Companion Diagnostics in Personalized Medicine and Cancer Therapy

Companion diagnostics (CDx) refers to a particular clinical diagnostic test that is under evaluation and is specifically linked to a known drug therapy. This linkage could be important in the therapeutic application and clinical outcome of a drug, such as with personalized medicine for oncology patients. The molecular diagnostics field plays a vital part in personalized medicine and has greatly expanded over the past twenty years, expanding by more than 20% annually compared to most other laboratory procedures. Research will continue to produce an increased understanding of disease processes, and diagnostics manufacturers will continue to expand and refine the technology and automation needed for clinical testing. Companion diagnostics, although smaller at present, is one of the fastest growing segments in the in vitro diagnostic (IVD) market. And while the concept of a drug-diagnostic combination is not new, it has only recently started to generate interest with the move of healthcare towards pharmacogenomics. This TriMark Publications report examines the use of companion diagnostics in personalized medicine and cancer therapy. The study provides a qualitative and quantitative review of the industry, including cancer biomarker tests, pharmacogenomics tests, recurrence prediction tests, blood-based technologies, proteomics and regulatory trends. Moreover, this analysis profiles the leading companies that are developing and manufacturing companion diagnostics solutions. Each company is discussed in extensive depth with a section on its history, product line, business and marketing analysis, and a subjective commentary of the company's market position. Detailed tables and charts with sales forecasts and market share data are also included.
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1. Overview 9
1.1 Statement of Report 9
1.2 About This Report 9
1.3 Scope of the Report 10
1.4 Objectives 11
1.5 Methodology 11
1.6 Executive Summary 13

2. Companion Diagnostics and Personalized Medicine 17
2.1 Scope of This Section 17
2.2 Introduction to Companion Diagnostics and Personalized Medicine 17
2.3 Drug Metabolism, Companion Diagnostics and Personalized Medicine 22
2.4 Examples of Personalized Medicine and Companion Diagnostic Tests 26
2.5 Personalized Medicine and Companion Diagnostic Testing Product Pipeline 29
2.6 The Personalized Medicine Coalition (PMC) 31
2.7 Regulatory Trends and Guidelines in the Personalized Medicine Space 38
2.7.1 The Changing Regulatory Landscape for Personalized Medicine 40
2.8 Companion Diagnostics Play an Increasing Role in Cancer Care 41
2.9 Specific Examples of Clinical Situations where Companion Diagnostics are being Deployed 42
2.9.1 Epidermal Growth Factor Receptor Assay 42
2.9.2 Individualized Warfarin Therapy 45
2.9.3 UGT1A1 Molecular Assay for Camptosar 46
2.9.4 Response to Gleevec in Gastrointestinal Stromal Tumors (GISTs) 46
2.9.5 LabCorp, ARCA Personalized Medicine Deal for Cardiovascular Diseases 46
2.9.6 Osmetech Licenses Epidauros Biotechnologie AG CYP2D6 Biomarker to Enter Companion Diagnostics 47
2.9.7 Roche�s Metastatic Melanoma Treatment, Zelboraf (vemurafenib) 47
2.9.8 Abbott�s Late-Stage NSCLC Treatment, Xalkori (crizotinib) 47
2.10 Diagnostic Tests for Personalized Analysis of Cancer Therapy Effectiveness 47
2.11 Value Chain 48
2.12 Impact of Companion Diagnostics/Personalized Medicine on Drug Clinical Trials 50

3. Companion Diagnostics: Qualitative and Quantitative Market Analysis 51
3.1 Market Analysis of Molecular Diagnostics and Companion Diagnostics 51
3.2 Costs of Companion Diagnostics in Healthcare Expenditures 52
3.3 Molecular Diagnostic Market 53
3.4 Molecular Diagnostics Technology Platforms and Their Impact on Clinical Medicine 55
3.5 Snapshot of Companion Diagnostics Industry Structure 57
3.6 The Case for Theranostics 58
3.7 Companion Diagnostics Market Analysis�Market Survey Data Characterizing the Qualitative and Quantitative Industry Parameters 59

4. Trends and Overview 62
4.1 Companion Diagnostics: Industry SWOT Analysis 62
4.2 Macro Trends in Companion Diagnostics 62
4.3 Challenges for Companion Diagnostics Development 66
4.4 Timeline for Impact of Various Segments in Companion Diagnostics 68
4.5 Use of Proteomics to Develop Individualized Tests 70
4.6 The Market Problem: Finding Value with Diagnostics for Personalized Medicine 71

