The role of the HPRA in the authorisation of veterinary medicinal products The role of the Health Products Regulatory Authority in the authorisation of veterinary medicinal products This presentation is intended to inform you about the authorisation of veterinary medicinal products in Ireland. It is arranged in a number of sections as follows: December 2016 22/09/2018

Overview Background Standards for authorisation Procedures for authorisation Information on authorised medicines Monitoring product safety To begin I will explain the reasons for regulation, as well as the historical context Then we will look at Standards for authorisation – the pillars against which medicines are judged Procedures are in place for authorisation – I will provide a brief overview of the national and EU systems for authorisation We will then explain – where you can find information on medicines, and what it means And finally the Monitoring product safety – even after a medicine has been authorised, our role continues in monitoring its ongoing quality, safety and effectiveness.

Background Legislation on the assessment of medicines had its origins in Europe in the aftermath of the tholidamide tragedy in the 1960s. This legislation required pharmaceutical companies to manufacture medicines to specified quality standards, as well as requiring that medicines be evaluated and authorised before they could be marketed. The same requirements were extended to veterinary medicines during the 1980s. Since then, there have been a number of significant legislative changes, including, In 1990, the requirement that residues of veterinary drugs be evaluated for consumer safety, and that safe residue limits be established throughout the European Community, In 1995, the creation of the European Medicines Agency as well as a centralized, European system as an alternative to the existing national authorisation systems in place in each Member State, In 2004, the creation of a decentralized authorisation procedure, as a mechanism to share the assessment work amongst Member States and to achieve harmonised assessment outcomes. Around this time too, new regulatory requirements for monitoring and reporting any reports of adverse effects to veterinary medicines were put in place. We have therefore had more than 30 years of regulatory controls on veterinary medicines, and they have become more progressive in their effect over this period.

Authorisation standards Quality Manufacturing process Product itself Safety Animal User Environment Consumer Efficacy Evidence that the product works The 3 pillars on which all medicines are based are quality, safety and efficacy. Quality relates primarily to 2 areas – Firstly, the manufacturing process, including quality control of the raw materials used; information on the controls applied during manufacture to ensure quality, and that the manufacture is conducted under Good Manufacturing Practice conditions. Secondly, the quality of the product itself, including details of the finished product specification and release limits, stability studies and simulated, in-use stability studies. The suitability of the container, including the size and presentation, labelling and packaging are also evaluated. The data are used as a basis for establishing the product storage and conditions of use. The assessment of product safety includes a requirement to test the product in the target species, usually at a multiple of the recommended dosage and for at least the minimum dosage period. An assessment of safety in pregnant or lactating animals is also undertaken. These studies are used to define warnings and precautions for use. User safety studies help define any risks to the user of the medicine, as well as the adequacy of any risk mitigation measures (e.g. use of child-resistant containers etc). Depending on the nature of the product, studies on the environmental impact are also required (how much of the product enters the environment? what happens it? And how long does it persist?). Finally, in the case of veterinary medicines used in food-producing animals, an assessment of the safety of residues and the adequacy of the withdrawal period must be undertaken. Safety studies must be undertaken under Good Laboratory Practice, being a standard for ensuring the quality and reproducibility of the study data. Efficacy means the ability of the medicine or vaccine to produce the desired effect. This is demonstrated usually by means of pre-clinical studies as well as clinical trials in the target species that are conducted in accordance with the principles of Good Clinical Practice. The data generated from these studies define the indications for use of the product.

Procedures for authorisation Centralised Decentralised Mutual recognition National In the European Union, veterinary medicines can be authorised by the centralised authorisation procedure or national authorisation procedures. The European Medicines Agency is responsible for the centralised authorisation procedure. This procedure results in a single marketing authorisation that is valid in all EU countries, as well as in the European Economic Area (EEA) countries Iceland, Liechtenstein and Norway. The centralised procedure is compulsory for medicines derived from biotechnology processes, such as genetic engineering and is optional for new or innovative medicines or medicines for new therapeutic areas of interest to animal health. Applications through the centralised procedure are submitted directly to the Agency, which advises the European Commission on the decision to grant a marketing authorisations. The marketing authorisation is valid throughout the EU. Each EU Member State has its own national authorisation procedures for the authorisation, within their own territory, of medicines that fall outside the scope of the centralised procedure. In Ireland, the HPRA is the competent authority for the authorisation of medicines under this procedure. Where a company wishes to market a veterinary medicine in several Member States, there are two possible routes available: Decentralised procedure Companies can apply for the simultaneous authorisation of a medicine in more than one EU country if it has not yet been authorised in any EU country and it does not fall within the mandatory scope of the centralised procedure. Mutual-recognition procedure Companies that have a medicine authorised in one EU Member State can apply for this authorisation to be recognised in other EU countries. In some cases, disputes may arise between the assessments carried out by Member States of the products concerned. These can be referred to the Agency for arbitration under a process known as a Referral procedure.

