Part of the MaRS BioEntrepreneurship series session: Clinical Trials Strategy Speaker: Sue Gilbert Evans This is available as an audio presentation: http://www.marsdd.com/bioent/feb12 Also view the event blog and summary: http://blog.marsdd.com/2007/02/14/bioentrepreneurship-clinical-trial-strategies-its-never-too-soon/

1. Logistics and Practicalities of
Phase I Clinical Research
Sue Gilbert Evans, M.Sc.
Director, Project Management
February 12, 2007

2. Session Overview
Introduction
Definitions
Stages of a Phase I Clinical Trial
Study Planning
Study Execution
Study Close-out
Special Considerations
Summary
Questions

3. 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

4. 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

5. Study Planning

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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)

13. 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

14. 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

15. 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

16. Study Execution

17. 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

18. 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

19. 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

20. Study Close-out

21. 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

22. 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

23. 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

24. 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%

25. 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

26. Questions ?