CONFIDENTIAL Copyright 2007. Cato Research Ltd. 1 How do clinical trials relate to the MRF1? Lynn Katsoulis SAPPRA 23 March 2007

CONFIDENTIALCopyright 2007. Cato Research Ltd.

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How do clinical trials relate How do clinical trials relate to the MRF1?to the MRF1?

How do clinical trials relate How do clinical trials relate to the MRF1?to the MRF1?

Lynn KatsoulisSAPPRA

23 March 2007


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Points of ViewPoints of View

Planners

Implementers

Report writers


3

Points of ViewPoints of View

Development plansDetails order and timing of data captureEnsure all data collected before needed

Non-clinical tests & Clinical trialsCollect data according to overall development planReport written after each experiment to trial

Regulatory SubmissionsMostly report entire processJustify next step which needs regulatory approval


4

Drug developmentDrug development

High risk industry Long and expensive process to prove drugs are safe and effective Development process costs up to $1.5 Billion

Manufacturing Characterize compound Ensure same compound is produced throughout experimental phase and

for each batch marketed Nonclinical experiments

Collect sufficient data to show lack of risk to subjects Clinical trials

Drugs given to carefully selected population Population expands throughout development process By end of development, should have sufficient data to extrapolate safety

and efficacy of product to general population


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Drug Development processDrug Development process

Non-clinical

Phase 1 Phase 2 Phase 3 Phase 4

Non-clinical

Nonclinical

Short term exposure

Long term exposure

Chemistry Manufacturing and Controls

mg - g Kg - tons

Clinical

Mar

keti

ng a

ppro

val

Fir

st h

uman

dos

e


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Regulatory Perspective:Regulatory Perspective:Building a CTDBuilding a CTD

Index

Application

Labeling/Summary(Annotated Package Insert)

Integrated Analyses of Safety, Effectiveness,Benefits/Risk

NonclinicalPharmacology/

Toxicology

Human PK/Bioavailability

/ Clinical/ StatisticalEstablishment Description

Chemistry

Clinical Full Reports

Chemistry TabularSummaries

Nonclinical TabularSummaries

Clinical TabularSummaries

Chemistry Data/Reports Nonclinical Full Reports

ChemistryData (GMP)

NonclinicalData (GLP)

Clinical CaseReport Forms

ClinicalData (GCP)

Investigators Brochure to Package Insert

Detailed Summaries

Reports

Data

FormAdministrative

Labeling

Executive Summary

Certifications


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Clinical Development StrategyClinical Development Strategy

Focus on the end goal - Reversed planning

Planning

Strategy

Package insert

Drug Development

MarketedMarketedProduct Product


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Drug Development Process:Drug Development Process:Steps from Test Tube to New Drug Application ReviewSteps from Test Tube to New Drug Application Review

http://www.fda.gov/cder/handbook/develop.htm


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Objective at Each StageObjective at Each Stage

Non-clinical Phase 1 Phase 2 Phase 3 Phase 4

-In vitro pharmacology-In vitro safety

-Respiratory, cardiac, hepatic, mutagenicity-In vivo safety

-Single dose / dose ranging-Repeat dose / dose ranging

-Proof of concept


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Toxicology Regulatory RequirementsToxicology Regulatory Requirements

From ICH Guidance for Industry: M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals


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Objective – Phase 1Objective – Phase 1


-Healthy volunteers-Tolerance-Dose range-Pharmacokinetics

-Several trials-About 5 to 30 subjects/trial


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Objective – Phase 2Objective – Phase 2


- Learn all there is to know about the drug

- Dose comparison (2a)- May be several trials- Proof of concept- Numbers to small to show

significant difference- 20 to 60 subjects/trial


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Objective - Phase 3Objective - Phase 3


- Statistical confirmation of Phase 2 trial

- Pivotal trials- Needs to be duplicated- Large trials

- 100s to 1000s of subjects/trial


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Objective - Phase 4Objective - Phase 4


Post-marketing observationsConfirm findings in general population

Collect safety data in large patient group

1000s of subjects/trial


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Objective - OverallObjective - Overall


