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The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Michael Caligiuri, MD(Co-host and Panelist)
OSUCCC-James
Director, OSUCCC; CEO, The James
Ellen Sigal, PhD (Co-host)
Friends of Cancer Research
Chair and Founder
James Doroshow, MD(Panelist) NCI Director, Division of Cancer
Treatment and Diagnosis
Eric Rubin, MD (Panelist) Merck VP, Oncology Clinical Research
Janet Woodcock, MD(Panelist) FDA Director, Center for Drug
Evaluation & Research
Robert Brueggemeier, PhD (Q&A Moderator) Ohio State Dean, College of Pharmacy
Public Session
3
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Brian Cummings Ohio State VP, Technology Commercialization
Anthony Dennis PhD BioOhio President and CEO
Richard Gaynor MD
Eli Lilly and Company
VP, Clinical Development & Medical Affairs, Oncology Business Unit
Courtney Granville PhD, MSPH Battelle Toxicologist/Study Director
Michael Grever MD
OSUCCC-James
Chair & Professor, Dept of Internal Medicine; Associate Dean of Medical Services; Co-Leader, Experimental Therapeutics Program
Additional Roundtable Participants
4
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Joanne Lager MD
Sanofi-Aventis
Senior Director and Oncology Drug Project Head
Michael Mitchell JD Ohio State Assistant VP and
Associate General Counsel
Christine Poon MBA Ohio State Dean, Fisher College of Business
David Roth MD Pfizer VP, Early Development,
Oncology Business Unit
David Schmickel JD, PhD FoxKiser Legal Counsel
Allen SingerDVM Battelle VP, Center for Life Sciences Research
Additional Roundtable Participants
5
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Ira Steinberg MD
Sanofi-Aventis
Associate VP & Global Medical Affairs Leader
Miguel Villalona MD
OSUCCC-James
Director, Division of Medical Oncology & Professor, Dept of Internal Medicine
Tim Wright Signal Hill Advisors Biotech and Pharmaceutical Consultant
Additional Roundtable Participants
OSU Comprehensive Cancer CenterColumbus, OH
May 4, 2011
Developing Experimental Drug Combinations: Opportunities and Challenges
James H. Doroshow, M.D.Director
Division of Cancer Treatment and Diagnosis, NCI
Challenges to Development of Combination Targeted Therapeutics
• Incomplete understanding of mechanisms of action for a growing number of targeted agents available for trial
• Inability to assess target effect– Lack of assays, imaging tools– Lack of assay standardization– Lack of commercially-available agents formulated for in vitro use– Lack of available investigational agents for in vitro use
• Lack of preclinical models for combinations– To evaluate efficacy, schedule effects, biomarker utility, toxicity
• Clinical trials methodology– Need to screen large numbers of patients?– Need for tumor biopsies?– Is histologic homogeneity relevant?– Pharmacokinetic interactions? SD vs RR?
• Intellectual property & regulatory challenges to novel combinations
Drug BiomarkerAnti-estrogens ER, PR, genomic signature
Trastuzumab Her2 FISH, IHC
EGFR small molecule inhibitors Mutation status
B-Raf, ALK inhibitors Mutation statusAnti-VEGF/VEGFR agents ??
IGF-I receptor antagonists ??
Src inhibitors ??Cdk/Cyclin D1 inhibitors ??
HDAC/DNMT inhibitors ??
Anti CTLA-4 Antibody ??
