Impact of Genomics on Clinical Trials and Medical Practice, The

1. Introduction

1.1. Overview
1.2. The Impact of Genomics in the Clinic
Definition and Scope of Clinical Genomics
Preclinical Versus Clinical Applications of Genomics
1.3. Impact of Data from the Human Genome
The Human Genome Project
Sidebar: Brief Timeline of Human Genomics
Peculiarities of the Human Genome
Advantages of a Genomics Approach
1.4. The Promise of Clinical Genomics
Sidebar: Our Genomic Destiny: Fact or Fiction?
Potential Impact on Medical Practice
-Personalized Medicine
-Toxicogenomics: Fewer Adverse Drug Reactions
-Predicting Disease
Sidebar: NHGRI’s Vision for the Future of Genomics
-Improving Clinical Trials
-Predicting Response to Drugs
-Better Drug Design
1.5. Challenges in the Field
Scientific Challenges
-Variation in Drug Response
-Disease Complexity
-Characterization of Genetic Variation
-Genome Complexity
Technological Challenges
-DNA Technologies
-Microarrays
-Regulatory Challenges
-The FDA
-Congress
Legal Challenges
-Intellectual Property
-Liability
Sidebar: The Biojudiciary Project
Economic Challenges
Sociological and Cultural Challenges
-Medical Education
-Patient Acceptance
-Ethical Considerations

Chapter 2. Applications of Genomics in Clinical Trials and Medicine

2.1. Prediction, Detection, and Diagnosis of Disease
2.2. Predicting Response to Drugs
Historical Perspective
Pharmacogenomics
2.3. Factors Influencing Response to Drugs
Drug Metabolism
-Pharmacogenomics of Phase I Drug Metabolism
-Pharmacogenetics of Phase II Drug Metabolism: N-Acetyltransferase
-Pharmacogenetics of Phase II Drug Metabolism: Thiopurine S-Methyltransferase
Drug Transporters
Genetic Polymorphism of Drug Targets
Genetic Variants with Indirect Effects on Drug Response
2.4. Personalized Medicine
Variation in Gene Expression
Cancer Classification, Diagnosis, and Prognosis
-Cancer Classification
-Cancer Diagnosis
Sidebar: Cancer Genome Anatomy Project
-Cancer Prognosis
2.5. Toxicogenomics
2.6. Determining Risk of Disease
Inherited Genetic Variation
Sidebar: Categories of Inherited DNA Diseases
Single-Gene Genetic Disorders
-Monogenic Trait Example: Cystic Fibrosis
Multifactorial Disorders
-Multifactorial Disease Example #1: Alzheimer’s Disease
-Multifactorial Disease Example #2: Cancer
Sidebar: Genetic Origin of Cancers
Screening Newborns
2.7. Gene Therapy
2.8. Identifying Individuals
Paternity Testing
Forensics
Identifying Remains
2.9. Proteomics

Chapter 3. Genomic Technologies for the Clinic

3.1. Overview
3.2. Detecting DNA Variation
Single Nucleotide Polymorphisms
Haplotypes
-HapMap Project
-Selected Companies Active in Haplotypes
3.3. SNP Genotyping Methods
Sidebar: SNP Detection
Evaluating SNP Technologies for Clinical Applications
-Cost of SNP Genotyping
-Success Rates
-Accuracy
Throughput Considerations
Selected Companies Active in SNP Genotyping
-Sequenom
-Illumina
-Affymetrix
-PerkinElmer
-Third Wave Technologies
-Applied Biosystems Group
-Beckman Coulter
3.4. Gene Expression Detection
Methods for Measuring Gene Expression
-DNA Microarrays
-DNA Synthesis
-DNA Deposition
Box Feature: Gene Expression Database
Computational Issues
Evaluating the Technologies
Cross-Platform Comparisons
Selected Companies Marketing Gene Expression Microarrays
-Affymetrix
-Agilent Technologies
-Applied Biosystems
-CombiMatrix
-Brinkmann Instruments
3.5. RNA Interference
Selected Companies Active in RNAi Therapy
-Alnylam Pharmaceuticals
-Sirna Therapeutics
-Acuity Pharmaceuticals
3.6. Other Technologies
Epigenetic Markers
-Sequenom’s Approach
-Epigenomics’ DNA Methylation Technique
Alternative Splicing
Proteomics

Chapter 4. Advances in Clinical Genomics Applications

4.1. Overview
4.2. Toxicogenomics
Adoption of Clinical Toxicogenomics Tests
Case Study #1: First Microarray Approved for Treatment Decisions
Sidebar: P450 Drug Interaction Card
Case Study #2: First Pharmacogenetic Test Approved As Companion to Therapy
Case Study #3: TPMT
4.3. Clinical Trials
4.4. Clinical Oncology
Case Study #1: Cancer Gene Expression
-Agendia’s MammaPrint Gene Expression Assay
-Genomic Health’s Oncotype DX
Case Study #2: Genentech’s Herceptin and Her-2
Case Study #3: BRCA1 and BRCA2 Genes and Myriad Genetics
Box Feature 4.1: Human Cancer Genome Project
4.5. Infectious Diseases
Case Study: HIV and AIDS
Other Applications for Genomics to Infectious Diseases
4.6. Newborn Screening
4.7. Genomics and Race
BiDil: The First Race-Based Drug
4.8. Genomics and Drug Labeling

