Highlights of the 2012 Revised EU Pharmacovigialnce Regulations

Sidney Kahn
Note: The views expressed in this article are those of the author and do not necessarily represent those of his/her employer, GxP Lifeline, its editor or MasterControl, Inc.

In December 2010, the European Commission (EC) published legislation for implementation in July 2012 that made the most sweeping changes to European pharmacovigilance since 1995. Directive 2001/83/EC, covering non-centrally approved products, was amended by 2010/84/EU, and Regulation EC/726/2004, governing centrally approved products and European Medicines Agency activities, was amended by 1235/2010. The goals of the new requirements are to:

  • Clarify the roles and responsibilities of marketing authorization holders
  • Strengthen industry pharmacovigilance (PV) systems
  • Collect better data by simplifying requirements, reducing duplication of effort, and decreasing administrative burdens
  • Free resources by rationalizing and simplifying adverse drug reaction and periodic safety update (PSUR) reporting
  • Establish a clear legal framework for post-authorization monitoring of safety and effectiveness
  • Improve proactive, proportionate collection of high quality safety data
  • Support effective risk management planning
  • Increase the understanding and trust of patients and prescribers by greater transparency and better communication of safety information.

The new regulations replace Volume 9A with sixteen Good Pharmacovigilance Practice (GVP) guideline modules and five Annexes to be adopted in stages, with some provisions of Volume 9A temporarily remaining in effect; details can be found at http://bit.ly/OWQ8AM.

The sole route for submission of all individual safety reports for EU authorized products will be electronically to EudraVigilance, replacing all existing requirements and prohibiting any European member state-specific additions.

The GVP modules completed as of 25 June 2012 comprise:

  • I. Pharmacovigilance systems and their quality systems
  • II. Pharmacovigialnce system master file
  • V. Risk management systems
  • VI. Management and reporting of adverse reactions to medicinal products
  • VII. Periodic safety update reports
  • VIII. Post-authorization safety studies
  • IX. Signal management

None of the remaining modules have been finalized as of mid-December 2012.

Highlights of the New Legislation

A complete description of these regulations and guidances exceeds the scope of this article, which presents selected highlights of the new provisions.

  1. Changes in European Medicines Agency pharmacovigilance structures and operations

    The structures, functions, and authority of the European Medicines Agency and individual European member states change significantly. The Pharmacovigilance Working Party (PhVWP) is replaced by the Pharmacovigilance Risk Assessment Committee (PRAC), with greater scope and authority for risk management of all European Union (EU) products, including:

    • detection, assessment, minimization and communication of the risk of adverse drug reactions
    • design and evaluation of post-authorization safety studies
    • evaluation of pharmacovigilance audits
    • monitoring the effectiveness of pharmacovigilance activities and risk management systmes
    • evaluating safety issues for nationally approved products

    Regulatory agency costs for the additional work will be funded by user fees, still to be established.

  2. Changes in adverse drug reaction reporting

    The sole route for submission of all individual safety reports for EU authorized products will be electronically to EudraVigilance, replacing all existing requirements and prohibiting any European member state-specific additions. All concerned parties will access safety data only via EudraVigilance.

    All postmarketing serious suspected adverse drug reactions, regardless of expectedness, must be submitted to EudraVigilance within 15 calendar days and all EU non-serious adverse drug reactions within 90 calendar days. Marketing authorization holders must submit all reports, even those from consumers that are denied by a health professional. Since EudraVigilance will not have the necessary capabilities before 2015, complex interim arrangements apply (http://bit.ly/Q57FJk).

    For multisource products, European Medicines Agency (EMA) will ultimately take responsibility for monitoring the medical literature for adverse drug reactions to prevent duplicative reporting.

  3. Changes in safety monitoring

    The periodic reporting of safety information probably represents the most substantial change, placing much greater emphasis on benefit / risk analysis and linkage to the EU risk management plan (RMP). A Periodic Benefit Risk Evaluation report largely following the ICH E2CR2 draft guideline, also designated a "PSUR," replaces the current volume 9A PSUR format and content. Arrangements for transitioning from the old to the new PSUR are at www.hma.eu/80.html.

