Logistics and Practicalities ofPhase I Clinical Research
Sue Gilbert Evans, M.Sc.Director, Project Management
February 12, 2007
Session Overview
Introduction
Definitions
Stages of a Phase I Clinical TrialStudy Planning
Study Execution
Study Close-out
Special Considerations
Summary
Questions
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
The leading privately owned, early phase CRO specializing inthe measurement of CNS drug effects
Typical Phase I Endpoints
Pharmacokinetic parameters (parent drug, principalmetabolite(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
Study Planning
Planning
Concept ProtocolBudget/Contract
Planning/Logistics
Discussobjectives
Propose design
Select doses
Preclinicalsafety profile
Predicted AEs
Scientificintegrity
Feasibility
Logistics
Drug supply
Data analysisstrategy
Costs
Mutualassumptions
StudySchedule
Legal terms
Third-partysuppliers
Study Concept ! Protocol Development
Determine study objectives
Design the treatment regimen and build time and eventsschedule
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 BudgetsFactors 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
Pre-study
Availab
ilit
y o
f su
bje
ct
po
pu
lati
on
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 ConsiderationsRegulations: “GXP”
GCP (Good Clinical Practices)
GLP (Good Laboratory Practices)
GMP (Good Manufacturing Practices)
Other: e.g., FDA 21-CFR-Part 11 (electronic records, electronicsignatures)
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 forsubmission
Respond to Committee’s questions before unconditionalapproval
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)
25 WksTotal
3 WksDraft Report
3 WksDatabase Lock
8 WksStudy Conduct
4 WksRecruitment &Study Initiation
3 WksIRB Approval
3 WksCTA Approval
2 WksProtocol Approval
2 WksStudy Synopsis
3 WksContract Execution
Sample Project Plan
Study Scheduling Example
Sample sizeN=48 complete
Group 1Dose N=18
RandomizeN=54
Group 2Dose N=18 Group 3
Dose N=18
~ 10% attrition
Group 1Admit N=22
Group 2Admit N=22 Group 3
Admit N=22
Stand-bys
TotaleligiblesubjectsrequiredN=66
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
Study Execution: In the Clinic
RegulatoryApprovals
DrugShipment
SubjectAssessmen
t Visits
TreatmentPhase
Follow-upPhase
First Subject First Visit
First Subject Dosed
Last SubjectLast Visit
Milestones:
Clinic Events: Example
8:408:308:208:108:00Dose*0h
8:238:138:037:537:43Subject Questionnaire
8:208:108:007:507:40Blood collection
8:188:087:587:487:38Vital signs
8:158:057:557:457:3512-lead ECG
8:108:007:507:407:30Rest Time
8:057:557:457:357:25Start telemetry
8:007:507:407:307:20UrinePredose
Continuous telemetry through
24h
54321EventsNominal timeDay 1
Subject NumberTreatment Day 1
Time & Events: Subject Breakdown view Cohort A
Study Execution: Behind the Scenes
Source datareview,QC/QA
Drugaccountability
Safety datareview
Subjectcontact/retention
CRFTranscription
/Entry
Sampleprocessing
& shipments
Datacleaning &
queries
Sponsormonitoring
visits
Supplies &Equipment
Maintenance
Subjectenrolmenttracking
ProjectManagement
&Coordination
Study Close-out
Study Close-out
Data queryresolution
Final drugaccountability
& return
Preparerecords forarchiving
Sponsorclose-out
visit
Databaselock
PrepareFinal Report
Unblindeddata review
Phase 1: Special Considerations
FIH / dose escalation studies
Dose
Level 1
Review
Safety
Data
Dose
Level 2Safe?
Yes
No
Review
Safety
Data
Safe?
Yes
No
Terminate
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
Abuse Liability
32%
Ascending Dose/FIM
27%
Drug Interaction
17%
Alcohol Interaction
13%
Other
11%
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 experimentaldesign:Clinical logistics and procedures
Selection and recruitment of patient populations
Drug supply issues
Partner with a clinical site as early as possible
Questions ?