Pharmacovigilance Report and Analysis 2009

Content

1 Executive Summary
1.1 Aims, Scope and Format of the Report
1.1.1 The Problems Discussed in this Report
1.1.2 Terms in this Report
1.2 Chapter Breakdown
1.3 Future Costs
1.4 Research Methodology

2 History and Contexts of Pharmacovigilance
2.1 Pharmacovigilance: Watching the Drugs
2.1.1 Pharmacovigilance as Data Collection
2.1.2 The Future Trajectory of Pharmacovigilance
2.1.3 Pharmakon: Treatment and Poison
2.2 Adverse Drug Reactions (ADRs) are not "Side Effects"
2.2.1 ADRs are Informative
2.2.2 ADRs and Drug Development
2.3 Risk versus Harm
2.3.1 Monitoring Older Drugs vs. Newer Drugs
2.4 Pharmacovigilance History and Expansion
2.4.1 Established in 1971 by the WHO
2.4.2 Ever-Increasing Scope and Involvement
2.4.3 Sources of Pharmacovigilance Information
2.4.4 International Collaboration
2.4.5 The Uppsala Monitoring Centre (UMC)
2.5 "Phase IV" Clinical Trials: Filling the Gaps in Clinical Trials
2.5.1 Animal Models are Imperfect
2.5.2 Clinical Trials Look First for Efficacy, Second for Side Effects
2.5.3 Pharma Companies Not Presenting Full Clinical Trials Data
2.5.3.1 Ongoing Case: AstraZeneca and Seroquel
2.5.3.2 Pharmacovigilance and Clinical Trial Results
2.5.4 Pharmacovigilance and Under-Represented Groups
2.6 Reportage
2.6.1 Spontaneous Reporting: The Primary Source of Pharmacovigilance Information
2.6.1.1 Professional versus Patient Reporting Systems
2.6.1.2 Media Announcements and ADR Reports
2.6.2 Avoiding Human Error: "Never Events"
2.6.2.1 Prescribing and Dispensing Errors
2.6.2.2 Diminishing Punitive Reactions
2.6.3 Information from Hospitals: An Untapped Resource
2.6.4 Standardising Measurements and Definitions
2.6.5 mEDRA and the DOI System
2.7 Medical Pluralism: Patients Seek Advice and Treatment from a Variety of Sources
2.7.1 Tapping the Web: What Patients Say to Each Other
2.7.2 Tracking Advice: Internet Searches for Information
2.8 Effectiveness vs. Efficacy: In-Life Use vs. Clinical Use
2.8.1 Pharmacovigilance Assessments Must Consider How People ACTUALLY Use the Drug
2.8.2 Case Study: Viagra as Party Drug
2.8.2.1 Viagra and HIV: Is Viagra Helping Spread STDs?
2.8.3 Case Study: Pseudoephedrine and Methamphetamines
2.8.3.1 Pseudoephedrine Pharmacovigilance: Was the Public Helped or Harmed by Withdrawal?
2.8.4 The Viagra Case vs. The Pseudoephedrine Case
2.9 Patient Noncompliance
2.9.1 Noncompliance and Drug Effectiveness
2.9.2 Monetary Costs of Noncompliance
2.9.3 Can Pharmacovigilance Programs and Compliance Programs be Combined?
2.10 Risk Management
2.10.1 Making Choices For Patients
2.10.2 Relative Dangers
2.10.3 Stages of Risk Analysis and Management
2.10.4 Different Parties and Their Risk Management Assessments
2.11 Communicating Risk
2.12 Action Plan for Safety Issues

3 Pharmacovigilance Regulatory Bodies by Region
3.1 Increasing Mandatory Pharmacovigilance
3.2 WHO
3.3 European Union: EudraVigilance
3.3.1 Volume 9
3.3.2 United Kingdom: Medicines and Healthcare Products Regulatory Agency
(MHRA) and the Yellow Card Scheme
3.3.3 MHRA and Black Triangle Warnings
3.4 Bilateral Agreements: EMEA / FDA
3.5 FDA: Becoming Much More Conservative
3.5.1 Comparative Assessments
3.6 Japan has Rigorous Post-Marketing Drug Regulation
3.6.1 Standard Method for Drug Withdrawal
3.6.2 A System Worth Imitating
3.7 Companies Watching Each Other
3.7.1 Will Patients Access Pharmacovigilance Data?
3.7.2 Consumers of Data as well as Drugs?

