Pharmacovigilance and Drug Safety

Laws

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: