1. Chris Holmes Principal, WCI Consulting Ltd
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

2. Contents Pharmacovigilance (PV) environment Best Practices Forum
Top 10 issues
Current industry responses
Conclusions

3. Pharmacovigilance environment
Move beyond compliance to proactive, medically driven safety risk management
Constantly evolving regulatory environment with increased enforcement
Increased interest in drug safety by stakeholders, desire for more transparency
Increasing workload

4. Industry response to current environment
Existing
Future

5. 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
12 large and medium pharmaceutical companies
In-house lawyers

6. *Source: pvnet Members, not prioritized
Top 10 PV Issues*
QP-PV role and responsibilities
Contractual arrangements
Governance & Quality Management System
Increased enforcement of Regulations
Formalised Signal Management process
Submission of Risk Management Plans (RMPs)
Developing RMPs across product lifecycle
Aligning PV organisation to enable proactive safety
Individual reporting of ICSRs
Maintaining efficient PV process
*Source: pvnet Members, not prioritized

7. 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 & promptly

8. 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

9. 2. Contractual arrangements
MAH must have “detailed and clear documented contractual arrangements” in place
MAH must provide authorities with “information on such arrangements”
Closer collaboration with legal and commercial functions required for compliance
Defined process for early involvement of PV in portfolio decisions and due diligence

10. 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 companies
Create ‘PV Handbook’ for inspection readiness in all affiliates
Establish Operational Risk Management framework
Proactive, systematic approach to identifying and mitigating compliance risks

11. 3. Single global Quality Management System Operations & Compliance framework
Failure , Effect,
Cause, Risk index
People
Process
Technology
Governance
Structure F E C R

12. 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

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

14. 5. Formalised signal management processes Benchmark findings
pvconnect
pvnet
Have SOPs describing signal detection and evaluation processes
73%
(11/15)
93%
(13/14)
Treat inquiries from regulatory agencies/DSMBs as signal sources
(8/11)
86%
(12/14)
Specify timelines to ensure timely evaluation of signals
46%
(5/11)
50%
(7/14)
Document actions taken for signals that progress to further evaluation
80%
(12/15)
79%
(11/14)
Document actions taken for signals that do not progress to further evaluation
29%
(4/14)
Have signal detection processes integrated into risk management plans
13%
(2/15)
36%
(5/14)

15. 5. Formalised signal management processes Industry responses
Signal detection SOPs integrated into Safety Risk Management processes
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)

16. 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)

17. 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

18. The development of RMPs is currently largely driven by regulatory needs in EU Source: pvnet survey
Only 1 company has a finalised SOP for RMP development, though 4 more have them in draft
Responsibility for monitoring implementation and effectiveness is PV in 4 companies and a mix of functions in others e.g. clinical

19. 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

20. 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

21. 9. Expedited Reporting of Individual Case Safety Reports
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 measures

22. 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 surveillance
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)

23. 10. Maintain efficient PV process
Simplify global routine PV processes
Align global roles and responsibilities, strengthen links with affiliates
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

24. Imperatives
Understand all potential compliance exposures as inter-related
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

25. Thank you
Chris Holmes WCI Consulting Ltd