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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
New approaches in early clinical drug developmentcontent
• Introduction: the classical approach
• Why look for alternatives?
• Alternative approaches
• Conclusions
Center for Clinical Pharmacology Leuven, Belgium
2003; 2: 123-131
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
New approaches in early clinical drug developmentwhy look for alternatives? (1)
I. Kola et al. Nat Rev Drug Disc 2004; 3: 711-716
New approaches in early clinical drug developmentwhy look for alternatives? (2)
I. Kola et al. Nat Rev Drug Disc 2004; 3: 711-716
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
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
New approaches in early clinical drug developmentmicrodosing for PK assessment
New approaches in early clinical drug developmentmicrodosing for CNS penetration & ROC
Bergstrom et al., Biol Psych 2004
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
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)
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
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
New approaches in early clinical drug developmentsurrogate markers / endpoints (2)
… surrogates are not always a dream come true...
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
New approaches in early clinical drug developmentexperimental medicine (1)
P.J. Goadsby et al.
NEJM (2002)
triptans
CGRP release
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
New approaches in early clinical drug developmentexperimental medicine (3)
Baseline CGRP
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
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
New approaches in early clinical drug developmentearly patient exposure: target validation (1)
Proof of Principle (POP)or
Proof of Concept (POC)
TARGET
HIT ?
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
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