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.

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].

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 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 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.

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.

Pharmacovigilance is the pivotal process for ensuring a company’s products remain on the market. In reality the business faces the challenges of increasingly complex and constantly changing worldwide regulations, requiring higher levels of inter-disciplinary expertise, together with demands to improve public safety. The safety arena continues to be in the media spotlight so it is important that the patient is the primary focus and Pharmacovigilance is handled effectively with the correct tools to detect and respond to any safety concerns with a product.

Many Pharma companies have increased the number of qualified staff to comply with these strict reporting requirements and increased workload but are now facing economic pressures due to shrinking budgets. Therefore it is important to scrutinize costs, as more is expected with less available resource.

Outsourcing occurs when an organisation employs a contract service provider to perform services that would normally be performed “in-house”. Outsourcing is undertaken by companies to reduce fixed overhead costs, avoid high upfront investments, secure additional capacity, increase resource flexibility or augment the performance of an activity that is not considered a core area of the business.

Off-shoring occurs when the work is outsourced to lower cost countries such as India or China rather than Europe or the US to reduce the labour costs. However there can be disadvantages as quality will suffer where staff have insufficient knowledge of the worldwide regulations and limited Pharmacovigilance experience or training.

It is possible for a company to outsource the entire Pharmacovigilance function or specific aspects only. However it is important to remember that although the Marketing Authorisation Holder (or manufacturer in the US) can delegate some or all Pharmacovigilance activities it must retain overall responsibility for the safety of the products.

What are the benefits of out-sourcing on an interim basis or for specific projects?

• To fill any gaps in a Pharmacovigilance team such as in times of sickness, maternity leave, during periods of recruitment or training of staff.
• To fill short-term skill gaps to help in times of workload peaks
• Use of a virtual team works as and when projects demand and allows for particular individuals to be brought in when specific expertise is required
• Use of interim staff can bring in strategic direction to a company without huge investment
• Benefit in expertise in a specific area by use of personnel who are effective from day one
• Ability to tap into highly specialist areas as and when needed and quickly
• Flexibility – you only pay for what you use so do not incur costs of a full-time salaried position

What are the benefits of outsourcing the Pharmacovigilance System?

• The technical requirements of operating and supporting a regulatory compliant Pharmacovigilance system can be expensive and very sophisticated and may exceed the skills of the company IT team
• The associated software and other Pharmacovigilance system costs require scalability and cost structures that Pharmacovgilance Service Providers can accommodate
• Pharmacovigilance systems upgrade or replacing an existing system can be costly and time consuming. The migration of data from different systems can be expensive and difficult
• Use of an off-site Pharmacovigilance system may be less expensive than in-house installation
• Does not require the large first year cost normally accrued with an in-house system
• Outsourcing can provide an immediate, multi-location Pharmacovigilance network with minimal IT investment

What specific Pharmacovigilance tasks can be out-sourced?

• Pharmacovigilance for a specific trial or series of studies including clinical trial site set-up
• EU Qualified Person Responsible for Pharmacovigilance (QPPV) and Deputy QPPV
• Post-Marketing Pharmacovigilance; the entire process from initial receipt of an AE through to expedited reporting
• Generation of Clinical Trial Annual Safety Reports and Periodic Safety Reports
• Adverse Event Management including holding and maintaining the Safety Database and Case Entry of AEs, coding, narrative writing, QC, expedited reporting of AEs.
• Development of Safety Specifications and Risk Management Plans
• Signal detection and evaluation
• Safety issue investigation and generation of ad-hoc reports for submission to Regulatory Authorities
• Literature Screening
• Process design and SOP development
• Pharmacovigilance audits, mock inspections and due diligence
• Pharmacovigilance training
• Generation of Safety Agreements for licensing or distribution partners or third parties involved with pharmacovigilance activities

What are the benefits and risks of outsourcing specific tasks?

Out-sourcing clinical trials can be useful when a company lacks experience in a new therapeutic area or a specific type of study. It can be especially useful for companies who may have limited experience in clinical trials as the out-sourcing company can provide expertise in study protocol, study start-up and selection of investigators. The company must determine if it will also outsource the process of handling of AEs throughout the study, entry into a safety database and expedited reporting to investigators and Regulatory Authorities. It is important to choose a partner with sufficient experience and capacity if the trials are particularly large and located in multiple sites across the globe.

Out-sourcing the QPPV can be of obvious benefit to smaller organisations. The QPPV needs to be available 24/7 and is a highly skilled individual with expertise in Pharmacovigilance. There is risk involved in out-sourcing this function if the QPPV lacks sufficient experience or company infrastructure to take on the role or has conflicting interests which may impact on their availability.

Outsourcing the Pharmacovigilance database results in reduced cost for database infrastructure and reduced license costs for software programmes.

Outsourcing the entire Post-Marketing function can be especially beneficial to new and emerging companies who may historically only have experience with products in development and have limited experience of handling Pharmacovigilance when a product comes to market. This will allow the company to buy-in expertise while developing a Pharmacovigilance department of their own and will reduce costs in terms of investment in a safety database and validation of systems and processes. Similarly this can be useful for companies with relatively small volumes of AEs reported annually as the IT costs of systems and updating these systems and re-validation when regulations change are minimised. While small and medium companies may out-source pharmacovigilance as it is not economical to have an in-house department, larger companies may out-source for efficiency. Risks involved are ensuring that the outsourcing partner has a robust, validated system capable of meeting complex requirements worldwide and sufficient processes and procedures and appropriately qualified staff in place with sufficient knowledge of the Pharmacovigilance requirements to handle the entire process.

Outsourcing allows flexibility as a company will be able to manage peaks and troughs that can occur with workload. For example with products that are taken seasonally such as products for colds and flu or hayfever – adverse events tend to peak at certain times of the year and are directly related to sales; specific adverse event reporting increases following media attention; adverse event reporting tends to be high following the launch of a new product and can increase following identification of a potential safety issue. This variation in workload requires companies to try to plan staff to meet peak demands resulting in some resources being under utilised during slack periods. For a company with older products with established safety profiles no new knowledge is likely to be gained from generating PSURs and single case processing, even though the processes must occur to maintain regulatory compliance. The benefits of out-sourcing include freeing up valuable resource time within the company allowing the company to focus attention where needed. These resources can be re-directed to strategic business objectives and not routine data discovery and data entry.

Conversely a company with a single proprietary product which accounts for a significant proportion of the company’s annual revenue may decide only to out-source specific Pharmacovigilance tasks or may decide to maintain Pharmacovigilance in-house.

Out-sourcing literature screening can be beneficial for generic companies where the frequency of searching required to meet the Pharmacovigilance requirements leads to the generation of hundreds of articles which require review to determine if the cases qualify for expedited reporting.

Out-sourcing of generation of safety agreements with third parties is especially useful for those companies operating as virtual companies. There are often complex arrangements for Pharmacoviguilance provision between multiple parties. In a pharmacovigilance inspection any partner could be interviewed by the Competent Authorities and is an area where there are often inspection findings. It is important that all responsibilities in terms of Pharmacovigilance between all parties are specified in detailed documents. Safety agreements need to be drawn up by individuals with expertise in this area and this may be lacking in virtual companies.

Out-sourcing Pharmacovigilance provides a cost effective solution especially for small and medium sized companies. Complying with Pharmacovigilance regulations requires highly trained staff to accurately code and clinically assess cases, enter the cases into a safety database and determine whether particular cases qualify for expedited reporting. This Pharmacovigilance team needs to be familiar with regulatory requirements at regional, national and international levels. An outsourcing partner can provide this capability. There are a variety of out-sourcing options available ranging from individual contractors and Pharmacovigilance consultants, specialist Pharmacovigilance consultancies, and CROs or Pharmacovigilance Service Providers. These individuals may operate from a single site or may have offices spread across several countries which could be beneficial if a presence is required in a specific territory to meet the local Pharmacovigilance requirements.

