Pharmacovigilance and Other Pharma Regulatory Developments 2010-2020

1. Executive Summary
1.1 Overview
1.2 Chapter Breakdown
1.3 Drug Safety Monitoring in 2010
1.4 Research and Analysis Methods

2. Introduction to Drug Safety Monitoring
2.1 What Are ADRs?
2.1.1 Never Events
2.1.2 ADRs Are Not Side Effects
2.1.3 Differing Terminology
2.2 The First Step: Establishing Safety in Clinical Trials
2.2.1 Phase I Trials
2.2.2 Phase II Trials
2.2.3 Phase III Trials
2.3 Phase I-III Trials Have Their Limitations
2.3.1 ADRs With a Long Latency Period May be Problematical
2.3.2 Clinical Trials - Representative Enough of Patients?
2.3.3 Foreign Clinical Trials May Be Under-Appreciated
2.3.4 Ethnic Differences Lead to Varying Safety and Efficacy Profiles
2.3.5 Averaging Results Can Hide Significant Data
2.3.6 Mixing Medicines
2.4 The Second Step: Post-Marketing Surveillance
2.4.1 Phase IV Trials: Just a Marketing Tool?
2.4.2 Pharmacovigilance
2.4.2.1 Thalidomide and the WHO Programme for International Drug Monitoring
2.4.2.2 Vioxx: a More Recent Problem
2.4.3 Spontaneous Reporting to Collect ADR Data
2.4.4 Data Mining Identifies Significant Events

3. Global Pharmaceutical Regulation 2010-2020
3.1 The WHO Programme for International Drug Monitoring
3.1.1 Members and Associates
3.1.2 Collecting Data at the Uppsala Monitoring Centre
3.1.3 VigiBase
3.1.3.1 Searching the VigiBase
3.2 The ICH is Another Example of Global Collaboration
3.2.1 History of the ICH
3.2.2 Creating Harmony in Regulatory Affairs
3.2.3 The Trickle-Down Effect

4. US Pharma Regulation: Vioxx and Beyond
4.1 The FDA is the Leading Pharmaceutical Regulatory Body
4.2 Post-Vioxx Criticism
4.3 Spontaneous Reporting in the US
4.4 MedWatch and Mobiles
4.5 The FDA Amendments Act 2007: Tightened US Drug Regulation
4.5.1 Using Healthcare Records for a More-Intensive Approach
4.5.2 Evaluating Potential Risks at the Application Stage
4.5.3 Communicating Safety Concerns to the Public
4.6 Case Study: Raptiva (Efalizumab)

5. Europe and the EMA
5.1 The CHMP Pharmacovigilance Working Party
5.2 EudraVigilance is the EMA’s ADR Database
5.2.1 The EudraVigilance Post-Authorisation Module (EVPM)
5.2.2 The UK’s Yellow Card Scheme is an Example of Patient Reporting
5.3 EMA Has Made Progress in Recent Years
5.3.1 Timely Access to Innovative Medicines
5.3.2 Early Risk Management Planning
5.3.3 The EMA is Keen to Increase Transparency
5.3.4 There Has Been Greater Collaboration with the FDA
5.4 The Road Map to 2015
5.5 EU Legislation Will Soon Be Changing

6. Japanese Pharmacovigilance
6.1 Japan is the World’s Second Largest Pharmaceutical Market
6.2 Japanese Drug Approval and Regulation
6.2.1 The MHLW Monitors New Drugs
6.2.2 Periodic Safety Update Reports (PSURs)
6.2.3 Drugs Re-examined after 4-10 Years
6.2.4 Ad Hoc Drug Re-evaluation
6.2.5 Model to Be Copied?
6.3 ADR Reporting in Japan
6.3.1 Increased Numbers of Approvals, Increased ADR Reports
6.4 The Challenge of Drug Lag
6.4.1 Case Study: Iressa (Gefitinib)
6.4.2 Case Study: Usevir (Sorivudine)
6.4.3 The PMDA Aims to Overcome Drug Lag
6.5 Mid-term Plans: Japan’s Road Maps
6.5.1 The Second Mid-term Plan, 2009-2013

