Published on June 4, 2007
Logistics and Practicalities of Phase I Clinical Research Sue Gilbert Evans, M.Sc. Director, Project Management February 12, 2007
Session Overview Introduction Definitions Stages of a Phase I Clinical Trial Study Planning Study Execution Study Close-out Special Considerations Summary Questions
The leading privately owned, early phase CRO specializing in the measurement of CNS drug effects Expertise in Phase I and CNS studies First in Man/Ascending Dose Ethanol and Drug-drug interactions Proof of concept Bridging studies World leader in human abuse liability Toronto based 80 bed facility in a state-of- the-art medical setting/favourable cost and tax environment Team of internationally recognized scientists providing comprehensive drug development services
Typical Phase I Endpoints Pharmacokinetic parameters (parent drug, principal metabolite(s), reference drugs) Pharmacodynamic parameters Biomarkers Cognitive and psychomotor function Early efficacy markers (scales, questionnaires, etc.) Drug binding profiles (e.g., PET, fMRI) Safety parameters Vital signs ECG, cardiac telemetry Clinical labs (hematology, chemistry, urinalysis, other) Adverse events
Planning Budget/ Planning/ Concept Protocol Contract Logistics Discuss Scientific Costs objectives integrity Mutual Propose design Feasibility assumptions Select doses Logistics Study Schedule Preclinical Drug supply safety profile Legal terms Data analysis Predicted AEs strategy Third-party suppliers
Study Concept ! Protocol Development Determine study objectives Design the treatment regimen and build time and events schedule Practical considerations: Sample size and population Issues affecting subject recruitment, compliance & retention Number and feasibility of procedures Requirements for staff and equipment Safety considerations Ethical considerations Volume of blood draws per subject Monitoring expected/unexpected adverse events Decision to proceed to higher doses
Clinical Trial Budgets Factors for budget planning Study procedures Advertising & recruitment costs, stipends Laboratory / analytical costs Medical supervision Housing & Supplies Project Management & Administration Protocol & Report preparation Regulatory applications & drug supply costs Phase I study budgets vary widely $100,000 up to >$1,000,000 Depends on many factors: e.g., complexity, sample size, duration
Subject Recruitment: Lasagna’s Law Availability of subject population Pre-study During Study Post-study Harris EL, Fitzgerald JD (eds). The Principles and Practices of Clinical Trials. Edinburgh: E & S Livingstone; 1970
Subject Recruitment & Retention Recruiting methods: Subject database Advertising (media, strategic ad placement) Word-of-mouth and referrals Capitalizing on time of year Financial compensation “Competition” for subjects Study design considerations: Inclusion/Exclusion criteria Number and type of study procedures Overall duration of study Length of inpatient stays Frequency and time-of-day for outpatient visits Lifestyle and dietary restrictions
Regulatory Considerations Regulations: “GXP” GCP (Good Clinical Practices) GLP (Good Laboratory Practices) GMP (Good Manufacturing Practices) Other: e.g., FDA 21-CFR-Part 11 (electronic records, electronic signatures) Health Canada: Clinical Trial Application Healthy normal volunteers: 7-day target for approval Patient populations: 30-day approval Ethics Committee Determine frequency of meetings and requirements for submission Respond to Committee’s questions before unconditional approval
Drug Supply Where is drug coming from? (Canada / USA / Europe) Is a controlled substance involved? (Canada: OCS; USA: DEA) Drug format and preparation requirements Powdered substance Liquid solutions Small batches with limited stability data Over-encapsulated product (for blinding purposes) Finished product Storage conditions Temperature monitoring during transit (HC Guide-00069) Appropriate on-site storage (access, temperature monitoring)
Sample Project Plan Contract Execution 3 Wks Study Synopsis 2 Wks Protocol Approval 2 Wks CTA Approval 3 Wks IRB Approval 3 Wks Recruitment & 4 Wks Study Initiation Study Conduct 8 Wks Database Lock 3 Wks Draft Report 3 Wks Total 25 Wks
Study Scheduling Example Sample size Randomize N=48 complete N=54 ~ 10% attrition Group 1 Dose N=18 Total Stand Group 2 eligible -bys Dose N=18 Group 3 Group 1 subjects Dose N=18 Admit N=22 required Group 2 N=66 Admit N=22 Group 3 Admit N=22
Other Logistics Lab services Non-drug supplies (pK tubes, labels, equipment) Source document development Database design and Case Report Form (CRF / eCRF) development Setting up other special tests (e.g., cognitive tests) Protocol-specific staff training Clinic scheduling Staff scheduling Meal planning vs. protocol
Study Execution: In the Clinic Regulatory Drug Approvals Shipment Subject Treatment Follow-up Assessmen Phase Phase t Visits First Subject First Subject Last Subject Milestones: First Visit Dosed Last Visit
Clinic Events: Example Time & Events: Subject Breakdown view Cohort A Treatment Day 1 Subject Number Day 1 Nominal time Events 1 2 3 4 5 Continuous telemetry through 24h Predose Urine 7:20 7:30 7:40 7:50 8:00 7:25 7:35 7:45 7:55 8:05 Start telemetry 7:30 7:40 7:50 8:00 8:10 Rest Time 12-lead ECG 7:35 7:45 7:55 8:05 8:15 Vital signs 7:38 7:48 7:58 8:08 8:18 Blood collection 7:40 7:50 8:00 8:10 8:20 Subject Questionnaire 7:43 7:53 8:03 8:13 8:23 Dose* 0h 8:00 8:10 8:20 8:30 8:40
Study Execution: Behind the Scenes Source data CRF Subject Safety data review, Transcription enrolment review QC/QA /Entry tracking Project Sponsor Data Management monitoring cleaning & & visits queries Coordination Subject Supplies & Sample Drug contact/ Equipment processing accountability retention Maintenance & shipments
Study Close-out Final drug Prepare Data query accountability records for resolution & return archiving Sponsor Database Unblinded Prepare close-out lock data review Final Report visit
Phase 1: Special Considerations FIH / dose escalation studies Review Dose Safety Level 1 Data Review Yes Safety Dose Safe? Data Level 2 Yes No Safe? Terminate No Terminate
Phase 1: Special Considerations Special tests and procedures, on- or off-site PET, fMRI, pharmacodynamic biomarker assays Special populations Novel compounds Biologics Special safety monitoring requirements Special drug procurement or preparation methods Meetings with regulatory agencies (FDA, Health Canada) Scheduling logistics Expiry dates of drug supply Safety data review during dose escalation
Ventana’s Early Phase Experience Completed Trials- Past 3 Years Other 11% Abuse Liability Alcohol Interaction 32% 13% Drug Interaction 17% Ascending Dose/FIM 27%
Summary Phase I studies are diverse in design, size, complexity and duration Consider dose selection and experimental design (enlist KOLs as appropriate) Plan for study logistics in parallel with experimental design: Clinical logistics and procedures Selection and recruitment of patient populations Drug supply issues Partner with a clinical site as early as possible
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