Download - How do clinical trials relate to the MRF1?
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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
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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
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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
Non-clinical Phase 1 Phase 2 Phase 3 Phase 4
-Healthy volunteers-Tolerance-Dose range-Pharmacokinetics
-Several trials-About 5 to 30 subjects/trial
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Objective – Phase 2Objective – Phase 2
Non-clinical Phase 1 Phase 2 Phase 3 Phase 4
- 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
Non-clinical Phase 1 Phase 2 Phase 3 Phase 4
- 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
Non-clinical Phase 1 Phase 2 Phase 3 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
Non-clinical Phase 1 Phase 2 Phase 3 Phase 4
- 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 Phase 1 Phase 2 Phase 3 Phase 4
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
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2
3
4
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8
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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