5. Biomarker Tests Co-developed with Cancer Therapeutics as Companion Diagnostics 72
5.1 Sector Overview 72
5.1.1 Impact of New Technology Platforms 72
5.1.2 Impact on Drug Discovery 73
5.1.3 Biomarkers as Endpoints in Drug Discovery 73
5.1.4 Targeted Therapy 74
5.2 Companion Diagnostics on the Market 75
5.3 Epidermal Growth Factor Receptor Companions 75
5.3.1 Bevacizamab (Avastin) 76
5.3.2 EGFR for CRC and Camptosar (Irinotecan) 77
5.3.2.1 Companion Diagnostic Test Developed for UGT1A1 for Irinotecan 77
5.3.2.2 Companion Diagnostic Test Developed for Bristol-Myers� SPRYCEL 77
5.3.3 EGFR Express and Erbitux (Cetuximab) 77
5.3.4 HER2 and Heceptin (Trastuzumab) 78
5.3.4.1 Bayer�s Advia Centaur HER2/neu Assay 80
5.3.4.2 Companies Marketing HER2/neu Assays 80
5.3.5 Iressa and Tarceva Companion Test 80
5.3.6 Tykerb (GlaxoSmithKline (GSK)) and Vectibix (Amgen) Companion Tests 80
5.3.7 EGFRx� Assay 81
5.3.8 Monogram eTag 81
5.3.9 Veripath OncoDiagnostics EGFR PharmDX 82
5.3.10 NSCLC Patients with EGFR Mutation 82
5.3.11 A Personalized Medicine Program for CML 82
5.4 Companions Based on Myriad�s IVDMIA Technology 82
5.4.1 Myriad�s TheraGuide 5-FU 82
5.4.2 Myriad�s BRCA Companion Diagnostics Testing for BioMarin�s PARP Inhibitor BMN 673 83
5.5 Companions for Tyrosine Kinase Inhibitors: Erlotinib and Gefitinib 83
5.5.1 TheraScreen: EGFR29 83
5.5.2 The K-RAS Mutation Detection Kit 83
5.6 Irinotecan and UGT1A1 84
5.7 Gleevec (Imatinib) Companions 84
5.7.1 DakoCytomation�s c-Kit (9.7) pharmDx 84
5.8 Companion Diagnostics Involving Metabolizing Enzymes 85
5.8.1 Companions for TMPT, CYP2C9 and UGT1A1 Enzymes 85
5.8.2 Companions for Aromatase Inhibitors 85
5.8.3 Companions for Actos and Avandia 86
5.9 Drivers and Barriers to Companion Diagnostics 86
5.10 Partnerships with Pharma Companies to Identify Therapeutic Targets 87
5.11 Circulating Tumor Cell Assay: Prognostic and Predictive Factors for Breast Cancer 87
5.12 Companion Diagnostics Used by Clinical Service Laboratories 88
5.13 New Technologies and Products under Development 89
5.13.1 OncoMethylome (now MDx Health) 89
5.13.2 Ventana Medical Systems Inks Companion Diagnostic Deal with Syndax for Lung Cancer Drug 89
5.13.3 Abbott Expands Agreement with GSK to Include Development of a Companion Diagnostic Test for the PRAME Antigen 90
5.14 Pharmacogenomics Tests 90
5.14.1 MGMT Methylation Assay 90
5.14.2 Other Pharmacogenomic Opportunities 90
5.15 Recurrence Prediction Tests 91
5.16 Blood-based Technologies 91
5.16.1 Oncotech 91
5.17 Monogram Biosciences HIV Personalized Platform 92
5.18 Wako LBA\AFP Test for Liver Cancer 92
5.19 Future Developments for Companion Diagnostics 92
5.20 Drug Response Predictors 93

