1. TAIEX Workshop on the Implementation of EU Pharmacovigilance Legislation - BELGRADE 2015 - CLAUDIA PANAIT TAIEX Expert – European Commission Legal Adviser Ministry of Health, ROMANIA

2. Regulatory framework and procedures for taking regulatory actions to safeguard public health, with examples of major regulatory actions in EU Directive 2010/84/EU Regulation (EU) No. 1235/2010 Regulation (EU) No. 520/2012 Directive 2012/26/EU Regulation (EU) No.1027/2012

3. Main procedures and regulatory arrangements reporting any adverse reactions to medicinal products establishing the medicinal products safety profile at European level monitoring and evaluation of the medicinal products safety

4. Legal framework New EU legislation: Regulation (EC) no. 726/2004 and Directive (EC) nr. 2001/83, the Community code relating to the medicinal products for human use, as ammended = assessment of the product quality, safety and efficacy Authorizing : - benefit-risk balance - scientific analysis The evolution in time of the benefit-risk balance means pharmacovigilance activity !

5. In Romania National Agency of Medicines and Medical Devices (NAMMD) National Pharmacovigilance Centre = the competent authority to supervise the safety of the medicinal products for human use marketing authorisation : quality, safety and efficacy.

6. Introduction to the new European System The concept of additional monitoring and the black symbol (since 2012) Any new medicinal products, authorised after 1 september 2013, subject to a supplementary supervision will include the black symbol in the Patient Information Leaflet (PIL) and in the Summary of the Product Characteristics when it is subject to marketing in the European Union. The New Legislation is applicable to the authorized medicinal products after 1 January 2011. The updated list of the medicinal products subject to additional monitoring: on the site of the EMA, also published by the national regulatory authorities in the MS This list is updated on a monthly basis.

7. Pharmacovigilance activity Pharmacovigilance = the science and activities relating to the detection, assessment, understanding and prevention of adverse reactions or any other medicines-related problems. The term derives from farmaco (in Greek language „medicinal product”) and vigilantia (in Lating language „vigilance, care”).

8. Objectives: preventing harm from adverse reactions in humans; promoting the safe use of medicinal products. Common effort : doctors, pharmacists, nurses, patients, owners of marketing authorisation,NAMMD, any other competent authorities in the European Union, along with EMA and European Commission. Pharmacovigilance contibuting to the protection of patient an public health !

9. Reaching the objects a better collection of information on the medicinal products and their safety; an immediate and consistent evaluation of the aspects related to the medicinal products safety; efficient regulatory actions; patients involvement on reporting the adverse reactions; increase of the transparency level; provide a right communication.

10. Adverse reactions (AR) = one of the causes of morbidity and mortality increase. Adverse reactions and medication errors: can affect achieving the full benefits of treatment and may burden the health system. Increasing access to new treatments: accompanied by the need to monitor side effects and to promote drugs safety and effectiveness.

11. The side effects: loss of confidence in the health system lack of adherence to treatment financial losses financial cost to the health system financial losses for the pharmaceutical industry

12. Suspected adverse reactions = a noxious and unintended response to a drug Response = a causal relationship between the drug and a side event is at least a reasonable possibility. RA: may be the result of using a drug under the terms of the marketing authorization as well as outside the terms of the marketing authorization or following professional exposure. Conditions of use of the drug outside the terms of the marketing authorization include: the use outside the approved indications ("off-label"), overdose, misuse, abuse and medication errors.

13. What happens to the reports on adverse reactions? Transmitted to ANMDM (post, fax, email). Recorded, collected, validated and medically evaluated and sent into the European database (Eudravigilance) of the EMA, to OMS (VigiBase) and to DAPP. All EU Member States transmit RA reported on their territory to the European database. RA gathering across Europe in one spot: -facilitates monitoring the safety profile of drugs on European level -enables early detection of potential safety symbols.

14. How to report a adverse reactions? By printing the reporting form from the website of the NAMMD (www.anm.ro ). Print the form, complete the form with complete information and send it to NAMMD, by post, fax or e-mail. For any questions, queries or supplementary questions regarding adverse reactions report, the professionals and patients may contact the phone number available for adverse reactions.

15. Safety symbol = the information regarding a new or previously incomplete adverse reactions, received from one or more sources, which may be caused by a medicinal product and which needs an additional investigation. Sources: Reports on adverse reactions Clinical studies Literature in the field Evaluation of the safety symbols is necessary to establish if there is or not a casual relationship between the adverse reactions and the suspected medicinal product.

16. Medicinal products subject to an additional monitoring WHAT does the black triangle mean? If a medicinal product is labelled with the black triangle, it means that the medicinal product is monitored even more carefully than other medicines !!! All the medicinal products are carefully monitored after marketing in EU. This generally happens due to less information available on that medicine product than on other medicines, for example in case of a new medicine product marketing or because there are limited information on its long term use. It doesn’t mean the medicine is not safe !!!

17. The regime of additional monitoring is always applied in the following situations: when the medicinal product containes a new active substance authorized in EU after 1 January 2011; when it is a biological medicinal product (a vaccine or a medicinal product derived from plasma/blood), authorized in EU after 1 January 2011; when the medicinal product is subject to a conditional approval (the company trading the medicinal product should supply more data on it) or when it has been authorized in exceptional conditions (there are special reasons due to which the company cannot supply a complete set of data); when the company trading the medicinal product is required to provide supplementary studies (for example to supply more information on the long term use of the medicinal product or on a rare adverse reaction determined during the clinical studies).

18. PRAC Any other medicinal products may be subject to the additional monitoring when indicated by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Agency for the Evaluation of Medicinal Products !

19. European list of medicinal products under additional monitoring EMA first published this list in April 2013 Reviewed every month by the PRAC. A medicinal product can be included in the list when it is authorised for the first time or at any time on itse life cycle. A medicinal product is subject to additional monitoring for five years or untill the PRAC decides to remove it from the list. Always available on the site of the EMA, being also published by the national agencies in the field of medicinal products in the MS

20. In Romania, NAMMD recommends: Before using a medicinal product, patients must carefully and completely read the Leaflet accompaning the respective medicinal product. In case of appearing or suspected undesirable effects or lack of efficacy, NAMMD reccommends to its patients to contact the doctor for a medical evaluation and to establish a therapeutic conduct. Patients or consumers should not stop or change the medication without first consulting a healthcare professional. The adverse reaction reports are used only for scientific evaluation of the medicinal products all the personal data are processed in compliance with the legislation in the field of data protection. NAMMD is not able to offer individual medical reccomendation or to confirm that the undesiderable effects are caused by the medicinal product administration.

21. REPORTING THE MEDICINES’ADVERSE REACTION = main factor in MONITORING AND REASSESSMENT OF SAFETY PROFILE OF THE MEDICINAL PRODUCTS

22. Monitoring How to establish the safety profile of the medicinal products? throughout its whole existence, by permanent collection of the adverse reactions (RA) by detecting and managing the safety symbols The medicinal products are continuously monitored in order to detect, assess and prevent the adverse reactions! In that way, monitoring, managing ans assessing the adverse reactions, within the pharmacovigilance activity, is one of the main factora in establishing the safety profile of the medicinal product, both at national and European level. Safety profile = all the known information regarding a medical product safety (identified adverse reactions and the risk of such events)

23. Preauthorization : quality, efficacy and safety the quality and efficacy of a medicinal product is demonnstrated before marketing, safety cannot be entirely determined due to the safety limits approved at the authorization moment for marketing. There is the possibility that some serious adverse reaction cannot be detected within the development/test syage, appearing with a low frequency and after a long exposure (i.e. 1 AR at 1000, 10000 patients). Examples: blood dyscrasias, severe cutaneuous reactions, hepatotoxicity at some patients etc. The Postauthorization requires: continuous monitoring of the safety profile !

24. The scope of monitoring To detect, assess and prevent the adverse reactions ! The adverse reactions reports: registered, collected, validated, medically evaluated and transfered to the European data base (Eudravigilance), to the WHO (VigiBase) data base and to the authorization for place on the market owners. European data base on adverse reactions EudraVigilance = Continuous monitoring of the safety profile and detection of safety symbols

25. How is provided the continuous monitoring of the safety profile of medicinal products? By collecting data on medicinal products and on their use and by assessing them In that way there is determined the positive character of the Benefit/Risk Report

26. Reassessment Safety symbols Periodically updated reports on safety Arbitration procedures

27. European pharmacovigilance actions for medicinal products safety (1) After a safety symbol validation and confirmation, the derived data are transfered, for assessment at European level (PRAC), which is expected to make recommendations on further actions and measures to be taken to reduce at minimum the risks associated with medicinal products use..

28. The PRAC recommendations amendments to the Information on medicinal product (PIL), medicinal products reformulations, additional measures for reducing the risk at minimum (i.e. direct communications to professionals, training programs for professionals and/or patients), performing post-authorisation clinical studies on efficacy or safety, etc.

29. European pharmacovigilance actions for medicinal products safety (2) European pharmacovigilance actions for medicinal products safety (2) After assesing all the available data (from AR, clinical studies, literature in the field) there is determined that the risks exceed the benefits of a medicinal product. In such cases, by the EU recommended the suspension/removal of the authotization for place on the market !

30. Examples: Tetrazepam (decision on suspension of the marketing authorization (APM) for medicinal products containin tetrazepam in May 2013) Ketoconazol (APM decision to suspend marketing for oral ketoconazole) Combined hormonal contraceptives (modification of the information regarding the medicinal product, DHPC distribution, training programs for doctors and patients, post- authorization safety studies) Domperidone (APM decision to remove all the oral administration pharmaceutical forms of a concentration higher than 10 mg, APM decision to remove all the rectal administration pharmaceutical forms of a concentration from 10 mg to 60 mg, APM decision to remove the combined products contaning domperidone/cinnarizine, modification of the information regarding the medicinal products, post- authorization studies, studies regarding the medicines use)

31. Conclusions (1) NAMMD together with the European bodies and Member States, is paying more attention on surveying the medicines safety by developing regulation requirements on pharmacovigilance within the post-authorization period, as basis for decisions regarding the risk during the life cycle of the medicinal product.

32. Conclusions (2) Is important to understand the decision making on medicinal products safety in the EU: at the moment of indentifying a safety problem, the situation is analyzed at national level and it is reported to the EU member states and to the EMA, to start a safety profile assessment of the medicinal product at European level.

33. THANK YOU FOR ATTENTION !