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									Pharmacovigilance and Drug Safety:
Top 10 Issues facing Compliance and Legal

Pharmaceutical Regulatory Compliance Congress and Best
Practices Forum
November 8th 2007
Washington DC

Chris Holmes
Principal, WCI Consulting Ltd

•   Pharmacovigilance (PV) environment
•   Best Practices Forum
•   Top 10 issues
•   Current industry responses
•   Conclusions
  Pharmacovigilance environment

• Move beyond compliance to proactive, medically driven
  safety risk management

• Constantly evolving regulatory environment with increased

• Increased interest in drug safety by stakeholders, desire for
  more transparency

• Increasing workload
Industry response to current environment


An Industry Forum has benchmarked current practices
and developed future practices

         • 12 large pharmaceutical and biotechnology
           companies, since 2001
         • Heads of Pharmacovigilance

         • 26 medium sized companies, inc. Rx, OTC,
           Devices, Generics
         • Heads of Pharmacovigilance

         • 12 large and medium pharmaceutical
         • In-house lawyers
             Top 10 PV Issues*

       1.    QP-PV role and responsibilities
       2.    Contractual arrangements
       3.    Governance & Quality Management System
       4.    Increased enforcement of Regulations
       5.    Formalised Signal Management process
       6.    Submission of Risk Management Plans (RMPs)
       7.    Developing RMPs across product lifecycle
       8.    Aligning PV organisation to enable proactive safety
       9.    Individual reporting of ICSRs
       10.   Maintaining efficient PV process

*Source: pvnet Members, not prioritized
    1. QP-PV role and responsibilities
    Clarified in EU Volume 9a, January 2007

•   Establish/maintain/manage MAH PV system

•   Overview of safety profiles, emerging safety concerns

•   Single contact point for Authorities

•   Ensure execution of PV obligations:
    •   collection of ADRs at one point in the EU
    •   preparation of reports e.g. PSUR, PASS
    •   continuous post-authorization PV evaluation

•   Ensure that requests from Authorities are answered fully &
      1. QP-PV role and responsibilities
      Industry Responsibilities have been clarified in Vol. 9a

• Provide overview of, and direct access to, information regarding
  safety profiles, emerging safety concerns

• Ensure adequate representation in medical governance

• Assign sufficient authority to actively manage PV system
    • Develop Performance Mgt to support safety objectives
    • Increase employee awareness of safety responsibilities, ensure effective
      mechanisms in place to enable issues to be captured
     2. Contractual arrangements

• MAH must have “detailed and clear documented contractual
  arrangements” in place

• MAH must provide authorities with “information on such

• Closer collaboration with legal and commercial functions
  required for compliance

• Defined process for early involvement of PV in portfolio
  decisions and due diligence
    3. Governance & Quality Management System

• Detailed Description of Pharmacovigilance System (DDPS)
  required for submissions in EU
    • More transparency of how MAH PV system works
    • Template based on Volume 9a expectations
    • Emerging good practice, key document for Inspections

• Need to align and simplify SOPs across PV and operating

• Create „PV Handbook‟ for inspection readiness in all affiliates

• Establish Operational Risk Management framework
    • Proactive, systematic approach to identifying and mitigating
      compliance risks
3. Single global Quality Management System
Operations & Compliance framework

             Identify                          Analyse

              F    E   C    R                  F   E   C   R
              Failure , Effect,
             Cause, Risk index

       Monitor                    Technology
                                                            & Plan

                                                            F   E   C   R

                                  & Report
    4. Increased enforcement of Regulations

• Recent shift towards stricter enforcement of
  stricter EU rules

• EU inspections becoming routine
    • Each Member State responsible for inspections
    • Need for clear and consistent inspection standards
    • Need to keep abreast of „Hot Topics‟ as inspection standards and
      focus varies

• New EU Penalties legislation (July, 2007)
    • Applies to centrally authorized products
    • Financial penalties to MAHs in respect of infringements
    • Financial risk associated with non-compliance: up to 5% of total EU
      annual turnover per annum
       5. Formalised signal management processes

• Signal Management becoming more proactive and formalised
• pvnet benchmark data shows maturing approach
Nothing      Use of some ad     Use of             Use of              Full data
formal       hoc reports        regulatory         modeling tools      warehouse
beyond       primarily          methodologies      to explore          incorporating
PSUR / ASR   looking at AE      (e.g., EBGM)       “what-if”           cross-
reports      counts and         and thresholds     scenarios           organizational
             frequencies                                               data (e.g.,
Limited                         Use of external    Electronic
                                                                       marketing, etc.)
signal       Consistent local   data sources for   tracking of
detection    SD SOPs            background         signal life-cycle   Thought leader in
SOPs                            values             from detection      SD approaches &
                                                   to resolution       methodologies
                                Global SD SOPs
                                                   SD processes        Established
                                                   integrated with     communication
                                                   risk mgt plans      plan between
 1 - Basic          2                  3                  4               5 - Mature
5. Formalised signal management processes
Benchmark findings

                                          pvconnect   pvnet
Have SOPs describing signal detection       73%       93%
and evaluation processes                    (11/15)   (13/14)

Treat inquiries from regulatory             73%       86%
agencies/DSMBs as signal sources            (8/11)    (12/14)

Specify timelines to ensure timely          46%       50%
evaluation of signals                       (5/11)    (7/14)