7. Post-Marketing Surveillance Will Always Be Key to Drug Safety
7.1 There are Limitations to Current Post-Marketing Surveillance
7.1.1 Passive Rather Than Active
7.1.2 Reactive in Nature
7.1.3 Duplicate Reporting is Hard to Detect and Prevent
7.1.4 The Challenge of Under-Reporting
7.1.5 Sometimes Not Enough Information is Reported
7.2 Spontaneous Reporting on the Increase
7.3 Global Harmonisation and Cooperation
7.3.1 Harmonisation Will Require Compatibility
7.4 Transparency: the Defining Characteristic of Future Pharmacovigilance
7.4.1 Transparency and the Approval Process
7.4.2 Where Patients Obtain Information
7.5 Prescription Event Monitoring as Proactive Pharmacovigilance
7.6 Case Clusters and Pharmacoepidemiology
7.6.1 Pharmacoepidemiological Studies to Establish Safety
7.6.2 Healthcare Databases for Pharmacoepidemiological Studies
7.6.3 Using Pharmacoepidemiology for Staggered Approval
7.7 EIDOS: A New Way of Classifying ADRs
7.8 Pharmacogenomics Can Help to Identify Safety Concerns
7.8.1 Pharmacogenomic Tests Will Become More Common
7.8.2 Pharmacogenomics and Labelling
7.8.3 Future Challenges for Pharmacogenomics
7.9 Pharmacovigilance 2010-2015
7.9.1 Global Cooperation Will Continue
7.9.2 Patients Will Become More Involved
7.9.3 Risk Management Planning for Drug Approvals
7.9.4 Staggered Approval
7.9.5 Being Active: Pharmacoepidemiology
7.9.6 Embracing Social Media
7.10 Pharmacovigilance 2015-2020

8. A Move to Live Licensing?
8.1 Live Licensing Has Strengths and Weaknesses
8.1.1 Meeting Unmet Needs
8.1.2 The Rule of Three
8.1.3 Long-Latency ADRs Can Be Detected More Readily
8.1.4 Live Licensing - Commercially Beneficial?
8.1.5 An Increase in Recalls/Withdrawals?
8.1.6 Communicational Matters for Companies
8.1.7 The Industry Will Need to Avoid Public Mistrust
8.2 Measures Being Taken
8.3 Fast-Tracking Drug Reviews
8.3.1 The US: Fast-Track and Priority Reviews
8.3.1.1 Fast-Track Approach for Serious Diseases
8.3.1.2 Priority Review is an Option Available to More Drugs
8.3.2 Japan’s Priority Review
8.3.3 Accelerated Assessment in the EU
8.4 Regulators Can Conditionally Approve Drugs
8.4.1 EMA: Conditional Marketing Authorisation (CMA)
8.4.2 Case Study: Cayston (Aztreonam)
8.4.3 Case Study: Votrient (Pazopanib) and Sutent (Sunitinib)
8.4.4 Japanese Conditional Authorisation
8.4.5 US Accelerated Approval
8.5 Expanded Access and Compassionate Use Are Different from Conditional Approval
8.5.1 The EMA and Compassionate Use
8.5.1.1 Case Study: Tamiflu IV (Oseltamivir)
8.5.1.2 Case Study: Relenza IV (Zanamivir)
8.6 Off-Label Use as a Potential Threat to Live Licensing
8.7 Rate of Progress and Likelihood of Success
8.8 Live Licensing 2010-2020
8.8.1 Priority Reviews - the Most-Likely Pathway to Live Licensing?
8.8.2 Conditional Approvals Will Be Phased In
8.8.3 Pharmacogenomics and a More Dynamic Approval Process
8.8.4 What Live Licensing Will Mean for Pharmaceutical Manufacturers
8.9 The Costs of Pharmacovigilance 2010-2020
8.9.1 Pharmacovigilance Spending is Often Linked to R&D Spending
8.9.2 Pharmacovigilance Spending Will Increase More Than R&D Spending
8.9.2.1 Pharmacovigilance Costs and Rapidly-Expanding Markets
8.9.3 Some Measures Will Reduce Costs
8.9.4 The Costs of Pharmacovigilance 2010-2015
8.9.5 The Costs of Pharmacovigilance 2015-2020

