Personalized Medicine - scientific & commercial aspects

Introduction

Abstract

Summary

The aim of personalized medicine or individualized treatment is to match the right drug to the right patient and, in some cases, even to design the appropriate treatment for a patient according to his/her genotype. This report describes the latest concepts of development of personalized medicine based on pharmacogenomics, pharmacogenetics,pharmacoproteomics, and metabolomics. Basic technologies of molecular diagnostics play an important role, particularly those for single nucleotide polymorphism (SNP) genotyping. Diagnosis is integrated with therapy for selection of the treatment as well for monitoring the results. Biochip/microarray technologies are also important and finally bioinformatics is needed to analyze the immense amount of data generated by various technologies.

Pharmacogenetics, the study of influence of genetic factors on drug action and metabolism, is used for predicting adverse reactions of drugs. Several enzymes are involved in drug metabolism of which the most important ones are those belonging to the family of cytochrome P450. The knowledge of the effects of polymorphisms of genes for the enzymes is applied in drug discovery and development as well as in clinical use of drugs. Cost-effective methods for genotyping are being developed and it would be desirable to include this information in the patient's record for the guidance of the physician to individualize the treatment. Pharmacogenomics, a term that overlaps with pharmacogenetics but is distinct, deals with the application of genomics to drug discovery and development. It involves the mechanism of action of drugs on cells as revealed by gene expression patterns. Pharmacoproteomics is an important contribution to personalized medicine as it is a more functional representation of patient-to-patient variation than that provided by genotyping.A 'pharmacometabonomic' approach to personalizing drug treatment is also described.

Biological therapies such as those which use patient's own cells are considered to be personalized medicines. Vaccines are prepared from individual patient's tumor cells. Individualized therapeutic strategies using monoclonal bodies can be directed at specific genetic and immunologic targets. Ex vivo gene therapy involves the genetic modification of the patient's cells in vitro, prior to reimplantation of these cells in the patient's body.

Various technologies are integrated to develop personalized therapies for specific therapeutic areas described in the report. Examples of this are genotyping for drug resistance in HIV infection, personalized therapy of cancer, antipsychotics for schizophrenia, antidepressant therapy, antihypertensive therapy and personalized approach to neurological disorders. Although genotyping is not yet a part of clinically accepted routine, it is expected to have this status by the year 2016.

Several players are involved in the development of personalized therapy. Pharmaceutical and biotechnology companies have taken a leading role in this venture in keeping with their future role as healthcare enterprises rather than mere developers of technologies and manufacturers of medicines.

Ethical issues are involved in the development of personalized medicine mainly in the area of genetic testing. These along with social issues and consideration of race in the development of personalized medicine are discussed. Regulatory issues are discussed mainly with reference to the FDA guidelines on pharmacogenomics.

Increase in efficacy and safety of treatment by individualizing it has benefits in financial terms. Information is presented to show that personalized medicine will be cost-effective in healthcare systems. For the pharmaceutical companies, segmentation of the market may not leave room for conventional blockbusters but smaller and exclusive markets for personalized medicines would be profitable. Marketing opportunities for such a system are described with market estimates from 2012-2022.

Profiles of 281 companies involved in developing technologies for personalized medicines, along with 501 collaborations are included in the part II of the report. Finally the bibliography contains over 650 selected publications cited in the report.The report is supplemented by 65 tables and 18 figures.

Table of Contents

Table of Contents

PartI

0. Executive Summary 20

1. Basic Aspects 22

• Definition of personalized medicine 22
• History of medical concepts relevant to personalized medicine 23
• Molecular biological basis of personalized medicine 25
• The human genome 25
• ENCODE 26
• Chromosomes 27
• Genes 27
• The genetic code 27
• Gene expression 27
• DNA sequences and structure 28
• Genetic variations in the human genome 28
• Single nucleotide polymorphisms 29
• Copy number variations in the human genome 29
• Insertions and deletions in the human genome 31
• Large scale variation in human genome 32
• Structural variations in the human genome 32
• Mapping and sequencing of structural variation from human genomes 33
• 1000 Genomes Project 34
• Role of DNA sequencing in the development of personalized medicine 35
• Human Variome Project 35
• Interconnected genetic and genomic patterns in human diseases 36
• Basics technologies for developing personalized medicine 37
• Definitions of technologies relevant to personalized medicine 37
• Problems with the ICH definitions of pharmacogenomics and pharmacogenetics 37
• 'Omics' and personalized medicine 38
• Relationship of various technologies to personalized medicine 38
• Conventional medicine versus personalized medicine 39
• Role of genetics in future approaches to healthcare 39
• Genetic medicine 39
• Human disease and genes 39
• Genetic and environmental interactions in etiology of human diseases 40
• Role of genetics in development of personalized medicines 40
• Genetic databases 41
• Genetic epidemiology 41
• Limitations of medical genetics and future prospects 41
• Genetics vs. epigenetics 42
• Role of systems biology in personalized medicine 42
• Systems pharmacology 43
• Systems medicine 44
• Synthetic biology and development of personalized medicines 45
• A personalized approach to environmental factors in disease 45
• Reclassification of diseases 46

