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Pharmacovigilance: Risk Management in Practice

At present adverse drug responses (ADRs) are the sixth largest cause of death in the US. Drug safety is a huge issue facing the industry today and the risk is high with the possible loss of a key revenue producing drug coupled with potentially damaging litigation. The financial risk facing Merck on the withdrawal of Vioxx was considerably beyond the loss of its $2.5 bn yearly revenues.

On the announcement of the withdrawal of Vioxx from the market, Merck immediately lost 27% of its market capitalisation $27bn was lost in share value in one day. The exposed health risk was devastating with over 80 million prescriptions written in the five years that Vioxx was on the market. FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks. The situation with Vioxx has been the catalyst for increased attention to drug safety and the reassessment of risk management within the pharmaceutical industry.

It was pharmacovigilance that made the risks associated with Vioxx apparent. However, were the checks adequate? Could the risks have been detected earlier? And what is being done to improve the risk-benefit assessment for a drug?

A large part of pharmacovigilance is the detection and appropriate assessment of safety signals. New technologies are enabling more accurate assessment of signal detection, and better analysis of large sets of data in a database. The early identification of a health safety signal is an important aspect of pharmacovigilance. A more accurate risk-benefit assessment can be made if there is a significant quantity of good quality safety data.

Although the FDA appears to favour policies that suggest it is increasingly risk averse, both it and the EMEA are faced with the apparently opposing challenge of encouraging the pharmaceutical industry to produce more drugs. Incentives for innovative drugs that increase the medical options and improve healthcare are being developed. An important aspect of the role of the regulatory authorities will be the accurate and effective communication of safety related information.

Pivotal period of change

The pharmaceutical market is entering a pivotal period of change that could well see altered working patterns with a greater emphasis on pharmacovigilance. The impact of the Vioxx case has been significant. This visiongain report contains 147 pages of high level research and analysis. The Vioxx case is examined and the consequent changes in both the FDA and EMEA's pharmacovigilance requirements assessed. Strategies for optimising pharmacovigilance activities are considered as the focus on drug safety increases.

Why you should buy this report

• The risks associated with a drug withdrawal are too large to ignore.
• Pharmacovigilance inspections are a challenge but a vital part of drug development
• Various anticipated changes in aspects of pharmacovigilance are examined in detail to enable accurate assessment of each.
• The key differences of the US and European systems are outlined.
• The potential for the improved paediatric incentives to encourage paediatric drug development in Europe is discussed.
• How the anticipated changes will impact pharmacovigilance budgets is assessed.

Table of Contents

• 1. Executive Summary
• 2. Introduction - Pharmacovigilance as an aspect of Risk Management
  • 2.1. Drug Safety Problems Can Only Be Minimised and Not Eliminated
  • 2.2. Drug Withdrawal Has Increased in the Past Decade
  • 2.3. Pharmaceutical Companies Increase Emphasis on Pharmacovigilance
• 3. Aspects of Pharmacovigilance - Who Makes Reports, When and to Whom
  • 3.1. Adverse Drug Reactions (ADRs) are Always Unexpected
    • 3.1.1. Periodic Safety Update Reports (PSURs)
    • 3.1.2. Definitions and Acronyms
  • 3.2. Sources of Information on Drug Safety
  • 3.3.
  • 3.4. Where are Safety Reports Made?
    • 3.4.1. Possible Assessments of a Safety Report
  • 3.5. What are the Possible Outcomes to Safety Reports?
    • 3.5.1. Corrections – Black Box Labelling
    • 3.5.2. Drug Recall and Withdrawal
  • 3.6. The Right Strategy For a Drug Withdrawal
• 4. Case Studies - Pharmacovigilance in Action
  • 4.1. Vioxx
    • 4.1.1. When Was The Cardiovascular Risk Known?
    • 4.1.2. Vioxx Media Controversy
    • 4.1.3. Merck Worked with the FDA
    • 4.1.4. The Vioxx Court Case: Did Merck Know Before Launch that Vioxx Was a Health Risk?
    • 4.1.5. The Political Impact of Vioxx Litigation in the US
    • 4.1.6. Was the Vioxx Event a Failure or Success of Pharmacovigilance?
    • 4.1.7. Pharmacovigilance Practices Should Include Data From All Information Sources
    • 4.1.8. Could Another Vioxx Happen Now?
  • 4.2. Seroxat
    • 4.2.1. Seroxat: The FDA and EMEA's Response to AEs
• 5. Evaluation of the US Pharmacovigilance System
  • 5.1. CDER Structured to Improve Pharmacovigilance
  • 5.2. Current Regulations and the FDA
    • 5.2.1. Characteristics of a Good Case Report
    • 5.2.2. Assessing the Signal
    • 5.2.3. Features To Include in a Case Series
  • 5.3. Important Safety Signals
    • 5.3.1. Investigating Safety Signals
  • 5.4. MedWatch
  • 5.5. Drug Safety Oversight Board (DSOB)
    • 5.5.1. Drug Watch Page
  • 5.6. Risk Management Strategy
    • 5.6.1. Pharmacovigilance Plan
  • 5.7. Anticipated Changes in the FDA Reflect Increased Emphasis on Safety
    • 5.7.1. Postmarketing Monitoring of Safety Devices - Paediatric Risk
    • 5.7.2. The FDA's Use of Approvable Letters is Questioned
    • 5.7.3. FDA Concerns May Result in Longer Trials
    • 5.7.4. New Research Demonstrates Difficulties Facing the FDA
• 6. Evaluation of the EU pharmacovigilance system
  • 6.1. EU Directives
  • 6.2. The CHMP Makes Pharmacovigilance Decisions
    • 6.2.1. SOPs Assist With AE Reporting
  • 6.3. EudraVigilance
    • 6.3.1. EudraVigilance Reporting Rules
  • 6.4. MedDRA
  • 6.5. Volume 9A
    • 6.5.1. The Role of the PhV QP
  • 6.6. ERMS
    • 6.6.1. Examples of the Impact of the ERMS
  • 6.7. Anticipated Changes to the EU System of Pharmacovigilance With Increased Emphasis on Safety
• 7. EU and US Pharmacovigilance Compared
  • 7.1. Differences Start With Terminology
  • 7.2. Paediatric Regulations Are Currently Very Diverse
  • 7.3. EMEA Heading Towards Increased Inspections
  • 7.4. Continuing Amendments To Regulations Will See Increasing Similarity
• 8. How Companies Optimise the System of Pharmacovigilance
  • 8.1. Risk Management to Become a Large Part of Drug Company Culture (Considered Throughout Drug Development)
  • 8.2. Pharmacogenomics Could Identify High Risk Patients
  • 8.3. Clinical Trial Improvement and Other Signal Reporting Measures
    • 8.3.1. Spontaneous reports
    • 8.3.2. Case Series
    • 8.3.3. Stimulated Reporting
    • 8.3.4. Active Surveillance
    • 8.3.5. Sentinel Sites
    • 8.3.6. Drug Event Monitoring
    • 8.3.7. Registries
    • 8.3.8. Comparative Observational Studies
    • 8.3.9. Cross-sectional Study
    • 8.3.10. Case-control Study
    • 8.3.11. Cohort Study
    • 8.3.12. Targeted Clinical Investigations
    • 8.3.13. Descriptive Studies
    • 8.3.14. Epidemiological Studies
    • 8.3.15. Drug Utilisation Study
  • 8.4. Paediatric Signal Detection Optimisation
  • 8.5. Data Mining Methods
  • 8.6. Do Epidemiological Studies Improve Pharmacovigilance?
  • 8.7. Will Increased Transparency Improve Pharmacovigilance?
  • 8.8. Patient and Physician Reporting
• 9. Pharmacovigilance for Paediatric Indications
  • 9.1. Legislation for Pharmacovigilance in Children
  • 9.2. Restraints to R&D for Paediatric Drugs
  • 9.3. Financial Incentives for Paediatric Drug Development
  • 9.4. Pharmacovigilance in Paediatric Patient Populations
  • 9.5. Forecasts After Regulatory Developments
  • 9.6. Paediatric Pharmacovigilance Included in RMP
  • 9.7. Paediatric Prozac Exemplifies Pharmacovigilance Issues
    • 9.7.1. Communication of Paediatric Risk
  • 9.8. Does Ketek Demonstrate the Potential Risks of Paediatric Incentives?
  • 9.9. Paediatric Drug Market Stimulation
• 10. Practical Tips To Pass an Inspection
  • 10.1. Short Notice - So Always Be Prepared!
  • 10.2. Pharmacovigilance Summary Document Will Become Surprisingly Long
  • 10.3. Be in the Know
  • 10.4. Staff Training is Vital
  • 10.5. Will Inspections Become More Stringent and Frequent?
• 11. Signal Detection Within Pharmacovigilance
  • 11.1. What is a Signal?
  • 11.2. Signal Detection
  • 11.3. Signal Strengthening
  • 11.4. How is a Signal Analysed?
  • 11.5. Signal Assessment and Risk-benefit Reassessment
• 12. Expected Changes in Pharmacovigilance
  • 12.1. Pharmacovigilance Will See Increased Transparency
  • 12.2. Increased Public Reporting
  • 12.3. Single Pharmacovigilance Departments Will Become More Common
  • 12.4. Risk Management from Drug Discovery/Development to Clinical Trials and Post-launch Surveillance Will Become Common Practice
  • 12.5.  Drug Companies Will Have to Pay for This Increased Pharmacovigilance
  • 12.6. Pharmacogenomics May Identify High Risk Patients
  • 12.7. Trials Will Increase in Length and Size to Accommodate More Safety Data
  • 12.8. DTC Will Decline
  • 12.9. Communication Concerning New Drugs Must Focus on Safety
  • 12.10. Patient and Doctor Reporting Will Both Increase
• 13. Conclusion – Drug Safety Will Become the Dominant Theme of the Drug Regulatory Bodies
  • 13.1. All Drugs Have Some Risk
  • 13.2. Initiatives to Strengthen Drug Safety - Learning From Vioxx
  • 13.3. Communication of Risk is Key
• 14. Appendix 1: Questionnaire at a Recent visiongain Conference on Pharmacovigilance
• 15. Appendix 2: visiongain

 

List of Figures and Tables

Figure 1.1, The Signal Detection Sequence Within Pharmacovigilance

Figure 5.1, FDA Organisational Structure for Postmarket Drug Safety

Figure 6.1, An SOP for SAE Reporting

Figure 8.1, Sources of ADR Reports to the MHRA, 2005

Figure 11.1, The Signal Detection Sequence Within Pharmacovigilance

Table 2.1, WHO list of Common ADRs

Table 2.2 Recent Drug Market Recalls, 2000-2006

Table 3.1, Causality Assessment if Adverse Reactions are Suspected

Table 6.1, Drug Approvals Agencies Within the EU

Table 7.1, Features of The US and EU Pharmacovigilance Regulatory Systems

Table 7.2, The Key Differences Between Paediatric Regulations in the US and the EU

Table 8.1, Number of AE Reports (London Hospitals) Via the Yellow Card Scheme, 1997-2005

Table 9.1, Important Diseases Found in Paediatric Patients

 

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