Pharmacovigilance and Drug Safety

What Is A Pharmacovigilance Safety Database?

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

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.

ICSRs: Definition, Features and Pharmacovigilance Services’ Roles (Part Two)

Individual Case Safety Reports (ICSRs) are vital drug safety documents required by EU pharmacovigilance law for each and every medicine or medicinal product a Marketing Authorisation would apply to.  In the first part of our overview of we discussed their definition and key formatting required by regulators. There was also a brief mention of the roles external pharmacovigilance services often undertake for small to medium pharmaceutical companies in relation to ICSRs. In the second and final part, we will examine the type of key content the regulators require, and again touch upon services often used by small to medium sized Marketing Authorisation Holders.

In particular, Volume 9a of The Rules Governing Medicinal Products in the European Union [1] makes reference to compliance with ICH E2A by ensuring the ICSR contains a “case narrative”, meaning a comprehensive and complete medical description of the case. This should include [2]:

• Patient characteristics
• Diagnosis
• Therapy Details
• Medical History
• Narrative of Clinical events
• Known adverse reactions alongside the relevant outcome
• Results of laboratory tests along with the normal ranges
• “any other information that refutes or confirms an adverse reaction” [2]

As well as inclusion of component items, the report must follow the formatting guidelines as a matter of obligation rather than the regulators preference. Volume 9a is quite clear that this may require some of the information stipulated to be repeated [2]. The format must also apply when new information is added for follow-up reporting, which should be clearly delineated from the original case narrative.  Except to describe results of standard tests, abbreviations are to be avoided [2].

Pharmaceutical companies clearly have complex legal obligations in this area of drug safety monitoring. Many choose to outsource the compilation of ICSRs to external pharmacovigilance services providers for this very reason. Whilst there is a provision for times when information is not available in some circumstances, incorrectly submitted ICSRs are to be avoided at all costs. Many external providers offer a ‘complete’ service, processing the necessary data into the final format for compliant electronic submission. This can be of particular value to small to medium sized companies where it may sometimes be the case that not all available staff have current training and experience in the exacting requirements for both ICSR format and content.

References:

1. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Part III, p.159-171 [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].
2. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Part III, Article 5.1, p. 164. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

Individual Case Study Reports: Definition, Features and Pharmacovigilance Services’ Roles (Part One)

Individual Case Safety reports (abbreviated to ICSRs) are a core component of pharmacovigilance services and drug safety. Volume 9a of the The Rules Governing Medicinal Products in the European Union provides instructions on how to comply with the regulations to correctly compile each ICSR ^[1]. In the first of our two part examination of ICSRs here, we will provide the regulatory definition of an ICSR and begin to introduce their formatting. Brief reference is also provided to the practice of outsourcing either elements or the entirety of the compilation process.

Annex 1.1 of Volume 9a of The Rules Governing Medicinal Products in the European Union provides a binding definition of an ICSR:

“A document providing the most complete information related to an individual case at a certain point in time.” ^[2].

Each is subject to three basic and compulsory rules ^[3]:

1. They may be required for Periodic Safety Update Reporting or Expedited Reporting depending on the nature of the case.
2. ICSRs must be submitted electronically
3. Supporting documentation must be described within the ICSR

The necessary format begins to be defined by Volume 9a, Part III, Article 5.1, according to the guidelines of ICH E2A, ICH E2BM, ICH E2D, ICH-M1, ICH-M2 ^[3]. These documents can be found at http://www.ich.org/products/guidelines.html. The format must also comply with the’ Applicable Electronic Reporting Guidelines’ contained within Part III, Article 2 of Volume 9a ^[4]. This is a list of obligations for all pharmacovigilance services staff to follow the latest available version of:

• applicable ICH guidelines ^[4];

• instruction on terms of pharmaceutical dosage forms:

“The Standard Terms on Pharmaceutical Dosage Forms as published by the Council of Europe as ‘Standard Terms on Pharmaceutical Dosage Forms, Routes of Administration and Containers’ in the latest version ^[4];

• EMEA/115735/2004:

“Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety Reports (ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilance during the Pre- and Post-authorisation Phase in the European Economic Area (EEA)” ^[4];

• EMEA/H/20665/04:

The EMEA Guidance ‘Technical Documentation – EudraVigilance Human Version 7.0 Processing of Safety Messages and ICSR(s) ^[4]

• ENTRC4:

‘Detailed Guidance on the European database of Suspected Unexpected Serious Adverse Reactions (EudraVigilance – Clinical Trial Module) ^[4]

Before beginning to consider the content required within each ICSR, it becomes clear that the obligation to present the report in a standardised format presents a challenge to staff within pharmacovigilance units. The regulations are both complex and precise, and the correct formatting is an obligation rather than the regulators’ preference Yet within small to medium sized companies, staff may not all have been explicitly trained to compliantly compile an ICSR. Many outsource the data processing and document presentation to external pharmacovigilance services providers. Some providers are able to offer more support for timely submission in the correct format by providing input into decisions on whether ICSRs should be subject to expedited reporting. In the second part of our overview of ICSRs, we will move on to examine key regulatory requirements for content.