9. Expert Opinion
9.1 Interview with Dr Marie Lindquist, Director, Uppsala Monitoring Centre (UMC)
9.1.1 The Reactive Nature of Pharmacovigilance
9.1.2 Involving the Public in Pharmacovigilance
9.1.3 Transparency and Pharmacovigilance
9.1.4 How Pharmacovigilance Should Be Perceived
9.1.5 Live Licensing and Future Pharmacovigilance
9.2 Dr Graeme Ladds, Director, Pharsafer Associates Ltd
9.2.1 Current Pharmacovigilance Practice
9.2.2 Transparency in Pharmacovigilance
9.2.3 The Costs of Pharmacovigilance
9.2.4 Responsibility in Pharmacovigilance
9.2.5 The Move to Live Licensing
9.2.6 The Future of National Pharmacovigilance

10. Conclusions
10.1 International Collaboration Will Increase
10.2 Greater Transparency in Pharmacovigilance Processes
10.3 Epidemiological Studies Will Be Applied More Widely
10.4 Pharmacogenomics Will Become Important in Drug Approval
10.5 A Shift Towards Live Licensing?

List of Tables
Table 2.1 Definitions for Pharmacovigilance, 2010
Table 3.1 Members of the Programme for International Drug Monitoring, 2010
Table 3.2 Members of the ICH, 2010
Table 3.3 National Bodies Represented at the ICH-GCG, 2010
Table 5.1 Sources of Spontaneous Reports Received by MHRA via its Yellow Card Scheme, 2004-2009
Table 5.2 Objectives and Outcomes of the EMA’s Road Map
Table 6.1 Re-examination Period Lengths for Different Drug Types
Table 6.2 Standard and Priority Review Times in the US, EU and Japan
Table 7.1 Weaknesses in Pharmacovigilance Practices, 2010
Table 7.2 Where US Residents Report ADRs, 2008
Table 7.3 Strengths and Weaknesses of PEM, 2010
Table 7.4 EIDOS Definitions, 2010
Table 8.1 Strengths and Weaknesses of a Live Licensing System
Table 8.2 Global Pharmaceutical R&D Spending: Regional Breakdown, 2009
Table 8.3 Global R&D Spending, 2009-2015
Table 8.4 Global R&D Spending, 2015-2020
Table 8.5 Global Pharmacovigilance Spending, 2009-2015
Table 8.6 Global Pharmacovigilance Spending, 2015-2020

List of Figures
Figure 2.1 Incidence Rates of Drug-Induced Lung Disease Linked to Arava and Iressa, 2007
Figure 2.2 Events in the Lifecycle of Vioxx
Figure 3.1 Origin of ICSRs Held in the VigiBase Database, 2010
Figure 4.1 Origin of the 490,000 ADR Reports Added to the AERS Database, 2009
Figure 4.2 ADR Reports Received by the FDA from Patients and Healthcare Professionals, 2000-2010
Figure 5.1 Approval Pathways Available in the EU, 2010
Figure 5.2 Spontaneous ADR Reports Received by MHRA, 2008-2009
Figure 5.3 Spontaneous Reports Received by MHRA from Patients (Including Parents and Carers), 2004-2009
Figure 5.4 ADR Reports MHRA Received From Doctors and Pharmacists, 2004-2009
Figure 6.1 The Japanese Regulatory Process, 2010
Figure 6.2 Sources of ADR Reports Received by the PMDA, 2004-2008
Figure 6.3 Trends in Japanese Drug Approvals and ADR Reports, 2004-2008
Figure 7.1 Where US Residents Report ADRs, 2008
Figure 8.1 The Pharmacogenomic Pathway for Establishing Causality of an ADR
Figure 8.2 Global Pharmaceutical R&D Spending: Regional Breakdown, 2009
Figure 8.3 Global R&D Spending, 2009-2020
Figure 8.4 Global Pharmacovigilance Spending, 2009-2015
Figure 8.5 Global Pharmacovigilance Spending: Market Breakdown, 2009
Figure 8.6 Global Pharmacovigilance Spending: Market Breakdown, 2020
Figure 8.7 Forecast for Pharmacovigilance Spending Outside the US, EU and Japan, 2009-2020
Figure 8.8 Global Pharmacovigilance Spending, 2015-2020
Figure 8.9 Global Pharmacovigilance Spending, 2009-2020