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.

EU Regulation For Pharmaceutical Product Registration And Pharmacovigilance Services Input

Your pharmacovigilance system could consist of an in-house team or an external expert company providing a pharmacovigilance service – either way, one thing is for sure, you will waste time and money without a very basic understanding of EU rules on product pharmaceutical registration and pharmacovigilance. This article succinctly explains the key concepts of marketing authorisation in the EU via the Centralised Procedure, Mutual Recognition Procedure and Decentralised Procedure. This guide to basic concepts allows you to gain entry level understanding of the three main regulatory pathways before moving on to work with consultants from your pharmacovigilance services.

The Three Vital Routes to Pharmaceutical Product Registration

Any pharmaceutical product which needs a marketing authorisation in order to be sold in one or more EU countries is going to need to follow one of the legal routes in order to be registered:

“Centralised Procedure” – Regulation (EC) No 726/2004

“Mutual Recognition Procedure”

“Decentralised Procedure” – Directive 2001/83/EC.

As well as these three routes, there are some national authorisations which could allow a product to be marketed in the particular member state or states granting them. This can be an avenue to pursue in order to apply for authorisation under the Mutual Recognition Procedure. Wherever the single national marketing authorisation is will become the country which assumes responsibility for monitoring and safety assessment for that particular product.

Key Concepts of The Centralised Procedure

Administration of this legal route to marketing authorisation is the responsibility of the EMEA. A single application is made with the aim of gaining marketing authorisation throughout all the countries of the EU, Iceland, Norway and Liechtenstein. Once products meet the market, the European Commission is then the responsible agency. This Centralised Procedure should be used for new products and those containing novel substances which are designed to treat serious illness. It is also the route for all biotechnology medicines,

One EU countries regulatory authority becomes the official  Rapporteur, and will be responsible for the initial assessments for the Marketing Authority application. A second agency is appointed as the official Co-Raportuer and between the two agencies, the responsibility for safety assessment and monitoring is shared once the product is introduced to the market.

The regulations are stringent and as such, it is essential that the applicants company uses an experienced in house or externally hired pharmacovigilance services company throughout the application process- and of course, after the product has reached the market

Key Concepts of  Mutual Recognition Procedure

When a product has had a marketing authorisation issued by a single EU country but is required to be marketed in other EU countered, the Mutual Recognition Procedure may be the answer. Should an application be successful, in essence, the marketing authorisation is copied by the other countries involved. The nation which issued the marketing authorisation on a national level is known as the ‘Reference Member State’. The other countries the product is applying to be sold in are  known as the ‘Concerned Member States’. After an application has been entered, there will be a 90 day period during which the ‘Concerned Member States’. Enter an assessment phase. If the application is successful, the original marketing authorisation issued by the ‘Reference Member State’ is adopted into identical authorisations by the ‘Concerned Member States’.

If the application is not successful due to objections raised by any of the ‘Concerned Member States’, the matter is subject to referral to the EMEA. There will be a debating process to try to resolve any problems, and should this fail the next step would be binding arbitration. Whilst there are mechanisms in place, there is no substitute for the services of competent pharmacovigilance solutions companies.

Key Concepts of The Decentralised Procedure

This concerns when there is a product for which there has not so far been any marketing authorisation granted in any country in the EU. A dossier will be copied and circulated to all the EU countries in which as marketing authorisation is sought. The company who submit the application are able to decide which country should be the ‘Reference Member State’ under this procedure. The company must prepare a preliminary report within 120 days and circulate it to every ‘Concerned Member State’. If the application is not accepted, it does continue, into a facilitation period. If this remedy is still not successful to resolve the problems, binding arbitration will be imposed.

The Decentralised Procedure again obviously requires expert input at every step of the way from the company’s in house or external pharmacovigilance team.

This summary of the nature of the three legal routes to product registration in the EU should help when deciphering some of the industry jargon surrounding gaining EU product registration. This can assist you in dealing with either an in-house pharmacovigilance department or any external pharmacovigilance services provider.