El Futuro de la Innovación en EspañaLa Aproximación del Investigador Básico y Aplicado

Carlos Cordón-Cardó, M.D., Ph.D.Profesor y “Vice-Chair,” Departamento de Patología

Profesor, Departamento de UrologíaDirector Asociado, Herbert Irving Comprehensive Cancer Center

Columbia University

V Foro Europeo de Política Farmacéutica

Madrid – 25 de Mayo, 2009

PharmaBiotech

DiagnosticsDevices

Creation of unimagined products, services and businesses:Integration of IHx, Dx and Rx.

Universities &Government

Labs

PhysiciansHospitalsPharmacy

OtherCaregivers

DISCOVERY AND INNOVATIONMostly Still Developing in University-Based Settings

DISCOVERY AND INNOVATIONUniversity-Based Efforts – Spain vs Europe vs USA

Performance on Innovation at Universities:

Spain 3.6 licenses/year – €45,000/yr EU 11.2 licenses/year – €266,800/yrUSA 26.3 licenses/year – €7,000,000/yr

Turning innovations into technologies reflects in the market, resulting in increased jobs, taxes, and exports. USA Universities have developed “Technology Transfer Offices.”

Patent layers and biotechnology consultants.Particular focus on start-up companies.

(Source: Capital IQ, Windhover, Burrill Analysis)

INDUSTRY TRENDS AND RELEVANCE OF BIOTECHNOLOGY

COLUMBIA UNIVERSITY

Per year: 300 invention disclosures, 50 license deals, 100 industry sponsored agreements, and more than 10 new start-up companies.

50 technology transfer specialists, including 15 licensing officers with academic & industry experience, and 5 in-house attorneys.

Since 1983: Office has filed over 3500 inventions and 1000 patents.

Since 1983: 93 companies based on Columbia's technologies have been created, 65 of which are still active today – 33 were venture-backed, 12 have gone public, and 9 have been acquired.

Major support of an educated investment community.

MANDATES OF THE BASIC/CLINICAL INVESTIGATOR

Bring competitive grants/improve outcomes – Pathway to discovery.

Excel in research/clinical service activities.

Pharma contracts – Philanthropy funds.

Pathway to discovery – Patenting – Creation of new company –Development of IP portfolio – Licensing

FROM THE BENCH TO THE BEDSIDE

ImPath – Created with $2 Million Dollar (1989); Public IPO (1995); Acquired by Genezyme ($350 Million Dollar – 1998). Today serves over 12,000 hospitals and 3,000 clinics (valued at $2.5 Billion Dollar).

Roche Diagnostics – Over $3 Billion Dollar/year.

Vysis – Creation with $6 Million Dollar – IPO followed by acquisition by Abbot for $450 Million Dollar.

• VC & “angels” are hesitant to invest.Business models are changingMore financing of projects

• Higher bar for regulatory approval & reimbursement compression.

• Capital efficiency required.

BUT…

• Rate of start-ups around the world are increasing (go figure…)

ECONOMIC UNCERTAINTIES IMPACT ON ENTREPRENEURIAL START-UPS

It’s a fabulous time to be an investor!(…tougher to be a company looking for financing)

CAUSES FOR ADVERSE OUTCOME IN CANCER

LIMITED BIOLOGY KNOWLEDGE

SUBOPTIMAL TUMOR TARGETING

INSUFFICIENT TUMOR DOSE

POOR CORDINATION – MULTIMODAL Rx

LATE DIAGNOSIS OF DISEASE

Women679,510

2009 Estimated USCancer Cases

Men720,280

CANCER STATISTICS (2009)1:2 MEN / 1:3 WOMEN

1:6 CANCER TREATED PATIENTSWILL DEVELOPED A SECOND CANCER

Spain: 185,000

MANAGEMENT & COST IN ONCOLOGY

96,553

$86,894

$84,525

$81,658

$49,907

0 20,000 40,000 60,000 80,000 100,000

Medicare Cost per patient from diagnosis to death scaled to 2001 costs

Bladder Cancer

Colorectal Cancer

Breast Cancer

Prostate Cancer

Lung CancerLung Cancer

Prostate Cancer

Breast Cancer

Colon Cancer

Bladder Cancer

Costs per patient from diagnosis to cure/death“Medicare Service” (Seguridad Social USA) –2001

[USA Dolars]

Breast Cancer – Cost 2007“Targeted Therapies” - Herceptin

Breast Cancer – Cost 2001$84,500

Breast Cancer – Cost 2007$165,500

““Predictive Molecular StudiesPredictive Molecular Studies””$1,500$1,500--3,5003,500

MANAGEMENT & COST IN ONCOLOGY

HEALTH CARE RELATED EXPENSES

Oncológy-Related Costs Represent 15% ofHealth-Related Expenses

Public and Private Cost of Health (USA- 2006)2.1 Trillion Dolars

Projected Public & Private Cost of Healthy (USA- 2016)4 Trillion Dolars

20 cent of each Dolar will be expende on Health

MANAGEMENT & COST IN ONCOLOGY

(Source: Center for Medicare & Medicaid Services)

Program Administration

7%

Prescription Drugs10%

Investment7%

Nursing Home Care6%

Dental Services

4%Hospital Care31%

Physician & Clinical

Services21% Other

Spending*14%

*Other spending: Other professional services, other personal healthcare, home healthcare, durable medical products, government public health activities

HEALTH CARE RELATED EXPENSES

13.7%

13.6%

11.6%

7.9%7.5%

5.7%

5.5%

5.4%

5.0%

4.6%

4.6%

4.3%

3.5%3.1% 2.1%2.0% Cost of diagnostic services represent

2%-4% of the final expenses.

