• 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.

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.

After approval in the EU, the company holding the marketing authorisation is required by regulation to continue monitoring safety. It must enter reports of suspected ADRs on a validated safety database and review the data for signals of possible new adverse reactions or other concerns. Any change to the balance of benefits and risks must be reported to the regulatory authorities, in addition to the reporting of individual cases and periodic safety update reports.

For products with national marketing authorisation in the EU, the regulatory authority in the Member State where the product is marketed has responsibility for reviewing safety by examining the safety reports that it receives from the company and directly from health professionals working in that country. The national regulatory authority also reviews PSURs from companies. It enters the case reports it receives onto the Eudravigilance database, held by EMEA.

For mutual recognition and centrally authorised products, the responsibility for monitoring safety rests with the EU regulatory authority that acted as Rapporteur or Reference Member State. However, each national regulatory authority will still receive local reports of adverse reactions from companies and health professionals and must enter these onto the Eudravigilance database. The EMEA acts as a coordinating body for the safety activities for centrally authorised and mutual recognition products, but the safety reviews are performed by assessors in the Member State regulatory authorities.

The Committee on Medicinal Products for Human use (CHMP) – comprised of representatives of each of the EU regulatory authorities – is involved at intervals with review of the PSURs for centrally authorised products and with safety issues arising post-marketing. These are channelled through its Pharmacovigilance Working Party (PhVWP), which comprises pharmacovigilance representatives from each Member State.

Legislation provides mechanisms for referral of important safety issues potentially affecting public health throughout Europe to the CHMP by the PhVWP. There are complex procedures for examining the benefit-risk balance of products if there are major safety concerns, and for making recommendations to the European Commission for suspending or revoking marketing authorisation.

There are two main strands to the assessment of safety of marketed medicines: spontaneous reporting and post-authorisation studies. However, it should be pointed out that company-sponsored research may be continuing in countries  where the product is not yet marketed, in order to obtain marketing authorisation there. Safety information from those studies is required by regulation to be reported to the competent authorities where the drug is marketed. In the same way, studies may be set up looking at new indications for the marketed drug, or use in new populations, or with different dosage forms. All of these may generate data on adverse reactions that is relevant to the marketed product and which is legally required to be forwarded by the sponsor company to the competent regulatory authorities.

There are EU laws – regulations and directives – on the one hand, and national laws on the other. An EU regulation, when it comes into effect, is in force in all the Member States of the European Union. An EU directive, however, must first be enacted in national law in each EU Member State, within a specified time-frame. In addition to those national laws that promulgate the EU directives, there may also be national laws that concern pharmacovigilance.

The principal EU laws concerning pharmacovigilance are:

• Directive 2001/83, amended by Directive 2004/27. This concerns all medicinal products, although for pharmacovigilance it is most relevant to products authorised by the national, mutual recognition and decentralised procedures. The Member States are the licensing authorities in these procedures.
• Regulation 726/2004. This concerns centrally authorised products. The European Commission is the licensing authority for these products.
• Directive 2001/20. This is the Clinical Trials Directive and includes extensive coverage of pharmacovigilance for interventional clinical trials pre- and post-authorisation.

Guidelines

The EU laws make reference to guidelines drawn up by the European Commission which provide detail and interpretation. These guidelines are not considered to be voluntary – they are mandatory as far as companies are concerned. The guidelines are also directed at regulatory authorities, with detailed requirements for the way that they carry out pharmacovigilance as well. They comprise:

• Volume 9A of the Rules Governing Medicinal Products in the European Community – for post-authorisation pharmacovigilance
• Volume 10 of the Rules Governing Medicinal Products in the European Community. This applies to clinical trials pre- and post-authorisation and incorporates the guideline Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use

In addition to these laws and regulatory guidelines, there are various voluntary guidelines. These are mostly generated by two organizations:

the Council for International Organizations of Medical Sciences (CIOMS)
the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals (ICH).

CIOMS is a body set up under World Health Organization and UNESCO. It has developed a series of guidelines on pharmacovigilance, drawn up by a committee of volunteers from Industry, regulatory authorities, WHO and others. The main guidelines concern the international reporting form (CIOMS I); periodic safety update reports (CIOMS II); core data sheets (CIOMS III); benefit-risk assessments (CIOMS IV); practical issues in pharmacovigilance (CIOMS V); clinical trial safety data (CIOMS VI); and development safety update reports (CIOMS VII).

Whilst CIOMS guidelines are very influential they are not “official” regulatory guidelines, have no legal force and generally just provide a consensus on good practices and new methodologies.

ICH consists of representatives of the regulatory authorities in the EU, Japan and US, with representatives of the corresponding industry regional organizations and Health Canada and WHO as observers. ICH establishes guidelines applicable to the EU, US and Japan through a series of expert working groups. There is a stepwise development of the guidelines. At Step 4, there is consensus internationally and at Step 5, an agreement by the regulators that they will introduce the guidelines into legislation, although there may be some divergence when these are actually put into effect in the different regions.

The three areas covered by ICH guidelines are Efficacy, Safety and Multidisciplinary. Paradoxically, the “Efficacy” guidelines include clinical (human) safety, whereas the “Safety” guidelines concern only pre-clinical (animal toxicology) safety.

The main guidelines concerning pharmacovigilance are: