+ status : PSMStatus

CDISC Domain Analysis Model – Structured Protocol Package (draft)

Although it is sometimes the case that a protocol specifies the plan for both primary and correlative studies, best practice is that each instance of a study (correlative or primary) should have its own protocol

StudyMethodology

StudyStatisticalConsideration

StudyOrganization

StudyObjective (the "what")

+ description : PSMDescription+ intentCode : SET ENUMERATED+ primaryObjective : TEXT+ secondaryObjective : SET TEXT+ statementOfPurpose : TEXT

StudyBackground (the "why")

+ Attribute1+ description : PSMDescription+ justificationOfApproach : PSMDescription+ justificationOfObjectives : PSMDescription+ populationDescription : PSMDescription+ rationaleForAnalysisApproach : PSMDescript...+ rationaleForControl : PSMDescription+ rationaleForDesign : PSMDescription+ rationaleForEndpoints : PSMDescription+ rationaleForMasking : PSMDescription+ summaryOfPreviousFindings : PSMDescription

...

StudyPlan (the "how","where", "when", "who")

+ description : PSMDescription

«document»StudyProtocol

+ shortTitle : TEXT

SupplementalMaterial

+ description : PSMDescr...+ ID : SET PSMID+ type+ version

SponsorStudyManagementProjectPlan

SiteStudyManagementProjectPlan

SiteSubjectManagementProjectPlan

1..*

1

StudyObligation

+ commissioningParty+ description : PSMDescription+ responsibleParty+ type : ENUMERATED

ActivityManagementPlan

StudyEvent

+ code+ description+ endDateTime+ name+ result+ startDateTime+ type

*

Resource

Milestone

0..*

1 1

1..* 1..*1

Best practice and/or business process conventions may dictate that one of the set of ID #s be designated as the 'primary' or 'global' ID with all other elements of the set linked to the primary #.

Constraint

1

0..*

BusinessRule

1

0..*

Waiver

0..*

1

StudyEventRelationship

+ type

EligibilityCriterion

A Clinical Trial is a Study with type= "intervention" with subjects of type="human".

Subtype specifies phase for clinical trials, cohort for studies.

Variance

1

0..*

Endpoint

+ code+ description : TEXT+ type : ENUMERATED = primary, secondary+ threshold

*

Measure

1

1..*

assesses / is assessed by

Randomization

+ minimumBlockSize+ maximumBlockSize

DesignCharacteristic

+ detailedMethodCode+ detailedMethodDescription+ summaryCode+ summaryDescription+ synopsis+ type : test value domain = a,d,f,g

0..*

0..1

informs / is informed by

Control

The value set for "type" is "Randomization", "Masking", "Control", "Configuration", "Concurrency", "Scope" and "Bias".

We may need a complex datatype, e.g., "characteristic" with attributes "synopsis", "type", "description" and "code" to be used across multiple classes

Masking

+ level+ objectOfMasking (set)+ procedureToBreak+ unmaskTriggerEvent (set)

«document»Amendment

ResearchProgram

+ type

+ target0..*

+ source

1

*

*

1..1

*

1..*

«Placeholder»StudyParticipant

Document

+ author : SET+ description : PSMDescription+ documentID+ ID : SET PSMID+ status : PSMStatus+ title+ type : ENUMERATED = formal plus non-formal subtypes+ version

1

0..*

modifies / is modified by

Study

+ startDate+ endDate+ studyID : SET PSMID+ name+ type+ subtype+ status+ randomizedIndicator+ otherStudyCharacteristics+ description : PSMDescription

is executed according to the plan contained in / contains the plan for

1

1can have / is associated with

+ primaryStudy1

+ correlativeStudy

0..*

PSMID

+ source+ date+ value

PSMDescription

+ synopsis : TEXT+ summaryDescription : TEXT+ detailedDescription : TEXT+ externalReference : SET+ graphics : ED

Protocol View of Domain Space Analysis Model

Note: Going forward, we need to expand this datatype to include graphics (e.g., using HL7's ED datatype.

