Combination Drug/Diagnostic Products: Pathways to R&D and Commercial Success
By Hermann A.M. Mucke, PhD
Michael S. Goodman
Table of Contents
CHAPTER 1
THE BURNING PLATFORM: COSTS, COMPLICATIONS, COMPLIANCE
1.1. Drug Development Expenses Are Increasing at an Alarming Rate
1.2. Postlaunch Adverse Reactions Are Increasing
1.3. Strategies for Streamlining Drug Development and Use
Individualized Drug Dosing
Monitoring Patient Response to a Drug or Drug Candidate
CHAPTER 2
BIOMARKERS: AXIS OF INNOVATION FOR DIAGNOSTICS AND THERAPEUTICS
2.1. Limitations of Protein Biomarker Discovery in Blood
2.2. Examples of Drug/Diagnostic Combinations Currently in Use
Genomic Health: Oncotype DX
Clinical Data: Phase III Tandem of Vilazodone and Marker
Roche: C-Reactive Protein as a Response Biomarker with Antibody Therapy
Oncogene Science: HER2/neu Testing with Herceptin and Vascular Endothelial Growth Factor and KDR Testing with Nexavar
Sidebar: Monogram Biosciences’ Trofile Assay: Co-developed for Use with Pfizer’s Celsentri for HIV
Celera Genomics: Cirrhosis in Chronic Hepatitis C Patients
2.3. Existing Biomarkers Used as Diagnostics
Apolipoprotein E Genetic Variants and Alzheimer’s Disease
Imatinib (Gleevec): A Genomically Targeted Therapy
Thiopurine Methyltransferase
Irinotecan (Camptosar)
Warfarin
CHAPTER 3
DIAGNOSTIC TOOLS TO IMPROVE DRUG DISCOVERY AND THE PRESCRIPTION OF LICENSED DRUGS
3.1. Discovering New Drugs that Work Well in the Entire Population
3.2. Discovering New Targeted Drugs Aimed at Genomic Subpopulations
3.3. Approaches to Improve the Safety and Efficacy of Drug Development
“Rescue” of Products in Late-Stage Trials Due to Adverse Drug Reactions
Creation of New Drugs for Particular Subpopulations of “Good Responders”
3.4. Improving the Prescription of Licensed Drugs
Preprescription Screening to Identify Patients at Risk for Adverse Drug Reactions
Postmarketing Surveillance of Approved Drugs
Preprescription Screening to Identify Good Responders
Use of Efficacy Data in Drug Marketing
CHAPTER 4
THE LABORATORY: CLINICAL DIAGNOSTICS DELIVERY MODEL
4.1. Quality Assurance and Validation Requirements of Pharmacogenomic Testing
4.2. National Academy of Clinical Biochemistry Guidelines and Recommendations
4.3. Metabolism Gene Variants as Markers for Therapeutic Response
Cytochrome P450 System
CYP2D6
CYP2C9
CYP2C19
CHAPTER 5
APPLYING DIAGNOSTICS TO HEALTH CARE AND THERAPEUTIC DEVELOPMENT
5.1. Open Databases as a Platform for Diagnostics/Therapeutics Co-development
5.2. Test Validation Is Key
5.3. Opportunities for Future Pharmacogenetic/Drug Companion Tests: 3 Examples
Abacavir (Ziagen)
Amoxetine (Strattera)
Proton Pump Inhibitors
CHAPTER 6
ASSESSING THE MARKET POTENTIAL FOR COMBINATION PRODUCTS: PATHWAYS TO SUCCESS
6.1. CHI Insight Pharma’s Proprietary Survey Results
Characteristics that Recommend a Drug for Combination Rx/Dx Development
Disease States Best Suited for Combination Rx/Dx Development
6.2. Market Dynamics
The Molecular Diagnostics Segment Shows Robust Growth
A Diagnostic Market Characterized by Consolidation
The US Diagnostic Market: Historically Low Expectations
6.3. Trends in Drug/Diagnostic Development Point to Growth
The Industry Sees Broad Opportunities for Combination Rx/Dx Development
Projected Growth in the Rx/Dx Pipeline
6.4. Big Pharma’s Reluctance to Abandon the Blockbuster Model
6.5. Industry Views on Where and When Combination Strategies Will Be Deployed
Commentary from Industry Leaders, by Sector
Players Poised to Succeed in the Brave New World of Targeted Therapies and Companion Diagnostics
6.6. Pathways to Successful Development of Combination Drug/Diagnostic Products
Momentum Toward the Concept of Parallel Development of the Drug and the Diagnostic
Momentum Toward a Developmental Focus on Both the Disease and the Therapy
6.7. Reimbursement and Regulatory Incentives Will Drive Adoption
Diagnostic Coding Requirements: An Outdated Hurdle to Adoption?
A Case Study in Reimbursement for a Molecular Diagnostic: Genomic Health’s Oncotype DX
6.8. Understanding Specific Disease-Related Diagnostic Opportunities in the Cancer Space
6.9. Sectors and Strategies that Will Drive Combination Drug/Diagnostic Development
What Types of Companies Will Pursue a Combination Model?
What Execution Strategy Will Most Companies Pursue?
CHAPTER 7
INTELLECTUAL PROPERTY PROTECTION
7.1. Where We’ve Been
7.2. Where We’re Going
7.3. Implications for Technological Protection and Remuneration
7.4. Strategies in Play
Therapy-Centric
Genetic/Proteomic Discovery
Diagnostic-Centric
7.5. A Snapshot of Drug/Diagnostic Patent Applications Filed in the Second Quarter of 2005
Cancer
Respiratory Diseases
Neurodegenerative Diseases
Viral Infections
CHAPTER 8
REGULATORY CONSIDERATIONS: RECENT FDA REGULATIONS AND GUIDANCES
8.1. The Regulation of Combination Products
8.2. FDA’s Office of Combination Products (OCP)
8.3. The OCP’s Charter: GMP Requirements and Adverse Event Reporting
8.4. FDA Endorses Retrospective Studies
8.5. Real-Time Review
8.6. Relevant and Recent Regulatory Actions Bearing on Combination Drug/Diagnostics
510(k) or Full Premarket Approval (PMA)?
Draft Guidance for Industry, Clinical Laboratories, and FDA Staff; In Vitro Diagnostic Multivariate Index Assays (FDA; September 2006)
Summary
Draft Guidance for Industry and FDA Staff, Commercially Distributed Analyte- Specific Reagents (ASRs): Frequently Asked Questions (FDA; September 2006)
Essential Regulatory Elements
Definition of an ASR: The Key Delineation
The Advanced Laboratory Diagnostics Act of 2006 (House of Representatives; May 2006)
Drug-Diagnostic Co-development Concept Paper (FDA; April 2005)
Memorandum of Understanding between the FDA, NCI, and CMS (FDA, NCI, CMS; January 2006)
CHAPTER 9
THE FUTURE IS NOW: CLINICAL TRIAL UPDATE
9.1. MINDACT
Trial Summary
9.2. TAILORx
Trial Summary
References
Glossary of Selected Terms
Company Index with Web Addresses