Lack of Molecular Markers with Proven Clinical Utility
Concept Feasibility & Development Validation Launch
Target Application Platform Feasibility Development Analytical Validation
Preclinical Modeling
Specimen SOPs
Assay Transfer
Clinical Validation
Support NCI Clinical
Trials
Transfer to Scientific
CommunityBiopsy Assays
γ-H2AX Protein(tumor)
DNA Damaging Agents ELISA P P l
γ-H2AX Protein(tumor)
DNA Damaging
AgentsqIFA P P P P P l l l
Top 1 Protein TOPO Inhibitors ELISA P P P l P
METTK domain and Grb2
Docking SiteKinase Inhibitors
IFACommerci
al Reagents
P P l l l l
METTK domain and Grb2
Docking SiteKinase Inhibitors
IFACustom
ReagentsP P P l
PARG mRNA PARP Inhibitors RT-qPCR P P P P P P P R
PARP 1 mRNA PARP Inhibitors RT-qPCR P P P P P P P R
PARP 1,2 Activity(PAR levels)
PARP Inhibitors IA P P P P P P P l l
PARP 2 mRNA PARP Inhibitors RT-qPCR P P P P P P P R
Stem Cell Proteins -ALDH 1A1-OCT 3/4-NANOG-CD44v6
Tumor Stem Cell Inhibitors IFA P l H l
KEY:l In Progress P Completed X Dropped
l Delayed CA Commercially Available NA/UIN Not Applicable or Uninformative
l Technical Difficulty H On Hold R Ready
Pharmacodynamic Assay Development
Challenges to Development of Combination Targeted Therapeutics
• Incomplete understanding of mechanisms of action for a growing number of targeted agents available for trial
• Inability to assess target effect– Lack of assays, imaging tools– Lack of assay standardization– Lack of commercially-available agents formulated for in vitro use– Lack of available investigational agents for in vitro use
• Lack of preclinical models for combinations– To evaluate efficacy, schedule effects, biomarker utility, toxicity
• Clinical trials methodology– Need to screen large numbers of patients?– Need for tumor biopsies?– Is histologic homogeneity relevant?– Pharmacokinetic interactions? SD vs RR?
• Intellectual property & regulatory challenges to novel combinations
• COMBO set 1– 87 compounds of diverse mechanism– Includes many older FDA-approved anticancer agents
• FDA-approved COMBO set (9/09):
NCI “COMBO Plates”Plated Compounds for Combination Studies
Molec. Cancer Ther. 9:1451-1460, 2010
Challenges to Development of Combination Targeted Therapeutics
• Incomplete understanding of mechanisms of action and a growing number of targeted agents available for trial
• Inability to assess target effect– Lack of assays, imaging tools– Lack of assay standardization– Lack of commercially-available agents formulated for in vitro use– Lack of available investigational agents for in vitro/in vivo use
• Lack of preclinical models for combinations– To evaluate efficacy, schedule effects, biomarker utility, toxicity
• Clinical trials methodology– Need to screen large numbers of patients?– Need for tumor biopsies?– Is histologic homogeneity relevant?– Pharmacokinetic interactions? SD vs RR?
• Intellectual property & regulatory challenges to novel combinations
Challenges to Development of Combination Targeted Therapeutics
• Incomplete understanding of mechanisms of action and a growing number of targeted agents available for trial
• Inability to assess target effect– Lack of assays, imaging tools– Lack of assay standardization– Lack of commercially-available agents formulated for in vitro use– Lack of available investigational agents for in vitro/in vivo use
• Lack of preclinical models for combinations– To evaluate efficacy, schedule effects, biomarker utility, toxicity
• Clinical trials methodology– Need to screen large numbers of patients?– Need for tumor biopsies?– Is histologic homogeneity relevant?– Pharmacokinetic interactions? SD vs RR?