Activity

+ name : TEXT+ description : TEXT+ type = {TEMPORAL/NON-TEMPORAL}+ anchorPoint : TIMINGSPECIFICATION+ relativeTime : TIMINGSPECIFICATION

ActivityRelationship

is managed by / manages

Note: The various plans (PlannedAnalysisEvents, DataSafetyMonitoringBoardPlan, DosingPlan, SiteMonitoringPlan, AccrualPlan, DataManagementPlan, InvestigationalPharmacyPlan etc) draw upon the activities in Activity and perform some kind of management on it. A given plan may have both scheduled/determined activities and contingent activities with associated triggers.

Note: We should consider the perspective of an event as the trigger for the execution of one or more activities.

StudyDesign

+ description : PSMDescription

*

1..1

*

ClinicalDevelopmentPlan

describes/is described by

*

1

IntegratedDevelopmentPlan

0..*

*

Note: IS the definition correct? Is research program a subtype of document? There are at least 3 other types of programs that supply context to functional roles including Business Portfolio, Therapeutic Program and Clinical Program with as yet unexplained relationships to study. CommunicationRecord

*

1..*

references/is referenced by

Communication

+ dateTime

Note: This is an act which must be attributed appropriately.

PSMStatus

+ effectiveEndDate+ effectiveStartDate+ statusValue

Note: This class represents a logical not a physical document. Specificially it is not meant to represent a report which is a logical representation of data gathered from across the model.

CDISC Model – Next Steps

Once the model is complete, it will be mapped to the Clinical Trials DMIM and essentially to the HL7 Reference Information Model (RIM)

Some of the subject areas of the CDISC Model are further ahead than others: – Meta-data (ODM) to RIM mapping is already in progress– Structured Protocol Representation is very actively modeling at

present and have begun early mapping to RIM.

Both these areas hope to work towards developing HL7 v3 message specifications in late 2005 - 2006

HL7 Development Framework (HDF) – Model Flow

Technical CommitteeDomain AnalysisModel(s)(integrated models ofbusiness requirementsstated in businesslanguage)

Technical CommitteeProactive1 Domain MessageInformation Models

Public HealthReporting DMIM

Clinical TrialsDMIM

RCRIM DMIM3

RCRIM DMIMn

Technical CommitteeSponsored Standards

RMIM, HD/HMD, MessageTypes, Schemas

Annotated ECG

Clinical Genomics

Clinical Trial Registries

OCSR

ICSR

CT Laboratory

Business Inputs

Regulatory AgencyProjects(e.g. aECG,Product Label,Case Investigation,ICSR,Janus, ...)

Other RCRIMConstituents'Projects (e.g., CTRegistries, caBIG)

CDISC Standards

Mapping/ IntegrationBoth input and outputrevised as necessary

TechnicalSpecificationBoth input and outputrevised as necessaryStandards mustderive from DMIMs

DM

IMs

mus

t

deriv

e fr

om R

IM

RIMincluding bounddatatypes and

vocabulary

Stability

SPL

Future Standards

1 Proactive indicates models inform standards, rather than being revised after the fact to conform to standards

DM

IMs

inco

rpor

ate

thes

efo

r in

tero

pera

bilit

y

CMETsPatterns (e.g., Clinical Statement,Medication Model)Other TC's DMIMs (e.g., StructuredDocuments, Laboratory, Pharmacy,Clinical Genomics)Other supporting HL7 standards(e.g., GELLO)

ODM

special mapping projectfor GAP Analysis

MappingBoth input and outputrevised as necessary

Lab

SDTM

Case InvestigationDomain SpaceAnalysis Model(DSAM)

special mappimg projectdue to scope of DSAM

Process Flow - Requirements to Message specification

Requirements

(CDISC, FDA, NCICB, Pharma,

vendors, etc.)