2. Molecular Diagnostics in Personalized Medicine 48

• Introduction 48
• Molecular diagnostic technologies 48
• PCR-based methods 49
• DirectLinear™ Analysis 49
• Denaturing high-performance liquid chromatography 50
• Multiplex Allele-Specific Diagnostic Assay 50
• Representational oligonucleotide microarray analysis 50
• Restriction fragment length polymorphism (RFLP) 50
• Real-time PCR for detection of CNVs 50
• Non-PCR methods 51
• Arrayed primer extension (APEX) 51
• Enzymatic Mutation Detection (EMD) 51
• DNA sequencing 51
• Sanger-sequencing technology 52
• ABI PRISM® 310 Genetic Analyzer 53
• High-throughput paired end transcriptome sequencing 53
• Emerging sequencing technologies 53
• 4300 DNA analyzer 54
• Apollo 100 54
• "Color blind" approach to DNA sequencing 55
• Cyclic array sequencing 55
• CEQ™ 8000 55
• DeepCAGE sequencing 55
• Electron microscope-based DNA sequencing 56
• Genometrica® sequencer 56
• GS-FLEX system (Roche/454) 57
• IBS sequencing technology 58
• Illumina Genome Analyzer System 58
• MegaBACE 500 59
• Microdroplet-based PCR for large-scale targeted sequencing 59
• Multiplex amplification of human DNA sequences 59
• Nanoscale sequencing 60
• Polonator sequencer 60
• RainStorm™ microdroplet technology 61
• Sequential DEXAS 61
• SOLiD technology 62
• Sequencing by hybridization 63
• Whole genome sequencing 63
• Bioinformatic tools for analysis of genomic sequencing data 63
• Detection of single molecules in real time 64
• Direct observation of nucleotide incorporation 64
• Molecular Combing 64
• Nanopore sequencing 64
• DNA sequence by use of nanoparticles 64
• Zero-mode waveguide nanostructure arrays 65
• Future prospects of sequencing 65
• Role of sequencing in development of personalized medicine 65
• Biochips and microarrays 66
• Application of biochip technology in developing personalized medicine 66
• Standardizing the microarrays 68
• Biochip technologies 68
• GeneChip 69
• AmpliChip CYP450 69
• Microfluidics 70
• Lab-on-a-chip 71
• Micronics' microfluidic technology 71
• LabCD 71
• Microfluidic automated DNA analysis using PCR 72
• Integrated microfluidic bioassay chip 72
• Electronic detection of nucleic acids on microarrays 72
• Strand displacement amplification on a biochip 73
• Rolling circle amplification on DNA microarrays 73
• Universal DNA microarray combining PCR and ligase detection reaction 73
• Protein biochips 74
• ProteinChip 74
• LabChip for protein analysis 75
• TRINECTIN proteome chip 75
• Protein expression microarrays 76
• Microfluidic devices for proteomics-based diagnostics 76
• New developments in protein biochips/microarrays 76
• Protein biochips/microarrays for personalized medicine 77
• SNP genotyping 77
• Genotyping and haplotyping 78
• Haplotype Specific Extraction 79
• Computation of haplotypes 79
• HapMap project 80
• Haplotyping for whole genome sequencing 81
• Predictingdrug response with HapMap 81
• Companies developing haplotyping technology 81
• Technologies for SNP analysis 82
• Biochip and microarray-based detection of SNPs 83
• SNP genotyping by MassARRAY 83
• Biochip combining BeadArray and ZipCode technologies 83
• SNP-IT primer-extension technology 84
• Affymetrix Variation Detection Arrays 84
• Use of NanoChip for detection of SNPs 84
• Electrochemical DNA probes 85
• Single base extension-tag array 85
• Laboratory Multiple Analyte Profile 85
• PCR-CTPP (confronting two-pair primers) 86
• SNP genotyping on a genome-wide amplified DOP-PCR template 86
• TaqMan real-time PCR 86
• Non-Enzymatic Amplification Technology 86
• SNP genotyping with gold nanoparticle probes 87
• Locked nucleic acid 87
• Molecular inversion probe based assays 87
• Pyrosequencing 88
• Reversed enzyme activity DNA interrogation test 88
• Smart amplification process version 2 89
• Zinc finger proteins 89
• UCAN method (Takara Biomedical) 89
• Mitochondrial SNPs 90
• Limitations of SNP in genetic testing 90
• Concluding remarks on SNP genotyping 90
• Companies involved in developing technologies/products for SNP analysis 91
• Impact of SNPs on personalized medicine 92
• Detection of copy number variations 93
• Study of rare variants in pinpointing disease-causing genes 93
• Optical Mapping 94
• Role of nanobiotechnology in molecular diagnostics 94
• Cantilevers for personalized medical diagnostics 95
• Nanopore-based technology for single molecule identification 95
• Role of biomarkers in personalized medicine 96
• Biomarkers for diagnostics 96
• Biomarkers for drug development 97
• Application of proteomics in molecular diagnosis 97
• Proteomic strategies for biomarker identification 97
• Proteomic technologies for detection of biomarkers in body fluids 97
• Protein patterns 98
• Layered Gene Scanning 98
• Comparison of proteomic and genomic approaches in personalized medicine 99
• Gene expression profiling 99
• DNA microarrays 100
• Analysis of single-cell gene expression 100
• Gene expression profiling based on alternative RNA splicing 101
• Whole genome expression array 102
• Tangerine™ expression profiling 102
• Gene expression analysis on biopsy samples 103
• Profiling gene expression patterns of white blood cells 103
• Serial analysis of gene expression (SAGE) 104
• Multiplexed Molecular Profiling 104
• Gene expression analysis using competitive PCR and MALDI TOF MS 105
• Monitoring in vivo gene expression by magnetic resonance imaging 105
• Companies involved in gene expression analysis 105
• Monitoring in vivo gene expression by molecular imaging 106
• Molecular imaging and personalized medicine 107
• Glycomics-based diagnostics 107
• Combination of diagnostics and therapeutics 107
• Use of molecular diagnostics for stratification in clinical trials 108
• Companion diagnostics 108
• Companies involved in companion diagnostics 109
• Point-of-care diagnosis 111
• Companies developing point-of-care diagnostic technologies 112
• Point-of-care diagnosis of infections 114
• Advantages versus disadvantages of point-of-care diagnosis 114
• Future prospects of point-of-care diagnosis 115
• Genetic testing for disease predisposition 115
• Preventive genetics by early diagnosis of mitochondrial diseases 115
• Direct-to-consumer genetic services 116
• Role of diagnostics in integrated healthcare 117
• Concept of integrated healthcare 117
• Components of integrated healthcare 118
• Screening 118
• Disease prediction 118
• Early diagnosis 118
• Prevention 118
• Therapy based on molecular diagnosis 118
• Monitoring of therapy 119
• Advantages and limitations of integrated healthcare 119
• Commercially available systems for integrated healthcare 119
• Future of molecular diagnostics in personalized medicine 120

3. Pharmacogenetics 122

• Basics of pharmacogenetics 122
• Role of molecular diagnostics in pharmacogenetics 123
• Role of pharmacogenetics in pharmaceutical industry 124
• Study of the drug metabolism and pharmacological effects 124
• Causes of variations in drug metabolism 124
• Enzymes relevant to drug metabolism 125
• Pharmacogenetics of phase I metabolism 125
• CYP450 125
• P450 CYP 2D6 inhibition by selective serotonin reuptake inhibitors 127
• Cytochrome P450 polymorphisms and response to clopidogrel 128
• Lansoprazole and cytochrome P450 128
• Glucose-6-phosphate dehydrogenase 128
• Pharmacogenetics of phase II metabolism 129
• N-Acetyltransferase 129
• Uridine diphosphate-glucuronosyltransferase 130
• Measurement of CYP isoforms 130
• Polymorphism of drug transporters 131
• Genetic variation in drug targets 131
• Polymorphisms of kinase genes 132
• Effect of genetic polymorphisms on disease response to drugs 132
• Ethnic differences in drug metabolism 133
• Gender differences in pharmacogenetics 133
• Role of pharmacogenetics in drug safety 134
• Adverse drug reactions 134
• Adverse drug reactions in children 135
• Adverse drug reactions related to toxicity of chemotherapy 135
• Genetically determined adverse drug reactions 135
• Malignant hyperthermia 137
• Pharmacogenetics of clozapine-induced agranulocytosis 137
• Role of pharmacogenetics in warfarin therapy 137
• Role of pharmacogenetics in antiplatelet therapy 138
• Role of pharmacogenetics in carbamazepine therapy 140
• Role of pharmacogenetics in statin therapy 140
• FDA consortium linking genetic biomarkers to serious adverse events 141
• Therapeutic drug monitoring, phenotyping, and genotyping 141
• Therapeutic drug monitoring 142
• Phenotyping 142
• Genotyping 143
• Genotyping vs phenotyping 143
• Phenomics 144
• Limitations of genotype-phenotype association studies 145
• Molecular toxicology in relation to personalized medicines 145
• Toxicogenomics 145
• Biomarkers of drug toxicity 145
• Drug-induced mitochondrial toxicity 146
• Companies involved in molecular toxicology 146
• Gene expression studies 147
• Pharmacogenetics in clinical trials 147
• Postmarketing pharmacogenetics 148
• Clinical implications of pharmacogenetics 148
• Application of CYP450 genotyping in clinical practice 148
• Pharmacogenomic biomarker information in drug labels 148
• Genotype-based drug dose adjustment 149
• Use of pharmacogenetics in clinical pharmacology 149
• Application of CYP2C19 pharmacogenetics for personalized medicine 149
• Genotyping for identifying responders to sulfasalazine 149
• HLA alleles associated with lumiracoxib-related liver injury 150
• Pharmacogenetic basis of thiopurine toxicity 150
• Tranilast-induced hyperbilirubinemia due to gene polymorphism 150
• Linking pharmacogenetics with pharmacovigilance 151
• Genetic susceptibility to ADRs 151
• Linking genetic testing to postmarketing ADR surveillance 151
• Recommendations for the clinical use of pharmacogenetics 151
• Limitations of pharmacogenetics 152
• Pharmacoepigenomics vs pharmacogenetics in drug safety 152
• Future role of pharmacogenetics in personalized medicine 153

4. Pharmacogenomics 154

• Introduction 154
• Basics of pharmacogenomics 155
• Pharmacogenomics and drug discovery 155
• Preclinical prediction of drug efficacy 157
• Pharmacogenomics and clinical trials 157
• Impact of genetic profiling on clinical studies 158
• Limitations of the pharmacogenomic-based clinical trials 159
• Pharmacogenomic aspects of major therapeutic areas 160
• Oncogenomics 160
• Oncogenes 160
• Tumor suppressor genes 161
• Cardiogenomics 162
• Neuropharmacogenomics 164
• Pharmacogenomics of Alzheimer's disease 164
• Pharmacogenomics of depression 165
• Pharmacogenomics of schizophrenia 165
• Companies involved in neurogenomics-based drug discovery 166

5. Role of Pharmacoproteomics 168

• Basics of proteomics 168
• Proteomic approaches to the study of pathophysiology of diseases 168
• Single cell proteomics for personalized medicine 169
• Diseases due to misfolding of proteins 169
• Therapies for protein misfolding 170
• Significance of mitochondrial proteome in human disease 171
• Proteomic technologies for drug discovery and development 171
• Role of reverse-phase protein microarray in drug discovery 171
• Role of proteomics in clinical drug safety 171
• Toxicoproteomics 172
• Application of pharmacoproteomics in personalized medicine 173

6. Role of Metabolomics in Personalized Medicine 174

• Metabolomics and metabonomics 174
• Metabolomics bridges the gap between genotype and phenotype 174
• Metabolomics, biomarkers and personalized medicine 175
• Metabolomic technologies 175
• Urinary profiling by capillary electrophoresis 176
• Lipid profiling 176
• Role of metabolomics in biomarker identification and pattern recognition 177
• Validation of biomarkers in large-scale human metabolomics studies 177
• Pharmacometabonomics 177
• Metabonomic technologies for toxicology studies 178
• Metabonomics/metabolomics and personalized nutrition 178

7. Personalized Biological Therapies 180

• Introduction 180
• Recombinant human proteins 180
• Therapeutic monoclonal antibodies 180
• Cell therapy 181
• Autologous tissue and cell transplants 181
• Stem cells 181
• Role of stem cells derived from unfertilized embryos 181
• Cloning and personalized cell therapy 182
• Use of stem cells for drug testing 182
• Gene therapy 182
• Personalized vaccines 183
• Personalized vaccines for viral diseases 183
• Personalized cancer vaccines 183
• Antisense therapy 183
• RNA interference 184
• MicroRNAs 185

8. Personalized Medicine in Major Therapeutic Areas 186

• Introduction 186
• Management of infections 187
• Management of HIV 187
• CD4 counts as a guide to drug therapy for AIDS 187
• Drug-resistance in HIV 187
• Genetics of human susceptibility to HIV infection 188
• Measurement of Replication Capacity 189
• Personalized vaccine for HIV 189
• Prevention of adverse reactions to antiviral drugs 189
• Pharmacogenetics and HIV drug safety 190
• Pharmacogenomics of antiretroviral agents 190
• Role of diagnostic testing in management of HIV 191
• Role of genetic variations in susceptibility to HIV-1 191
• Personalized treatment of hepatitis B 191
• Personalized treatment of hepatitis C 192
• Responders vs non-responders to treatment for hepatitis C 192
• Drug resistance in hepatitis C 193
• Personalized management of tuberculosis 194
• Personalized management of fungal infections 194
• Psychiatric disorders 195
• Psychopharmacogenetics/psychopharmacodynamics 195
• Serotonin genes 195
• Calcium channel gene 196
• Dopamine receptor genes 196
• COMT genotype and response to amphetamine 196
• Methylenetetrahydrofolate reductase 196
• Genotype and response to methylphenidate in children with ADHD 197
• Personalized antipsychotic therapy 197
• Personalized antidepressant therapy 199
• EEG to predict adverse effects and evaluate antidepressant efficacy 200
• Individualization of SSRI treatment 201
• Role of protein sFRP3 in predicting response to antidepressants 202
• Treatment resistant depression 202
• Vilazodone with a test for personalized treatment of depression 203
• Neurological disorders 203
• Personalized management of Alzheimer's disease 203
• Personalized management of Parkinson's disease 205
• Discovery of subgroup-selective drug targets in PD 205
• Personalized management of Epilepsy 206
• Choice of the right AED 206
• Pharmacogenetics of epilepsy 206
• Pharmacogenomics of epilepsy 206
• Drug resistance in epilepsy 207
• Future prospects for management of epilepsy 209
• Personalized management of migraine 209
• Individualization of use of triptans for migraine 210
• Multitarget therapeutics for personalized treatment of headache 210
• Personalized management of stroke 210
• Brain imaging in trials of restorative therapies for stroke 211
• Decisions for evacuation of intracerebral hemorrhage 211
• Revascularization procedures in chronic post-stroke stage 211
• Personalized treatment of multiple sclerosis 212
• Immunopathological patterns of demyelination for assessing therapy 213
• Personalizing mitoxantrone therapy of multiple sclerosis 213
• Fusokine method of personalized cell therapy of multiple sclerosis 213
• MBP8298 214
• Pharmacogenomics of IFN-β therapy in multiple sclerosis 214
• T cell-based personalized vaccine for MS 216
• Personalized management of pain 216
• Pharmacogenetics/pharmacogenomics of pain 216
• Mechanism-specific management of pain 217
• Preoperative testing to tailor postoperative analgesic requirements 217
• Personalized analgesics 218
• Signature of pain on brain imaging 218
• Cardiovascular disorders 219
• Role of diagnostics in personalized management of cardiovascular disease 219
• Testing in coronary heart disease 219
• SNP genotyping in cardiovascular disorders 220
• Cardiovascular disorders with a genetic component 220
• Gene variant as a risk factor for sudden cardiac death 222
• KIF6 gene test as a guide to management of heart disease 222
• SNP Chip for study of cardiovascular diseases 223
• Pharmacogenomics of cardiovascular disorders 223
• Modifying the genetic risk for myocardial infarction 223
• Management of heart failure 224
• β-blockers 224
• Bucindolol 224
• BiDil 224
• Management of hypertension 225
• Pharmacogenomics of diuretic drugs 226
• Pharmacogenomics of ACE inhibitors 226
• Management of hypertension by personalized approach 226
• Prediction of antihypertensive activity of rostafuroxin 227
• Pharmacogenetics of lipid-lowering therapies 228
• Polymorphisms in genes involved in cholesterol metabolism 228
• Role of eNOS gene polymorphisms 229
• The STRENGTH study 229
• Personalized management of women with hyperlipidemia 230
• Thrombotic disorders 230
• Factor V Leiden mutation 231
• Anticoagulant therapy 231
• Antiplatelet therapy 232
• Nanotechnology-based personalized therapy of cardiovascular diseases 232
• Project euHeart for personalized management of heart disease 233
• Concluding remarks 233
• Personalized management of pulmonary disorders 234
• Role of genetic ancestory in lung function 234
• Personalized therapy of asthma 234
• Biomarkers for predicting response to corticosteroid therapy 235
• Genetic polymorphism and response to β2-adrenergic agonists 235
• Genotyping in asthma 235
• IgE as guide to dosing of omalizumab for asthma 236
• Lebrikizumab for personalised treatment of asthma 236
• Personalized management of chronic obstructive pulmonary disease 237
• Personalized management of skin disorders 237
• Genetic testing for personalized skin care 238
• Management of hair loss based on genetic testing 238
• Personalized therapy of rheumatoid arthritis 238
• Genetics and epigenetic aspects of rheumatoid arthritis 239
• Variations in the effectiveness of various treatments of RA 239
• Biomarkers for personalizing therapy of rheumatoid arthritis 240
• DIATSTAT™ anti-cyclic citrullinated peptides in rheumatoid arthritis 240
• Personalization of COX-2 inhibitor therapy 241
• Personalization of infliximab therapy 241
• Personalized approaches in immunology 241
• Role of Mannose-binding lectin in personalized medicine 242
• Pharmacogenetics and pharmacogenomics of immunosuppressive agents 242
• Personalized management of patients with lupus erythematosus 242
• Personalized management of diabetes 243
• Management of genetic disorders 244
• Personalized treatment of cystic fibrosis 244
• Personalized management of gastrointestinal disorders 245
• Personalized therapy of inflammatory bowel disease 245
• Personalized management of lactose intolerance 245
• Personalized approaches to improve organ transplantation 246
• Personalization of kidney transplantation 246
• Personalization of cardiac transplantation 246
• Prediction of rejection to tailor anti-rejection medications 247
• Personalized immunosuppressant therapy in organ transplants 247
• Role of immunological biomarkers in monitoring grafted patients 248
• Improved matching of blood transfusion 249
• Personalized approach to addiction 249
• Pharmacogenetics of drug addiction 249
• Genetic polymorphism and management of alcoholism 249
• Personalized therapy for smoking cessation 250
• Antidepressant therapy for smoking cessation 250
• Effectiveness of nicotine patches in relation to genotype 251
• Personalized approaches to miscellaneous problems 251
• Hormone replacement therapy in women 251
• Personalized treatment of malaria 251
• Personalized management of osteoporosis 252
• Personalized management of renal disease 252
• Gene associated with end-stage renal disease 253
• Personalized care of trauma patients 253
• Personalized anticoagulation 254
• Personalized hyperbaric oxygen therapy 254
• Personalized preventive medicine 255
• Personalized nutrition 256
• Nutrigenomics 256
• Genomics of vitamin D and calcium supplementation 257
• Nutrigenomics and functional foods 257
• Nutrigenetics and personalized medicine 257
• Nutrigenomics and personalized medicine 258
• Nutrition and proteomics 258
• Personalized diet prescription 258
• Personalized physical exercise 259
• Variations in response to aerobic exercise 259
• Variations in exercise-induced muscle hypertrophy and strength 260

9. Personalized Therapy of Cancer 262

• Introduction 262
• Challenges of cancer classification 262
• Relationships of technologies for personalized management of cancer 263
• Impact of molecular diagnostics on the management of cancer 263
• Analysis of RNA splicing events in cancer 264
• Analysis of chromosomal alterations in cancer cells 265
• Cancer classification using microarrays 265
• Circulating cancer cell analysis for personalizing therapy 266
• Detection of loss of heterozygosity 266
• BEAMing technology for analysis of circulating tumor DNA 266
• Diagnosis of cancer of an unknown primary 267
• Diagnostics for detection of minimal residual disease 267
• DNA repair biomarkers 267
• Fluorescent in situ hybridization 268
• Gene expression profiling 268
• OnkoMatch tumor genotyping 269
• Gene expression profiles predict chromosomal instability in tumors 269
• Isolation and characterization of circulating tumor cells 270
• Modulation of CYP450 activity for cancer therapy 270
• Pathway-based analysis of cancer 271
• Conversion of gene-level information into pathway-level information 271
• Personalized therapies based on oncogenic pathways signatures 271
• Quantum dot-based test for DNA methylation 272
• Role of molecular imaging in personalized therapy of cancer 272
• Functional diffusion MRI 272
• FDG-PET/CT for personalizing cancer treatment 273
• Image-guided personalized drug delivery in cancer 273
• Tumor imaging and elimination by targeted gallium corrole 273
• Future prospects of molecular imaging in management of cancer 274
• Unraveling the genetic code of cancer 274
• Cancer prognosis 274
• Detection of mutations for risk assessment and prevention 275
• Impact of biomarkers on management of cancer 276
• HER-2/neu oncogene as a biomarker for cancer 276
• L-asparaginase treatment of cancer guided by a biomarker 276
• Oncogene GOLPH3 as a cancer biomarker 277
• Predictive biomarkers for cancer 277
• Sequencing to discover biomarkers to personalize cancer treatment 277
• Systems biology approach to discovery of radiation sensitivity biomarkers 278
• VeraTag™ assay system for cancer biomarkers 278
• Determination of response to therapy 279
• Biomarker-based assays for predicting response to anticancer therapeutics 279
• ChemoFx cell culture assay for predicting anticancer drug response 279
• Ex vivo testing of tumor biopsy for chemotherapy sensitivity 279
• Genomic approaches to predict response to anticancer agents 280
• Gene expression patterns to predict response of cancer to therapy 280
• Genomic analysis of tumor biopsies 280
• Genotype-dependent efficacy of pathway inhibition in cancer 281
• Mutation detection at molecular level 281
• RNA Disruption Assay™ 281
• Role of genetic variations in susceptibility to anticancer drugs 282
• Non-genetic factors for variations in response of cancer cells to drugs 282
• Proteomic analysis of tumor biopsies to predict response to treatment 282
• Real-time apoptosis monitoring 283
• Serum nucleosomes as indicators of sensitivity to chemotherapy 283
• Targeted microbubbles to tumors for monitoring anticancer therapy 284
• PET imaging for determining response to chemotherapy 284
• PET imaging with tyrosine kinase inhibitors 284
• Tissue systems biology approach to personalized management of cancer 285
• Molecular diagnostics combined with cancer therapeutics 285
• AmpliChip P53 as companion diagnostic for cancer 285
• Aptamers for combined diagnosis and therapeutics of cancer 286
• Monoclonal antibodies for combining diagnosis with therapy of cancer 286
• Molecular profiling of cancer 286
• Targeted cancer therapies 287
• Targeting glycoproteins on cell surface 287
• Targeting pathways in cancer 287
• Targeted personalized anticancer medicines in clinical use 287
• Functional antibody-based therapies 288
• Personalized cancer vaccines 289
• Antigen-specific vaccines 289
• Active immunotherapy based on antigen specific to the tumor 290
• Tumor-derived vaccines 290
• FANG vaccine 291
• MyVax 291
• OncoVAX 291
• Tumor cells treated with dinitrophenyl 292
• Prophage 292
• Melacine 292
• Patient-specific cell-based vaccines 293
• Dendritic cell-based vaccines 293
• Adoptive cell therapy 294
• Combination of antiangiogenic agents with ACT 296
• Genetically targeted T cells for treating B cell malignancies 296
• Genetic engineering of tumor cells 297
• Hybrid cell vaccination 297
• Personalized peptide cancer vaccines 297
• Current status and future prospects of personalized cancer vaccines 298
• Personalized radiation therapy 299
• Role of nanobiotechnology in personalized management of cancer 300
• Design of future cancer therapies 301
• Screening for personalized anticancer drugs 301
• Role of epigenetics in development of personalized cancer therapies 301
• Personalized therapy of cancer based on cancer stem cells 302
• Role of oncoproteomics in personalized therapy of cancer 302
• Cancer tissue proteomics 303
• Role of sequencing in personalized therapy of cancer 303
• Pharmacogenomic-based chemotherapy 304
• Whole genome technology to predict drug resistance 304
• Anticancer drug selection based on molecular characteristics of tumor 304
• Testing microsatellite-instability for response to chemotherapy 304
• Pharmacogenetics of cancer chemotherapy 305
• CYP 1A2 305
• Thiopurine methyltransferase 306
• Dihydropyrimidine dehydrogenase 306
• UGT1A1 test as guide to irinotecan therapy 307
• Role of computational models in personalized anticancer therapy 307
• A computational model of kinetically tailored treatment 307
• Mathematical modeling of tumor mivroenvironments 308
• Therapy resistance in cancer 308
• Mechanism of therapy resistance in cancer 309
• Overexpression of multidrug resistance gene 309
• P53 mutations 309
• Detection of drug resistance 310
• Anaplastic lymphoma kinase 310
