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].

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.

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.

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.