References:

1. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Part III, p.159-171 [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

2. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Annex 1.2, p. 197-198. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

3. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Part III, Article 5.1, p. 164. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].
4. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Part III, Article 2, p. 161-163. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

EU Qualified Person Real Life Batches Of Medicine – part 3

The first part of our series about the EU Qualified Person (EU QPV) explained their necessary training and experience. The second part provided an overview of their general responsibilities within pharmacovigilance services including why their appointment becomes necessary by law in the day to day operations of any pharmaceutical company. In our third part, we will examine their duties regarding the quality control of every single individual batch of medicine to reach the market, according to the relevant European law 2001/83/EU.

In order to market any medicinal product within the EEA, a pharmaceutical company must be in possession of a Marketing Authorisation granted by the relevant authorities within the EU country concerned. European Directive 2001/83/EU stipulates a QPPV must be appointed to oversee the pharmacovigilance services of the company concerned. This could mean working within an in-house service, or as is common within medium sized pharmaceutical companies, forming part of a team provided by an outsourced professional pharmacovigilance services company.

At the point at which the medicinal products are to be placed upon the market, the QPPV has a particular duty which no other professional could discharge. They must create a record testifying legally compliant quality control has been undertaken. This information should be entered “in a register or equivalent document provided for that person” for each and every production batch. This register is therefore a key document to demonstrate adequate controls are in place and it must be constantly updated. It can be said it is intended as a method to create transparency regarding the quality control applied to every single batch – after all, these are the end products which the public are going to be exposed to. The register must therefore be made available for inspection by officials from the relevant authority within the EU country concerned without exception ^[1].

The register must be maintained for the “period” stipulated by the EU country concerned, but the Directive also makes it clear that the absolute minimum period permissible is going to be five years. The requirement for the register to always be kept up to date means the QPPV must consistently provide their services to the pharmaceutical company year in year out. In this way, the law provides a verifiable framework by which quality control is documented for every batch of every medicinal product sold ^[1].

The QPPV is therefore a central agent who assumes the lead role in pharmacovigilance services, which ultimately aim to ensure that every single medicine legally available throughout the EEA has the best possible safety profile for public protection. Their role is indispensable and the law is clear that there is no possibility of appointing any other professional to provide discharge their duties ^[2]. This is one fundamental reason why companies often work with an external provider, who are able to supply a QPPV. QPPVs are not commonly found within the staff teams of certainly small to medium sized companies, and an external appointment may still be required by even the largest of pharmaceutical companies.

References:

1. Directive 2001/83/EC of The European Parliament and of the Council of 6 November 2001 on The Community Code Relating to Medicinal Products for Human Use. Official Journal L – 311, 28/11/2004, P. 67 – 128; Article 51, Clause 3.

2. Directive 2001/83/EC of The European Parliament and of the Council of 6 November 2001 on The Community Code Relating to Medicinal Products for Human Use. Official Journal L – 311, 28/11/2004, P. 67 – 128; Article 49, Clause 1.

The Role of The EU Qualified Person for Pharmacovigilance – part 2

The first part in our series discussed the minimum requirements for the professional training and experience for an EU Qualified Person (QPPV) for pharmacovigilance services throughout the EEA. The second part of our series moves onto the responsibilities held by each QPPV for manufacturing and initial quality control verification, which will begin to explain why their appointment is obligatory within any pharmaceutical company’s pharmacovigilance services. In order to do this, we are going to examine the exact specifications contained within Directive 2001/83/EU, the law providing the primary definition of the role of all QPPVs.

Why are QPPVs so important?