• Metabolic profiling of cancer 310
• Management of drug resitance in cancer 310
• Chemogenomic approach to drug resistance 310
• Determination of chemotherapy response by topoisomerase levels 311
• Management of drug resistance in leukemia 311
• Resistance to vaccines in cancer recurrence after surgery 312
• Systems biology approach to drug-resistant cancer 312
• Personalized therapy of cancer metastases 312
• Personalized management of cancers of various organs 312
• Personalized management of brain tumors 312
• Biosimulation approach to personalizing treatment of brain cancer 313
• Companion diagnostic for viral gene therapy of brain cancer 313
• Drug resistance in GBM 313
• Genetics and genomics of brain cancer 313
• Prognosis of glioblastoma multiforme based on its genetic landscape 315
• Molecular diagnostics for personalized management of brain cancer 316
• Personalized chemotherapy of brain tumors 317
• Supratentorial hemispheric diffuse low-grade gliomas 318
• Personalized therapy of oligodendroglial tumors (OTs) 319
• Personalized therapy of neuroblastomas 319
• Personalized therapy of medulloblastomas 320
• Personalized management of germ cell brain tumors 320
• Personalized management of meningiomas 321
• Personalized management of breast cancer 321
• Developing personalized drugs for breast cancer 322
• Gene expression plus conventional predictors of breast cancer 323
• Her2 testing in breast cancer as a guide to treatment 324
• HER2/neu-derived peptide vaccine for breast cancer 325
• Molecular diagnostics in breast cancer 326
• Pharmacogenetics of breast cancer 327
• Proteomics-based personalized management of breast cancer 327
• Predicting response to chemotherapy in breast cancer 328
• Prediction of resistance to chemotherapy in breast cancer 331
• Prediction of adverse reaction to radiotherapy in breast cancer 332
• Prediction of recurrence in breast cancer for personalizing therapy 332
• Prognosistic tests for breast cancer 334
• Racial factors in the management of breast cancer 336
• RATHER consortium to study personalized approach to breast cancer 336
• TAILORx (Trial Assigning Individualized Options for Treatment) 337
• Tamoxin therapy for ER-positive breast cancer 337
• Triple negative breast cancer 338
• Trends and future prospects of breast cancer research 338
• Understanding tumor diversity in mouse mammary cancer model 340
• Personalized management of ovarian cancer 340
• Early diagnosis of ovarian cancer 340
• Determining response to chemotherapy in ovarian cancer 341
• Prognosis of ovarian cancer based on CLOVAR 341
• Recurrent and drug-resistant ovarian cancer 341
• Pathway targeted therapies for ovarian cancer 343
• Personalized management of head and neck cancer 344
• Relevance of biomarkers of HPV-related head and neck cancer 344
• Personalized management of hematological malignancies 345
• Personalized management of acute lymphoblastic leukemia 345
• Personalized management of acute myeloid leukemia 346
• Personalized management of chronic lymphocytic leukemia 347
• Personalized management of multiple myeloma 347
• Personalized management of myelodysplastic syndrome 349
• Personalized management of lymphomas 349
• Personalized management B cell lymphomas 349
• Personalized vaccine for follicular lymphoma 350
• Companion diagnostic for treatment of lymphoma with Adcentris™ 350
• Personalized management of hepatocellular carcinoma 351
• Personalized management of gastrointestinal cancer 351
• Personalized management of esophageal cancer 351
• Personalized management of gastric cancer 352
• Personalized management of colorectal cancer 352
• Sequencing for personalized management of colorectal cancer 355
• Systems biology approach to drug resistance in colorectal cancer 356
• Resistance to targeted EGFR blockade in CRC 356
• Personalized management of liver cancer 357
• Personalized management of lung cancer 357
• Crizotinib for personalized management of NSCLC 357
• Determination of outcome of EGFR tyrosine kinase inhibitor treatment 358
• Development of resistance to EGFR inhibitors 359
• Molecular subtyping of lung cancer 360
• Personalized therapy of NSCLC based on KIF5B/RET fusion oncogene 360
• Role of a new classification system in the management of lung cancer 361
• Selecting therapy of cancer arising from respiratory papillomatosis 361
• Testing for response to chemotherapy in lung cancer 361
• Testing for prognosis of lung cancer 362
• Testing for recurrence of lung cancer 362
• Personalized management of malignant melanoma 362
• Inhibitors of BRAF mutation for metastatic melanoma 363
• Management of drug-resistant metastatic melanoma 363
• Vaccine for malignant melanoma based on heat shock protein 364
• Personalized management of pancreatic cancer 364
• Biomarkers of pancreatic cancer 365
• Histone modifications predict treatment response in pancreatic cancer 365
• Personlized management of prostate cancer 365
• Diagnostics for guiding therapy of prostate cancer 365
• Prolaris assay for determining prognosis in prostate cancer 366
• Detection of prostate cancer metastases 366
• Early detection of cancer recurrence and guiding treatment 367
• Effects of of lifestyle changes shown by gene expression studies 367
• Personalized peptide vaccine for prostate cancer 367
• Future of cancer therapy 368
• Challenges for developing personalized cancer therapies 368
• Cancer Genome Atlas 368
• COLTHERES consortium 369
• Computer and imaging technologies for personalizing cancer treatment 369
• Genomic Cancer Care Alliance 369
• Global Cancer Genomics Consortium 370
• Integrated genome-wide analysis of cancer for personalized therapy 370
• International Cancer Genome Consortium 370
• PREDICT Consortium 371
• Companies involved in developing personalized cancer therapy 372

