Pharmacovigilance and Drug Safety

Spontaneous reporting

This is the reporting by healthcare professionals (and in some countries, patients, relatives and others) “spontaneously” of their suspicion of an adverse reaction having occurred. The reporting might be directly to the company marketing the product, or it could be made to the regulatory authority. If there has been spontaneous reporting of a suspected ADR to a pharmaceutical company (including reporting to any employee, such as sales representatives or to contractors) there are legal obligations on the company to report serious reactions within a specified time frame to the regulatory authority (“expedited reporting). This takes place to the authorities in that country where the report was received and possibly to other regulatory authorities also. For non-serious reactions, reports usually have to be included in periodic safety update reports (see below).

In addition, the pharmaceutical company has to identify reports of adverse reactions published in the medical and scientific literature (by a process of weekly “literature screening”) and cases must be reported by the company in a similar way to the regulatory authorities.

The authorities in turn are required to report to each company anonymised information on the serious adverse reactions that they have received in relation to that company’s marketed products. There are also requirements for companies to report spontaneous cases of serious adverse reactions that they have received from certain regulatory authorities to their own authorities. There are mechanisms in place to identify and remove duplicate reports.

All these cases – ‘Individual Case Safety Reports’ (ICSRs) – are entered on the company’s safety database and on the regulatory authority’s safety database. They are examined individually and in the aggregate for a product in order to identify clusters of reports that could represent a signal of a previously unknown adverse reaction or drug interaction or some change in the character of a known adverse reaction. It may also be possible to recognise a new risk factor for a reaction to a product, such as a sub-group of patients at particular risk.

The main limitation of spontaneous reporting schemes is that there is under-reporting of adverse reactions, as in most countries the process for the initial reporter (i.e. the healthcare professional) is voluntary and unpaid. However, their main purpose is not the quantification of the frequency of adverse reactions, but the identification of signals.

In addition to the national regulatory agency databases of spontaneous reports and the company databases, there are two over-arching international databases. The EMEA maintains the EUDRAVIGILANCE safety database, including ICSRs received from all companies with products marketed in the European Economic Area, reports received by the national regulatory agencies in the EEA, and serious cases from clinical trials. This database is linked electronically to the national regulatory agency databases and exchanges data with them and with the company databases electronically.

In addition, the World Health Organization operates a global scheme involving national collaborating centres (most of the national regulatory agencies worldwide) and a coordinating centre in Sweden – the Uppsala Monitoring Centre (UMC). The regulatory authorities send the UMC all serious adverse reaction reports that they have received. The UMC database (“Vigibase”) is the only database in the world that includes all the regulatory authority and company ADR reports. The UMC has a panel of independent experts who review the data for signals of new adverse reactions. Aggregate data from Vigibase are made available to pharmaceutical companies for purchase.

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.