Document actions taken for signals that     80%       79%
progress to further evaluation              (12/15)   (11/14)

Document actions taken for signals that     80%       29%
do not progress to further evaluation       (12/15)   (4/14)

Have signal detection processes             13%       36%
integrated into risk management plans       (2/15)    (5/14)
     5. Formalised signal management processes
     Industry responses

• Signal detection SOPs integrated into Safety Risk Management

• Consistent responsibilities and accountability for signal detection
  and management, especially between pre- and post-marketing

• Benefit-risk evaluation procedures documented and clear
  accountability determined
    • Vol 9a: “The MAH shall forthwith inform the authorities of any other
      new information which might influence the evaluation of benefits and
      risks of the medicinal product concerned”
   • Industry suggestion: decision tree based on public health impact

• Perform proactive internal audits (Regulators are auditing signal
  detection processes)
         6. Submission of Risk Management Plans

• Obligation to submit an EU-Risk Management Plan (RMP)
    •   Application for a new MA (new active substance)
    •   Application for significant change in a MA (new dosage form)
    •   On request of Competent Authority (pre- and post authorization)
    •   On initiative of Applicant/MAH (when “safety concern” identified)

• EU and US requirements similar in practical application
    • companies tending to be driven by EU requirements as US is currently
      less onerous

• Monitoring is key*
    • 83% of RMPs have proposed studies, only 9% reliant on standard PV
      alone (with no proposal for additional studies or other actions)
    • Of the proposed studies, a third had not provided an update where one
      was expected and additional third had not yet started the studies
    • MHRA and EMEA considering enforcement mechanisms
* source: MHRA (ISoP Annual Conference Oct 2007)
    7. Development of lifecycle Safety Risk Management

• Drive towards more proactive, systematic approach to identifying
  potential safety concerns

• FDAAA grants FDA sweeping new authority to require:
   • Post-marketing studies and clinical trials
   • Safety labeling changes
   • Risk evaluation and mitigation strategies (REMS)

• Companies are formalising risk management activities earlier in
  the product lifecycle (pvnet)
   • PV is generally accountable for safety risk management activity
                          The development of RMPs is currently largely
                          driven by regulatory needs in EU
                          Source: pvnet survey

                                    When is RMP initiated                        • Only 1 company has a
                                                                                   finalised SOP for RMP
                 7                                                                 development, though 4
                 6                                                                 more have them in draft
# of companies

                 3                                                               • Responsibility for
                 2                                                                 monitoring implementation
                 1                                                                 and effectiveness is PV in
                 0                                                                 4 companies and a mix of
                     Pre-clinical      Phase I       Phase II   After Phase II
                                                                                   functions in others e.g.
                                          Lifecycle stage

    7. Development of lifecycle Safety Risk Mgt
    Industry responses

• Define risk mgt approach from First-In-Man or earlier and
  throughout lifecycle:
    • Formalise processes and tools
    • Implement Safety Management Teams for Clinical Development
      Projects (see CIOMS VI)
    • Define responsibilities for risk identification, mitigation, monitoring of
      implementation and effectiveness

• Ensure consistent global communication on medical safety risks

• Ensure a single safety risk management plan exists for all
  development and key marketed products
    8. Aligning PV organisation to enable proactive safety

• Increase employee awareness of safety responsibilities
    • Training Curricula & toolbox for all employees

• Attract and retain high quality competent resources
    • Improved recruitment & assessment process
    • Career Path alignment with key functions e.g. Clinical

• Improved capability e.g. safety risk mgt, epidemiology
    • PV competency framework

• Balance workload requirements and maintain compliance
    • Define and implement new roles with clear responsibilities
    • Implement capacity planning process
9. Expedited Reporting of Individual Case Safety

• Clock for expedited reporting: starts “Day 0” as soon as
  the minimum information has been received by:
    • Any personnel of the MAH or
    • Any organization having a contractual arrangement with the
      MAH, including CROs, marketing partners, medical
      representatives etc

• Partner agreements impacted and will need reviewing to
  ensure that they meet new standards

• Impact on process metrics and other compliance
    10. Maintain efficient PV process

• Efficient routine PV process are required to manage growing
  scope and volume of data
   • pvnet: avg 10% increase in ADR volume for last 7 years

• pvnet data shows increase in productivity, data quality
  compliance and increased investment in proactive safety
   • pvnet: 2005 v 2006 (12 of Top 25 Pharmacos)
       • 10% increase in productivity
       • 30% increase in „Scientists‟ effort on routine PV, corresponding
         reduction in Physician and Data Processor effort.
       • 15% increase in signals generated by internal process (rather
         than notified by external agencies)
10. Maintain efficient PV process

• Simplify global routine PV processes

• Align global roles and responsibilities, strengthen links with

• Harmonise product International Birth Dates to streamline
  PSUR processes

• Improve automation
    • Automate ADR data entry (e.g. call centre, key affiliates)
    • Run automatic quantitative analysis for signals
    • Automatic PSUR compilation

• Understand all potential compliance exposures as inter-

• View Drug Safety, Medical Affairs, and Quality Operations
  exposure from an integrated perspective
   • Align approach to policies, QMS, training and audits

• Review global infrastructure for PV and partner functions

• Ensure in-house legal counsel support to PV
Thank you

                  Chris Holmes
                WCI Consulting Ltd
                + 44 7785 280043


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