DomainAnalysis

Model

(UML classdiagram)

HL7 Clinical Trials

DMIM

RMIM &Message Types

will be mapped to the DMIM/RIM

Req. will be Modeled intothe DAM

specificationswill be derivedFrom DMIM

DAM = Domain Analysis ModelDMIM= Domain Message Information ModelRMIM=Refined Message Information Model

NCICB Internal Clinical Trials Modeling Effort

Part 2

Design Clinical Trials related classes as an extension to caBIO model

Focus on Results and Outcomes reporting requirements. Use the areas identified during Outcomes KA analysis

Identify and develop Use Cases to support this effort and scope the model in this Phase

Focus on Intervention Trials ONLY for the first iteration of the model

The data source for these objects would be C3D, therefore limit the scope of the model based on what is available in Oracle Clinical

Since C3D is based on CDEs, this Clinical Trials UML model will be CDE based

The Clinical Trials UML classes/objects developed here MAY serve as Clinical Trials API’s to C3D (Oracle Clinical)

Clinical Trials Modeling - Objectives

Clinical Trials Modeling – Objectives (cont’d.)

The CT APIs will eventually be used to retrieve data and build Decision Support Applications

Ensure integration with other NCICB Clinical Trials related UML models (classes) – thru interfaces – caBIO, SPORES, etc.

Long Term Objectives

The model should be reflective of the CDISC Domain Analysis Model in future phases

The model should also be reflective of the HL7 CT DMIM – ensure placeholders and structure to be able to receive data from HL7 v3 messages (some of this will happen naturally since the CDISC DSAM is being adopted by HL7 as the Domain model for HL7 Clinical Trials committee and will be mapped to the HL7 CT DMIM)

Data Areas Identified by Outcomes Requirements

Response

Biomarkers Modulation

Survival

Disease Recurrence

Adverse Events

Quality of Life

Baseline Data

Clinical Trials Modeling – Sample Use Cases

RESPONSE– Do men with early stage prostate cancer suffer complications after

treatment with Proscar has ended? (Show patient data where Disease Stage Numeric = I and where the Adverse Event Onset Date is after the Treatment End Date)

DISEASE RECURRENCE– What is the average time to disease progression (in days) for all

patients on breast cancer trials? What is the most common reason for progression?

SURVIVAL– Is a high BMI associated with lower survival among breast cancer

patients? Is there a correlation between BMI and disease stage? Metadata Loader – Implementation of HMD meta loader

Example Use Case Documentation

Name/Query:

Is a high BMI associated with lower survival among breast cancer patients? Is there a correlation between BMI and Disease Stage?

Source: Center for Cancer Research KA Report

Detail: The user is able to view survival status of breast cancer patients and determine if a high BMI is associated with a lower survival status (1 or 5).

Background:

BMI is calculated from a patient’s height and weight. Survival Status is based on caDSR DEs.

Purpose: This will provide the survival rate and disease stage values for breast cancer patients with various BMI measurements.

Potential CDEs used for this Query:

The user selects to generate a report of Survival status for breast cancer patients. The system responds by requesting the user to select a set of breast cancer trials. Patient IdentifierProtocol NumberPatient Survival Status Patient Body Mass Index Measurement (can also be calculated by the system using height and weight CDEs)Diagnosis DateDisease Stage NumericPrimary Site of Disease Name

Valid Values/ Meanings Associated with Potential CDEs:

Patient Survival Status :

3 ALIVE DISEASE STATUS UNKNOWN1ALIVE WITH DISEASE2ALIVE WITH NO EVIDENCE OF DISEASE5DIED4UNKNOWN

Use Case #3 – Survival – Across Trials

Key Features of the Clinical Trials Model

Completely based on CDEs– CDEs from CCR Context with CS/CSI of C3D– all the class attributes are existing CDEs– only CDEs with a workflow status of “Released” have been used– actual CDE Long Name captured in the EA as Alias– experimenting with adding a Tag in EA for capturing the PublicID– currently using 210 CDEs from a total set of 576 from CCR context

Although currently focused on C3D, the model is a generic Clinical Trials model to support other data sources in future iterations

cd Data Model

Study

Agent

StudyAgent

Subject

Event Assessment

DrugAdministration

Protocol

DiseaseStudyDisease

Histopathology

StudySite QualitativeAdverseEvent

SpecimenCollection

DiseaseResponse

Organ

StudyObjective StudyBackground

Endpoint

LesionEvaluation

Site

AgentSynonym

Procedure

Imaging

Radiation

Surgery

Sample

Observation

QuantitativeResults

Genomic MicroSpecimen Base

EligibilityCriteria

Hook to existing caBIO class.

CancerDiagnosis

SubjectAssignment

EventRelationshipSubjectDisease

1..*

0..*

1..*0..*

0..*

1..*

1..*

0..*

1

participate

1..*

0..*

1..*

1..*

0..*

0..1

0..*

1

0..*

1..* 1

1..*0..*

0..*

1..*

0..* 1..*

1..* 0..*

0..* 0..*

0..*

1..*

Clinical Trials UML Class Diagram (work-in-progress)

Clinical Trials UML Diagram

cd Data Model

Study

Agent

- name: string- commercialVsINDindicator--NEW:

StudyAgent

Subject

- id: - initialsName: - medicalRecordNumber: int- age: - addressPostalCode: - subjectID: int- genderCategory: string- raceCategory: string- ethnicityCategory: string- eligibilityMetInd: - effectiveDate: date- eligibilityWaiverReason: string- firstLiveBirthAgeInYears: int- pregnancyLiveBirthCount: int- menopauseAgeInYears: int- ICFSignedDate: date

Event

- id: - epochName--NEW: string- visitName??: string- visitDescription??: string- courseDayNumber: number- startDate: date- endDate: date- durationUOM: string- duration: int- courseNumber: int- courseStartDate: date- courseStopDate: date- courseDisposition: char- totalDoseValue??: string

Assessment

- onsetDate: date- ??neurologicCriteria??: string- conditionResult: string- changeFromPreviousInd: string- imageEvaluationResult: string- ??abnormalConditionDetectionTextType??: string

DrugAdministration

- actualDose: int- actualDoseUnitOfMeasure: string- routeName: string- medicationSchedule-movetoRegimen?: string- frequency: string- totalDailyDoseValue: int

Protocol

- id: - number: string- longTitleText: string- shortTitleText: string- navyNCINumber: - activationDate: date- amendementDate: date- amendmentIdentifier: int- closureDate: date- suspensionDate: date- phaseCode: string- statusCode: string- typeCode: string- monitorCode: string- blindingIndicator: boolean- diseaseCode: strinbg- sponsorCode: string- multiInstitutionInd: boolean- targetAccrualNumber: int- precisText: string

Disease

- CDUScode:

StudyDisease

Histopathology

- breastCancerInvasiveHistology: string- breastCancerInSituHistology: string- description: string- grade: string- confirmationDate: date- lungScore: string- findingsGrossExamResult: string- reportDescriptiveText: string- reportIdentifier: int- responseSpecimenCriteria: string- ?responseAssessmentInd-Delete?MoveToAssessment?: string- benignTissueChange: string

StudySite

- id: - role--NEW: string- piName: string

Qualitative

- survivalStatus: string- deathDate: date- deathCause: string- deathCauseText: string- performanceStatus: string- painIndex: int

AdverseEvent

- onsetDate: date- resolvedDate: date- ctcCategory: string- ctcTermType: string- ctcAttributionCode: string- ctcGrade: int- ctcVersionNumber: string- seriousReason: string- outcome: string- action: string- therapy: string- therapyDate: date- therapyDelayDuration: string- therapyIntensity: string- conditionPattern: int- courseInclusionInd: boolean- descriptionText: string- reporterFirstName??: string- reporterLastName??: string- similarAEDescription??: string- similarAENumber??: int- directedMeasureName: string

SpecimenCollection

- collectionDate: date- type: string- siteType-DELETE: string- collectionMethod: string- criteriaType: string- condition???: string

DiseaseResponse

- assessmentType: string- bestAssessmentType: string- bestResponseDate: date- progressionDate: date- diseaseProgressionInMonths: int- noteText: string

