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.

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].

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].

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.

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 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.

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

• 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.

Issues in pharmacovigilance outsourcing and consulting

Companies may seek to outsource some or most of their drug safety surveillance activities or to obtain the services of consultants for a variety of reasons:

• To save on recurring personnel and infrastructure costs

• To provide for flexibility to cover times of high work throughput

• To cover temporary gaps in workforce

• To obtain specific expertise and support not available in house

The nature of the work and functions outsourced can include any or all of the following, both for clinical trial and post-marketing spontaneous adverse event reporting:

• Safety data receipt, triage, database entry, coding narrative and medical review

• Expedited reporting to regulatory authorities, including electronic reporting

• Preparation of periodic safety update reports, US periodic reports, annual safety reports

• Signal detection and evaluation

• Literature screening for safety issues and case reports

• Qualified Person for Pharmacovigilance for Europe and local Qualified Person

• Evaluation of benefit and risk for a product

• Preparation of development risk management plan, RMP, RiskMAP and REMS

• Preparation of Detailed Description of Pharmacovigilance System

• Preparation or review of safety data exchange agreements with third parties / business partners

• Pharmacovigilance training, inspection readiness training

• Organisation set up or organisational change

• Preparation of SOPs and other controlled quality documents

• System evaluation, database evaluation, database validation

• Pharmacovigilance audit, development of corrective action plan, implementation of CAPA

• Labelling evaluation and variations; preparation of Company Core Safety Information and Development Core Safety Information

• Responses to regulatory authority enquiries about safety

• Dossier preparation for product registration

• Crisis management

• Support for medicolegal activities and litigation defense

• Evaluation of options for pharmacoepidemiology studies

• Assessment of published reports

Clearly there are different levels of skills, experience and knowledge required for the various activities. This is reflected in the types of organisation that are available for outsourcing of pharmacovigilance work. Individual consultants or contractors may act as an interim resource, sitting in the client company for a period of days, weeks or months, working as if a member of the client pharmacovigilance team. There are also agencies (e.g. Harten Group) that specialise in this type of arrangement and have numerous pharmacovigilance freelance consultants on their books.

At the other extreme of the spectrum, the client may wish to outsource most of the pharmacovigilance activities, routine and non-routine, to a contract organisation (a “PV service provider”). These companies may be very large Contract Research Organisations (CROs) such as Quintiles or Parexel, that concentrate on clinical research, but carry out pharmacovigilance activities as well. There are also specialist PV service providers, such as PrimeVigilance Ltd, PharSafer and Vigilex, that carry out all pharmacovigilance activities but do not perform clinical trials. In the case of PrimeVigilance, there is an interesting model in that routine pharmacovigilance activities are carried out in Eastern and Southern Europe, where overheads are lower than in Western Europe and N.America, but where there is a strong emphasis on quality management. This is combined with a specialist consulting arm and a specialist phase 4 CRO to provide the possibility of a comprehensive range of services from one organisation.

Other clients may need a more limited range of routine activities, such as individual case processing, expedited reporting and PSUR preparation, but not involving other elements. Again, the large CROs may do this work, although the cost can sometimes be prohibitive. The specialist PV providers may be able to provide a competitive approach in terms of cost-effectiveness without sacrificing quality. In addition, there are a number of companies operating in India that carry out this basic work: whilst cost may be reduced there could be concerns about the ability to keep control of events and of quality this far removed geographically.

Specialist pharmacovigilance consultancies do not generally include a provision for safety database and expedited reporting, although some have made arrangements with third parties to perform this function. Again there is a range of expertise available among consultancies, some such as Elliot Brown Consulting, based in the UK, having medically trained staff as well as involving former senior regulators and an international network of pharmacovigilance associates. A similar model is provided by Pietrek Associates. Such companies are able to offer high end consulting on serious safety issues affecting a client’s products, as well as more mundane activities such as auditing, PSUR writing and review etc. While cost can sometimes seem high for these consultants, experience and knowledge may result in less time being taken to complete a project than might be the case with less experienced contractors.

There is a dilemma for companies wishing to outsource pharmacovigilance activities. On the one hand, many companies still consider pharmacovigilance merely to consist of a routine activity necessary for compliance with regulations, but basically a drain on resources and a cost with no benefit. On the other hand, there may be a recognition that safety issues, unless identified early and managed properly, can ruin a company financially. However, more enlightened companies realise that high quality safety data and effective pharmacovigilance are in effect a form of life insurance, protecting patients and products and ultimately the company itself.

Regardless of the type of pharmacovigilance service provider, contractor or consultant used, there is an important concept that the company that is holder of the marketing authorisation (manufacturer in the US) can delegate some or most pharmacovigilance activities, but must retain overall responsibility for the safety of its products. Thus, there needs to be clear accountability, a transparent management hierarchy and a robust decision-making process within the client company. In addition, it is essential that there is comprehensive and detailed contractual documentation specifying which party carries out each of the various pharmacovigilance activities. Only in this way can the legal obligations of the client company be satisfied and the patients’ interests protected.