Any pharmaceutical company wishing to market any medical product (eg- a pharmaceutical medicine) within the EEA must become a Marketing Authorisation Holder (MAH) for each and every individual product placed onto the market. The granting of a Marketing Authorisation (MA) can be seen as an exercise in public protection in that it requires that a comprehensive and appropriate pharmacovigilance system is established and maintained for each individual product before, during and after it is ever placed on the EEA market. And one key element of the laws governing the Marketing Authorisation is the stipulation without exception that a QPPV must be appointed to fulfil certain crucial roles within that pharmacovigilance system.

Manufacturing and initial quality control

PPVs are highly qualified, highly skilled professionals who are charged with a variety of roles defined within Article 51 of Directive 2001/83EC. Each country within the EEA must be certain that a QPPV is fulfilling a number of roles for each MAH. They must ensure that all medicinal products which have been manufactured within the country in question have been produced and checked in full compliance with the laws of that country. They must furthermore ensure that the manufacturing and checking process also meets the requirements of the MA legislation.

Should the medicinal products in question be sourced from another country, the QPPV must verify that each production batch has been subject to testing conducted within the (recipient) country for:

• A comprehensive quantitative analysis of the product as a whole
• A comprehensive quantitative analysis of the product’s active substances as an absolute minimum
• All other quality testing and/or verification procedures required by the MA

Should the company wish to market the product in another EEA country, providing it has been subjected to the above three quality control criteria, it does not need to be re-subjected to those criteria in the ‘new’ country. As you might expect, this allowance is only permissible providing the correct reports are available, signed off by the QPPV in the ‘original’ EEA country concerned.

If the medicines or medicinal products have been sourced from a third EEA country, it is necessary to verify that the quality controls upheld by the manufacturing process (and by necessity therefore the elements of pharmacovigilance services) were appropriate. The standards should be at least equivalent to the QPPVs work of verifying that the product has been subjected to quantitative analysis; its active components have been subjected to quantitative analyses; and that all other quality control testing has taken place in compliance with the requirements of the MA.

The law is very practical and does recognise those cases where the QPPV would be duplicating quality control work already performed and verified within suitable settings in other countries. Should the quality controls we have already discussed have been carried out correctly and to equivalent standards within the country of origin, under a formal arrangement with EU authorities, documentation alone becomes the issue for those products. The law does not require the QPPV to perform a second round of quality control here, since it has simply already been done.

In summary, the duties above represent only a ‘layman’s guide’ to the exacting stipulations of Directive 2001/83/EU – quality professional pharmacovigilance advice is individually tailored to each situation as it arises. Having said this, it does help to understand the initial stipulations of 2001/83/EU, since it becomes clear that there is no other professional within any pharmaceutical company who is able by law to fulfil their duties. The next part of our series about the work of the QPPV within pharmacovigilance services moves onto examining their role in ensuring quality control for each real life batch of medicine sold within the EEA as the product lifespan unfolds.

The Role of The EU Qualified Person for Pharmacovigilance – part 1

The role played by an EU Qualified Person for Pharmacovigilance (QPPV) within any pharmaceutical company intending to market its products within the EU or any independent pharmacovigilance service is simply pivotal. As the law stands at the moment, without their co-ordination of all pharmacovigilance activities, no company could become a legal Marketing Authorisation Holder (MAH) for products within the European Economic Area (EEA). The first part in our series examining the professional development, role and necessity of the QPPV will examine the route laid down under European pharmacovigilance law which any person wishing to become a QPPV must follow.

The requirements for the qualifications and professional experience an EU QP must possess are laid out explicitly within the text of Directive 2001/83/EU. Article 49 stipulates the minimum acceptable academic requirements as four years at university level, culminating in a diploma, certificates or “other evidence of formal qualifications” (Directive 2001/83/EU, Article 49, subsection 2). Study must be within the sphere of pharmacy, medicine, vetinary medicine, chemistry, pharmaceutical chemistry and technology or biology.

There are a set of permissible variations. The first is that the university course may be three and a half years instead of four, if it is followed by appropriate practical and theoretical training lasting at least one year. It must include a minimum component of six months of work within a pharmacy open to the public. And the applicant should then have this experience reflected in a university level examination.

The second is regards occasions when there are two courses at university level or at a level regarded as equivalent to university within a particular EU country. If one course lasts four years and the other lasts three years, the three year course is acceptable for the purposes of the journey to becoming a QP providing certain conditions are met. It must culminate in a diploma, certificate or “other evidence of formal qualifications” and be considered equivalent to the four year course in terms of qualification (and this implies content, knowledge, achievement, etc) within that EU country.