6. Business and Regulatory Trends in the Companion Biomarker Testing Sector 94
6.1 Industry Consolidation 94
6.2 Breath of Product Offering and Pricing 95
6.3 Government Regulation of Medical Devices 95
6.3.1 FDA Guidance on Drug Test Co-development 97
6.3.2 Device Classes 97
6.3.3 Investigational Use of IVDMIAs 98
6.3.4 Post-market Requirements 98
6.3.5 Voluntary versus Required Submissions 98
6.3.6 Examples of Recent Voluntary Genomic Data Submissions 98
6.3.7 FDA Labeling Implications and Rules 99
6.3.8 Regulatory Activities in Companion Diagnostic Testing�Translation of Diagnostic Testing Results into Clinical Practice 99
6.4 Strategic Business and Marketing Considerations 100
6.5 Commercial Opportunities in Companion Markers 100
6.6 Moderators of Growth 101
6.6.1 Roadblocks to Integrating Companion Biomarkers into Clinical Practice 102
6.6.2 Management of Targeted Therapeutics by Third-Party Payers 102
6.7 Biotechnology Industry Trends 102
6.8 Pharmaceutical Industry Trends 103
6.9 Acquisition, License Agreement, Partnerships 104
6.10 Legal Developments 107
6.11 Sales and Marketing Strategies for Tumor Marker Tests 109
6.11.1 International Markets 110
6.11.2 Europe 110
6.11.3 Central and South America 111
6.11.4 Asia-Pacific 111
6.12 Product Commercialization 112
6.13 Reimbursement 112
6.14 Self-Referral Rules 113
6.15 Health Insurance Portability and Accountability Act 114
6.16 Clinical Laboratory Improvement Amendments (CLIA) 115
6.17 In Vitro Diagnostic Directive (IVDD) and Medical Device Regulations 115
6.18 FDA�s Quality System Regulation (QSR) 116
6.19 The FDA�s OIVD on IVDMIAs 116
6.20 FDA�s Qualification of Cancer Biomarkers 117
6.20.1 Regulatory Perspectives of Biomarker Validation 117
6.21 Genetic Tests and Medical Records 118
6.21.1 Laws against Genetic Discrimination 119
6.22 Global Drivers of Clinical Laboratory Testing 119
6.23 Global Outlook 120
6.24 Oncology Biomarker Qualification Initiative 121
6.25 FDA Critical Path 122
6.25.1 Examples of Drugs being Hindered due to Lack of Compliance with FDA Directives 122
6.26 Biomarkers and FDA�s Voluntary Genomic Data Submission 122
6.27 From Personalized to Predictive Medicine 122
6.28 Analysis of Cost-Effectiveness at the Individual Level 122
6.29 The Patient and Advocate Perspective: An Evolution of Influence 122
6.30 Real-World Experiences Translating the Vision of Personalized Medicine into Practice 123
6.30.1 Evolving Business Models in Companion Diagnostics and Personalized Medicine 123
6.30.2 Current Pharma/Diagnostics Business Model Examples 124
6.31 Reimbursement and Value Creation 124
6.32 What is the Role of Governmental Agencies in Driving the Adoption of Companion Diagnostics? 125
6.33 What is the Role of the Insurance Industry in Driving the Adoption of pharmacogenomics (PGx)? 125
6.34 What is the Role of the Pharma Industry in Driving the Adoption of PGx? 125
6.35 FDA Guidance Document on Co-development 125
6.36 What is the Role of the Diagnostic Industry in Driving the Adoption of PGx? 126
6.37 What is the Future Role of PBMs in Laboratory Services? 126