• Intellectual property & regulatory challenges to novel combinations
Modeling Therapeutic Combinations in NCI 60
For any 2-drug combination:
MCF7DU-145
PC-3UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
MALME-3M
Bars to right indicate overall benefit to using combo relative to best single-agent results
Bars to leftindicate loss
of benefit relative to best single-agent results
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
MALME-3MLOX IMVI
U251SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
-10 -5 0 5123127_226080
Doxorubicin + Rapamycin Bortezomib + Cladribine (2CDA)
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
MALME-3MLOX IMVI
U251SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
Cel
l line
-10 -5 0 5 10 15 20 25681239_606869
Cel
l lin
e
cellname
CCRF-CEMHL-60(TB)K-562MOLT-4RPMI-8226SRA549/ATCCEKVXHOP-62HOP-92NCI-H226NCI-H23NCI-H322MNCI-H460NCI-H522COLO 205HCC-2998HCT-116HCT-15HT29KM12SW-620SF-268SF-295SF-539SNB-75SNB-19U251LOX IMVIMALME-3MM14MDA-MB-435SK-MEL-2SK-MEL-28SK-MEL-5UACC-257UACC-62IGROV1OVCAR-3OVCAR-4OVCAR-5OVCAR-8NCI/ADR-RESSK-OV-3786-0A498ACHNCAKI-1RXF-393SN12CTK-10UO-31PC-3DU-145MCF7MDA-MB-231/ATCCHS 578TBT-549T-47DMDA-MB-468
CCRF-CEMHL-60(TB)K-562MOLT-4RPMI-8226SRA549/ATCCEKVXHOP-62HOP-92NCI-H226NCI-H23NCI-H322MNCI-H460NCI-H522COLO 205HCC-2998HCT-116HCT-15HT29KM12SW-620SF-268SF-295SF-539SNB-75SNB-19U251LOX IMVIMALME-3MM14MDA-MB-435SK-MEL-2SK-MEL-28SK-MEL-5UACC-257UACC-62IGROV1OVCAR-3OVCAR-4OVCAR-5OVCAR-8NCI/ADR-RESSK-OV-3786-0A498ACHNCAKI-1RXF-393SN12CTK-10UO-31PC-3DU-145MCF7MDA-MB-231/ATCCHS 578TBT-549T-47DMDA-MB-468
cellname
C
C
718781
_70754
5718
781_45
388226
080_71
8781
609699
_71878
1718
781_10
2816
732517
_71878
1675
74_718
781718
781_10
5014
226080
_40996
2226
080_22
1019
123127
_22608
0681
239_10
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681239
_70754
5681
239_60
6869
732517
_755
732517
_22101
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517_24
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83265_
732517
747971
_12275
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971_71
423613
327_72
1517
123127
_74575
0750
690_10
2816
19893_
241240
609699
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6609
699_82
151609
699_70
7545
613327
_10501
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127_31
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266046
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266046
_10501
4
718781
_70754
5718
781_45
388226
080_71
8781
609699
_71878
1718
781_10
2816
732517
_71878
1675
74_718
781718
781_10
5014
226080
_40996
2226
080_22
1019
123127
_22608
0681
239_10
5014
681239
_70754
5681
239_60
6869
732517
_755
732517
_22101
9732
517_24
6131
83265_
732517
747971
_12275
8747
971_71
423613
327_72
1517
123127
_74575
0750
690_10
2816
19893_
241240
609699
_26604
6609
699_82
151609
699_70
7545
613327
_10501
4123
127_31
2887
266046
_19893
266046
_10501
4
Challenges to Development of Combination Targeted Therapeutics
• Incomplete understanding of mechanisms of action and a growing number of targeted agents available for trial
• Inability to assess target effect– Lack of assays, imaging tools– Lack of assay standardization– Lack of commercially-available agents formulated for in vitro use– Lack of available investigational agents for in vitro/in vivo use
• Lack of preclinical models for combinations– To evaluate efficacy, schedule effects, biomarker utility, toxicity
• Clinical trials methodology– Need to screen large numbers of patients?– Need for tumor biopsies?– Is histologic homogeneity relevant?– Pharmacokinetic interactions? SD vs RR?
