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European medicines legislation and pharmacovigilance

Published on 20/10/10 at 12:04pm

During the past decade, changes in European medicines legislation and guidelines have increased the scope and regulatory scrutiny of pharmacovigilance activities, requiring ever greater interaction between pharmacovigilance and regulatory affairs.

One of the outcomes of the EU Commission’s review of the EU medicines regulatory framework in 2001 was to integrate pharma-covigilance requirements within the marketing authorisation (MA) approval process itself, rather than considering them to be post-authorisation commitments. To this end Directive 2001/83/EC was amended by Directive 2004/27/EC to require all EU marketing authorisation applications (MAAs) to contain a detailed description of the applicant’s pharmacovigilance system (DDPS) in Module 1.8.1 of the MAA in electronic common technical document (eCTD) format. Although there is no set format for a DDPS Volume 9A of The Rules Governing Medicinal Products in the European Union, Guidelines on Pharmacovigilance for Medicinal Products for Human Use describes the elements that a DDPS should include, in Part I, Section 2.2.3.

Variations regulation in pharma

The implementation of the Variations Regulation (EC/1234/2008) in January 2010 further strengthened the link between MAs and the pharmacovigilance system used to support their approval. MA holders (MAHs) are now required to submit variations (mostly in the form of type IA immediate notifications) if the DDPS they have submitted as part of an MAA is updated - for example a change in their Qualified Person for Pharmacovigilance (QPPV) or safety database). This requires pharma-covigilance and regulatory affairs departments to work together to maintain the DDPS and formally notify the regulatory authorities of changes to it.

Core labelling

One of the longest established links between pharmacovigilance and regulatory affairs concerns the maintenance and updating of the safety information contained in company core datasheets (CCDS), the company core safety information (CCSI). Pharmacovigilance is responsible for the completeness and accuracy of the CCSI, with regulatory affairs being responsible for the maintenance of the CCDS as a whole. The CCSI consists of all relevant safety information (e.g. contraindications, adverse drug reactions, precautions and warnings, etc.) that the MAH requires to be included in the product information for a medicinal product in all countries where it is marketed.          

Therefore if the pharma-covigilance department decide that a change to the CCSI is required (e.g. the addition of a new undesirable effect or contraindication) then the regulatory affairs department will be required to submit variations to the regulatory authorities to ensure that this change is reflected in the locally approved product information (e.g. SmPC). The supporting data to justify such variations should be provided by the pharmacovigilance department.

Periodic reports drug safety reports

European Competent Authorities (CAs) require the submission of periodic safety reports for both the development and post-marketing phase of a medicinal product’s life-cycle. The post-marketing reports, periodic safety update reports (PSURs), are based on the ICH E2C format. Volume 9A, Part I, Section 6 provides a detailed description of what these reports should contain, when they should be submitted and to whom. It is clear from these requirements that the preparation of PSURs requires a multi-disciplinary approach including significant input from regulatory affairs. The same is true of Annual Safety Reports (ASRs), soon to be replaced by Development Safety Update Reports (DSURs) based on the ICH E2F guideline, which must be submitted to CAs and Ethics Committees for investigational medicinal products.

Risk Management Plans (RMPs)

As well as DDPSs the imple-mentation of Directive 2004/27/EC in 2005 also introduced the requirement for applicants to include a description of the risk management system that would be used to support the product ‘where appropriate’ in their MAAs. This is done by including an EU-RMP in Module1.8.2 of the application in eCTD format. The template for EU-RMPs can be found on the EudraVigilance website. ‘Where appropriate’ means that an EU-RMP will be required for all MAAs concerning new chemical entities and biologicals (including biosimilars). They may also be required for existing authorised products if the MAH submits a major variation to add a new indication, patient population (e.g. paediatric indication) or formulation, or if that product has, or develops, a significant safety issue. If the applicant considers that an EU-RMP is not required (e.g. the product is a well established generic) a justification as to why this is the case should be provided in Module 1.8.2 of the MAA in place of the EU-RMP.

Benefit-Risk Management Plans (BRMPs)

In the case of advanced therapy medicinal products (ATMPs), such as gene therapy, cell therapy and tissue engineering, there are already additional requirements to include details of an efficacy follow-up system and efficacy follow-up plan in the RMPs for these products, in effect turning these into benefit-risk management plans. This, together with the proposed changes to EU medicines legislation that are currently being debated by the European Parliament, gives a strong indication that EU-RMPs for conventional medicinal products will soon evolve into BRMPs.

Pharmacovigilance now critical path for all new medicinal products

As a result of the above - and future proposed - changes in legislation and guidelines, pharmacovigilance has been firmly placed on the critical path for the approval of all new medicinal products. MA applicants are now required to design and describe their pharmacovigilance and risk management systems prior to MAA submission, and to maintain and update them as and when required. The adequacy of these systems will be assessed and approved by the regulatory authorities, not only as part of their review of the original MAA, but throughout the product’s life-cycle. Continuous and close co-operation between regulatory affairs and pharmacovigilance is therefore required to meet these formal regulatory requirements.

Keith Wibley is director, pharmacovigilance at NDA. For more information visit:

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