7. Companies Entering the Companion Diagnostics Market 127
7.1 Industry Overview 127
7.1.1 20/20 GeneSystems, Inc. 127
7.1.2 Abbott Molecular, Inc. 128
7.1.3 Affymetrix, Inc. 130
7.1.4 Agendia BV 132
7.1.5 Agensys, Inc. 134
7.1.6 Agilent Technologies 134
7.1.7 Almac Group 135
7.1.8 AMDL, Inc. 136
7.1.9 Applied Biosystems 137
7.1.10 Asuragen, Inc. 138
7.1.11 Aureon Laboratories Corporation 139
7.1.12 Beckman Coulter, Inc. 140
7.1.13 Becton, Dickinson and Company (BD) Diagnostics - TriPath 141
7.1.14 Biocode Hycel 142
7.1.15 BioCurex, Inc. 142
7.1.16 Biodesix 143
7.1.17 Biomarker Technologies, LLC 144
7.1.18 Biomedical Diagnostics, LLC 144
7.1.19 Biomerica 144
7.1.20 bioM�rieux, Inc. 145
7.1.21 Biomira, Inc. 145
7.1.22 BioModa, Inc. 146
7.1.23 Bruker Daltonics 147
7.1.24 Byk Gulden 147
7.1.25 Cangen Biotechnologies, Inc. 147
7.1.26 Caprion Proteomics 148
7.1.27 Celera Diagnostics 150
7.1.28 Cepheid, Inc. 150
7.1.29 Clarient, Inc. 152
7.1.30 Claros Diagnostics 153
7.1.31 Clinical Data, Inc.: PGxHealth and Cogenics 153
7.1.32 Correlogic Systems, Inc. 155
7.1.33 CytoCore, Inc. (Formerly Known As Molecular Diagnostics, Inc.) 156
7.1.34 Cytogen Corporation (now EUSA Pharma) 156
7.1.35 Dako (Formerly DakoCytomation) 157
7.1.36 DiaDexus 158
7.1.37 DiagnoCure 159
7.1.38 DRG International 161
7.1.39 EDP Biotech Corporation 162
7.1.40 Eisai Co., Ltd. 162
7.1.41 Epigenomics 163
7.1.42 EXACT Sciences Corporation 164
7.1.43 Exagen Diagnostics 166
7.1.44 Gene Logic, Inc. 166
7.1.45 Genesis Genomics, Inc. (now known as Mitomics) 167
7.1.46 GenMark Diagnostics 168
7.1.47 Genomic Health 168
7.1.48 Gen-Probe, Inc. 168
7.1.49 Health Discovery Corporation 169
7.1.50 Hologic, Inc. (Formerly Cytyc Corporation) 170
7.1.51 Ikonisys, Inc. 171
7.1.52 Illumina 171
7.1.53 Immunomedics 172
7.1.54 Incyte 173
7.1.55 InterGenetics 173
7.1.56 Ipsogen 174
7.1.57 Johnson & Johnson 174
7.1.58 LabCorp 176
7.1.59 Life Technologies Corporation 176
7.1.60 Matritech, Inc. 177
7.1.61 Miraculins 179
7.1.62 Mitsubishi Kagaku latron 180
7.1.63 Monogram Biosciences (formerly ViroLogic Inc.) 180
7.1.64 Myriad Genetics, Inc. 181
7.1.65 NimbleGen Systems 183
7.1.66 Northwest Biotherapeutics, Inc. 184
7.1.67 Novartis MDx 185
7.1.68 Nycomed 185
7.1.69 Oncotech, Inc. 185
7.1.70 Oncothyreon, Inc. (Formerly known as Biomira) 186
7.1.71 Orion Genomics 187
7.1.72 Oxford BioTherapeutics (formerly Oxford Genome Sciences) 187
7.1.73 Panacea Pharmaceuticals, Inc. 188
7.1.74 Polymedco, Inc. 188
7.1.75 Power3 Medical Products 189
7.1.76 Prometheus 190
7.1.77 Proteome Systems Limited 190
7.1.78 Qiagen N.V. 190
7.1.79 Roche Molecular Diagnostics 192
7.1.80 Sanko Junyaku Co. Ltd. 193
7.1.81 SensiGen, LLC 193
7.1.82 Siemens Healthcare Diagnostics, Inc. 194
7.1.83 SuperArray Bioscience Corporation 194
7.1.84 Third Wave Technologies, Inc. (now owned by Hologic) 194
7.1.85 Tosoh Biosciences 195
7.1.86 TrimGen 195
7.1.87 Upstream Biosciences, Inc. 195
7.1.88 Ventana Medical Systems, Inc. 196
7.1.89 Veridex, LLC 198
7.1.90 Vermillion, Inc. (Formerly Ciphergen) 198
7.1.91 Vertex Pharmaceuticals, Inc. 199

Appendix 1: FDA Guidance for Industry: Pharmacogenomic Data Submissions 200
A1.1 Introduction 200
A1.2 Background 200
A1.3 Submission Policy 201
A1.3.1 General Principles 201
A1.3.2 Specific Uses of Pharmacogenomic Data in Drug Development and Labeling 203
A1.3.3 Benefits of Voluntary Submissions to Sponsors and FDA 204
A1.4 Submission of Pharmacogenomic Data 205
A1.4.1 Submission of Pharmacogenomic Data During the IND Phase 205
A1.4.2 Submission of Pharmacogenomic Data to a New NDA, BLA or Supplement 206
A1.4.3 Submission to a Previously Approved NDA or BLA 207
A1.4.4 Compliance with 21 CFR Part 58 207
A1.4.5 Submission of Voluntary Genomic Data from Application-Independent Research 208
A1.5 Format and Content of a VGDS 208
A1.6 Process for Submitting Pharmacogenomic Data 209
A1.7 Agency Review of VGDSs 209

