Weight and consequences of post-marketing (-approval) experience.

In the European Union the term pharmacovigilance is normally used to describe post-marketing or, more precisely, post-approval experience after the regulatory approval of drugs and their introduction to the market under defined conditions. The term describes activities used to gather information on the effects of medicinal products, with emphasis on those aspects which have not, or could not have been, detected in the pre-approval phase of the development of the product. The term was first introduced in France more than two decades ago when authorities there set up and developed a national system to determine possible adverse reactions caused by medicinal products and to confirm or reject these reactions. In addition to this pharmacovigilance system, nationally agreed and implemented methods for collecting, reporting, and imputing suspected adverse drug reactions have been used. When the term was included in the European regulations for medicines its meaning was extended to include all regulatory aspects of the evaluation of proprietary medicinal products resulting from, and relevant to, the description of the regulatory status and use of medicinal products after post-marketing authorisation of the product in the Union or in any of its member states. Pharmacovigilance is necessary for many reasons and provides important information about the safe use of medicines. It should be recognised that at the time of approval of a drug there are major limitations to knowledge about all those drugs which contain new active ingredients or possess other features relevant to their clinical effects. The patient group included in a pre-approval clinical trial is normally highly selected, owing to requirements related to the methodology of the trial, and is not, or only to a certain extent, representative of the population which will subsequently use the drug. Thus the information obtained will be incomplete and will not apply to all circumstances, contributing to the individual responses to exposure to a drug. Age and many constitutional factors, comorbidity, comedication are among those factors of major importance to an individual person’s response. Other factors are limited numbers of exposed patients and limited duration of exposure. Targeted approaches to the detection, evaluation, and follow up of specific risks, and targeted approaches to determine the frequency of risks or their underlying mechanisms are often missing or incompletely considered. Such limited knowledge at the time of approval means among other things that there are uncertainties about the frequencies of rare adverse reactions and almost no information about very rare or less frequent adverse reactions. Long term exposure effects on therapeutic or adverse effects are limited or non-existent. Mechanisms underlying adverse effects or predisposing conditions in patients are either studied only to the extent required by the clinical trial protocol or are lacking because insufficient consideration was given to the direction in which studies might have been planned and organised. Prevention of specific adverse reactions caused by the use of a medicinal product has normally only been studied to a limited extent, and most adverse reactions have not even been identified or could not possibly have been identified. The purpose of pharmacovigilance as described in the European regulations is given in the Notice to Marketing Authorisation Holders Pharmacovigilance Guidelines dated 29 January 1999 (CPMP/PhvWP/108/99):