Protocol Complexity as a Factor in Vendor Management Compliance Risk

1. Protocol Complexity as a Factor in Vendor Management Compliance Risk Marta Fields Director, Clinical QA Seattle Genetics

2. 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

3. 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 Simple Study Study Logistics Study Participants

4. StudyModel Clinical Trial Database Clinical Drug Supply SPONSOR Safety System Study Mgmt Tool CRF CRA SAEs Drug supply Clinical Sites

5. Compliance Approach • Routine monitoring and site audits • Internal audit of safety reporting • Part 11 assessment of internal systems

6. 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 Relatively Simple Study Study Logistics Study Participants

7. Study Model Bioanalytical Lab Central Lab All lab values Clinical Trial Database Clinical Drug Supply SPONSOR Safety System Study Mgmt Tool CRF CRA SAEs Drug supply Clinical Sites Home Health

8. 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

9. Global single armmulti-center HTN trial (40-60 sites) Central lab(s) Primary endpoint (blood pressure) PK - Home Health Nurse SAEs reported directly to sponsor andCRO Sites monitored by sponsor andCRO 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 Moderately Complex Study Study Logistics Study Participants

10. Study Model Bioanalytical Lab Central Lab Central Lab All lab values Clinical Trial Database Clinical Drug Supply SPONSOR Safety System Study Mgmt Tool CRF CRA Drug Supply Depot SAEs Drug supply Home Health Clinical Sites CRO

11. 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

12. 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 Complex Study Study Logistics Study Participants

13. Study Model Bioanalytical Lab Central Lab Central Lab File Server Dose Calc Tool Clinical Drug Supply SPONSOR Safety System Study Mgmt Tool IVRS Provider EDC PRO/QOL Vendor CRA Drug Supply Depot SAEs Drug supply Home Health Clinical Sites CRO

14. 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

15. 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 Highly Complex Study Study Logistics Study Participants • 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

16. Study Model Bioanalytical Lab Samples Immuno- histochemistry Lab Results Central Imaging Reader Central Lab Central Lab Quantitative Data File Server Dose Calc Tool Clinical Drug Supply SPONSOR Safety System Scans Study Mgmt Tool IVRS Provider EDC PRO/QOL Vendor CRA Drug Supply Depot SAEs Drug supply Home Health IVRS transactions eCRF Data Enrollment & Drug Re-supply Data Samples Clinical Sites CRO CRO Results Samples

17. 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 CROsfor 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

18. Study Model Clinical Trial Database Clinical Drug Supply SPONSOR Safety System Study Mgmt Tool CRF CRA SAEs Drug supply Clinical Sites

19. Study Model Bioanalytical Lab Samples Immuno- histochemistry Lab Results Central Imaging Reader Central Lab Central Lab Quantitative Data File Server Dose Calc Tool Clinical Drug Supply SPONSOR Safety System Scans Study Mgmt Tool IVRS Provider EDC PRO/QOL Vendor CRA Drug Supply Depot SAEs Drug supply Home Health IVRS transactions eCRF Data Enrollment & Drug Re-supply Data Samples Clinical Sites CRO CRO Results Samples

20. 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

21. 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

22. Acknowledgements • Ken Strode – Director Quality Assurance at Stiefel, a GSK company