Recognising that a veterinary medicine has been authorised Marketing authorisation numbers Nationally authorised products must display a VPA number – e.g. VPA 10333/113/1 Centrally authorised products bear an EU number – e.g. EU/2/11/199/001 Once approved as having met the EU standards, a veterinary medicine is granted a marketing authorisation. In the case of medicines that have been granted a national authorisation, the labelling of the product will bear a ‘Veterinary Product Authorisation’ number. The VPA number will be clearly displayed on the product and, in the case of medicines used in food-producing animals, is used for record keeping by vets and farmers. In the case of In the case of medicines that have been centralised authorisation following an opinion of the European Medicines Agency, they also carry a marketing authorisation number on their labelling and packaging. This number commences with the letters ‘EU’. Unless all the required information can fit on the product labelling, the required information allowing for the safe and proper use of a medicine is available on the package leaflet that accompanies the medicine. The basis for this information, all of which has to be approved, is a document known as the Summary of Product Characteristics (SPC) of the medicine. Both the EMA and the HPRA publish the SPCs of all authorised veterinary medicines on their websites.

You can find more information about authorised veterinary medicines, as well as about the authorisation procedures on our website, www.HPRA.ie . You can also use the search facility to access the SPC of an authorised product, or by using the ‘Advanced search’ link, to filter the HPRA database to identify e.g. products for a particular species containing a particular active substance. You can also identify safety advisory notices, as well as pertinent regulatory guidance notices. Information on how to report a suspected adverse reaction to a veterinary drug is also available. This includes an electronic form for making on-line reports. There are about 1300 authorised veterinary medicines in Ireland, including about 100 centrally-authorised products. The HPRA receives approximately 100 new product applications each year, while about 70 medicines are withdrawn annually. We process nearly 1500 applications for an amendment or variation to authorised veterinary medicines annually and deal with 100s of other applications. This means that information on products is continually being updated. We authorise new products on a weekly basis, but any changes to existing medicines are uploaded to our website each day. This means that our website is the most authoritative source of information on authorised veterinary medicines in Ireland. Other veterinary medicines might also be available in Ireland, including those authorised by the Department of Agriculture for special disease situations, or by the HPRA for use in clinical trials. The HPRA has a special application system for the classification of borderline products. Details of this system are available on our website.

Monitoring veterinary medicines Adverse reactions, including reports of lack of efficacy, to veterinary medicines Reactions in humans using veterinary medicines Other incidents e.g. residue violations, environmental effects Where an adverse reaction to a veterinary medicines is suspected, it should be notified immediately to the veterinarian, who, in turn, should report it either to the company involved or to the HPRA. There are special forms for making such reports. Details are available on the HPRA website. Adverse reactions are defined as a reaction which is harmful and intended and which occurs at doses normally used in animals. This term should also be understood as including reports of lack of expected efficacy of a veterinary medicine. Whether reports are made to the company or the HPRA, the HPRA will be informed and will undertake an assessment of the report, so establish if it is linked with the use of a particular veterinary medicine. Companies are required to collate all reports involving each authorised product and to submit a consolidate report to the HPRA at periodic intervals. By this means, the HPRA is able to monitor the ongoing benefit/risk profile of a medicine and to take any necessary regulatory action to safeguard human and animal health, e.g. by requiring new or enhanced precautions for use warnings. Reports of adverse effects in humans to exposure to a veterinary medicine, as well as and reports of unintended adverse effects of use on the environment are also monitored by the HPRA.

Conclusion www.hpra.ie The authorisation system for veterinary medicines is complex, but thorough. Medicines are approved only following a benefit risk evaluation. The product information is carefully sculpted, based on studies and clinical trials submitted in the company’s application dossier. Product performance is dependent on it being stored appropriately and used according to the directions on the product labelling. Even then, there is a possibility that occasionally the use of a medicine may result in an adverse reaction. By reporting such reactions, we can establish if the benefit/risk profile has changed significantly and if so, we can take any necessary regulatory action to improve the situation. Further information of the role of the HPRA and the regulation and safety of veterinary medicines is available on our website www.HPRA.ie. Thank you