Protocol Complexity as a Factor in Vendor Management Compliance Risk

Marta FieldsDirector, Clinical QA

Seattle Genetics

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Plan for today

Describe a study scenario Determine who the participants are Look at study interfaces Plan a compliance strategy Add complexity and determine its impact

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Simple Study

Single arm, multi-center hypertension trial (10-20 sites) in one country

Local lab Primary endpoint (blood

pressure) measured by Principal Investigator staff and reported on paper CRF

SAEs reported directly to sponsor

Sites monitored by sponsor CRAs

Data management performed by sponsor

Sponsor Principal Investigators

Study Logistics Study Participants

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Study Mgmt Tool

CRA

Clinical Trial Database

Safety System

CRF

Clinical Sites

Study Model

Clinical Drug Supply

Drug supply

SAEs

SPONSOR

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Compliance Approach

Routine monitoring and site audits Internal audit of safety reporting Part 11 assessment of internal systems

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Relatively Simple Study

Single arm, multi-center hypertension trial (20-40 sites) in one country

Central lab Primary endpoint (blood

pressure) measured by Principal Investigator staff

PK draws by Home Health Nurse

SAEs reported directly to sponsor

Sites monitored by sponsor CRAs

Data management performed by sponsor

Sponsor Principal Investigators Home Health Care Nurses Central Lab Bioanalytical Lab

Study Logistics Study Participants

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Study Mgmt Tool

CRA

Clinical Trial Database

Safety System

CRF

Clinical Sites

Central Lab

Study Model

Clinical Drug Supply

Drug supply

SAEs

All lab values

SPONSOR

Home Health

BioanalyticalLab

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Compliance Approach

Routine monitoring and site audits Internal audit of safety reporting Part 11 assessment of internal systems Annual audit of Central Lab

Audit of PK Bioanalytical Lab

Audit of Home Health Nurses Often individuals working from home office Need to assess compliance with protocol sequence

requirements

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Moderately Complex Study

Global single arm multi-center HTN trial (40-60 sites)

Central lab(s) Primary endpoint (blood pressure) PK - Home Health Nurse SAEs reported directly to sponsor

and CRO Sites monitored by sponsor and CRO

CRAs Data management Import/Export licenses Competent Authority approval Drug depot required

Re-label of drug supply

Sponsor Principal Investigators Central Lab Home Health Care Nurses Contract Research

Organization CRAs Drug Safety Regulatory

Drug Depot

Study Logistics Study Participants

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Study Mgmt Tool

CRA

Clinical Trial Database

Safety System

CRF

Clinical Sites

Central Lab

Study Model

Clinical Drug Supply

Drug supply

SAEs

All lab values

SPONSOR

Home Health

CRO

Central Lab

Drug SupplyDepot

BioanalyticalLab

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Compliance Approach Routine monitoring and site audits

International site audits

Internal audit of safety reporting Audit flow of data from CRO to internal Safety group

Part 11 assessment of internal systems Annual audit of Central Lab

May involve laboratories in US/EU/ROW

Audit of Home Health Nurses Audit of CRO

CRAs/Document Management/Project Management

Management of Import/Export licenses Qualification of Drug Depot

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Complex Study

International trial - larger sample size (80-250 sites)

IVRS - randomization and drug supply

EDC Dose titration based upon

blinded lab value Complicated interface

between lab, dose calculation tool and site

Primary endpoint is a lab value Patient reported outcomes used

for Quality of Life measures

Sponsor Principal Investigators Central Lab Home Health Care Nurses Contract Research Organization Drug Depot IVRS Provider PRO/QOL Vendor EDC Vendor

Study ParticipantsStudy Logistics

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Study Mgmt Tool

CRA

Safety System

Clinical Sites

Central Lab

Study Model

Clinical Drug Supply

Drug supply

SAEs

SPONSOR

Home Health

CRO

Central Lab

Drug SupplyDepot

BioanalyticalLab

PRO/QOL Vendor

IVRS Provider

Dose Calc Tool

EDC

File Server

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Compliance Approach Coordination of global program – defined roles and

responsibilities Routine monitoring and site audits Internal audit of safety reporting

Part 11 assessment of internal systems Validation of Dose Calculation tool

Annual audit of Central Labs Audit of Home Health Nurses Audit of CRO Management of Import/Export licenses Qualification of Drug Depot

Training on dose titration rules and use of tools, with unblinded monitoring/audit of actual dosing decisions

Clear, unambiguous IVRS specifications Audit of validation Unblinded audit of treatment assignments

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Highly Complex Study

Large multi-center, international oncology study (>250 sites) CT/MRIs required for

primary endpoint of progression free survival

Need for CD30+ tumor expression at randomization

Multiple CROs needed to address specific regional requirements

Sponsor Principal Investigators Central Lab Home Health Care Nurses Contract Research Organization Drug Depot IVRS Provider PRO/QOL Vendor EDC Vendor Immunohistochemistry lab Independent Radiology Review

center

Study ParticipantsStudy Logistics

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Study Mgmt Tool

CRA

Safety System

Clinical Sites

Central Lab

Study Model

Clinical Drug Supply

Drug supply

SAEs

SPONSOR

Home Health

CRO

Central Lab

PRO/QOL Vendor

IVRS Provider

Dose Calc Tool

File Server

Central Imaging Reader

CRO

Immuno-histochemistry

Lab

Scans

Quantitative Data

Samples

ResultsBioanalytical

Lab

Results

Samples

Samples

IVRS transactions

Drug SupplyDepot

Enrollment & Drug Re-supply Data

eCRF Data

EDC

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Compliance Approach Coordination of global program – defined roles and responsibilities Routine monitoring and site audits w/ emphasis on radiology standard

of care Internal audit of safety reporting Part 11 assessment of internal systems Annual audit of Central Labs Audit of Home Health Nurses Audit of CRO – could be multiple CROs for each region Management of Import/Export licenses Qualification of Drug Depot Management of dose titration Clear, unambiguous IVRS specifications Ongoing management of Central Radiology Review Center

Review of process to identify, QC, and catalogue images Validation of computerized imaging analysis software

Audit of IHC laboratory

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Study Mgmt Tool

CRA

Clinical Trial Database

Safety System

CRF

Clinical Sites

Study Model

Clinical Drug Supply

Drug supply

SAEs

SPONSOR

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Study Mgmt Tool

CRA

Safety System

Clinical Sites

Central Lab

Study Model

Clinical Drug Supply

Drug supply

SAEs

SPONSOR

Home Health

CRO

Central Lab

PRO/QOL Vendor

IVRS Provider

Dose Calc Tool

File Server

Central Imaging Reader

CRO

Immuno-histochemistry

Lab

Scans

Quantitative Data

Samples

ResultsBioanalytical

Lab

Results

Samples

Samples

IVRS transactions

Drug SupplyDepot

Enrollment & Drug Re-supply Data

eCRF Data

EDC

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Conclusions As protocols increase in complexity, the

number of participants and resulting interfaces with service providers also increase

Potential for communication breakdown and errors based upon mistaken assumptions increases

Compliance requires planning on all fronts and must account for complexity

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Recommendations

Write elegant protocols – limit endpoints to those required to achieve target label

Map your interfaces – understand what compliance issues need to be managed

Service Providers Pre-qualify service providers Document roles and responsibilities in Scope of

Work Document communication plans Monitor service providers

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Acknowledgements

Ken Strode – Director Quality Assurance at Stiefel, a GSK company