4 Future Keywords: Transparency and Communication
4.1 Moving from Pharmacovigilance to Live Licensing
4.1.1 Meetings, Conversations, Communication
4.1.2 Successful Pharmacovigilance Does Not Make Headlines, but It Could
4.1.3 The Goal of Transparency: Redeeming the Public Trust
4.2 Hospitals Reduce Lawsuits by Apologising: Can Big Pharma Follow Suit?
4.2.1 Why Hospitals Traditionally Don't Apologise
4.2.2 New Approach: Frank Admissions of Fault, and Apologies
4.2.3 Hospital Apology Success Rates
4.2.4 Can Pharma Duplicate This Success?
4.2.5 What if a Pharma Apology Made Headlines?
4.2.6 Does Pharma Have Much to Lose?
4.2.7 What Pharma Stands to Gain
4.3 T&C: Between Big Pharma and Regulatory Bodies
4.3.1 The WHO: Resolution Against Misleading Promotion
4.4 T&C: Between Big Pharma and Patients
4.4.1 Patient Compliance: Improved by Comprehension?
4.4.2 Individual Communication: Drug-Specific Forums on Company Websites?
4.4.3 Fostering Reportage: Company-Run Forums
4.4.4 Forums and Real-Time data: The Move to Live Licensing
4.4.5 Engaging Patients in Their Own Treatment
4.4.6 Communicating Ignorance: Crucial for the Transition to Live Licensing
4.5 Amongst Patients: Networking, Wikis, Blogs, Online Forums
4.5.1 Online Forums: The Power of Disinterest
4.5.2 Disease Blogs: Telling the Entire Story
4.5.3 Sales Personnel Forums: Not Good for Public Relations
4.6 T&C: Between Pharma and the Media
4.6.1 Communicating Effort: Stressing Pharmacovigilance
4.6.2 The Media and Individuals Distrust Pharma
4.6.3 Public Relations Case Study: Rezulin
4.7 T&C: Informing Doctors
4.7.1 What Doctors Know: Case Study: Zyprexa
4.7.2 Doctors Receiving Incorrect Information
4.8 Clinical Trials: Full and Impartial Reportage
4.8.1 Impartial Information: Assessing Risk
4.8.2 Informing Sales Representatives
4.8.3 Suspicious Approvals: Lexapro for Children
4.8.4 Case Study: AstraZeneca and Seroquel
4.8.5 Big Pharma Underwriting New Assessment Trials
4.8.6 Industry-Mediated or Media-Mediated Access to Information
4.9 Internal Communications: Company Departments Need to Share Information More Effectively
4.10 Exposing Links: Pharma and Academia
4.10.1 Pharma and Research Institutions
4.10.2 "Gifts" to Medical Schools, Medical Students, and Doctors
4.10.3 Good or Bad: Should Pharma Continue to Fund and be Allied with Medical Schools?
4.10.4 The 2008 and 2009 Harvard Medical School Protests and Inquiries
4.11 T&C: Between Countries - Centralised Databases and Standardised Reference Points
4.11.1 International Outsourcing of Clinical Trials
4.11.2 Involving Non-WHO Countries

5 Tailoring to Individuals and to Regions
5.1 Changing the One-Pill-Fits-All Paradigm
5.2 Looking for Case Clusters
5.3 Patient Registries
5.3.1 Registries By Disease
5.3.2 Registries By Drug Exposure and Diseases
5.3.3 The Case of Clozapine
5.3.4 Limiting Access to Registries: NOT for Prescriber Use
5.4 Designing Patient Registries
5.4.1 Size
5.4.2 Rationale / Purpose
5.4.3 Cost / Benefit
5.4.4 Preserving Privacy
5.5 Tailoring to Regions
5.5.1 The Developing World
5.5.2 The Developed World
5.6 Tailoring to Individuals
5.6.1 Best Care versus Ideal Care
5.6.2 Pharmacovigilance and Behaviour
5.6.3 Genomics / Pharmacogenomics
5.6.3.1 Expected Advantages of Pharmacogenomics
5.6.3.2 Slow Progress of Applicable Pharmacogenomics
5.6.4 Live Licensing

6 Pharmacovigilance and Live Licensing / Conditional Approval
6.1 Live Licensing and Increased Transparency
6.2 Supporting Drug Evolution
6.2.1 More Drugs Withdrawn under a Live Licensing Paradigm
6.2.2 Closely Tracking and Learning from ADRs
6.3 Live Licensing May Not be Cheaper Overall
6.4 Gaining Patient Trust: The First Major Obstacle
6.4.1 Old and New Paradigms Running Concurrently
6.5 Difficulties of Live Licensing: Monitoring Response, Tabulating Information
6.5.1 Responding Quickly
6.5.2 Assessing Response Without a Control Group
6.5.3 Self-Aware Patients
6.5.4 Distributing Information: Updating Data
6.6 Sensitive Pricing
6.6.1 Pricing for Regional Effectiveness
6.6.2 Pricing for Regional Affluence
6.6.3 Pricing for Performance: How Pharmacovigilance Will Facilitate This Inevitability

