IR

Global Perspectives on Regulatory Actions

Abstract

  • Date of Safety Alerts: September 23, 2010

  • Agencies: US Food and Drug Administration (FDA) and European Medicines Agency (EMA) issued safety alerts for medicines containing rosiglitazone.

  • Objective: Monitor actions of national regulatory authorities (NRAs) in 10 low- and middle-income countries to examine time lag between safety alerts and regulatory actions.

  • Findings:

    • NRAs outside Africa took actions within 2 weeks.

    • Median time lag for 7 of the 8 African NRAs was 43 days with high variability in response times.

  • Recommendation: Strengthen systems in low- and middle-income countries for timely management of emerging safety issues.

Keywords

  • pharmacovigilance

  • rosiglitazone

  • drug safety

  • FDA

  • Africa

  • Asia

Introduction

  • Safety Alerts:

    • FDA announced a requirement for the manufacturer to create a restricted access program for rosiglitazone.

    • EMA suspended the marketing authorization for all rosiglitazone-containing medications in the EU.

  • Reasons for Actions: Based on data revealing elevated risks of cardiovascular events, including:

    • Acute myocardial infarction

    • Stroke

  • Stringent Regulatory Authorities (SRAs):

    • Defined by inclusion in the International Conference on Harmonization, legally binding agreements, and their ability to influence global drug safety standards.

  • Role of National Regulatory Authorities (NRAs): Assess emerging safety risks against benefits and make informed decisions on medicine availability post-approval.

  • Current Challenges in LMICs:

    • Variability in pharmacovigilance systems leading to gaps in infrastructure and practices.

    • Lack of capacity for ongoing benefit-risk analyses post-approval.

    • Need for global safety information exchange, facilitated by WHO.

Pharmacovigilance Systems in LMICs

  • World Health Organization (WHO):

    • Role in publishing safety data through newsletters.

    • Assessing pharmacovigilance capacity is critical for countries lacking essential system components.

  • Concept of Drug Lag and Safety Lag:

    • Drug Lag: Delay in the introduction of essential medicines approved by SRAs into developing countries.

    • Safety Lag: Time taken for NRAs in LMICs to respond to SRAs' safety alerts.

Methodology

  • Countries Studied: 10 NRAs

    • 8 from Africa: Ghana, Kenya, Namibia, Nigeria, Tanzania, Senegal, South Africa, Uganda.

    • 2 from outside Africa: India and Indonesia.

  • Data Sources:

    • Surveillance of global regulatory activities.

    • Reviews of websites of NRAs and interviews with key informants.

  • Calculation of Time Lag: Median time lag calculated from the date of first SRA announcement to regulatory actions taken by NRAs.

Results

  • Time Lag Findings:

    • Regulatory actions from two NRAs (India, Indonesia) occurred within 2 weeks;

    • Median time lag in African NRAs was 43 days.

    • Notable outlier: South Africa with a 285-day response time.

  • Regulatory Actions by Country:

    • Ghana: Action on November 29, 2010 (67 days lag).

    • Kenya: Action on October 13, 2010 (20 days lag).

    • Namibia: Action on November 10, 2010 (48 days lag).

    • Nigeria: Action on October 9, 2010 (16 days lag), with detailed risk management commitments.

    • Tanzania: Action on November 5, 2010 (43 days lag).

    • Uganda: No date available for action.

    • Senegal: Action on October 12, 2010 (19 days lag).

    • South Africa: Action on July 5, 2011 (285 days lag).

    • India: Action on October 7, 2010 (14 days lag).

    • Indonesia: Action on September 24, 2010 (1 day lag).

Sales Data Overview

  • Global and regional sales of rosiglitazone-containing products (2007-2010):

    • Decline in sales in the US and EU post-March 2007 alerts, yet modest growth in rest of the world.

    • Notable milestones impacting sales dynamics include safety alerts and risk analysis publications.

Discussion

  • Case Study Significance:

    • Regulatory decisions made by the FDA and EMA highlight the importance of ongoing benefit-risk evaluations for drugs like rosiglitazone.

  • Evidence of Safety Risks:

    • Meta-analysis showing increased risk of myocardial infarction (OR = 1.43, 95% CI: 1.03-1.98).

    • Observational studies link rosiglitazone to higher risks of stroke (HR = 1.27), heart failure (HR = 1.25), and overall mortality (HR = 1.14).

  • Regulatory Changes:

    • FDA lifted some restrictions on November 25, 2013, based on the RECORD trial results.

  • Need for Continuous Benefit-Risk Evaluation:

    • Regulatory authorities must update their decisions based on new data to ensure ongoing safety of medications.

  • Observed Regulatory Delays:

    • Delays linked to lack of systems for utilizing external safety alerts effectively.

  • Recommendations:

    • Emphasize global collaboration and systematic approaches in responding to safety alerts.

Conclusion

  • Call to Action:

    • Low- and middle-income countries must implement systems for prompt identification and management of safety issues for registered products.

  • Future Directions:

    • Improve standards and sharing practices to mitigate safety lag and enhance drug safety, ensuring a more equitable global health system.

  • Implementation of Metrics:

    • Use metrics like the Indicator-Based Pharmacovigilance Assessment Tool to track and monitor performance in pharmacovigilance systems.

Author Note

  • Study presented at the 27th International Conference on Pharmacoepidemiology & Therapeutic Risk Management, Chicago, Illinois, August 14-17, 2011.

Declaration of Conflicting Interests

  • No conflicts of interest were reported.

Funding

  • The authors received no financial support for this work.

References

  • Include multiple cited works regarding regulations, pharmacovigilance guidelines, studies, and meta-analyses.

  • Specific articles detailing actions taken by the FDA and EMA regarding rosiglitazone are highlighted throughout this transcript.