Chapter 5. Business and Strategic Factors

5.1. Overview
5.2. Patient Stratification
Impact on Clinical Trials
Impact on the Market
5.3. Scientific Issues
Can Clinical Genomics Deliver on Its Promise?
Can the Influence of Genes on Drug Response Be Quantified?
5.4. Standardization and Quality Control
5.5. Physician and Payer Response
5.6. Drug-Diagnostic Codevelopment: Theranostics
5.7. The Regulatory Environment
FDA Guidelines on Pharmacogenomics "Home-Brew" Testing, In Vitro Diagnostics, and the FDA
5.8. Cost-Benefit Analysis
Evaluating the Cost of Clinical Genomics
Factors Influencing Costs
Comparing Genomics With Other Testing and Treatment Options
Noteworthy Indications
5.9. Niche Markets for Clinical Genomics
Opportunity in Rare Diseases
Outlook for Toxicogenomics
Projected RNAi Market

Chapter 6. Expert Interviews

Edward Abrahams, PhD, Executive Director, Personalized Medicine Coalition (PMC)
Charles R. Cantor, PhD, Chief Scientific Officer SEQUENOM
Mickie Henshall, Product Manager, Molecular Diagnostics, Illumina, Inc.
William Craumer, Director, Corporate and Marketing Communications, Illumina, Inc.
Mark A. McCamish, MD, PhD, Chief Medical Officer, Perlegen Sciences

Chapter 7. Selected Company Profiles

Affymetrix
Agendia
Alnylam Pharmaceuticals
Applied Biosystems Group (ABI)
Agilent
Beckman Coulter, Inc.
Brinkmann Instruments (A Member of the Eppendorf Group)
CombiMatrix Corporation
DnaPrint Genomics Inc.
Encode (Subsidiary of deCODE)6
Epigenomics AG
ExonHit Therapeutics
Genaissance Pharmaceuticals
Gene Logic
Genomic Health
Genpathway Inc.
Gentris
Iconix Pharmaceuticals, Inc.
Illumina
Invitrogen
Myriad Genetics
Nanogen
NitroMed, Inc.
PathWork Informatics
Perlegen Sciences
PTC Therapeutics, Inc.
Roche Molecular Diagnostics
SEQUENOM, Inc.
Sirna Therapeutics
Third Wave Technologies, Inc.
Vanda Pharmaceuticals

List of Tables

Table 1.1. Stages of Clinical Trials
Table 2.1. Genomic Features with Clinical Applications
Table 2.2. Genetic Pathways That Could Alter Drug Efficacy and Safety: ADME
Table 2.3.Classes of Genetic Variation in Drug Metabolism
Table 2.4. Examples of Cytochrome P450 Gene Variation and Drug Interaction
Table 2.5. Examples of Genetic Variation in Drug Targets Affecting Drug Response
Table 2.6. Selected Toxicogenomics Databases
Table 2.7. Examples of Monogenic Diseases for Which Clinical Tests Are Available
Table 2.8. Examples of Genes Contributing to Complex Diseases
Table 2.9. Cancers with a Strong Genetic Component
Table 3.1. Types of DNA Variation
Table 3.2. Factors Influencing Genotyping Costs
Table 3.3. Criteria for Evaluating SNP Genotyping Accuracy
Table 3.4. Steps in Microarray Experiments
Table 3.5. Informatics Issues Associated with Microarrays
Table 3.6. Selected Companies Marketing Microarrays or Related Tools or Services
Table 4.1. Correlation of UGT1A1 Variants with Risk of Toxicity
Table 4.2. Selected Assays Used to Screen Newborns for Genetic Diseases
Table 4.3. Examples of Drugs Reported to Evoke Different Responses in Different Racial or Ethnic Groups
Table 4.4. Selected Drugs for Which the Target Population May Be Determined by Genetic Testing (U.S. prescribing information)
Table 4.5. Prescribing Information for Drug-Metabolizing Enzyme Genotypes
Table 5.1. Savings Resulting from Patient Stratification in a Breast Cancer Study
Table 5.2. Efforts to Standardize Gene Expression Data
Table 5.3. Factors Increasing or Decreasing Costs Associated With Genomic Technology
Table 5.4. Quick Reference on Pharmacogenomic Submissions
Table 5.5. Framework for Evaluating the Potential Cost-Effectiveness of Clinical Genomics Therapies

List of Figures

Figure 1.1. Preclinical Versus Clinical Applications of Genomics
Figure 1.2. Personalized Medicine
Figure 1.3. Taking Genomics to the Clinic
Figure 2.1. Estimated U.S. Cancer Deaths by Type, 2005
Figure 3.1. Single Nucleotide Polymorphisms
Figure 3.2. A Haplotype Block
Figure 3.3. Functional Genomic Analysis of Gene Expression
Figure 3.4. Microarray Analysis
Figure 3.5. Diagram of Short Interfering RNAs
Figure 4.1. Distribution of Drug-Metabolizing Enzymes in the Population
Figure 4.2. Roche Diagnostics' AmpliChip CYP450 Figure 4.3. Effect of UGT1A1 on Irinotecan Metabolism
Figure 4.4. Distribution of TPMT Activity in Unrelated Adults
Figure 4.5. Estimated Growth of Genomics in U.S. Clinical Trials
Figure 4.6. Applications of Genomics in Drug Development
Figure 4.7. Application of Gene Expression Testing in Breast Cancer
Figure 5.1. How Patient Stratification Using Genomics Can Be Beneficial
Figure 5.2. Impact of Various Factors on Variation of Patient Response to Warfarin
Figure 5.3. Breakdown of Spending on Health Care in the United States, 2002
Figure 5.4. Codevelopment of Drugs and Diagnostics
Figure 5.5. Current and Possible Future Applications of Diagnostics
Figure 5.6. Limits to Genomic Predictions of Drug Efficacy
Figure 5.7. RNAi Market Forecast