However, this 3% guides the 97% of the total cost for management.

In certain cases, we could either delay or defray such expense.

Most appropriate intervention in some cases is “not to treat.”

MANAGEMENT & COST IN ONCOLOGY

THE CHANGING FOCUS IN HEALTH CARE

THE STRATEGIC FUTURE OF HEALTHCARE

Economic Unsustainability Reform and Rational Care

Confronting the Imbalance Between Infinite Demand and Finite Resources

or

Access,Cost,

Qualityof care

Molecularand

PersonalizedMedicine

Proficientuse of

Information(e.health)

THE STRATEGIC FUTURE OF HEALTHCARE

TO GIVE EACH PATIENT A BETTER CHANCE

OF CURE BY OPTING FOR THE MOSTAPPROPRIATE THERAPY,

OFFERING GOOD QUALITY OF LIFE, AND PRESERVING MORAL INTEGRITY.

PERSONALIZED & PREDICTIVE MEDICINE

PROSTATE CANCER ANALYSIS: GLEASON GRADE

Normal Prostate

Case 1 (Gleason 6) Case 2 (Gleason 6)

Patient Outcome?

PROSTATE CANCER BIOPSY: GLEASON GRADE

Different Histopathology in Similar Grades

LYMPH NODE – GERMINAL CENTER MULTIPLEXING PROTEIN DETECTION

EMA = Red, Ki67 = Blue, pAkt = Green

KEPLER’S SUPERNOVAChandra/Hubble/Spitzer

TECHNOLOGY IS “HERE”BUT IN OTHER AREAS OF KNOWLEDGE

SYSTEMS PATHOLOGYINTEGRATION OF CLINICAL VARIABLES,HISTOLOGICAL FEATURES, AND MOLECULAR PROFILES, ALLOWING INDIVIDUAL PREDICTION ASSESSMENT.

APPLICATION OF TECHNIQUES IN OBJECT-ORIENTED IMAGE ANALYSIS, PATTERN RECOGNITION, & QUANTITATIVE BIOMARKER MULTI-PLEXING.

COMPLEX DATASETS ARE ANALYZEDBY SUPERVISED MATHEMATICAL APPROACHES, INCLUDING MACHINE LEARNING ALGORITHMS AND NEURAL NETWORKS.(Capodieci et al, Nature Meth 2:263, 2005; Saidi et al, Nature Clin Pract 4:39, 2007; Cordon-Cardo et al, JCI 117:370, 2007; Tabesh et al, Trans Med Imaging 26:1366, 2007; Donovan et al, JCO 26:3923, 2008; Donovan et al, J Urol In Press 2009)

SEGMENT, CLASSIFY, FEATURE EXTRACTION

Original image

1403

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0≤++

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1000~~~~~

−≥++

−−++

−=BGR

BR

BGR

BRYYY

YYYYY

YYHueDiff

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BB YYY

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Magic Developer StudioMagic Developer Studio – New Project

Magic Developer Studio – New Project

CYTOKERATIN 14

CYTOKERATIN 18

CD 34

PTEN

NEW ADVANCES IN MULTIPLEXING PROTEIN DETECTION

Green: AMACR

Blue Nuclei: DAPI

Red: AR

Orange: AMACR(+) Epi Gland

Green: AMACR(-) Epi Gland

Blue: AR(-) / AMACR(-) Nuclei

Red: AR(+) / AMACR(-) Nuclei

Light Blue: AR(-) / AMACR(+) Nuclei

Light Pink: AR(+) / AMACR(+) Nuclei

Pink: Stromal Nuclei

Note: AMACR = Alpha-methylacyl-CoA racemase

AR = Androgen Receptor

PREDICTION OF TIME TO CLINICAL FAILURE – BIOPSY STUDY

(Donovan et al, J Urol - In Press 2009)

Prob

abili

ty o

f Rem

aini

ng

Clin

ical

Fai

lure

-Fre

e

Actual Time to Clinical Failure (months)

PREDICTION OF TIME TO CLINICAL FAILURE – RISK GROUPS

P < 0.0001

PREDICTIVE ACCURACY: 92% - SPECIFICITY: 91%; SENSITIVITY: 90%

Low-Risk (257 Pts., 252 Clinical Failure-Free)

High-Risk (88 Pts., 63 Clinical Failure-Free)n = 345

(Donovan et al, J Clin Oncol 26:3923, 2008)

Validation - n = 385 HR = 11

PSA Gleason Stage

5.1 ng/ml 3+4 T1c

AUA Clinical Judgment

Online Tools

SystemsPathology

Intermediate

Low85%Free

High RiskPx⊕ SCORE

46

Risk Assessment

Disease Progression in 2.5 months

Intermediate

Case #3: 62 y/o male with no family history of PrCa, negative DRE,and mildly elevated PSA.