7 Unique Visiongain Interviews
7.1 Interview with Dr. Barry Arnold, EU Qualified Person for Pharmacovigilance, AstraZeneca
7.1.1 On the Ideal Goal of Pharmacovigilance
7.1.2 On the Rarity of the Most Serious Events
7.1.3 On Discovering Rare Events: The Rule of Three
7.1.4 On Communicating Newly Discovered Side Effects
7.1.4.1 Drug Withdrawal as Extreme Measure
7.1.4.2 Communicating Risk
7.1.5 On Drug Withdrawal and the Media
7.1.6 On Good Pharmacovigilance NOT Making Headlines
7.1.7 On the Current Rising Costs of Pharmacovigilance
7.1.7.1 On the Cost Contribution of More Reporting
7.1.7.2 On the "Downstream Costs" of Pharmacovigilance
7.1.7.3 On the Future Costs of Pharmacovigilance
7.1.8 On Governments Redirecting Pharmacovigilance Costs
7.1.9 On Government Investment vs. Company Investment in Pharmacovigilance
7.1.9.1 On the Number of Industry vs. Government Pharmacovigilance Personnel
7.1.10 On the Number of Pharmacovigilance Personnel Per Portfolio
7.1.11 On Vioxx as Failure or Success
7.1.12 On the Future: More Risk-Averse or Towards Live Licensing / Conditional Approval?
7.2 Dr. Graeme Ladds, Founder of PharSafer Associates Ltd.
7.2.1 On Outsourcing Pharmacovigilance
7.2.1.1 On the Cost-Effectiveness of Outsourcing
7.2.1.2 On Transferring Pharmacovigilance from Outsourced to In-House Databases
7.2.2 On What Pharmacovigilance Is, and How Success is Measured
7.2.3 On Looking for Non-Drug Reasons for ADRs
7.2.4 On the Future Costs of Pharmacovigilance
7.2.5 On the Costs of Databases
7.2.6 On Countries Leading the Way in Pharmacovigilance Co-ordination
7.2.7 On Access to the WHO Database
7.2.8 On Vioxx as Success or Failure of Pharmacovigilance
7.2.9 On Stem Cells, Tissue Therapies, and New Complexities of Pharmacovigilance
7.3 Comments from Dr. Jan-Willem van der Velden, MD., Senior Vice President of Global Drug Safety, International Institute for the Safety of Medicines Ltd. (ii4sm).
7.3.1 On the Ideal Goal of Pharmacovigilance
7.3.2 On Future Costs of Pharmacovigilance
7.3.3 On Measurements of Success
7.3.4 On Vioxx as a Success or Failure of Pharmacovigilance

8 Scope and Costs of Pharmacovigilance
8.1 Costs of Pharmacovigilance for the Next 5 to 15 Years
8.2 The Costs of Reputation Loss
8.3 Current Scope and Limits of Pharmacovigilance
8.3.1 Actual Risk
8.3.2 Perceived Risk
8.4 Future Aspects
8.4.1 Cosmetics
8.4.2 Tissues / Stem Cells
8.5 Public Health and Pharmaceutical Growth

9 Conclusions
9.1 Pharmacovigilance Increasing and Expanding
9.1.1 Scope: More Products
9.1.2 Expansion: Doing More with Data
9.2 Regulatory Bodies and the Public Demand More from Pharmacovigilance
9.3 Pharmacovigilance: A Crucial Beginning in the Move to Live Licensing

List of Tables
Table 1.1 EU and US Pharmacovigilance Terminology
Table 2.1 Risks of Death for Various Activities
Table 2.2 Types and Progressive Stages of Risk Analysis / Management
Table 2.3 Parties and Motivations Involved in Therapeutic Risk Management
Table 2.4 Risk Communication Responsibilities of Companies, Doctors and Patients
Table 2.5 Types of Responses to New Safety Information, from Least to Most Aggressive
Table 5.1 Behavioural Tailoring Considerations
Table 8.1 Hypothetical Costs of Pharmacovigilance, 2009-2024

List of Figures
Figure 6.1 Traditional Drug Development Progression
Figure 6.2 Model of Development for Live Licensing
Figure 8.1 Costs of Pharmacovigilance, 2009-2024

AIDS Healthcare Foundation
American Medical Student Association (AMSA)
Amgen
AstraZeneca
Cambridge Antibody Technology
Centers for Disease Control and Prevention (CDC)
Commission on Human Medicines (CHM)
Committee for Medicinal Products for Human Use (CHMP)
Daiichi Sankyo Co
Eli Lilly
European Agency for the Evaluation of Medicinal Products
European Assocation of Hospital Pharmacists
European Commission
European Hospital and Healthcare Federation (HOPE)
European Medicines Agency (EMEA)
European Network for Patient Safety (EuNetPas)
European Society of Pharmacovigilance (later the International Society)
Forest Laboratories
Genentech
GlaxoSmithKline
Human Genome Sciences
Institute for Health Improvement (IHI), USA
International Society of Pharmacovigilance (ISoP)
Medicines and Healthcare products Regulatory Agency (MHRA)
Merck
multilingual European Registration Agency (mEDRA)
National Council on Patient Information and Education (US)
National Institute for Health and Clinical Excellence (NICE)
National Patient Safety Agency (NPSA)
National Patient Safety Agency (NPSA)
No Free Lunch
Pfizer
Pharmaceutical Group of the European Union (PGEU)
PricewaterhouseCoopers
RBPGB Public Liasion Group
Roche
Royal Pharmaceutical Socity of Great Britain (RPSGB)
Sorry Works!
STD Prevention and Control Services, San Francisco Department of Public
Health
The Pharmaceutical Research and Manufacturers of America (PhRMA)
University of Illinois Hospital
University of Michigan Health System
Uppsala Monitoring Centre (UMC)
US Department of Justice
Warner-Lambert Company
World Health Organization (WHO)