Pharmacovigilance Audits: Is the USA behind the curve?

FOCUSED. TRUSTED. GLOBAL.

Pharmacovigilance Audits: Is the USA behind the curve?

Michael BaptistQA Manager, Medpace


Objectives

o Definition of Pharmacovigilanceo What is postmarketing safety and pharmacovigilance

and why is it important o What is an adverse event (AE)o EU Requirementso Benefits of a PV programo PV audits and what it entailso Current trends to mitigate the requirement for PV

auditso 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 Requirementso 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 focusedo 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 Meetingo Review of applicable documentationo Interviews with key personnel relevant to the

subject mattero A demonstration to pertinent activities such as

case processingo Evaluation of search engines used to monitor AEs

reportedo Exit Meeting


PV Audits – Common trends

o Timelineso Unresolved Querieso Database entry errors of reported caseso Metrics o Training o Documentation issueso Coding Issues o Access and management of the Databaseo Data QCo 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 databaseo 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 scheduleo 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 complianceo 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 USo More discussion at the regulatory agencies in

providing industry guidelines/or guidance on PV

o Incentivizing big pharma in promoting PV discussions


Referenceso 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

Health & Medicine

Pharmacovigilance Audits: Is the USA behind the curve?