- Each phase provides information to progress to next step- Marketing approval based on pivotal trials


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Regulatory Perspective:Regulatory Perspective:Building a CTDBuilding a CTD

Index

Application

Labeling/Summary(Annotated Package Insert)

Integrated Analyses of Safety, Effectiveness,Benefits/Risk

NonclinicalPharmacology/

Toxicology

Human PK/Bioavailability

/ Clinical/ StatisticalEstablishment Description

Chemistry

Clinical Full Reports

Chemistry TabularSummaries

Nonclinical TabularSummaries

Clinical TabularSummaries

Chemistry Data/Reports Nonclinical Full Reports

ChemistryData (GMP)

NonclinicalData (GLP)

Clinical CaseReport Forms

ClinicalData (GCP)

Investigators Brochure to Package Insert

Detailed Summaries

Reports

Data

FormAdministrative

Labeling

Executive Summary

Certifications


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How is drug development changing?How is drug development changing?


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How is Drug Development Changing?How is Drug Development Changing?


Non-clinical Exploratory Confirmatory


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Change in GoalsChange in Goals

Non-clinical Exploratory

•Exploratory IND

•Several compounds

•Adaptive trials

Goal

•Compound selection based on clinical data

•Kill compounds earlier

•More compounds explored

Confirmatory• 2-3 doses

• Select responders

• Randomized exclusion

Goal•Increase success rate•Decrease cost of dev.


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Change in GoalsChange in Goals

Non-clinical Exploratory Confirmatory Post-marketing

• Carefully designed program

• Confirm safety

• Extend / Refine label


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Technologies AvailableTechnologies Available

Non-clinical

Phase 1

Phase 2

Phase 3

Phase 4

Adaptive Clinical Trial

Design

BiomarkersX-omics

Electronic DataCapture

Safety Database

Image Database

Electronic Patient Reported

Outcomes


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Role players in clinical trialsRole players in clinical trials

Sponsor (/CRO)

Regulatory

Authority

Investigator (/SMO)

EthicsCommittee

Participant / Subject

EthicsCommittee

Control use of Medical products - safety - efficacy - integrity

Patient protectionEnsure research is ethical - justice - non-malevolence - beneficence - respect for dignity


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Multifaceted Approach to Multifaceted Approach to Participant ProtectionParticipant Protection

Subject

Legislation

MC

C

EC

Aud

its

MC

C, E

C, S

pons

or

Informed Subjects

“deb

arm

ent”

of s

ever

ely

or p

ersi

sten

tly

non-

com

plia

nt in

dust

ry

mem

bers

Participant

Current system


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Global RA & EC Review TimesGlobal RA & EC Review Times

Quintiles data 2000 - 2006

0

1

2

3

4

5

6

7

8

9

10

Bel

gium

Aus

tria

Lith

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aC

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gM

alta

Nor

way

Por

tuga

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oman

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ussi

aS

erbi

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wed

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rland

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SA

loca

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sU

SA

cen

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site

Cze

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Est

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Fin

land

Hun

gary

Icel

and

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Latv

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Sw

itzer

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Liec

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Hon

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New

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Sin

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Gua

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Slo

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Phi

lippi

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Per

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urke

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love

nia

Cos

ta R

ica

Mex

ico

Spa

inS

outh

Afr

ica

Arg

entin

aS

outh

Kor

eaC

olom

bia

Pan

ama

Cro

atia

Indi

aV

enez

uela

Bra

zil

Chi

na

Mo

nth

s


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Major Markets for Drug SalesMajor Markets for Drug Sales

Conference on Harmonisation (ICH)Based on Declaration of Helsinki


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Quality and Drug DevelopmentQuality and Drug Development

Non-ClinicalNon-Clinical

ManufacturingManufacturing

DiscoveryDiscovery

QS

GMP

GLP

WHO:TDR/PRD/QSBR/01.1Quality standards in basic biomedical research”

ClinicaClinicallClinicaClinicall

GCP


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UNDP/World Bank/WHO (TDR)/ “Quality practices for regulated non-clinical R&D”

RESOURCESRESOURCES

RULESRULES

CHARACTERISATIONCHARACTERISATION

DOCUMENTATIONDOCUMENTATION

QUALITY QUALITY ASSURANCEASSURANCE

GXPGXP

Basic Principles of GXPsBasic Principles of GXPs

Result – high quality objective data collected in ethical manner


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Fundamentals of GLPFundamentals of GLP GLP

Resources Organisation, Personnel, Facilities, Equipment

Rules (SOPs and Protocols) Consistent procedures, Optimise processes, Commitments to quality,

Continuity, Training manuals, Reconstruction of study Characterisation

Test item - receipt, storage, control of use, disposal Documentation

Raw data, data collection & recording What? How? When? Who? Generated data should be identified and record directly, promptly, accurately, legibly and

indelibly by the person entering them, and be signed or initialed and dated

Quality Assurance Protocols and SOPs review, Planning (Master Schedule Sheet), Audits and inspections,

Distribution and archiving of QA reports


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Fundamentals of GCPFundamentals of GCP GCP (ICH E6, 21 CFR)

Resources Personnel have adequate education training and experience

Rules (Protocols) Consistent procedures, training records Patient protection – subject has to give individual informed consent

Control of clinical trial material CTM only to be used under protocol Receipt, storage, control of use, disposal

Documentation Raw data, data collection & recording What? How? When? Who? Generated data should be identified and record directly, promptly, accurately, legibly and

indelibly by the person entering them, and be signed or initialed and dated

Quality Assurance Site monitoring mandatory Sponsor or regulatory authority audits


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GXPs & Regulatory SubmissionsGXPs & Regulatory Submissions

In order for data to be accepted as support for a marketing application:Data needs to be collected according to GLP and GCP using GMP product

Needs to be shown in application

Audits and inspectionsHigh enrollers for pivotal studiesAny reason for suspicionSponsor or CRO audit


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Documents Used in Clinical TrialsDocuments Used in Clinical Trials

Investigator brochure (ICH template) All information available on drug Updated throughout development program Used as basis of package insert

Protocol (ICH template) Controlled document Needs regulatory and ethics committee approval If changed, amendment needs to be approved before being implemented

Procedures manual Not controlled Used for site specific, and non-essential details

Informed Consent Document (ICH template) Sufficient information to “enable” a subject to decide whether to participate

or not Clinical study report (ICH template)

Detailed report of findings from the clinical trial


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Clinical Trial DesignClinical Trial Design

Adequate control Pivotal trials need to be adequately controlled Blinding Randomization

Placebo controlled

Comparators If available, gold standard to be used

Dose comparison At least two doses of the drug are compared A dose-comparison study may include additional treatment groups, such

as placebo control or active control Dose-comparison trials usually include randomization and blinding of

patients and investigators


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Ascending Dose

Dose Titration

Dose Tapering

Dose 1

Dose 2

Dose 3

Dose 1

Dose 2

Dose 3

Dose 1

Dose 2

Dose 3


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Cross-Over

Group 1

Group 2

Treatment A

Treatment B Treatment A

Treatment B

ParallelGroup 1

Group 2

Treatment A

Treatment B


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Change to clinical trial designChange to clinical trial design

Currently:

In future:

All subjects Randomize

Placebo

Active

All subjects Response

Non-responder

Responder

Placebo

Active

Randomize


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Three Common Designs

1. Retrospective Hypothesis generating; usually needs confirmatory clinical trial(s)

2. Prospective a. No possible effect in marker negative group

Test must be available

b. Possible effect in marker negative group If test not available: benefit/risk must be acceptable for whole population, even

if efficacy is driven by marker positive group.


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1. Retrospective1. Retrospective


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2a. Prospective, screened2a. Prospective, screened


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2.b. Prospective, Stratified

R

R

R

R


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Herceptin

* From Press and Seelig, Targeted Medicine 2004, New York, November 2004