Whichever route is taken to fulfil the minimum duration requirements, the course of study must include theoretical and practical study of a set number of component studies as a bare minimum. These are all highly relevant to a future role within pharmacovigilance services: experimental physics; general and inorganic chemistry; analytical chemistry; pharmaceutical chemistry, (incorporating analysis of medicinal products), general and applied biochemistry (medical), physiology, microbiology, pharmacology, pharmaceutical technology, toxicology and pharmacognosy. There is a permissible variation should the person’s qualifications fall outside this remit, it the responsibility of the EU country in question to ensure that the knowledge requirements are somehow demonstrably fulfilled in another manner.

It is indeed stipulated that the weighting or balance of these study components should prove a suitable match for the responsibilities of a EU QP.

Following this study, to continue towards becoming an EU QP to work within pharmacovigilance services there is a minimum qualifying period during the which the applicant must have worked in a professional capacity in ‘undertakings’ (organisations) within which they undertake qualitative analysis of medicines, quantitative analysis of active substances and testing and verification for medicines quality control. Two variations are possible here. When the previous relevant studies lasted for a minimum of 5 years, the practical experience component can be one year long instead of two. If the initial study lasted six years, the practical component can then last a minimum of 6 months.

The route to becoming an EU QPPV is necessarily a highly regulated and strict sequence of steps, none of which can be omitted, since all will be relevant to future work to ensure the highest standards of public safety are maintained for medicinal products. The role itself simply demands it, as QPPVs are responsible for over-seeing the core elements of pharmacovigilance services for every pharmaceutical company. Having discussed these minimum requirements for an EU QP, the second part in our series will move onto discuss their real time responsibilities within pharmacovigilance for any Marketing Authorisation Holder (MAH) or any company wishing to become one within the EEA.

EU Regulation for Pharmaceutical Product Registration and Pharmacovigilance Services Input

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.

Pharmacovigilance and Drug Safety

The role of this site is to provide information on how drugs are developed and the role of pharmacovigilance in ensuring drug safety throughout the lifecycle of pharmaceutical products. We cover several different topics and, should you wish to investigate further, maintain links to some of the top experts and specialists in the field of pharmacovigilance. Our expert panel includes individuals with both industry and regulatory experience. We have access to people who have helped to define and shape the science of drug safety into what it is  today and are working on what pharmacovigilance will become in the future.

Many people believe the pharmaceutical industry to be a shady cartel developing poisonous concoctions with no control from governments or the scientific community. The Pharmacovigilance Information Service is here to share information about drug safety and to explain some of the steps that pharmaceutical companies are required to take in order to get their products to market and to keep them there. It also explains the safety roles that the regulatory bodies expect the pharmaceutical companies to fulfill.

DEVELOPMENT OF MEDICINES AND PHARMACOVIGILANCE IN THE EUROPEAN UNION: a guide for the perplexed

This review is intended as a brief introduction to understanding the complex environment in which medicines are developed and their safety monitored. Much of it is applicable generally, but the focus is on the situation in the UK and the European Union.

Risk Management Planning

A major change in the approach to drug safety surveillance after marketing has been introduced in the last 5 years in the EU in the form of risk management planning. This has been incorporated into EU law and is extensively covered by guidelines in Volume 9A. There has been a similar initiative by the US FDA.

For the EU, it is mandatory for companies to submit a Risk Management Plan in accordance with a detailed template and guideline at the time of application for a Marketing Authorisation for most products. Plans also have to be submitted if new safety concerns are identified for a marketed product and all plans must be updated as circumstances change.

Thus companies are required to specify at the time of first marketing areas of safety about which they are currently uncertain and how they will resolve this uncertainty. They must also indicate what measures they will take to reduce known risks and how they will test whether these measures work.

The EU Risk Management Plan (EU-RMP) has 3 main elements. First, a detailed consideration of what is known about the safety of the product, based on pre-clinical and clinical studies. This “safety specification” considers identified risks and potential risks – the latter being areas of uncertainty regarding safety. It also specifies what the limitations of the clinical research program are and what important information about safety is currently missing. In the second component, the “pharmacovigilance plan”, the company must indicate how it proposes to resolve the uncertainties – what extra studies it will carry out after marketing to fill the important gaps in knowledge. The third component is the “risk minimization plan”. This states how the company proposes to reduce the severity or frequency of known adverse reactions. This may involve special communication programs, or educational exercises, or perhaps registration programs for patients, doctors or pharmacists, or other measures. The pharmacovigilance plan and risk minimization plan must include timelines for setting up the programs and milestones for their evaluation.