Pharmacovigilance Audits: Is the USA behind the curve?

FOCUSED. TRUSTED. GLOBAL.
Pharmacovigilance Audits: Is the
USA behind the curve?
Michael Baptist
QA Manager, Medpace

Objectives
o Definition of Pharmacovigilance
o What is postmarketing safety and
pharmacovigilance and why is it important
o What is an adverse event (AE)
o EU Requirements
o Benefits of a PV program
o PV audits and what it entails
o Current trends to mitigate the requirement for PV
audits
o Value in US adopting a PV audit program
o How to balance overreach from passive safety
monitoring

What is Postmarketing PV?
o Pharmacovigilance stems from 2 words:
“Pharmakon” and “Vigilare”
o Pharmakon is the Greek word for Drug and Vigilare
is the Latin for Watch
o Pharmacovigilance (PV) is the practice of
monitoring the safety of an investigational
medicinal product (IMP) once it has been
approved for release on the market.
o Pharmacovigilance is an ongoing regulatory
requirement that lasts the lifespan of the
pharmaceutical product post-NDA approval*.

Why is Postmarketing PV important?
o During clinical trials, there is a limited scope of the population of
patients BUT once the NDA has been approved, there is a larger
demography compared to the population that was initially
involved with the clinical trial phase. Pharmacovigilance helps to
manage the quality, safety, and effectiveness of pharmaceutical
products post-NDA approval.
o In other words, postmarketing surveillance is important because it:
• Further refines, or confirms or denies, the safety of a drug
after it is used in the general population as larger numbers
of people who have a wide variety of medical conditions
become exposed to the pharmaceutical product
following NDA approval.*
*Source of Information: CFR – Medpace Safety group

What is an AE?
o An adverse event (AE) is any untoward occurrence experienced by
a patient who is administered/treated with a pharmaceutical
product (either investigational or approved). This occurrence can be
medical or non-medical.
o In Pharmacovigilance, adverse events do not have to have a causal
relationship with the investigational medicinal product
administration/treatment to be considered reportable to the FDA.
o Therefore: An adverse event can be any unfavorable and
unintended sign (e.g. abnormal laboratory finding), symptom (e.g.
nausea), or disease (e.g. cancer) temporally associated with the use
of a medicinal product, whether or not considered to be related to
the product.*
o An adverse event may also be a non-medical occurrence such as a
car accident, medication error or off-label use, whether or not it is
considered to be related to the medicinal product.*

EU Requirements
o The European Union is clear with respect to its expectations for
Pharmacovigilance as articulated in the Guideline on good
pharmacovigilance practices (GVP), of which Module IV addresses
Pharmacovigilance audits.
o The entry into force of the new legislation on pharmacovigilance in July 2012,
established legal requirements for competent authorities in the Member States
and the European Medicines agency (the Agency) and marketing
authorization holders to perform audits of their pharmacovigilance systems
[DIR Art 101(2), Art 104(2), REG Art 28f], including risk based audits of their
quality systems [IR Art 13 (1), Art 17 (1).]
o The overall description and objectives of pharmacovigilance systems and
quality systems for pharmacovigilance activities are referred to in Module I,
while the specific pharmacovigilance processes are described in each
respective Module of GVP.
o The marketing authorization holder in the EU is required to perform regular risk-
based audit(s) of their pharmacovigilance system [DIR Art 104(2)], including
audit(s) of its quality system to ensure that the quality system complies with the
quality system requirements [IR Art 8,10,11,12,13(1)]. The dates and results of
audits and follow-up audits shall be documented [IR Art 13(2)]
*Source of Information: – EMA Requirements on Pharmacovigilance

EU Requirements
o The responsibilities of the QPPV in respect of audit are
provided in Module I. Furthermore, the QPPV should receive
pharmacovigilance audit reports, and provide information to
the auditors relevant to the risk assessment, including
knowledge of status of corrective and preventive actions.
o The QPPV should be notified of any audit findings relevant to
the pharmacovigilance system in the EU, irrespective of where
the audit was conducted.
o The Agency shall perform regular independent audits of its
pharmacovigilance tasks [REG Art 28f] and competent
authorities in member states shall perform a regular audit of
their pharmacovigilance system [DIR Art 101(2)].

EU Requirements
o Included in their obligation to perform audits of their
pharmacovigilance Guideline on good
pharmacovigilance practices (GVP) – Module IV
EMA/228028/2012
o System/tasks, competent authorities in the Member
States and the Agency shall perform risk-based audits of
the quality system as well, at regular intervals according
to a common methodology to ensure that the quality
system complies with the requirements [IR Art
8,14,15,16,17(1)]. The dates and results of audits and
follow-up audits shall be documented.

EU Requirements - Reporting
o The marketing authorization holder shall place a note
concerning critical and major audit findings of any audit
relating to the pharmacovigilance system in the
pharmacovigilance system master file (PSMF) (see Module II).
Based on the audit findings*, the marketing authorization
holder shall ensure that an appropriate plan detailing
corrective and preventative action is prepared and
implemented.
o Once the corrective and preventive actions have been fully
implemented, the note may be removed [DIR Art 104(2), IR Art
13(2)]. Objective evidence is required in order that any note
of audit findings can be removed from the
pharmacovigilance system master file (see Module II).

EU Requirements - Reporting
o The marketing authorization holders should ensure that a list of
all scheduled and completed audits is kept in the annex to
the pharmacovigilance system master file ( IR Art 3(5)) and
that they comply with reporting commitments in line with the
legislation, GVP guidance and their internal reporting policies.
o The dates and results of audits and follow-up audits shall be
documented [IR Art 13(2)].

Benefits of PV - Auditing
o Drug safety is critical as lapses in the monitoring of drug
safety have fatal consequences.
o The continuous gathering of safety data on the profile of
drugs introduced into the market has aided the
mitigation of those drugs whose approval had adverse
safety implications.
o Drugs may be pulled off the market based on safety
reports generated from post market surveillance – e.g.
Vioxx, Thalidomide, Palladone, Accutane, e.t.c
o Vioxx had close to 60,000 fatalities, while Thalidomide
contribute to the “no limbs” baby syndrome in the 1960s
in the UK.
*

Benefits of PV - Auditing
o With the potential of risk to the general public, the
requirement for an auditing program for PV is a
necessity.
o In the EU, this became a requirement in July 2012 that is
monitored but this is NOT a requirement in the USA
o Self policing is an expectation that is held in good faith in
the US, where each entity ensures that there is an
independent assessment of their PV program.
o With auditing of PV, there is a reassurance of the
governance, systems, and operational tools in place to
monitor PV.
*

PV Audits and what it entails
o Audits have become one of the tools employed by
organizations to maintain and demonstrate their
oversight.
o An audit is an independent and systematic evaluation of
a process (es)/study/trial to ensure that pre-established
requirements are being performed as prescribed, in
other words – Expectations match Reality.
o There are several types of audits – TMFs, Databases,
Investigator Sites, Sponsor and
Pharmacovigilance/Safety
o Audits in general have become more frequent, more
structured and collaborative between the various
segments of the industry
o However, PV audits within the USA, is NOT a requirement
*

PV Audits - General
o Pharmacovigilance audit activities should verify, by examination
and evaluation of objective evidence, the appropriateness and
effectiveness of the implementation and operation of a
Pharmacovigilance system, including it’s quality system for
Pharmacovigilance activities”.
o “Pharmacovigilance audits may be defined as a critical review
and analysis of the compliance (with global and local
legislation, internal SOPs, contracts/agreements) of the systems
supporting the monitoring of adverse events and detection
signals”. “Its purpose is to provide assurance that the internal PV
(and related) systems are robust, in order to assure the
protection of public health”

PV Audits – Risk Based Approach
o A Risk-based approach can also be employed at
various levels in planning for Pharmacovigilance
audits- Strategic, Tactical and Operational
o These allow for a more robust approach in planning
the Pharmacovigilance audits
o Strategic Planning– Overarching and long term in
perspective
o Tactical Planning- Quality system focused
o Operational Planning – Procedures and
documentation

PV Audits - Planning
o Understanding the PV database to be audited and any high
level commitments in terms of contracts, service agreements
or task orders
o Understanding the internal procedures with respect to PV and
various regulatory paradigms that apply
o Understanding the PV plan (if there is one), timelines for
reporting, workflows for managing cases, metrics collated and
hand-over processes between functional groups
o Request access to database and create an agenda

PV Audits – performing the audit
o Opening Meeting
o Review of applicable documentation
o Interviews with key personnel relevant to the subject
matter
o A demonstration to pertinent activities such as case
processing
o Evaluation of search engines used to monitor AEs
reported
o Exit Meeting

PV Audits – Common trends
o Timelines
o Unresolved Queries
o Database entry errors of reported cases
o Metrics
o Training
o Documentation issues
o Coding Issues
o Access and management of the Database
o Data QC
o Hand-Offs

Current Trends to mitigate PV Audits
o Since PV audits are not mandatory in the US, some companies
employ self policing.
o Ensuring the validation of their PV database
o Leverage off the requirements set forth by the EU in order to
create a framework to monitor PV compliance.
o Include PV audits in their company audit schedule
o Increase training in PV for their Quality group that increase the
knowledge base of their auditors.
o Utilize their internal operational safety groups to track and
trend PV issues and ensure proper investigation that identify
risk

Value of a PV Program in the US
o As the US is one of the leading pharmaceutical
contributors globally, it is prudent that PV should be
given more legalized visibility.
o An average of 10 New Molecular Entities (NMEs) are
added to the drug market annually.
o In Clinical Trials, sponsors conduct audits at the CRO
delegated transfer obligations in order to demonstrate
their oversights.
o Sites participating in the trial also get audited extensively
by the sponsors and the regulatory agencies.
o Not many sponsors/CROs conduct PV audits in the US.
o Auditors have more relevant experience with site, TMF,
Database audits as compared to PV.

The Balance – A Pragmatic Approach
o EU requirement enforces compliance
o Entities have to include a PV program within their curricula
and ensure that their employees are aware and demonstrate
compliance.
o The legal requirement ensures governance by management
and reporting encourages evaluation for continuous
improvement but voluntary compliance is encouraged.
o The US can adopt an industry standard, and sponsors in drug
development can work in synergy to promote PV audits
o Quality Auditors should be trained in PV
o Company-wide awareness and governance for PV programs

Final Thoughts
o PV audits should be encouraged in the US
o More discussion at the regulatory agencies in
providing industry guidelines/or guidance on PV
o Incentivizing big pharma in promoting PV
discussions

References
o Vioxx -Reuters April 19, 2012
o Source of Information: CFR – Code of Federal Regulations Title 21, Sec. 314.80
o Guideline on good Pharmacovigilance practices (GVP), Module IV –
Pharmacovigilance audits, EMA, 26July2012
o Pharmacovigilance Auditing, Pam Bones, Lindsay Watt, Nazrul Khan, Louise
Alford, Calvin Johnson and Sandra Dunlavy
o Pharmacovigilance Audit by Janet Kinyua
o Pharmacovigilance Risk Management Audit by Virgilio Vinas
o Safety and Pharmacovigilance Audits- General Audit Concepts and
Overview, Michael Baptist October 2010, Kendle QA Training
o Medpace Safety Group - Pharmacovigilance
o Risk Assessment – Prioritizing and efficient Uses of Resources for Internal Audit
Systems, Michael Baptist, 29th SQA Annual Meeting Presentation
o Pharmacovigilance Audits, a Pivotal Link to Drug Safety, Michael Baptist

Pharmacovigilance Audits: Is the USA behind the curve?

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