New Approaches in Early Clinical Drug Developmentlvbortel/Sunday_7.pdf · New approaches in early...
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New Approachesin
Early Clinical Drug Development
26 August, 2007
Jan de Hoon, PhD, MD, MScCentre for Clinical PharmacologyUniversity Hospital Gasthuisberg
Leuven, Belgium
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New approaches in early clinical drug developmentcontent
• Introduction: the classical approach
• Why look for alternatives?
• Alternative approaches
• Conclusions
Center for Clinical Pharmacology Leuven, Belgium
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2003; 2: 123-131
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Clinical Drug Developmentan overview
Human clinical trials
Nonclinical studies
Stability and formulation development
Chemical synthesis scale-up
Compound optimization
Compound screening
Market
Target identification 1
Years CompoundsCost
100,0000
1US$802M12
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New approaches in early clinical drug developmentwhy look for alternatives? (1)
I. Kola et al. Nat Rev Drug Disc 2004; 3: 711-716
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New approaches in early clinical drug developmentwhy look for alternatives? (2)
I. Kola et al. Nat Rev Drug Disc 2004; 3: 711-716
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New approaches in early clinical drug developmentwhy look for alternatives? (4)
Clinical drug development
limited success rate (11%)30% lack of efficacyexponential increase in development costs
→ Challenge: better predict clinical efficacy at an earlier stage
“Prediction is very difficult,especially if it’s about the future…”.
Nils Bohr
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New approaches in early clinical drug developmentalternative approaches
microdosing or “phase 0”
US eIND & EU eCTA
surrogate markers
human models / experimental medicine / translational medicine
early patient exposure
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New approaches in early clinical drug developmentmicrodosing for PK assessment
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New approaches in early clinical drug developmentmicrodosing for CNS penetration & ROC
Bergstrom et al., Biol Psych 2004
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New approaches in early clinical drug developmentalternative approaches
microdosing or “phase 0”
US eIND & EU eCTA
surrogate markers
human models / experimental medicine / translational medicine
early patient exposure
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New approaches in early clinical drug developmenteIND & eCTA
US: exploratory Investigational New Drug (eIND)
“a clinical trial that is conducted early in phase I and involves limited human exposure, i.e. sub-pharmacologic doses of a product, or doses expected to produce a pharmacologic, but not a toxic, effect,…”
“eIND studies present fewer potential risks than do traditional phase I studies that look for dose-limiting toxicities,…”
EU: early phase I / expedited Clinical Trial Application (eCTA)
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New approaches in early clinical drug developmentalternative approaches
microdosing or “phase 0”
US eIND & EU eCTA
surrogate markers
human models / experimental medicine / translational medicine
early patient exposure
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New approaches in early clinical drug developmentsurrogate markers / endpoints (1)
What is a surrogate marker / endpoints?• substitute for a clinically meaningful endpoint• therapy-induced changes of a surrogate endpoint reflect
changes in a clinically meaningful endpoint
Cavea surrogate is only a surrogate...
CD4-count opportunistic infectionsHIV infection death
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New approaches in early clinical drug developmentsurrogate markers / endpoints (2)
… surrogates are not always a dream come true...
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New approaches in early clinical drug developmentalternative approaches
microdosing or “phase 0”
US eIND & EU eCTA
surrogate markers
human models / experimental medicine / translational medicine
early patient exposure
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New approaches in early clinical drug developmentexperimental medicine (1)
P.J. Goadsby et al.
NEJM (2002)
triptans
CGRP release
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New approaches in early clinical drug developmentexperimental medicine (2)
• 37-amino acid peptide
• Very potent vasodilating neuropeptide CGRP containing perivascular nerves in rat mesenteric resistance artery
N
A C D T CA VT HTL
R
N V G S K A F
VVKN
F V P T
LSRSGG AGL
S S
Human αCGRP
NH2
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New approaches in early clinical drug developmentexperimental medicine (3)
Baseline CGRP
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New approaches in early clinical drug developmentexperimental medicine (4)
CGRP-induced FBF response:
dose-dependent
CGRP (ng.min-1.dL-1 forearm)
0 1 3 10
FBF
(mL.
min
-1.d
L-1 fo
rear
m)
0
2
4
6
8
10
12
14
16
infused arm noninfused arm
n=12
inhibited by CGRP8-37*
CGRP (ng.min-1.dL-1 forearm)
0 1 3 10
FBF
(mL.
min
-1.d
L-1 f
orea
rm)
0
2
4
6
8
10
12
14
16
CGRP + PlaceboCGRP + CGRP8-37
n=6
* 333 ng.min-1.dL-1 forearmVanmolkot et al., Clin Pharmacol Ther 2006; 79: 263-73
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New approaches in early clinical drug developmentalternative approaches
microdosing or “phase 0”
US eIND & EU eCTA
surrogate markers
human models / experimental medicine / translational medicine
early patient exposure
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New approaches in early clinical drug developmentearly patient exposure: target validation (1)
Proof of Principle (POP)or
Proof of Concept (POC)
TARGET
HIT ?
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New approaches in early clinical drug developmentearly patient exposure: phase Ib / IIa (2)
0
20
40
60
80
100
2000-2002 2003 2004 2005 2006 (to date) Beyond 2006
Percentage of FIM trials in patients (Eli Lilly)
By courtesy of Richard Peck, Eli Lilly
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New approaches in early clinical drug developmentConclusions
We’ve got a new wonder drug! … we give it to you and
wonder what it will do