A Guide to Business and Regulatory Strategies for Companion Diagnostics and Individual Therapies

Table of Contents

Chapter 1: Executive Summary

Chapter 2: Introduction

• Personalized Medicine Perceived Issues
• Spear' s Seven Pharmacogenomic Myths
  • Commentary on the 7 Myths
    • Myth 1-PGx will Create Niche Markets
    • Myth 2-PGx Will Cut the Cost of Drug Development
    • Myth 3-Personalized Medicine is Limited by Technology
    • Myth 4-Co-development of Drugs and Diagnostics
    • Myth 5-Genes Determine Drug Response
    • Myth 6-PGx will Identify Drugs with Rare Side Effects
    • Myth 7-PGx will be Driven by Regulatory Issues
      • Excerpts from FDA Genomic Data Submission Guidance
      • Test Requirements
  • Pharmaceutical and Diagnostic Co-Development Process
• References

Chapter 3: Intellectual Property Guide

• Creating a Path for Success: Intellectual Property and Other Legal Issues Associated
• DxRx Collaborations
• Licensing Issues for Genetic Markers of Disease and Drug Responsiveness
  • Kenneth Sonnenfeld, Partner, Morgan & Finnegan, LLP, New York, NY
  • Dysautonomia Foundation
  • Sublicensing Issues
  • Examples of Patent Pools
    • Legislation Regarding Gene Patents
• Developing Products for Personalized Medicine: Application of the NIH
• Research Tools Policy
• What is the NIH Research Tools Policy?
  • The Four Principles
  • Conclusions for Personalized Medicine Product Development
  • The "Research Tool" Website
• References

Chapter 4: Regulatory

• FDA Perspectives on Pharmacogenetic Testing
  • Basic Definitions: Pharmacogenomic Test versus Pharmacogenetics
  • Pharma "OMICS" and Regulatory Issues
  • "Multiplex" and Regulatory Issues
  • New Indications-Familiar Questions
  • General versus Drug Specific Pharmacogenetic Tests
  • What Regulatory Pathway is Appropriate for YOUR Pharmacogenetic Test?
  • Pharmacogenetic Tests in Drug Labels
  • Making the Tests Available Depending on the Option
  • What are the Options?
    • ASR Definition
• FDA Guidance Publications
  • FDA Guidance Publications in Development
  • Device Advice
  • Tm Bioscience Cystic Fibrosis (CF) Gene Screening and Diagnostic
  • Regulatory Example
• Clinical Validation
  • Non-comprehensive Overview of Analytic and Clinical Parameters for Validation of
  • Companion Diagnostics
  • Cyclin D1 Assay Validation-Hypothetical Common Disease Scenario
    • Cyclin D1 Assay Validation Considerations
  • Diffuse Large B-cell lymphoma (DLBCL) Form of non-Hodgkin' s Lymphoma-
  • Less Common Disease Scenario
  • Molecular Validation Overview
    • CYP2D6 Gene Testing
    • UGT1A Companion Diagnostic
    • UGT1A Testing

Chapter 5: Contract Research Organizations (CROs)

• Use of Contract Research Organizations (CROs) for Diagnostic Development
• Interview with Richard N. Phillips, MSPH, Ph.D., Principal Consultant,
• Quintiles Consulting, Medical Device Development
• Client Questionnaire-MDCI®, Medical Device Consultants, Inc.,
• North Attleboro, Massachusetts
  • MDCI Client Questionnaire: Clinical Study Specifications
  • Ten Mistakes to Avoid When Bringing a Medical Device to Market in the U.S
• Follow-up Interview with Bill Morton, President, MDCI®-Diagnostic
• Commercialization
  • Nine Mistakes to Avoid When Bringing a Medical Device to Market in EUROPE
• Follow-up Interview with Bill Morton, President, MDCI®-CE European
• Commercialization

Chapter 6: Reimbursement

• CMS Reimbursement
• Private Payer Issues
• Local Medicare Coverage
• Follow-up interview with David Sholehvar, Director, Strategic Customers
• for Veridex
• BRCA1/2
• Chromosomal Banding (Cytogenetics)
• Secretary' s Advisory Committee on Genetics, Health, and Society (SACGHS)
• Case Study: Genomic Health' s OncoDX™ Breast Cancer Assay: Assess Risk,
• Determine Therapy Benefit, and Maximize Resource Utilization by
• Ted Snelgrove, Vice President of Marketing
• Multigene Assay to Predict Recurrence of Tamoxifen-Treated,
• Node-Negative Breast Cancer
  • Oncotype DX™ in Clinical Practice
  • Oncotype DX™ Prediction of Chemotherapy Benefit
  • Oncotype DX™ Health Economics Benefit Analysis
  • Health System Impact for Reclassification: "Back of the Envelope" Analysis
  • Genomic Health Breast Cancer Calculator
  • Conclusions from Economic Analysis
    • Payer Reactions

