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

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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 ?