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

Pharmaceutical Regulatory Compliance Congress and Best Practices ForumNovember 8th 2007Washington 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 responsibilitiesClarified 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 responsibilitiesIndustry 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 SystemOperations & Compliance framework

AnalyseAnalyse

Prioritise & Plan

Prioritise & Plan

Control & ReportControl & Report

MonitorMonitor

IdentifyIdentify

Peo

ple

Process

Technology

GovernanceStructure

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 processesBenchmark 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 processesIndustry 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 EUSource: 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

# o

f co

mp

anie

s

7. Development of lifecycle Safety Risk MgtIndustry 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