• Intellectual property & regulatory challenges to novel combinations
Principles of Combination Therapy:Then (1975) and Now (2010)
• Drugs are each active against the tumor in question (ORR)
• Drugs have different mechanisms of action to minimize resistance
• Drugs have different clinical toxicities to allow full dose therapy
• Intermittent intensive > continuous treatment for cytoreduction & to reduce immunosuppression
Frei, Cancer Res., 32: 2593, 1972DeVita, Cancer, 35: 98, 1975
• Agent has therapeutic effect on molecular pathway in vivo
• Agents have complementary effects on the same target or other targets in the same pathway or pathways that cross-talk to control tumor growth
• Toxicities do not overlap with cytotoxicsand are moderate to allow prolonged administration
• Schedule chosen to maximize target inhibition: Either continuous Rx or high dose to suppress target a reasonable goal
Kummar, Nat. Rev. Drug Disc., 9: 843, 2010
Cytotoxic Targeted
Accelerating Cancer Diagnosis and Drug Development
DCTD Division of Cancer Treatment and Diagnosis
Developmental Therapeutics
Jerry CollinsJoe TomaszewskiMelinda HollingsheadRalph ParchmentRobert KindersTom PfisterJay Ji
Center for Cancer Research
Yves PommierLee HelmanBob WiltroutShivaani KummarWilliam Bonner
DCTDJason CristofaroBarbara MrochowskiMichael Difilippantonio
CTEPJamie ZweibelJeff Abrams
Cancer ImagingPaula Jacobs
Cancer DiagnosisBarbara Conley
Approaches to solving the combinations problem in
oncology therapeutics
Eric H RubinMerck Research Laboratories
The Most Effective Treatments Involve Combinations
• Probability of drug-resistant cells = 1 – e[-x(N-1)],where N is number of cells and x is the spontaneous drug resistance rate– Assuming a resistance rate of 1 of every million cells, for a 1 mm3
tumor, this probability is 0.64
• Principles of combination chemotherapy– Additive or synergistic anti-tumor activity without additive toxicity– Non-cross-resistance
Combinations Problem in Oncology
• For every 10 new drugs approved, 45 trials would be required to test each possible 2-drug combination
• If the trials were done separately and sequentially, this would take about 90 years
• This problem is amplified by a need to identify responsive subgroups (e.g. by biomarkers)
The Combinations Problem in Cancer: Lung Cancer Example
New Compounds (5)– AKTi– HGFi– IGFRi– mTORi– CHK1i
Biomarkers (4)– RAS– IGFR– MET– EGFR
Possible drug doublets = (7 x 6)/2 -1 (SOC doublet) = 20 possible all comer ph2 trialsPossible biomarker groups (if independent) = 24 = 16 possible patient subgroupsPossible drug doublet-biomarker groups = 20 x 16 = 320 possible enrichment ph2 trials
Standard-of-care drugs (2)–EGFRi (e.g. erlotinib)–VEGFRi (e.g. bevacizumab)
Solutions to the Combinations Problem
1. Identify most promising combinations from preclinical studies and combine them early in the clinic– IGF1Ri + mTORi– AKTi + MEKi– Caveat is that the historical success rate of preclinical prediction is low
2. Use branched adaptive trials– BATTLE – lung cancer– I-SPY – breast cancer
Enhancer Screen for IGF1R inhibition
IGF1Ri-treated
cell lines(dalotuzumab)
UntreatedCell lines
Candidate Enhancers
siRNALibrary
mTOR shRNA
shRNA=small hairpin RNA
Rationale for Combined mTOR and IGFR1 Targeting
• mTOR is top hit in dalotuzumab enhancer screen
• IGF1R is top hit in ridaforolimus enhancer screen
Dalotuzumab Enhancer Screen
Anti-proliferative effect
pre-therapy on-therapy
Rationale for Combined mTOR and IGFR1 Targeting
Co-treatment with IGFR1 inhibitor prevents feedback activation of AKT by mTOR inhibition in preclinical models
Tabernero, et al., J Clin Oncol. 2008
pAK
T-S4
73 s
tain
ing
4EBP1
PI3K
TORC1
S6K
Rheb
S6
PIP3
Tuberin
PTEN
Akt PDK1
IRS
IGFR-1
RIDAFOROLIMUS
DALOTUZUMAB
Tumor sample of a patient on treatment with everolimus
Feedback activation of AKT following mTOR inhibition by rapalogs
Ridaforolimus (Rida) + Dalotuzumab (Dalo): Phase I Design
• Presented at oral session ASCO 2010– DiCosimo et al, abstract # 3008
• Serena Di Cosimo, Johanna Bendell, Andres Cervantes-Ruiperez, Desamparados. Roda, Ludmilla Prudkin, Mark Stein, Ann Leighton-Swayze, Yang Song, Scot Ebbinghaus, and José Baselga
Part A
5 dose levels37 patients
Cohort 112 patients
Cohort 213 patients
Part B - 2 dose cohorts
36
Example of a Partial Response to Ridaforolimus + Dalotuzumab
• 56 year-old female – Stage IV breast cancer
• ER+/PR+/HER2 neg, Ki67 20%• Adjuvant chemotherapy• 4 prior chemotherapy regimens
– Cyclophosphamide + doxorubicin, docetaxel + vinorelbine, paclitaxel + gemcitabine, capecitabine