10. Development of Personalized Medicine 376

• Introduction 376
• Non-genomic factors in the development of personalized medicine 376
• Personalized medicine based on circadian rhythms 376
• Cytomics as a basis for personalized medicine 377
• Intestinal microflora 377
• Gut microbiome compared to human genome 377
• Metabolic interactions of the host and the intestinal microflora 378
• Role of drug delivery in personalized medicine 378
• Personalized approach to clinical trials 379
• Use of Bayesian approach in clinical trials 379
• Individualzing risks and benefits in clinical trials 379
• Clinical trials of therapeutics and companion diagnostics 380
• Players in the development of personalized medicine 380
• Personalized Medicine Coalition 381
• European Personalized Medicine Diagnostics Association 382
• Role of pharmaceutical industry 382
• Production and distribution of personalized medicines 382
• Role of biotechnology companies 383
• Role of life sciences industries 383
• Role of molecular imaging in personalized medicine 384
• Molecular imaging for personalized drug development in oncology 384
• Molecular imaging and CNS drug development 386
• Companies involved in molecular imaging 387
• Role of the clinical laboratories 387
• Role of the US government in personalized medicine 388
• Department of Health and Human Services and personalized medicine 389
• Agency for Healthcare Research and Quality 390
• Comparative effectiveness research 390
• Role of the US Government agencies in personalized medicine 392
• NIH's Roadmap Initiative for Medical Research 392
• NIH and personalized medicine 392
• NIH collaboration with the FDA 393
• NIH and Genetic Testing Registry 393
• National Institute of General Medical Sciences 393
• National Institute of Standards and Technology 395
• Role of the Centers for Disease Control 396
• Role of academic institutions in the US 396
• Baylor College of Medicine 396
• Clinical Proteomics Program of NCI & FDA 396
• Coriell Personalized Medicine Collaborative™ 397
• Delaware Valley Personalized Medicine Project 397
• Duke University Medical Center and genomic medicine 398
• Evaluation of genetic tests and genomic applications 398
• Ignite Institute 399
• Indiana University Institute for Personalized Medicine 399
• Institute of Medicine's role in personalized medicine 400
• Jackson Laboratory for Genomic Medicine 400
• Johns Hopkins Center for Personalized Cancer Medicine Research 401
• Mayo Clinic's Center for Individualized Medicine 401
• Mt. Sinai Medical Center's Personalized Medicine Research Program 401
• P4 Medicine Institute 402
• Personalized Medicine Partnership of Florida 402
• Personalized oncology at Massachusetts General Hospital 402
• Personalized oncology at Oregon Health & Science University 403
• Pharmacogenetics Research Network and Knowledge Base 403
• Southeast Nebraska Cancer Center's Personalized Medicine Network 404
• Stanford Center for Genomics and Personalized Medicine 404
• UNC Institute for Pharmacogenomics and Individualized Therapy 404
• Wisconsin Genomics Initiative 405
• Role of academic collaborations with companies 405
• New York Genome Center 405
• Role of healthcare organizations 405
• Role of the medical profession 405
• The American Medical Association and personalized medicine 406
• Education of the physicians 406
• Off-label prescribing and personalized medicine 406
• Medical education 407
• Role of patients 407
• Public attitude towards personalized medicine 407
• Role of genetic banking systems and databases 408
• Role of biobanks in development of personalized medicine 408
• UK Biobank 408
• Biobanking and development of personalized medicine in EU 409
• CARTaGENE for biobanks in Canada 409
• Personalized medicine based on PhysioGenomics™ technology 410
• Role of bioinformatics in development of personalized medicine 410
• Exploration of disease-gene relationship 412
• Biosimulation techniques for developing personalized medicine 412
• Health information management 412
• Electronic health records 413
• Cost of EHR and savings on healthcare expenses in the US 413
• EHRs and genome-wide studies 413
• Linking patient medical records and genetic information 414
• Management of personal genomic data 414
• Use of EHRs for genetic research 415
• Use of EHRs for personalized drug discovery and development 415
• Personalized prognosis of disease 416
• Integration of technologies for development of personalized medicine 416
• Global scope of personalized medicine 417
• Personalized medicine in Canada 417
• Personalized medicine at Ontario Institute for Cancer Research 417
• Personalized Medicine Partnership for Cancer in Quebec 419
• Quebec Center of Excellence in Personalized Medicine 419
• Personalized medicine in the EU 419
• UK National Health Service and medical genetics 420
• Personalized medicine in Germany 420
• Personalized medicine in the developing countries 421
• Advantages and limitations of personalized medicine 422
• Limitations of personalized medicine 422
• Future of personalized medicine 424
• Ongoing genomic projects 424
• Understanding the genetic basis of diseases 424
• Personal Genome Project 424
• Genome-wide association studies 425
• The 1000 Genomes Project 426
• Genomics of aging in a genetically homogeneous population 426
• Translational science and personalized medicine 427
• Translation of genomic research into genetic testing for healthcare 427
• Long-term behavioral effects of personal genetic testing 428
• Personalized predictive medicine 428
• Opportunities and challenges 429
• Prospects and limitations of genetic testing 429
• Genetic testing and concerns about equality of healthcare 430
• Pharmacotyping 430
• Comparative-effectiveness research and personalized medicine 430
• Medicine in the year 2017 431
• Concluding remarks about the future of personalized medicine 431

11. Ethical and Regulatory Aspects of Personalized Medicine 434

• Introduction to ethical issues 434
• Ethical issues of pharmacogenetics 434
• Ethical aspects of genetic information 434
• Ethical issues of whole genome analysis 434
• Ethical aspects of direct-to-consumer genetic services 435
• Privacy issues in personalized medicine 436
• Genetic Information Nondiscrimination Act in the US 437
• Genotype-specific clinical trials 437
• Social issues in personalized medicine 437
• Race and personalized medicine 438
• Regulatory aspects 439
• CLSI guideline for the use of RNA controls in gene expression assays 440
• MicroArray Quality Control Project 440
• Regulatory aspects of pharmacogenetics 441
• Regulation of direct-to-consumer genetic testing 442
• Need for regulatory oversight of DTC 442
• FDA and pharmacogenomics 445
• FDA guidance for pharmacogenomic data submissions 445
• Joint guidelines of the FDA and EU regulators for pharmacogenomics 446
• Pharmacogenomic/pharmacogenetic information in drug labels 446
• FDA guidelines for pharmacogenomics-based dosing 447
• FDA and validation of biomarkers 447
• FDA and predictive medicine 448
• FDA regulation of multivariate index assays 448
• Evaluation of companion diagnostics/therapeutic 450

12. Commercial Aspects of Personalized Medicine 452

• Introduction 452
• Perceived financial concerns 452
• Personalized medicine and orphan drug syndrome 452
• Commercial aspects of pharmacogenomics 452
• Cost of DNA testing 452
• Cost of sequencing the human genome 453
• Cost of genotyping 455
• Cost of pharmacogenomics-based clinical trials 455
• Business development of pharmacogenomic companies 456
• Cost of personalized healthcare 456
• The rising healthcare costs in the US 456
• Genetic testing and cost of healthcare 457
• Reducing healthcare costs by combining diagnostics with therapeutics 457
• Cost-effectiveness of pharmacogenetic testing 458
• Cost-effectiveness of CYP genotyping-based pharmacotherapy 458
• Cost effectiveness of HIV genotyping in treatment of AIDS 459
• Cost-effectiveness of warfarin pharmacogenomics 459
• Cost-benefit analysis of KRAS and BRAF screening in CRC 459
• Lowering the high costs of cancer chemotherapy 460
• Overall impact of personalized medicine on healthcare 460
• Drivers for the development of personalized medicine 461
• Evolution of medicine as a driver for personalized therapy markets 461
• Collaboration between the industry and the academia 462
• Personalized medicine and drug markets 463
• Segmentation of therapeutic drug markets 463
• Reasons for increase of market values of personalized medicines 463
• Growth of markets relevant to personalized medicine 464
• SNP market 464
• Pharmacogenomics 464
• Pharmacogenetics 465
• Pharmacoproteomics 465
• Biochips 465
• Point-of-Care 465
• Markets for personalized medicines according to therapeutic areas 465
• Market for personalized cancer therapy 466
• Markets for personalized medicines according to geographical regions 466
• Market opportunities for personalization of medicine 466
• Impact of personalized medicine on other industries 467
• Strategies for developing and marketing personalized medicine 468
• Education of the public 468
• Role of the Internet in development of personalized medicine 469
• Marketing companion diagnostics for personalized medicine 469