Chapter 7: Business Models and Issues

• Introduction
• Market Incentives and the Business Model for Linked Dx/Rx Products
  • A General Added Value Scenario
  • Value Creation Due to Reduction in Uncertainty, (Exhibit 7.1)
  • Societal Cost-Effectiveness
  • Scenario Analysis-Who Captures the Value?
  • Current Pricing and Reimbursement Environments
  • Public Policy Implications
  • Follow-up Interview with Louis P. Garrison
  • Case-based Reasoning® Business Model
• Companion Diagnostic Commercialization Issues
  • Companion Diagnostic Development Checklist
  • Sales & Marketing Expectations

Appendix 1: 510(k) Substantive Equivalence Determination Decision Summary

Appendix 2: Evaluation of Automatic Class III Designation-Tag-It™ Cystic Fibrosis Kit

Appendix 3: AmpliChip CYP450 Test for CYP2C19-510(k) Summary

Appendix 4: Invader® UGT1A1 Molecular Assay 510(k) Summary

Table of Exhibits

• Exhibit 2.1 Major Players in the Pharma Industry
• Exhibit 2.2 Examples of Pharmacogenetics and the "Omics" in the Drug Development Process
• Exhibit 2.3 Erectile Dysfunction-2004
• Exhibit 2.4 Historical Comparison of Consumption to Modern Diseases
• Exhibit 2.5 Top 10 Anti-hypertensive Drugs-2004
• Exhibit 2.6 Typical Drug Timeline
• Exhibit 2.7 Size of the Genetics Effect versus Percentage Responder Genotypes and Possible Results
• Exhibit 2.8 FDA-approved Molecular Diagnostic Test Systems
• Exhibit 2.9 Capella University Poll
• Exhibit 2.10 Effect of CPY2C9 Genotype on Warfarin Response
• Exhibit 2.11 ALOX-5 Genotype and 5-lipoxygenase Inhibitor Response
• Exhibit 2.12 ALOX-5 Genotype and 5-lipoxygenase Inhibitor Response
• Exhibit 2.13 Drug Toxicity and Frequency of Genetic Mutation
• Exhibit 2.14 VIGOR Study
• Exhibit 2.15 Study Name versus Test Necessity
• Exhibit 2.16 Drug-Test Co-development Process
• Exhibit 2.17 Companion Co-Development Process Outline
• Exhibit 3.1 Intellectual Property and Other Legal Issues Associated With Dx/Rx Collaborations Source
• Exhibit 3.2 Contract Licensing Negotiations Drug versus Diagnostic
• Exhibit 3.3 Familial Dysautonomia Foundation versus MGH Organization Missions
• Exhibit 3.4 Patent Pooling Advantages and Disadvantages
• Exhibit 3.5 Examples of NIH Research Tools
• Exhibit 3.6 Internal, Commercial, and Research Product License Comparison
• Exhibit 3.7 Research Tools
• Exhibit 3.8 The Research Tool Website
• Exhibit 4.1 Analytic Phase Validation Parameters
• Exhibit 6.1 Fragile X PCR
• Exhibit 6.2 Immunoglobulin Gene Rearrangement PCR
• Exhibit 6.3 Factor V Leiden PCR
• Exhibit 6.4 January 2006 Clinical Laboratory Diagnostic Fee Schedule
• Exhibit 6.5 Medicare Parts A and B-Contractors
• Exhibit 6.6 Local Medicare Coverage Process
• Exhibit 6.7 Veridex' s CellSearch® Local Medicare Coverage Process
• Exhibit 6.8 BRCA1/2 Local Medicare Coverage Process
• Exhibit 6.9 Chromosomal Banding (Cytogenetics) Local Medicare Coverage Process
• Exhibit 6.10 Economic Rationale For Genomic Technologies and Symptomatic Care
• Exhibit 6.11 Economic Rationale For Genomic Technologies and Asymptomatic Care
• Exhibit 6.12 Economic Impact of Breast Cancer Testing
• Exhibit 6.13 General Schema for Health Economics: Rate of Adoption
• Exhibit 6.14 Risk of Recurrent versus Chemotherapy
• Exhibit 6.15 Sample of Risk/Benefit Information from Adjuvant Program
• Exhibit 6.16 Oncotype DX™: 21 Final Gene Set
• Exhibit 6.17 Oncotype DX™: >2600 Patients Studied
• Exhibit 7.1 Total Societal Value Creation Including Reduced Uncertainty
• Exhibit 7.2 Scenario I: Value Distribution ($): New Dx-No Tx Flexible Pricing; Dx Administered Pricing
• Exhibit 7.3 Scenario II: Value Distribution ($): New Dx-Some Tx Price Flexibility, Insurer Budget Constrained; Dx Administered Pricing
• Exhibit 7.4 Scenario III: Value Distribution ($): New Dx-No Tx Price Flexibility, Dx Some Price Flexibility, and IP Protection
• Exhibit 7.5 Scenario IV: Value Distribution ($): New Dx-Tx Can Raise Price, Dx Charged at Cost, Insurer Raises Premium
• Exhibit 7.6 Scenario V: Value Distribution ($): New Dx-Tx Pricing Flexible (value-based),Dx Pricing Flexible (value-based), Insurance Competitive
• Exhibit 7.7 Commercialization Timeframe
• Exhibit 7.8 Example of Commercialization Costs-Spending Cost of Goods versus Accumulated Deficit (in $ millions