Abstract
The Impact of Genomics on Clinical Trials and Medical Practice evaluates the
potential of clinical genomics to transform drug development and the practice
of medicine. The report projects significant growth opportunities in this
field, balanced with a realistic assessment of the challenges and hurdles to
bringing clinical genomics to mainstream medicine.
Clinical genomics is the application of large-scale, high-throughput genomics
technologies in clinical settings, such as clinical trials or primary care of
patients. Clinical genomics promises to allow a molecular understanding of
disease and drug response, with benefits in all areas of medicine.
Contributing to the growth of genomics, in 2005 the FDA issued guidelines for
applications of genomics in drug development, with the stated hope that
genomics will improve the safety and effectiveness of medicines. Given this
mandate, clinical genomics applications appear to have crossed a threshold
with the recent approval of several clinical genomics products. These
approvals are expected to provide important precedents for other product
approvals in the near future.
Examples reviewed in the report include the following:
- Roche Diagnostics' AmpliChip Cytochrome P450 Genotyping Test: In 2004 this
test, a DNA chip that identifies variations in two genes affecting response to
a wide variety of drugs, became the first microarray approved for treatment
decisions by the FDA.
Third Wave Technologies' Invader UGT1A1 Test: This test for detecting
heightened risk of adverse reaction to the chemotherapy drug irinotecan was
FDA-approved in 2005 as the first pharmacogenetic companion diagnostic paired
with a specific drug therapy. Genomics applications in clinical trials are
also dramatically rising. It is now estimated that about 20% of U.S. clinical
trials use some sort of genomics approach, with the highest percentage in
oncology trials. While this trend is expected to accelerate during the next
few years, the field still faces considerable regulatory, technical, economic,
and sociological hurdles. The full promise of clinical genomics applications
may not be fully realized for at least another ten to fifteen years. However,
as genomics transitions away from primarily research to more clinical
applications, the field will be ripe with business opportunities and the
report examines some of the business and strategic factors relevant to the
further adoption of genomics technologies in clinical trials and medical
practice.
This report is part of the CHA Advances MONITOR series. The CHA Advances
MONITOR series singles out markets, technologies, and industry sectors that
are characterized by propulsive growth and by the potential to change the
basis of competition in the pharmaceutical industry. We plan to visit these
subjects approximately every 2 years.
About the Author
Gwen Acton, Ph.D., is president of Vivo Group, a consulting firm specializing
in evaluation and management of genomics and life science technology. Prior to
this, Dr. Acton served as Director of Scientific Development at the Whitehead
Institute for Biomedical Research, and ran the operations of the Functional
Genomics Program at the Whitehead Institute/M.I.T. Center for Genome Research.
Dr. Acton received a doctorate in molecular biology and genetics from M.I.T.
and served as a faculty member at Harvard University in the Department of
Molecular and Cellular Biology.
Table of Contents
- Chapter 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
- References
- Index
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