Consequently, it remains important to choose your partner wisely so check out their credibility – qualifications and experience including any previous client recommendations. Has the partner an understanding of the Pharmaceutical industry and ability to demonstrate compliance with the regulations? Are they experienced in dealing with queries from Regulatory Authorities?  Finally, ensure that there is a detailed contractual arrangement in place which clearly describes the roles and responsibilities of each party for all aspects of Pharmacovigilance to be outsourced.

Adverse Drug Reaction (ADR)
A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function. A causal relationship between the medicinal product and an AE should at least be a reasonable possibility.  An ADR in post-marketing situations normally refers to ADRs occurring at therapeutic doses, but for the purposes of reporting any dosage should be considered.

Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered the pharmaceutical product that does not necessarily have to have a causal relationship with the treatment for which the product is used. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of the medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A pre-existing condition which, worsened in severity after administration of the product would also be considered as an adverse event.

For clinical studies, the definition of an Adverse Event includes any untoward events occurring at any time after the subject’s formal entry into the study (being after receipt of the signed informed consent) until the follow-up period as defined in the respective study protocol.

Annual Safety Report (ASR)
An aggregate Safety Report in the context of clinical trials, taking into account all newly available safety information produced during a defined reporting period. Where several clinical trials are conducted with the same Investigational Medicinal Product (IMP) the reporter should include a concise global analysis of the actual safety profile of the tested IMP based on the experience for all the clinical trials.

Company Core Data Sheet (CCDS)
This document is prepared by the Marketing Authorisation Holder and contains, in addition to safety information, material relating to indications, dosing, pharmacology and other aspects of the product.

Consumer
A person who is not a healthcare professional such as a patient, lawyer, friend or relative/ parents/ children of a patient.

Expedited Reporting
Notification (submission) of an ICSR in a designated format to the appropriate Regulatory Authorities in compliance with the parameters and timelines specified by legislation and local regulatory guidelines. An expedited report would be an ICSR meeting the criteria for rapid transmission to a Competent Authority.

Healthcare Professional
Within the EU, a healthcare professional would be described as a medically qualified doctor, dentist, pharmacist, nurse or coroner.  When the report originates from a pharmacist or nurse, further information should be sought from a medically qualified doctor responsible for the patient.

Individual Case Safety Report (ICSR)
A report received by a company or agency which describes an adverse event.

Investigator Brochure (IB)
A compilation of the clinical and non-clinical data on the Investigational Medicinal Product relevant to the study of the product in humans.

Investigational Medicinal Product (IMP)
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled in a different way from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form.

Marketing Authorisation (MA)
The approval granted by the Regulatory Authority to market a specific product in a particular country

Marketing Authorisation Holder (MAH)
The company named on the Marketing Authorisation for a specific product in a particular country.

Medicinal Product
A substance or combination of substances presented as having properties for treating or preventing disease in human beings; or a substance or combination which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

Concerned Member State (CMS)
The Regulatory Authority in whose territory a clinical trial with the IMP is being conducted or is involved in the registration of a medicinal product in the EU under Mutual Recognition Procedures, as distinct from the Reference Member State that initiated the Procedure.

Non-interventional Trial
A study where the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within the current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods should be used for the analysis of the collected data.

Pharmacovigilance
The process of monitoring, evaluating and improving the safety of medicines. It is carried out by pharmaceutical companies on their products and by government agencies on all medicinal products. Also, the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems (WHO).

Post-authorisation Study
A clinical study conducted within the conditions of the approved Summary of Product Characteristics or under normal conditions of use. A post-authorisation study may also be a Post-authorisation safety study (PASS).

Post-authorisation safety study (PASS)
A pharmacoepidemiological study or a clinical trial carried out in accordance with the terms of the Marketing Authorisation, with the aim of identifying or quantifying a safety hazard relating to an authorised medicinal product.

Risk Management System
A a set of Pharmacovigilance activities and interventions designed to proactively identify, characterise and prevent or minimise risks relating to Medicinal Products, including risk communication and the assessment of the effectiveness of risk minimisation and interventions.

Spontaneous Report
An unsolicited communication by a regulatory authority, healthcare professional, consumer or other person that describes an ADR/AE in a patient administered the Product and which does not derive from a study or any organised data collection scheme.