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
Contents
•
•
•
•
•
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
enforcement
• Increased interest in drug safety by stakeholders, desire for
more transparency
• Increasing workload
Industry response to current environment
Future
Existing
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
companies
• In-house lawyers
Top 10 PV Issues*
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
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
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
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
arrangements”
• 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
companies
• 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
Analyse
Identify
F
E
C
R
F
E
C
R
Failure , Effect,
Cause, Risk index
Governance
Structure
Monitor
Technology
Prioritise
& Plan
F
Control
& Report
E
C
R
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
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
modeling tools
to explore
“what-if”
scenarios
Use of external
data sources for
background
values
Electronic
tracking of
signal life-cycle
from detection
to resolution
Global SD SOPs
SD processes
integrated with
risk mgt plans
1 - Basic
2
3
4
pvnet
Full data
warehouse
incorporating
crossorganizational
data (e.g.,
marketing, etc.)
Thought leader in
SD approaches &
methodologies
Established
communication
plan between
stakeholders
5 - Mature
5. Formalised signal management processes
Benchmark findings
pvconnect
pvnet
73%
93%
(11/15)
(13/14)
Treat inquiries from regulatory
agencies/DSMBs as signal sources
73%
86%
(8/11)
(12/14)
Specify timelines to ensure timely
evaluation of signals
46%
50%
(5/11)
(7/14)
Document actions taken for signals that
progress to further evaluation
80%
79%
(12/15)
(11/14)
80%
29%
(12/15)
(4/14)
13%
36%
(2/15)
(5/14)
Have SOPs describing signal detection
and evaluation processes
Document actions taken for signals that
do not progress to further evaluation
Have signal detection processes
integrated into risk management plans
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)
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
• Only 1 company has a
finalised SOP for RMP
development, though 4
more have them in draft
When is RMP initiated
8
# of companies
7
6
5
4
3
2
1
0
Pre-clinical
Phase I
Phase II
Lifecycle stage
After Phase II
• Responsibility for
monitoring implementation
and effectiveness is PV in
4 companies and a mix of
functions in others e.g.
clinical
18
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
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
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)
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
Imperatives
• Understand all potential compliance exposures as interrelated
• 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
chris.holmes@wcigroup.com