    The most significant changes in the new PSUR include:

    • A modular structure including patient exposure, clinical usage, summary tabulations, and findings from studies, but no line listings of individual case reports
    • Signal and risk evaluation
    • Benefit evaluation, summarizing information on efficacy and effectiveness in authorized indication(s)
    • An integrated scientific evaluation of benefits and risks based on cumulative analysis, evaluation of safety signals, and effectiveness of risk minimization activities
    • Product-specific necessity and periodicity determined by the conditions of MA approval and the RMP and proportional to product risk
    • Not routinely required for low risk products without safety concerns (especially generics)
    • Direct electronic submission to EMA via an EU repository (to be established)
    • Assessment by the PRAC for the entire EU.
  4. Enhanced industry pharmacovigilance

    The Detailed Description of Pharmacovigilance System (DDPS) will be replaced by a much more detailed and comprehensive Pharmacovigilance System Master File (PSMF). While only "key elements" must be submitted with a marketing authorization application, the complete PSMF must be provided within seven days of a regulatory request. The marketing authorization holder must conduct regular internal audits against the PSMF and record the main findings, which will form the basis for regulatory compliance inspections. These provisions take effect (1) with any new MAA submitted after July 2012 (2) with the first product renewal application after July 2012 or (3) by July 2015, whichever is the earliest.

    Marketing authorization holders will be required to monitor EV for emerging safety signals for their products.

    Marketing authorization holders must implement detailed procedures for signal detection, evaluation, reporting, and communication and document the results of these activities in PSURs.

  5. Benefit / risk management

    The focus of pharmacovigilance shifts from assessing risk alone to evaluating the balance between benefits and risks by:

    • closer post-authorization safety monitoring
    • assessment of real world benefits and risks post-authorization
    • ongoing post-authorization development and efficacy follow-up
    The following provisions are intended to enhance benefit-risk assessment:
    • Risk management systems to be proportionate to identified risks. Risk management plans (RMPs) will be required for ALL products.
    • All new active moieties and biologicals (including biosimilars), identified by a black symbol in the prescribing information for health professionals and patients, will be subject to additional monitoring for five years. The PRAC may impose a similar requirement on an authorized product at any time.
    • Results of any required risk minimization measures must be monitored, acted upon, and included in the PSUR
    • Web publication of benefit/risk information in lay language, including an RMP summary, EMA public assessment reports, required risk minimization activities, and questionnaires regarding specific ADRs.
  6. Post-authorization studies

    In addition to safety studies (PASS), the new regulations include post-authorization studies of efficacy / effectiveness (PAES), if indicated by a potential change in the overall benefit-risk balance. PASS may be required for market authorization or at any other time to address an inadequately characterized safety concern.

    PASS may be initiated voluntarily by marketing authorization holders or required by an authority. For a mandated PASS, the protocol must be approved by the authority before study initiation. All EU PASS protocols must be registered in an EU electronic registry. The marketing authorization holder's Qualified Person for PV must immediately inform authorities of any safety concern identified in a study.

    PAES may be required when new clinical understanding and/or methodology indicate a possible need to revise previous efficacy evaluations. PAES guidance is not yet available.

  7. Miscellaneous provisions

    The new pharmacovigilance regulations contain provisions not previously part of medicinal product safety activities, including:

    • The necessity to expand marketing authorization holder PV activities to company functions beyond traditional drug safety departments
    • Monitoring and evaluating the environmental impact of drug residues
    • Unspecified preparations for public health threats, including pandemics, bioterrorism, product quality, and climate change

Summary and Conclusion

The new PV requirements affect all pharmaceutical companies with a presence in the EU, whether direct or indirect via partnerships or agreements. Regulatory compliance will require the involvement of multiple functional areas within marketing authorization holders, their partners, and support organizations. The new systems and activities create significant additional burdens of time and cost for both marketing authorization holders and regulatory agencies; while the stated public health goals are commendable, it remains to be seen whether the substantially increased requirements for data collection and analysis, extensive documentation, and public communication will in fact have the intended effect of enhancing the public health benefits of pharmacovigilance activities.

Principal References

Dr. Sidney Kahn's professional credentials include MB, ChB (Cape Town), Ph.D. (London), FRCPath (Chemical Pathology), and MFPM (UK). His academic career spanned 17 years in clinical laboratory medicine and basic research in neuroimmunology in the UK and USA. He spent the next 13 years at Bristol-Myers Squibb and Johnson & Johnson managing drug safety groups responsible for safety assessment of medicinal products throughout their lifecycle before establishing his own consulting practice, Pharmacovigilance & Risk Management Inc. in 2002. He is affiliated with Sciformix Corporation as Senior Principal, Pharmacovigilance Practice. Throughout his corporate career, he was actively involved in US and global activities to enhance pharmacovigilance, risk assessment, and risk management, including PhRMA representation to ICH on several MedDRA EWGs, the U.S. National Coordinating Council for Medication Error Reporting and Prevention, the PhRMA/FDA Electronic Regulatory Submissions Task Force, and the ICH Post-Marketing EWG. He was a member of the CIOMS-VI WG and the HL7 SPL Implementation Workgroup. Dr. Kahn is a frequent presenter at conferences and workshops in the USA, Europe, and Asia on all aspects of pharmacovigilance, risk management, and labelling.