Appendix 2: FDA Issues Draft Companion Diagnostic Guidance 211

Appendix 3: Histochemical Markers for Cancer 213

Glossary 214
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Figure 2.1: Personalizing Drug Treatment 18
Figure 2.2: Approaches to Personalized Medicine 19
Figure 2.3: The Phase I and II Processes of Drug Metabolism 22
Figure 2.4: Hepatic Distribution of Human CYP450 23
Figure 2.5: Relative Contribution of CYP450 Enzymes to Drug Metabolism 24
Figure 2.6: Genetic Components Determine Drug Metabolism 24
Figure 2.7: Personalized Medicine Drugs in Development 29
Figure 2.8: Healthcare Value Chain 49
Figure 3.1: From Genetic Content to Personalized Medicine 52
Figure 3.2: Impact of Diagnostic Testing on Healthcare Decision-Making 52
Figure 3.3: Impact of Diagnostic Testing on Healthcare Spending 53
Figure 3.4: Breakout of the Molecular Diagnostics Marketplace 54
Figure 3.5: Molecular Diagnostics Market Segmentation 55
Figure 3.6: Molecular Diagnostics Market Segmentation by Technology 55
Figure 3.7: Market Survey Respondent Demographics 60
Figure 3.8: Breakout of the Respondent Pool by Affiliation 60
Figure 3.9: Segmentation of the Personalized Medicine Market 61
Figure 4.1: Personalized Medicine Market Drivers 63
Figure 4.2: Challenges in the Personalized Medicine Space 64
Figure 5.1: Carcinogenesis is a Multi-Step Process 72
Figure 5.2: ASCO-CAP Guidelines for HER2 Testing in Breast Cancer: Equivocal Results with IHC 79
Figure 5.3: ASCO-CAP Guidelines for HER2 Testing in Breast Cancer: Results by FISH 79
Figure 7.1: Epigenomics Product Development Pipeline 163

Table 2.1: Timeline for Development of Companion Diagnostics 19
Table 2.2: Personalized Medicine at the Nexus Point 20
Table 2.3: Percentage of Non-Responders in Various Drug Classes 21
Table 2.4: High-Profile Drug Withdrawals from the Marketplace 21
Table 2.5: Metabolism of Drugs by Hepatic Enzymes 23
Table 2.6: Drug Metabolism Drives Drug Efficacy/Toxicity 25
Table 2.7: Population Frequency of the Various Cytochromes 26
Table 2.8: Selected List of Personalized Medicine Tests 28
Table 2.9: Personalized Medicine and Companion Diagnostics Product Pipeline 30
Table 2.10: Typical Response Rates in Therapeutic Areas 42
Table 2.11: Prevalence of People Taking Medications Metabolized by Liver Enzymes 43
Table 2.12: UGT1A1 Helps to Determine Risks Associated with Irinotecan 45
Table 2.13: Current Product Labels: Enzyme Metabolism 45
Table 3.1: Timeline for Impact of Various Molecular Diagnostics Technologies on Personalized Medicine 56
Table 3.2: Impact of Molecular Diagnostics Technologies on Therapeutic Areas in Personalized Medicine 56
Table 3.3: Challenges of Various Molecular Diagnostics Technology Platforms in Personalized Medicine 57
Table 3.4: FDA Classification of Diagnostics by Risk 59
Table 4.1: Personalized Medicine Industry SWOT Analysis 62
Table 4.2: Market Opportunities in Personalized Medicine 65
Table 4.3: Challenges for Market Adoption of Various Personalized Medicine Tests 66
Table 4.4: Hurdles to Personalized Medicine and Companion Diagnostics Development 67
Table 4.5: Timeline of Impact in Areas of Personalized Medicine 68
Table 4.6: Impact of Personalized Medicine on Various Therapeutic Areas 69
Table 5.1: Potential Benefits of Biomarkers as Companion Diagnostics 74
Table 5.2: Utility of Biomarker as Companion Diagnostics to Drug Development 74
Table 5.3: ASCO-CAP Guidelines for HER2 Testing in Breast Cancer: How to Interpret Test Results 78
Table 5.4: Device Submission Elements for the FDA 87
Table 6.1: List and Discounted Prices for Abbott Tumor Marker Tests 95
Table 6.2: Summary of Biomarker Use in the Commercialization of Novel Oncology Pharmacotherapeutics 123
Table 6.3: Pharmacoeconomic Challenges to the Implementation of Biomarkers as Companion Diagnostic Tests 123
Table 7.1: Major Players in Companion Diagnostics Sector 127
Table 7.2: Opportunities for Biomarkers in Cancer Diagnosis and Treatment 152
Table 7.3: Tumor Diagnosis Immunoassay 161
Table 7.4: Tumor Diagnosis Radioimmunoassay 162
Table 7.5: Summary of Matritech�s Product Development Programs 179
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