Ki67 High (26%)/AR High (4.5Index)

PSA Gleason Stage

5 ng/ml 6 T3

AUA Clinical Judgment

Online Tools

SystemsPathology

HighRisk

Intermediate

Low RiskPx⊕ SCORE

12

Risk Assessment

No Disease Progression in 172 months

HighRisk

Case #1: 59 y/o male in good health, suspicious DRE,elevated PSA, and by imaging stage T3.

Ki67 Low (1%)/AR Low (1.25Index)

RANGE OF TARGET MOTION DURING TREATMENT

(PTV-CTV) = Safety Margins:CTV – Prostate and seminal vesiclesPTV – 10 mm around CTV, except

6 mm at rectal interface

Diagnosis and Workup Tumor Phenotyping Treatment Planning

Treatment Delivery

FRACTIONATED RADIOTHERAPY

Diagnosis and Workup

Treatment Delivery

FRACTIONATED RADIOTHERAPY

(Collaboration with C. Ling & Z. Fuks)

Tumor Phenotyping

Treatment Planning

Treatment Delivery

Diagnosis and Workup

Tumor Phenotyping

SINGLE-DOSE RADIOTHERAPY Treatment Planning

STEREOTACTIC SINGLE-DOSE RADIOTHERAPY FOR BRAIN METASTASESRELATIONSHIP OF DOSE AND LOCAL CONTROL

UCSF Series; Shiah et al, IJROBP 1997

261 lesions in 119 patients with lung, breast, melanoma, renal, colorectal, testicular,

gynecological and thyroid tumors

Patients with metastatic breast, colorectal, lung, head and neck, liver, pancreatic, sarcoma, melanoma and other tumors

0 12 24 36 48

20

40

60

80

100

p=0.04

23-24 Gy (n=67; 82%)

21-22 Gy (n=42; 69%)

18-20 Gy (n=11; 25%)

p=0.18

Time (months)

Loca

l Rel

apse

-free

Sur

viva

l

Oligometastatic lesions (n=120) to soft tissues and boneGreco & Zelefsky, 2009 - Unpublished

50

p=0.03

18-23 Gy (N=35;80%)

24Gy (N=68;96%)

0 10 20 30 4070

80

90

100

Loca

l Rel

apse

Fre

e Su

rviv

al

Oligometastatic lesions (n=103) to the spineYamada, IJROBP, 112:650, 2008

Time (months)

Local Control of Oligometastatic Tumors The MSKCC Series of SD-IGRT

SYSTEMS PATHOLOGY PLATFORMINNOVATIVE AND SUPERIOR

1.0 2.08 3.0 4.0

Prostate BiopsyTest

Biopsy Gleason predicts

PSA-Rec

1.971.03

1.22

MammaPrint predicts time to

distant metastasis

(breast)

Oncotype DX predicts likelihood of distant recurrence (breast)

Percent positive biopsies predicts PSA-Rec

Reduction in breast cancer recurrence

(Herceptin)

PSA predictsPSA-Rec

3.21

ProstateNomogram

2.323.47

ProstatectomyTest

11.0HR

2.5

Predictive, personalized, and cost-effective; individualized patient management.

Diagnostic and prognostic approachthat “groups” patients into disease categories.

TECHNICAL, SOCIAL AND ETHICAL CHALLENGES

NOVEL METHOS, SUPER-SUBSPECIALIZED PROFESIONALS,INTEGRATED-MULTIDISCIPLINARY TEAMS

GENETIC DISCRIMINATION, INSURANCE POLICIES,PUBLIC DEBATE AND LEGISLATION

COST OF NEW TREATMENTS, EQUAL ACCESS TO CARE,INFORMED CONSENT AND CONFIDENTIALITY ISSUES

EDUCATIONAL AND ECONOMICAL CHALLENGES

REMODELING OF UNIVERSITY STRUCTURE TO INCORPORATEPROFESSIONAL TEAMS TO ASSIST INVESTIGATORS.

EMPOWERING VENTURE CAPITAL AND BANKING GROUPS TOPARTICIPATE IN FUNDING OF EARLY START-UPS.

EDUCATION OF SOCIETY AIM AT UNDERSTANDING THE VALUEOF INVESTING IN SCIENTIFIC INNOVATION.

CREATING NEW MODELS – PUBLIC/PRIVATE ENTERPRISES.

DESIGNING AND IMPLEMENTING CUSTOMIZATION OF HEALTHCARE – PERSONALIZED, PATIENT-CENTERED CARE .

FAILING TO PLAN IS PLANNING TO FAIL!