Organ

- id: int- name: string

StudyObjectiveStudyBackground

Endpoint

LesionEvaluation

- number: string- targetNontargetIdentificationText: string- evaluationNumber: int- measurementX: int- measurementY: int- measurementZ: int- measurementProduct: int- measurementMethod: string- bodySiteName: string- appearanceTextType: string- nodularQuantityNumber: int- flatQuantityNumber: int

Site

- nationalCancerInstituteInstituteCode:

AgentSynonym

Procedure

- name: string- bodySiteName: string

Imaging

- identifier: - contrastAgentEnhanceInd: boolean- enhancementDescriptiveText: string- rateOfEnhancementValueNumber: int

Radiation

- type: string- schedule: string- doseUOM: string- dose--NEW: string

Surgery

Sample

- IDnumber: int

Observation

- reportingDate--NEW: date

QuantitativeResults

- testName: string- UnitOfMeasure: string- highNormalValue: int- lowNormalValue: int- assayMethod--DraftNew: string- technique: string- assessmentMethod--NEW: string- patientPositionType: string- panelName: string- characterValue: string- numericValue: int- biomarkerInd--NEW: boolean- meansVitalStatusObtained: string

Genomic

MicroSpecimen

Base

EligibilityCriteria

- text: string- expectedAnswer: string

QOLIndicators

- smokingChangeFromBaselineInd: boolean- smokingQuitDurationMonthsNumber: int- alcoholConsumptionPastYearInd: boolean- alcoholUseChangeStatusInd: string- alcoholUseLifetimeInd: string- alcoholUseCurrentStatusInd: string- alcoholCurrentUseRange: string- alcoholType: string- alcoholStopUseAgeInYears: int- alcoholUseStopDate: date- alcoholUseStartYear: date- alcoholUseStartAgeInYears: int- alcoholUseDescriptiveText: string- moderateExerciseHoursPerWeek: int- moderateExerciseMonthsPerYearNumber: int- sedentaryExerciseDaysPerWeekNumber: int- sedentaryExerciseHoursPerDayNumber: int- strenuousExerciseHoursPerWeekNumber: int- strenuousExerciseMonthsPerYearNumber: int- aNAMResultAccruarcyInPercentage: int

Hook to existing caBIO class.

??attributeName?? = DEs that need reviewed before including as attributes.attributeName?? = remove due to personnel identification reasons?attributeName--NEW = attributes that do not have a supporting DE from C3D.

Bullpen

CancerDiagnosis

- diseaseStageTNM: string

Denotes model skeleton

SubjectAssignment

- id: int- arm: int- armTargetedAccrualNumber: int- CDUSSubgroup: string- registeringGroup: - registeringInstitutionCode: int

EventRelationship

SubjectDisease

- diagnosisCode: int- diagnosisName:

1..*

0..*

1..* 0..*

0..*

1..*

1..*

0..*

1

participate

1..*

0..*1..*

1..*

0..*

0..1

?Delete due to collectionMethod 2/2/05

0..*

1 0..*

1..* 1

1..*0..*

0..*

1..*

0..* 1..*

1..* 0..*

0..*0..*

0..*

1..*

Example – CDE Long Name as Alias

cd Data Model

Protocol

- id: - number: string- longTitleText: string- shortTitleText: string- navyNCINumber: - activationDate: date- amendementDate: date- amendmentIdentifier: int- closureDate: date- suspensionDate: date- phaseCode: string- statusCode: string- typeCode: string- monitorCode: string- blindingIndicator: boolean- diseaseCode: strinbg- sponsorCode: string- multiInstitutionInd: boolean- targetAccrualNumber: int- precisText: string

CDELong Name

Status and Next Steps

The CT model is scheduled to be complete in first week on April

Would like to begin meeting with other NCICB development teams by mid-March for model reviews

Will incorporate as much as possible of the CDISC Domain Analysis Model into this iteration

This is just the first Phase of the effort – additional requirements will be accommodated in future iterations

Implementation of this model will be done with other NCICB developers/members

Acknowledgements

Sue DubmanChristo AndonyadisDianne ReevesPeter Covitz

Bill McCurrySmita HastakBecky RiggleVal BraggCharles YaghmourJane Harrell