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Pharmacovigilance and Drug Safety:

Top 10 Issues facing Compliance and Legal


Pharmaceutical Regulatory Compliance Congress and Best
Practices Forum

November 8
th

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

Existing

Future

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.
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
9
a, 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
9
a 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

Prioritise

& Plan

Control

& Report

Monitor

Identify

Technology

Governance

Structure

Failure , Effect,

Cause, Risk index

F

E

C

R

F

E

C

R

F

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



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

pvconnect

pvnet

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

73%

(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

80%

(12/15)

29%

(4/14)

Have signal detection processes
integrated into risk management plans

13%

(2/15)

36%

(5/14)

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

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

When is RMP initiated
0
1
2
3
4
5
6
7
8
Pre-clinical
Phase I
Phase II
After Phase II
Lifecycle stage
# of companies
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


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



8
. Aligning PV organisation to enable proactive safety

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 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

Thank you

Chris Holmes

WCI Consulting Ltd

+
44 7785 280043


chris.holmes@wcigroup.com