Pharmacovigilance and Drug Safety

A safety database is both a core element of any pharmacovigilance system and a legal pre-requisite for pharmaceutical companies wishing to place a medicine or medicinal product onto any EU/EEA market ^[1]. To enter those markets, each product must first be granted a Marketing Authorisation (MA) by the regulatory authorities ^[1]. The safety database must already be in place and described within the Detailed Description of Pharmacovigilance System (DDPS) accompanying the MA application ^[1]. This article explains key functions of safety databases, to create a better understanding of their overall purpose.

Why have a Safety Database?

Safety databases should allow pharmaceutical companies to rapidly gather relevant information about the medicine or medicinal products in question. There will be information which needs to be supplied to regulatory authorities via statutory electronic reporting and the database must support this. The database must therefore be validated and acceptable to those regulatory authorities. In essence, the database must be entirely suitable to the task, in compliance with Part III of the relevant legislation, Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use ^[1]. Details of the database are assessed during the application stage for each MA, as they will form part of the DDPS ^[2]. To paint perhaps a more rapidly accessible picture here, the safety database is the tool used to help staff collate and analyse key drug safety data. One example could be any Adverse or Suspected Adverse Event Reports for one particular product. The database will be electronic but not ‘autonomous’: it will not perform tasks without key interaction by highly skilled staff, no matter which process is underway.

Signal Detection

A compliant, suitable Safety Database is able to process data related to signal detection. Signal detection essentially uses data to detect any new patterns or findings. These can be identified by analysing data tables according to principles of statistical disproportion. Upon detection the subsequent course will be variable but can involve action by the regulatory authorities.

Periodic Safety Update Reports Production (PSURs)

Any medicine or medicinal product granted an (EU) MA is legally required to become the subject of post-marketing Periodic Safety Update Reporting. PSURs are always more than an in-house assessment. Presented directly to regulatory authorities, as you might expect whenever drug safety is concerned, they will of course be subjected to an extremely thorough inspection of their contents. A comprehensive database will be able to process the required data in a manner which facilitates the production of PSURs in the appropriate format as far as those authorities are concerned. For example, modern databases integrate regionally-tailored support on regulations.

Statutory Electronic Reporting

Certain safety databases are able to incorporate functionality to file expedited and aggregate reports to regional regulatory authorities. Again, this would always take place with core staff input, rather than becoming any type of scenario where a computer simply somehow ‘spits out’ a report. Electronic reporting will be required within strict time deadlines and differing formats by differing authorities throughout the world. In the EU for example, expedited reporting is obligatory within 15 days of a spontaneous adverse drug reaction case report.

These are just some of the core functions of a suitable safety database, which make it easy to see why it’s one of the pillars of good quality drug safety monitoring. It may be web-based, but whatever the platform it will be electronic. It is not however necessary for pharmaceutical companies to purchase and install a dedicated ‘in-house’ safety database. Instead it is common to find them using commercially available fully compliant products introduced by external pharmacovigilance services firms, who simply provide them with the necessary ongoing support.

References:

1. EMEA. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

1. EMEA. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Article 2.2.3 d [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

The Detailed Description of the Pharmacovigilance System (DDPS) is one of a number of essential documents for every company’s pharmacovigilance system. Under EU Directive 2001/83/EC, any company wishing to market a medicinal product within the EEA needs to complete a Marketing Authorisation Application (MAA). This article provides an overview of the DDPS components and the route pharmaceutical companies often take to compile one.

The legal framework for the DPPS is contained within Volume 9A of “The Rules Governing Medicinal Products in the European Union” [1]. As noted, Article 2.1.5 states the Applicant for a Marketing Authorisation (i.e. – the company who wish to eventually place their medicinal products on sale) must provide a DDPS to accompany their application [2]. There may also be a requirement at this stage to provide a Risk Management Plan, which your pharmacovigilance services provider can assist you to produce. The DDPS needs to contain an “overview of the pharmacovigilance system providing information on the key elements of that system” [3]. It must include details of the specific European Qualified Person (QPPV) who is going to hold overall responsibility for the ensuing pharmacovigilance services.

The DDPS must then provide a set number of elements according to Volume 9A. Article 2.2.3 b sets out the detail required for where and how the overall organisation of the companies activities are to be performed. This includes details for the company’s databases, Individual Case Reports (ICRs) Periodic Safety Updates (PSURs) and the company structure itself during the lifetime of the product for which the MMA is pursued. Charts must be prepared describing positioning and relationships for pharmacovigilance units, managerial relationships and how the QPPV is positioned within the overall structure. There should also be detail on the work those pharmacovigilance units are to undertake and how safety reports will be routed. Documentation of all processes is obviously essential, and Volume 9a accordingly moves on to the level of documentation required.

Article 2.2.3 c  stipulates far too many documents to list individually within this brief overview. The key to 2.2.3 c is the clear demonstration that there will be proper written procedures applicable to the particular product throughout its lifespan. The DDPS therefore needs to explicitly indicate which topics from the set list are to be included and confirm adequate quality controls are going to be in place for each process.

Article 2.2.3 d moves onto the pharmacovigilance databases to be used. Including functionality, location, access, and compliance with internationally agreed standards according to those listed in Part III of Volume 9A. Then details of the contractual relationships between any other organisations or individuals who will be involved are to be described in quite some detail (2.2.3 e). It is also necessary to provide details of the training of all relevant staff (2.2.3 f). When describing the Quality Management System, as well as describing the Marketing Authorisation applicant, it is important to provide details of the relationships and organisational structure in regard to any sub-contractors (2.2.3 g). In a further separate section to 2.2.3 c, there is a requirement that documentation supporting the DPPS may need to be provided not only before authorisation but also afterwards. This could be for an “assessment or inspection” [4].

One of the difficulties faced by pharmaceutical companies is that while the content required for the DDPS is made quite clear the detail required is not explicitly provided within the wording of Volume 9A. Many companies work with outsourced pharmacovigilance services in order to ensure their DDPS draft meets the standards required. This can be more cost effective since some offer specialised templates, allowing for more efficient liaison to document and map the necessary relationships and processes.

References:
1. European Commission. EudraLex – Volume 9 Pharmacovigilance guidelines.2011. [ONLINE] Available at: http://ec.europa.eu/health/documents/eudralex/vol-9/index_en.htm. [Accessed 22 January 2011].

2. EMA. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

3. EMA. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011]; Article 2.2.1.

4. EMA. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011]; Article 2.2.1.