• 3 prior hormone therapies– Tamoxifen, fulvestrant, anastrazole
• Patient remained on study treatment for 9 months before progression
2 cycles
37
Summary of Efficacy Signals in Breast Cancer
• Overall, 10 of 23 breast cancer patients had objective evidence of anti-tumor activity– 6 of 11 (54%) patients with ER+/high proliferation breast tumors– 0 of 5 patients with ER+/low proliferation breast tumors
Breast Cancer Subpopulation N
FDG-PET PR (EORTC)
PFS > 6 months
Tumor Marker RECIST PR
n % n % n % n %ER+ 18 2 4 7 3ER+/high proliferation 11 2 4 5 3ER+/low proliferation 5 0 0 0 0HER2+ 3 3 0 2 0All breast cancer 23 5 22 4 17 8 35 3 13.0
PR=partial response; PFS = progression-free survival; tumor marker decline > 25% for CA-125, CA15.3 or CA27.29
Inter-Company 2 NME Combination
• Allosteric AKT inhibitor (MK-2206) + allosteric MEK inhibitor (AZD6244)
• Collaboration signed June 2009– First example of two companies collaborating on combining 2 NMEs in
early development
• First patient dosed in phase 1 trial December 2009• Results to be presented at ASCO 2011• Combination also to be studied in BATTLE2
Acknowledgements
• Merck– Gary Gilliland– Stephen Friend– Pearl Huang– Keaven Anderson– Li Yan– David Mauro
• Astra Zeneca– Alan Barge– Paul Smith– Ian Smith– Grahme Smith– Victoria Zazulina
• MD Anderson Cancer Center – Roy Herbst– Vali Papadimitrakopoulou– J Jack Lee– Don Berry
Michael Caligiuri, MDDirector, The Ohio State University Comprehensive Cancer CenterCEO, James Cancer Hospital and Solove Research Institute
42
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Success with New Trials at The James
Developed nude rat model of human primary CNS EBV+ lymphoma (PCNSL)
NCI R01 funded in 1997 Rat model of PCNSL: Identified
tumor upregulation of viral thymidine kinase by XRT & cytotoxicity with high dose AZT & GCV
Phase I clinical trial developed 1st Patient: cured of fatal EBV+
PCNSL (10 years disease-free survival)
43
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Success with New Trials at The James
44
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
An Astonishing Range of Molecular Interactions Occurs in Cancer Cells
Biochemical pathways control cancer-cell growth and survival of cancer cells
45
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Drugs Designed to Target Key Molecules In Biomedical Pathways
Blocks PI3K, which drives growth
Turns on protectivegenes that the cancer process has turned off
46
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Preclinical Evidence: Targeted Agents In Combination Will Improve Patient Outcomes
They cripple several key pathways simultaneously As a result, they may slow development of
resistance and extend patient lives
47
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Dr. Bhuvaneswari RamaswamyAssistant Professor of Medical OncologyThe Ohio State University School of Medicine and Public Health
A link to the full video will be sent to those participating virtually following the session.
48
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Major Stakeholders Need to Develop COOPERATIVE Policies and Procedures
Pharmaceutical industry
Regulatory agencies
National Cancer Institute
Academia
Patient advocacy groups
49
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Great FirstStep by FDA
50
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
CCCs & Academic Institutions Can Help
Basic research Patients
51
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
CCCs & Academic Institutions Can Help
Basic research Patients Science-based combination
strategies Pre-clinical studies
52
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
CCCs & Academic Institutions Can Help
Basic research Patients Science-based combination
strategies Pre-clinical studies Bring stakeholders together Academic expertise in
intellectual property CCCs can file
investigational new drug (IND) applications
53
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Today’s Roundtable
Battelle
BioOhio
Eli Lilly and Company
FDA
FoxKiser
Friends of Cancer Research
Merck
NCI
Ohio State
OSUCCC-James
Pfizer
Sanofi-Aventis
Signal Hill Advisors
54
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Solve Critical Business and Legal Issues:Co-developing Agents in Combination
Define roles Intellectualproperty
Commercialization
ProfitsPrices
AdverseEffects
Experimental combinations
Patentprotection
Financingthe science
Concentrated effort on broad
coalition
Createworkable template
Draw up agreements
55
The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute