Pharmacovigilance

Pharmacovigilance

The objective of developing and licensing new medicines is to improve the treatment and control of diseases. However, any drug exerting a pharmacological effect might also induce a negative or harmful effect on the body, or interact with other drugs or substances the recipient may be taking. It is critically important to monitor the side effects of all medicines from the first studies in humans and throughout the product’s life cycle. The science of collecting, monitoring, researching, assessing and evaluating information about the adverse effects of medicines is known as pharmacovigilance.

Legislation exists worldwide for the collection of safety information from the use of medicines in humans. In the clinical development phases, adverse event reporting in Europe is legislated by Directive 2001/20/EC and in the USA by 21 CFR 312.32. Clinical trial data is used to generate a benefit-risk profile of the medicine to enable the regulatory authorities to make a decision on whether it would be safe to license it. The safety information collected during the clinical development phase is the basis of the benefit-risk analysis. However, clinical trials are conducted under controlled conditions in specially selected populations. Once the medicine is licensed and available for general prescribing, continual monitoring of safety is essential and is legislated in Europe by Directive Council Regulation 2309/93 (Title II, Chapter 3), Commission Regulation EC 540/95, Directive 2001/83/EC, as amended by Council Directive 2004/37/EC and Commission Directive 2003/63/EC. Detailed guidance on the implementation of a pharmacovigilance system is described in Volume 9A Eudralex, EU Pharmacovigilance Rules for Human Medicinal Products, Notice to Marketing Authorisation Holders. In the USA, safety monitoring of licensed medicines is legislated by 21 CFR 314.80.

Information on the safety of marketed medicines is obtained from reports of adverse events from healthcare practitioners such as physicians, nurses, dentists and pharmacists. Patients themselves may also report side effects directly to the manufacturer of the medicine. These reports are known as individual case safety reports (ICSRs) and if they are serious and unexpected i.e. the adverse event has not been reported before, and therefore has not been included in the known safety profile (product data sheet or Summary of Product Characteristics), then it has to be reported by the manufacturer to the regulatory authorities in the countries where the medicine is marketed.

On a regular basis, manufacturers have to prepare reports containing all of the safety information collected on a specific medicine within a specified period of time (Periodic Safety Update Reports). These reports are produced on a frequent basis (every six months) when a product is first licensed. The reports are submitted to the regulatory authorities in the countries where the medicine is licensed (or where they are required), so that the benefit-risk can be continually assessed. If the benefit-risk ratio changes, the regulatory authorities might consider the risk too high and thus decide that the medicine must be withdrawn from the market.

The pharmacovigilance system in place within manufacturing companies is subject to regulatory inspection, to verify that processes are in place to ensure that safety issues can be identified and reported promptly, in order to safeguard the public. In addition, internal systems audits are conducted at intervals by the manufacturer’s own auditors, or independent contractors.

ADAMAS has the capability to conduct independent systems audits of manufacturers’, or delegated service providers’, pharmacovigilance activities. The objective of the independent audit is to assess compliance with worldwide regulatory requirements, and to provide advice on process improvements. ADAMAS also conducts ‘mock pharmacovigilance inspections’ to test the company’s inspection readiness in advance of a real regulatory authority inspection.

During a pharmacovigilance audit, all or some of the following will be assessed:

• The quality management system in place for the collection, processing (i.e. data entry into the adverse event database), coding, classification, medical review and regulatory reporting of ICSRs
• Training and qualifications of personnel employed to perform pharmacovigilance activities
• Confirming the role and responsibilities of the European Qualified Person for Pharmacovigilance
• Determining whether the database used for the collection and subsequent reporting of adverse events to regulatory authorities and other concerned parties is in compliance with international regulatory requirements i.e. a fully validated system
• Evaluating the systems in place for ongoing safety surveillance, including signal detection and risk management and/or risk mitigation strategies
• Assessing procedures for pharmacovigilance activities and worldwide literature review for product related adverse events
• Processes for the generation and review of periodic aggregate reports
• Procedures for the collection, assessment and evaluation of adverse events related to product quality complaints
• Assessment of procedures in call centres/medical information for identification and reporting of queries related to adverse events
• Ensuring systems are in place for urgent safety restrictions and product crises
• Ensuring contractual arrangements and oversight processes are in place for business partners and third party service providers
• Disaster recovery and business continuity plans

ADAMAS has conducted pharmacovigilance systems audits in the clinical development and post-marketing phases of the product life-cycle on a worldwide basis. In addition, ADAMAS has provided support and advice to many organisations, from virtual biotechnology companies to the top 10 global pharmaceutical companies, regarding their systems and readiness for regulatory inspections.