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Industry productivity has declined Source: PhRMA Annual Survey, 2000 # NMEs 10 30 Total R&D Investment ($ Billions) 20 40

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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

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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

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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

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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

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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

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Hit Target Affect Mechanism of Action Impact Disease Progression Paradigm for Preclinical and Clinical Drug Development What questions do we need to address?

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Oncology Imaging Examples 1)Functional Imaging PET Imaging dce MRI 2) Structural Imaging CT imaging (or MRI) 1)Functional Imaging PET Imaging dce MRI 2) Structural Imaging CT imaging (or MRI)

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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

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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

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FDG-PET for decision-making

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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)

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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

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1)Functional Imaging PET Imaging dce MRI 2) Structural Imaging CT imaging (or MRI) Oncology Imaging Examples dce MRI

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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

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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)

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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

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1)Functional Imaging PET Imaging dce MRI 2) Structural Imaging CT imaging (or MRI) Oncology Imaging Examples 2) Structural Imaging CT imaging (or MRI)

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Assessment of Tumor Size: 3D Volume Enables Earlier Termination or Acceleration (VirtualScopics Inc, NY) Tumor statistics:1D length2D cross-prod3D volume Baseline28.98711.7243728.60 6 Weeks28.27673.8318739.70 Tumor statistics:1D length2D cross-prod3D volume Baseline28.98711.7243728.60 6 Weeks28.27673.8318739.70 Tumor statistics:1D length2D cross-prod3D volume Baseline28.98711.7243728.60 6 Weeks28.27673.8318739.70

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Assessment of cavitated lesions 4 weeks after baselineBaseline scan

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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

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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?

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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

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Local Thickness and Bone Remodeling Changes over Time Femoral CartilageSubchondral Bone Plate Morphometry Baseline / 6 Months (Registered Overlays)

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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

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5-HT 1A receptor distribution in the human brain Pre synaptic autoreceptors Post synaptic receptors

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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?

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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.

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Healthy subject PD patient Hoehn-Yahr Stage 1 Functional Imaging with -CIT: Dopamine Transporter

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Longitudinal DAT Imaging in PD

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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.

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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.)

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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).

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Search For An Objective, Quantifiable, Reliable Marker of Somnolence or Diminished Arousal

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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

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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

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Acknowledgements Jeff Evelhoch Tim McCarthy Teresa McShane Peter Snyder Steve Williams Virtual Scopics Molecular Neuroimaging