Pharmacovigilance Audits

Introduction

The safety of drugs is of paramount importance to patients and healthcare professionals. The pharmaceutical industry has an ethical and legal responsibility to ensure that the products they sell will not harm the patients they are intended for. The repercussions of a new drug having a potentially serious side-effect profile are enormous for patients, healthcare professionals and the industry. Public pressure on industry and regulatory bodies to improve the monitoring of drug safety has led to greater scrutiny of the groups responsible within organizations, namely the pharmacovigilance departments. Regulatory bodies do not have the resources to closely monitor the safety of all drugs that are licensed in their regions and rely on the industry to do this. To ensure that the industry is meeting its legal responsibilities, pharmacovigilance inspections are held – the audit, that is conducted to prepare for an inspection by a government body, is an examination and verification of processes, data, and documentation relating to drug safety by a nongovernmental agency (such as a business partner, contractor, internal quality assurance, etc).

Objectives

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 its quality system for pharmacovigilance activities. In general, an audit is a systematic, disciplined, independent and documented process for obtaining evidence and evaluating the evidence objectively to determine the extent to which the audit criteria are fulfilled, contributing to the improvement of risk management, control and governance processes. Audit evidence consists of records, statements or other information, which are relevant to the audit criteria and verifiable. Audit criteria are, for each audit objective, the standards of performance and control against which the auditee and its activities will be assessed. In the context of pharmacovigilance, audit criteria should reflect the requirements for the pharmacovigilance system, including its quality system for pharmacovigilance activities, as found in the legislation and guidance.

Regulatory background

Marketing authorization holders (MAHs), or companies with an approved clinical trial application (CTA) in place may be subject to inspection at any time. Most inspectorates apply a risk assessment model to target limited resources at the highest risk areas.

In the United States (US), laws governing medicines are found in the Food Drug and Cosmetic Act [21 U.S.C. 301 et seq.] as well as other statutes. In addition to laws, the US Food and Drug Administration (FDA) has the power under law to create regulations, which are published in the Federal Register and in the Code of Federal Regulations. The FDA also issues guidance, which specify the agency’s current thinking and preferences on laws and regulations. While nonbinding, these Guidance are generally followed by the industry. European Union (EU) legislation is more complicated than in the US, because it derives from treaties and agreements between 27 different sovereign countries (Member States). The EU pharmacovigilance laws are specified in Regulations (laws directly applicable to all Member States, without the need for additional implementation at the national level); and Directives (which bind Member States to implement the contents of the Directive into their national laws within a certain period). There are also guidance documents on pharmacovigilance (which, although not law themselves, should be complied with), one such document being Volume 9a of the Rules Governing Medicinal Products in the European Union - Pharmacovigilance. In the EU, the European Medicines Agency (EMA) evaluates and supervises the approval and use of medicinal products that are centrally approved in the EU (a process whereby a single application leads to an EU-wide approval). In addition, products that are not centrally approved are evaluated and supervised either by individual national regulatory authorities, or by a group of member states’ regulatory authorities, with one of the member states acting as the “reference member state” and leading the process (known as the decentralized or mutual recognition procedures).

Example of auditing steps

• Opening / introductory meeting to "kick off" the audit

• Interviews with relevant personnel

• Document reviews

• Demonstration of activities (e.g. processing of an adverse event case)

• Tour of facilities (e.g. work areas, file storage and archiving)

• Closing / exit meeting to discuss preliminary results

• Follow-up on outstanding questions / requests

Audit process model

• Data collection: it might include checking the processes of processing of Safety Information, sources of Data, Safety Data Exchange Agreements, outsourcing to Contract Research Organizations (CROs), follow-up Data Collection, clear Definition of Start Date to correctly determine the reporting deadlines.

• Cases assessment: it might include who is assessing cases, if are all cases medically assessed, who is responsible for ensuring the consistency of coding key data items.

• Report for regulatory: it might include if all boxes been filled in correctly on reporting form, if reporting deadlines have been met, are metrics in place and regularly reviewed to ensure reporting deadlines are met, conductions a medical review for consistency of source documents, database records, and final MedWatch/CIOMS reporting forms.

• Analyze to detect signals: ensure that signaling and risk assessment activities are conducted, process for escalation of safety issues (including committees, responsibilities, actions taken, communication to regulatory authorities, institutional review boards, and so on) and if crisis management plans are in place.

• Additional items: review previous audit/inspection reports to ensure that follow-up commitments from previous inspections have been met, standard operation procedures and Work Instructions, Personnel Files, Metrics, Quality Systems, Vendors, Validation ( computer systems and business continuity plans), Personnel training and Archive/ Document storage Pharmacovigilance.

Conclusion

Pharmacovigilance audits are an important process to  verify the appropriateness and effectiveness of the pharmacovigilance system. It is important to keep track of all audit findings, ideally in a CAPA (corrective action preventive action) system. All findings should be monitored by the group responsible for quality and progress in fixing. Companies should ensure that pharmacovigilance departments are audited on a regular basis; this is not only a regulatory requirement but is also useful in identifying any areas that could be a regulatory risk. Exposure to interviews by auditors is also good preparation for inspections, as it is the process for understanding and responding to audit findings. Companies should also consider conducting mock inspections at intervals to test their inspection readiness.

References

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2. Jolley S. G. Preparing for a Safety Inspection. Drug Information Journal. 2011; 705–711. http://cesruc.org/uploads/soft/130303/1-130303193044.pdf. Accessed on 08/03/16.

3. Guideline on good pharmacovigilance practices (GVP) - Module IV – Pharmacovigilance audits (Rev 1). European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/08/WC500191778.pdf. Accessed 07/22/2016.

4. Global Monitoring of Medicine Safety. http://www.pfizer.com/files/health/medicine_safety/2-8_Global_Monitoring_of_Medical_Safety.pdf. Accessed 08/03/2016.

5. Pharmacovigilance Risk Management Audit [slide presentation]. http://pt.slideshare.net/clarityeye/audit-in-pharmacovigilance. June 2010. Accessed on 08/03/2016.

6. Jadhav D. Pharmacovigilance Risk-Based Audit Approach- Detailed summary (but not limited to). Linked In website. https://www.linkedin.com/pulse/pharmacovigilance-risk-based-audit-approach-detailed-jadhav. October 2015. Accessed on 08/03/16.

7. Vergallo G. Recent Developments in EU and US Pharmacovigilance Legislation. J Pharmacovigilance. 2013. http://www.esciencecentral.org/journals/recent-developments-in-eu-and-us-pharmacovigilance-legislation-2329-6887.1000e105.php?aid=10921. Accessed 08/03/2016.

8. Authoral work: Ferreira F.  (2016). Describe the various steps involved in conducting a pharmacovigilance audit; Post Graduate Diploma in Pharmacovigilance & Medical Writing, James Lind Institute.

Assessed and Endorsed by the MedReport Medical Review Board