Industry productivity has declined Source: PhRMA Annual Survey, 2000 # NMEs 10 30 Total R&D...
39
B iom arkers and M edicalImaging in C linicalT rials B iom arkers and M edicalImaging in C linicalT rials PfizerG lobalR esearch & D evelopm ent W orld W ide C linicalTechnology G roton Laboratories PfizerG lobalR esearch & D evelopm ent W orld W ide C linicalTechnology G roton Laboratories
Industry productivity has declined Source: PhRMA Annual Survey, 2000 # NMEs 10 30 Total R&D Investment ($ Billions) 20 40
Industry productivity has declined Source: PhRMA Annual Survey,
2000 # NMEs 10 30 Total R&D Investment ($ Billions) 20 40
Slide 3
All products and processes have performance limits and the
closer one gets to these performance limits, the more expensive it
becomes to squeeze out the next generation of performance
improvement. Richard N. Foster Examples: 1)Bell Labs recognized
electromechanical switches could not be made small enough so they
used quantum mechanics and developed the transistor. 2)Watson
Research Labs at IBM assessed the practical level of computer chip
density to impact the develop of the 43xx and 308x computer series
3)Pfizer
Slide 4
Why is Pfizer investing in technology development? Current
Pharma business model is under threat R&D spend per NDA
increased 4.4X 1990-2001 75% of R&D spend is on failed
candidates Many blockbusters' patents expiring in next 5 years
R&D bottleneck has shifted No longer limited by generation rate
of targets and chemical ligands Target generation from genomics,
proteomics Combinatorial chemistry Now the problem is finding out
what works and what doesn't, cheaply and efficiently
Slide 5
Developing biomarkers and quantitative imaging tools Long-term
development Beyond imaging Immediate and Near-term development
Oncology Osteoarthritis CNS Why is Pfizer investing in technology
development? Key issues for quantitative imaging
Slide 6
Developing quantitative imaging tools Issues Validation
criteria - Fit for purpose Reproducibility Establishing quality
standards Preclinical to clinical translation Focused on clinical
questions Relevant and appropriate models Public forums for
discussion, debate and consensus building Education Acceptance
Slide 7
Focusing on the issues Standardization of the methodology QA/QC
of equipment and analysis methods Reproducibility (test/retest)
Intra-subject Inter-subject Intra-site Inter-site Between
manufacturers Magnitude of the anticipated signal change Is it
significant? Is instrument noise greater than signal related to
disease? Coefficients of Variation
Slide 8
Hit Target Affect Mechanism of Action Impact Disease
Progression Paradigm for Preclinical and Clinical Drug Development
What questions do we need to address?
Imaging Tumor Metabolism/Function 18 F - FDG
(fluorodeoxyglucose) actually measures hexokinase activity (glucose
metabolism) phosphorylated to 18 F - FDG-6-PO 4 which is chemically
trapped within cells can be shipped to any PET or SPECT site 18 F -
FLT (fluorothymidine) actually measures thymidine kinase activity
(DNA synthesis) phosphorylated product is chemically trapped within
cells 11 C - thymidine incorporated into DNA very rapidly
metabolized 11 C - choline incorporated into cell membrane
phospholipid and chemically trapped after phosphorylation 15 O -
water blood flow 11 C CO blood volume 18 F misonidazole (FMISO)
image tumor hypoxia 11 C - methionine amino acid uptake and protein
metabolism 18 F - 17-estradiol 11 C - acetate measuring oxidative
activity
Slide 11
What questions do we need to address? Hit Target Affect
Mechanism of Action Impact Disease Progression Targeted
Radioligands FDG-PET FLT-PET FDG-PET ?? PET imaging
Slide 12
FDG-PET for decision-making
Slide 13
Slide 14
Baseline Treatment Day 7 Heart Kidney Bladder MetastaticTumor
FDG-PET Response Patient (DFCI) Metastatic GIST FDG-PET Response to
SU11248 in a patient resistant to Gleevec 50 mg/day (2 wks on 2 wks
off) Link metabolic response to plasma levels (PK) serum and biopsy
markers (PD)
Slide 15
SU11248 Phase 1 (PMCI) Baseline Day 14 FDGFLT Case History: 19
y.o. male with metastatic synovial sarcoma 50 mg/day SU11248 (4wks
on 2 wks off) Tumor Prior radiation field ASCO 2003 Abstract
#767
Permeable vesselNormal vessel Possible measures from dceMRI
blood flow blood volume permeability (dynamic contrast enhanced)
dceMRI time RR enhancement ratio (tissue:blood) fractional BV
Permeable vessel permeability blood flow
Slide 18
Hit Target Affect Mechanism of Action Impact Disease
Progression Paradigm for Preclinical and Clinical Drug Development
What questions do we need to address? dceMRI VEGF inhibitor
(angiogenesis inhibitors)
Slide 19
5 cm dceMRI lesion imaging 10 anatomical slices obtained within
a set field of view (FOV) every 11 sec as contrast agent is
injected at a constant rapid rate At baseline, operator must choose
the index lesion and center on that lesion at every subsequent scan
Illustration of a single anatomical slice from a 5 cm FOV in the
axial plane 3 cm pre-contrast post-contrast
Assessment of cavitated lesions 4 weeks after baselineBaseline
scan
Slide 23
Developing biomarkers and quantitative imaging tools Long-term
development Beyond imaging Immediate and Near-term development
Oncology Osteoarthritis CNS Why is Pfizer investing in technology
development? Key issues for quantitative imaging
Osteoarthritis
Slide 24
What are the problems with radiographic endpoints? Proper
positioning decades later still a controversy A 3-d structure
imaged on a 2-d plate/film superimposition magnification rotation
Sensitivity to detect change subjective scoring What are we
measuring? Fixed flexion? MTP? Template? Fluoroscopic?
Slide 25
Developing Technologies to Quantify Image-Based Data Current
Methods VirtualScopics Technology Inability to efficiently analyze
and display parameters of cartilage in 3D Inability to measure
detailed characteristics of the cartilage 3D Roughness 3D Volume
Detailed Measurements
Slide 26
Local Thickness and Bone Remodeling Changes over Time Femoral
CartilageSubchondral Bone Plate Morphometry Baseline / 6 Months
(Registered Overlays)
Slide 27
Developing biomarkers and quantitative imaging tools Long-term
development Beyond imaging Immediate and Near-term development
Oncology Osteoarthritis CNS Why is Pfizer investing in technology
development? Key issues for quantitative imaging CNS
Slide 28
5-HT 1A receptor distribution in the human brain Pre synaptic
autoreceptors Post synaptic receptors
Slide 29
CP xxx occupancy of the 5-HT 1A receptor in vivo baseline Post
10 mg of CP xxx How well does the compound penetrate the CNS? What
is the dose-related occupancy at the target sites? How selective is
the drug for its intended site?
Slide 30
Imaging in Parkinson's Disease Bridge between brain pathology
and clinical symptoms - Quantitative assessment of DA loss.
Repeated assessment Identify DA loss prior to symptoms.
PARKINSON (1817) CASE A.B. What words he still could utter were
monosyllables, and these came out, after much struggle, in a
violent expiration, and with such a low voice and indistinct
articulation, as hardly to be understood but by those who were
constantly with him.
Slide 34
DYSARTHRIC SPEECH AND PD The fundamental pathophysiology of PD
is a depletion of dopamine in the substantia nigra and the corpus
striatum Mainly motor symptoms and cognitive deficits Speech
alterations and hypokinetic dysarthria are integral parts of motor
disorders in PD First descriptions of dysarthria were based on
perceptual ratings and reported indistinctness of articulation,
weakness of voice, lack of inflection, burst of speech,
hesitations, and stoppages (Darley et al, 1975.)
Slide 35
QUANTITATIVE VOICE ACOUSTICS Tremor and falling pitch are seen
in the production of vowel /a/ in pa, for a single subject with
mild PD. Notice the instability of the fundamental frequency and
the amplitude (green and black lines in window B).
Slide 36
Search For An Objective, Quantifiable, Reliable Marker of
Somnolence or Diminished Arousal
Slide 37
What Will the Most Important Technology Be? Mathematics Image
generation and analysis (every modality) Proteomics, metabonomics,
genomics, lab biomarkers a math problem Multivariate signatures
from multiple sources of information will outperform the human
brain
Slide 38
What action can we take from here? Work with regulators and
academicians toward the development, validation and acceptance of
quantitative endpointsWork with regulators and academicians toward
the development, validation and acceptance of quantitative
endpoints Consider the development of safe harbors for biomarker
development with unknown implicationsConsider the development of
safe harbors for biomarker development with unknown implications
Gene expression profiling, proteomics, safety dataGene expression
profiling, proteomics, safety data
Slide 39
Acknowledgements Jeff Evelhoch Tim McCarthy Teresa McShane
Peter Snyder Steve Williams Virtual Scopics Molecular
Neuroimaging