Pharmacovigilance and EU-collaboration

In practical terms, pharmacovigilance means monitoring or surveillance of drug safety after authorisation.

Medical companies holding an authorisation for a veterinary medicine are obligated to collect reports of adverse events and lack of efficacy and submit them to the European adverse event database ’EudraVigilance Veterinary’. They are also obligated to monitor the collected data and analyse it to detect patterns indicating a previously unknown side effect or a new aspect of an already known side effect (e.g. change in frequency or seriousness/severity) for any of their products.

Similarly, National Authorities are also obligated to both collect and submit reports of side effects and lack of efficacy, but also to evaluate the analyses submitted by the medical companies and perform their own monitoring of data on safety and efficacy after authorisation of a medicine.

The most important source of data are the reports of side effects and lack of efficacy made by the veterinarians, animal professionals and animal owners, but information is also gathered from scientific literature, new clinical trials and other scientific experiments etc.

The Danish Medicines Agency continuously evaluate safety of veterinary medicines in several different ways:

• We monitor Danish reports of side effects and lack of efficacy for all veterinary medicines on the Danish market
• We are part of the coordinated EU-collaborative workshare, where we are responsible for monitoring of global data for select products on behalf of all of EU. All other EU-countries also participate in a similar way, ensuring that all products on the EU-market are monitored.

In this way, monitoring of drug safety for all marketed veterinary medicines is ensured.

Collaborative pharmacovigilance within the EU

There is an extensive collaborative workshare within the EU, ensuring continuous evaluation of global data on safety and efficacy for all veterinary medicinal products that are authorised in the EU. This European collaboration is coordinated by the European Medicines Agency (EMA) situated in Amsterdam in The Netherlands.

All veterinary medicinal products approved for use in more than one EU-country are included in the collaborative European pharmacovigilance. The responsibility is shared between all the EU-countries, and evaluations are presented and discussed in the Pharmacovigilance Working Party, which comprise of members with specialist knowledge of pharmacovigilance. The Pharmacovigilance Working party is a working party under the European Committee for Veterinary Medicinal Products (CVMP). All decisions regarding potential risk minimisation measures for centrally approved veterinary medicinal products are also discussed and adopted by the CVMP after discussion in the Pharmacovigilance Working Party.

Signals – Potential new side effects

If a new potential risk of a veterinary medicinal product is discovered during surveillance by a marketing authorisation holder (i.e. a medical company) or a national authority it is called ’a signal’. Signals may concern both a new potential side effect or a potentially changed aspect of an already known side effect (e.g. increased frequency or severity), but also potential lack of efficacy or unintended errors in prescription, dispensing or administration of a product, new risks to the user (i.e. the veterinarian, farmer or animal owner), or risks related to the environment or food safety.

Prescence of a signal does not necessarily mean, that there is a causal association between the veterinary medicinal product and the reported adverse events. It just means that something has come to the attention of the marketing authorisation holder or the authorities and is now being further investigated. Luckily, it is often found that there is no causal association or at least that there is no evidence of an association at this time point – in that case, the signal is ’refuted’.

An example of how causal associations may be tricky:
Every summer, a lot of people report getting rashes. Their skin turns red and sore and eventually scales. It is noticed, and quite well documented, that the occurrence of this rash correlate very well with the sale of ice cream – when ice cream sales increase, reports of rashes increase. Could it be that intake of ice cream causes the rash? Many of the reports even described eating ice cream on the day the rash started!
However, in this case there is no causal association. Rather, the skin rash and increase in ice cream consumption are both causally linked to wonderful summer weather, which lead to both sunburn and an increase in the sale of ice cream.

If a medical company detects a signal for their product, they should analyse all the available data and evaluate the likelihood of a causal association and the need for any risk minimisation measures. Then they submit the signal with their analysis to IRIS, which is EMA’s system for signal management. Both signals where the company conclude that there is a likely causal association to the product, and signals where the company’s analysis has concluded no causal association are submitted by to IRIS and are therefore visible in the database. Once submitted, a national agency such as the Danish Medicines Agency will also evaluate the signal and proposed conclusion, and either agree or propose changes. The signal assessment is then discussed by experts in the Pharmacovigilance Working Party and the final decision is subsequently made by the CVMP.

If a national agency detects a signal, which was not caught by the marketing authorisation holder, the information is sent to the marketing authorisation holder following endorsement by the Pharmacovigilance Working Party. The marketing authorisation holder is then given the opportunity to also analyse all data behind the signal and add any additional data they may have before a final conclusion on the causal association and any potential risk minimisation measures is made.

In this way it is ensured that signals are thoroughly evaluated, and all relevant information is examined, so that scientifically sound decisions are made.

Risk minimisation measures

I the case where a new causal association between an event (e.g. a new side effect) and a product is found to be likely, attempts are made to minimise the new risk as much as possible.

The most common measure applied is an update of the product information to include information on the new side effect. If considered necessary and possible, information on factors which may decrease the risk of occurrence or decrease the potential negative consequences of the side effect may be included. For example, this may include information on how, and/or to whom, the medicine should be administered, how to monitor before and during treatment or what to do if the side effect occurs.

Other risk minimisation measures may be e.g. direct communication to animal health care professionals and/or pharmacies or other distributors of the medicine, development of educational material or change of prescription status etc.

In very rare and serious cases, authorities or the marketing authorisation holder may decide to remove the medicinal product from the market. This may be temporary, while the issue is investigated and corrected, or it may in rare cases become permanent, if the issues are not able to be rectified.