phase i: overview - ich.org · overview of tm study types ... week 1 week 2 week 3 week 4 week 5...
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Phase I: OverviewNamrata Bahadur, MDHead of Clinical Development & Medical AffairsEmerging Growth MarketsMarch, Bangkok
© 2008 Novartis
The information within this presentation is based on the presenter’s expertise and experience, and represents the viewsof the presenter for the purposes of a training workshop
© 2008
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PK in Drug Development
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Mission Statement – Translational Medicine
…… drives Innovative and Cutting Edge Science from
Discovery to the Market through the selection, profiling and
effective global development of successful Novartis
medicines to enhance the quality of people’s lives
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TM Deliverables/Contributions• Coordination of external input (PoC Summit)• PoC Plan as approved by TRTD• PoC conduct (incl. studies preparing PoC)• Post-PoC and Peri-PoC plan• Preparation of the steps toward full development
TM’s Contribution to Development Process
Phase 3
ISA FDP SDP
Phase 2
Registration
Exploratory Phase
TM Contribution to IPT• Contribution to Full Development CDP• Support development program strategy• Conduct Profiling Clin. Pharm. Studies• Support steps toward commercialization• Conduct mechanistic studies
Early Project Team
sPoC
International Project Team
PoC
DDP
ALIGN@DDP Process
TM Discovery Profiling RES
→→ TM contributes to all phases of development conducting a multitude of clinical trials
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Overview of TM Study Types
• Exploratory Phase• First in man (FIM) study: a single dose safety & tolerability study in healthy
volunteers, or a single dose study in patients (depending on the indication). May already provide relevant PoC readout.
• Multiple dose safety & tolerability study in HVs or patients• *PoC study• Validation studies (e.g. supported by Clinical Innovation Fund)
*In many cases SD and MD safety & tolerability studies results are needed for preparation of PoC study
Confirmatory Phase• Human ADME study• Multiple pharmacokinetic studies, e.g. relative/absolute bioavailability, dose
linearity, investigation on factors food, age and gender, special populations (hepatic and renal impairment), drug-drug interaction studies
• Imaging/biomarker studies, “mechanistic” studies• ECG studies (preclinical signals?)• Phototoxicity study (preclinical signals?)• Abuse liability study (study in drug experienced subjects)
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The Package Insert
MoA
PK
ADME
Special Popn
Age
Renal
Hepatic
Gender
PD
QTc
DDI
Pediatric
Geriatric
Overdose
Dosing
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Types of studies – Classic Clinical PharmacologyAbout 60% of the studies run by TM are simple studies with
either a PK or safety focus
• FIM (Single dose S&T)
• QTc
• Drug/drug interaction
• Bio-equivalent
• Bio-availability (absolute or comparative)
• Food effect
• ADME
• Special populations
- Renal/ Hepatic/ Japanese
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Types of studies (2) – Complex scientific studiesAbout 40% of the studies run by TM are complex studies
with a Pharmacodynamic or safety focus
• FIM (Multiple dose S&T)
• POM
• POC
• Mechanistic
• Methodology
• PK/PD
• Adaptive
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Phase I (Healthy Volunteers) CROsSpecialized Hospital Clinics (Patients)
Study Sites
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TM is Global
East Hanover
Cambridge
Basel
TokyoTsukubaHorsham
BeijingShanghai
Mumbai
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Early Phase Studies to support PoC
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Single Ascending Dose Study: Classical Design
Randomized, double-blind, placebo-controlled, time lagged, parallel-group, ascending single dose study in HVs to explore safety, tolerability, pharmacokinetics and pharmacodynamics
week 1 week 2 week 3 week 4 week 5 week 6 week 7 week 8
Cohort 1 0.3 mg1) (seq. dosing)
10 mg fed
Cohort 2 1 mg
Cohort 3 3 mg
Cohort 4 10 mg
Cohort 5 30 mg
Cohort 6 100 mg
1) start dosing in sequence e.g. 48 hours apart
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Single Ascending Dose Study: Interleaved Design
Weeks Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8 Week9
A 5 mg 50 mg Plac
B 5 mg Plac 400 mg
C Plac 50 mg 400 mg
A 10 mg 100 mg
Plac
B 10 mg Plac 800 mg
C Plac 100 mg
800 mg
A 20 mg 200 mg
Plac
B 20 mg Plac 600 mg
C Plac 200mg 600 mg
Cohort 3
Cohort 2
Cohort 1
• Randomized, double blind, interleaved, ascending dose study with placebo substitution in 36 healthy volunteers (12 per cohort)
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Multiple Ascending Dose Study: Classical Design
• Design: Randomized, double-blind, placebo-controlled, parallel group, time-lagged, ascending multiple oral dose study
• Objectives: Safety, tolerability, PK and/or PD of ascending multiple oral doses in healthy volunteers
• Sample size: 24 – 36 subjects (depending on number of doses)
BaselineWeek 1Week 4
PD assessments
••••
••••
••••
•••••••Cohort 1 Screen Dose 1
Cohort 3 Dose 3
Cohort 2 Dose 2
Cohort 4 Dose 4/MTD
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Combination of SD/MD: Interwoven Design
Expa
nded
s
afet
y re
view
Week1 2 3 4 5 6 7 8 9
½ of SD 3mg
SD 10 mg
SD 25 mg
SD 50 mg Fast
SD 100 mg
SD 200 mg
MD 10 mg
MD 25 mg
MD 50 mg
MD 100 mg
½ of SD 3mg
SD 300 mg
MD 200 mg
MD 300 mg
Doses for SD cohortsSD 6 +7 optional1st Doses for MD cohortsMD 5 + 6 optional
Timing assumes no safety issues
SD 50 mg Fed
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The Spectrum of “POC”
Proof of Target*Proof of Mechanism
Proof of EfficacyProof of Commercialization
* Proof of Target Modulation
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Characteristics of PoC Trials• PoC trials typically are short and involve relatively few
patients/healthy subjects
• Studies should enable intelligent Go/No-Go decisions
• Studies often lack power for statistical significance
• This places an emphasis on the quality of the read-outs (e.g. pharmacodynamic parameters, biomarkers) to yield insights into the relevant human physiology
• To ensure high-quality read-outs investigators have to be adequately trained and relevant procedures closely monitored.
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Confirmatory Phase Study Examples
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PK: 2 period cross-over
WKs-2 0 1 2 3
Washout
Drug 1 Drug 1
Drug 2 Drug 2
Period 1 Period 2
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PK: 4 period cross-over
WKs-2 0 1 2 3 4 5 6 7
Washout
Drug 1 Drug 1
Drug 2 Drug 2
Period 1 Period 2 Washout
Drug 1 Drug 1
Drug 2 Drug 2
Period 3 Period 4Washout
Drug 3 Drug 3
Drug 4 Drug 4
Drug 3 Drug 3
Drug 4 Drug 4