13. References 470

Tables

• Table 1-1: Selected terms relevant to the concept of personalized medicine 22
• Table 1-2: Landmarks in the historical development of personalized medicine 23
• Table 1-3: Genetic variations in the human genome 28
• Table 2-1: Molecular diagnostic technologies used for personalized medicine 48
• Table 2-2: Applications of biochip technology relevant to personalized medicine 67
• Table 2-3: Companies developing haplotying technology 82
• Table 2-4: Technologies for SNP analysis 82
• Table 2-5: A sampling of companies involved in technologies for SNP genotyping 91
• Table 2-6: Comparison of proteomic and genomic approaches in personalized medicine 99
• Table 2-7: Selected methods for gene expression profiling 100
• Table 2-8: A selection of companies with gene expression technologies 105
• Table 2-9: Drugs requiring biomarker/companion diagnostic information in the label 108
• Table 2-10: Companies involved in companion diagnostics 109
• Table 2-11: Applications of point-of-care diagnosis 111
• Table 2-12: Companies developing point-of-care diagnostic tests 112
• Table 2-13: Companies offering genetic screening tests directly to consumers 116
• Table 3-1: Pharmacogenetic vs. pharmacogenomic studies 123
• Table 3-2: Enzymes relevant to drug metabolism 125
• Table 3-3: Examples of mutation of the enzyme CYP450 126
• Table 3-4: Frequency distribution of drugs metabolized by major isoforms of CYP450. 126
• Table 3-5: Commonly prescribed medications, which are metabolized by CYP2D6 126
• Table 3-6: Polymorphisms in drug target genes that can influence drug response 132
• Table 3-7: Effect of genetic polymorphisms on disease response to drugs 133
• Table 3-8: Examples of genetically determined adverse reactions to drugs 136
• Table 3-9: Examples of genotyping and phenotyping in some diseases 144
• Table 3-10: Companies with novel molecular toxicology technology 146
• Table 4-1: Role of pharmacogenomics in variable therapy targets 154
• Table 4-2: Role of pharmacogenomics in clinical trials 157
• Table 4-3: Examples of pharmacogenomics-based clinical studies 158
• Table 4-4: Tumor suppressor genes, their chromosomal location, function and associated tumors. 161
• Table 4-5: Gene polymorphisms relevant to cardiovascular disease management 162
• Table 4-6: Companies involved in cardiovascular genomics 164
• Table 4-7: A sampling of companies involved in neuropharmacogenomics 166
• Table 8-1: Important therapeutic areas for personalized medicine 186
• Table 8-2: Enzymes that metabolize antipsychotics 198
• Table 8-3: Enzymes that metabolize antidepressants 200
• Table 8-4: Gene expression as biomarker of response to IFN-β in multiple sclerosis 215
• Table 8-5: Genes that cause cardiovascular diseases 221
• Table 9-1: Factors that drive the development of personalized therapy in cancer 262
• Table 9-2: Impact of molecular diagnostics on the management of cancer 264
• Table 9-3: Marketed anticancer personalized medicines 287
• Table 9-4: Clinical trials of personalized cancer vaccines 298
• Table 9-5: Selected companies involved in developing personalized cancer therapies 372
• Table 10-1: Players in the development of personalized medicine 380
• Table 10-2: Members of the Personalized Medicine Coalition 381
• Table 10-3: Biobanks relevant to personalized medicine 408
• Table 10-4: Role of bioinformatics in the development of personalized medicine 410
• Table 10-5: Advantages of personalized medicine for the biopharmaceutical industry 422
• Table 10-6: Advantages of personalized medicine for the patients 422
• Table 10-7: Advantage of personalized medicine for the physicians 422
• Table 10-8: Advantage of personalized medicine for the healthcare providers 422
• Table 10-9: Limitations of personalized medicine 423
• Table 10-10: Methods of translational science that are relvant to personalized medicine 427
• Table 10-11: Companies involved in predictive healthcare 428
• Table 11-1: Drugs with genetic information in their labels 446
• Table 12-1: Drivers for the development of personalized medicine 461
• Table 12-2: Growth of markets relevant to personalized medicine 2012-2022 464
• Table 12-3: Markets for personalized medicine according to therapeutic area 2012-2022 466
• Table 12-4: Markets for personalized medicine in major regions 2012-2022 466
• Table 12-5: Lack of efficacy in current therapy 467
• Table 12-6: Impact of personalized medicine on other industries 467
• Table 12-7: Strategies to develop personalized medicine 468
• Table 12-8: Role of the Internet in development of personalized medicine 469

Figures

• Figure 1-1: Relation of personalized medicine to other technologies 38
• Figure 1-2: Relation of systems pharmacology to personalized medicine 44
• Figure 2-1:Role of sequencing in personalized medicine 66
• Figure 2-2: Role of biochips/microarrays in personalized medicine 68
• Figure 2-3: Affymetrix GeneChip technology 69
• Figure 2-4: Role of CYP450 genotyping in development of personalized medicine 70
• Figure 2-5: Role of SNPs in personalized medicine 78
• Figure 2-6: A scheme of integrated healthcare and personalized medicine 117
• Figure 3-1: Pharmacogenetics as a link between genotype and phenotype 122
• Figure 3-2: Role of pharmacogenetic technologies in personalized medicine 123
• Figure 4-1: Impact of new technologies at various stages of the drug discovery process 156
• Figure 4-2: Steps in the application of pharmacogenomics in clinical trials 158
• Figure 7-1: Role RNAi in development of personalized medicine 184
• Figure 8-1: A scheme of personalized approach to management of hypertension 227
• Figure 8-2: A scheme of personalized management of pain 216
• Figure 9-1: Relationships of technologies for personalized management of cancer 263
• Figure 10-1: Integration of technologies for the development of personalized medicine 416
• Figure 12-1: Evolution of personalized medicine as a market driver 462

PartII

14. Companies Involved in Developing Personalized Medicine 5 Introduction 5 Profiles 5 Collaborations 205

Tables

• Table 14-1: Top five companies involved in personalized medicine 5
• Table 14-2: Selected collaborations of companies in personalized medicine 205

Personalized Medicine - scientific & commercial aspects published by Jain Pharmabiotech in April 1, 2013. This report price starts from US $ 5000.

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