ÚSTAV PRO STÁTNÍ KONTROLU VETERINÁRNÍCH BIOPREPARÁTŮ A LÉČIV INSTITUTE FOR STATE CONTROL OF VETERINARY BIOLOGICALS AND MEDICINES

Transcription

1 ÚSTAV PRO STÁTNÍ KONTROLU VETERINÁRNÍCH BIOPREPARÁTŮ A LÉČIV INSTITUTE FOR STATE CONTROL OF VETERINARY BIOLOGICALS AND MEDICINES Brno-Medlánky, Hudcova 56a Tel.: (+420) Fax.: (+420) uskvbl@uskvbl.cz ANNUAL REPORT ON ACTIVITIES OF ISCVBM BRNO

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3 Basic information on the Institute, position of the Institute Founder: Ministery of Agriculture of the Czech Republic Name: Institute for State Control of Veterinary Biologicals and Medicines Adress: Hudcova 56a, Brno-Medlánky, Postal Code: Telephone: Fax : URL: uskvbl@uskvbl.cz Identification No: Bank account Current: /0710 Bank account Special: /0710 3

4 Contents 1. Introduction Quality assurance system Activitiy and cooperation with national, European and other international institutions Preparation and comments on legislation Ministry of Agriculture, State Veterinary Administration and other partners of the Institute in the CR Institutions of the EU and other foreign partners Activity of the Institute in Relation to Regulated Subjects Agenda of the Institute Activity of Section of marketing authorisation, registery of VTD and clinical evaluation Marketing authorisation of VMP Antibiotic policy Clinical evaluation of medicinal products and granting of import and use of medicinal products without marketing authorisation Veterinary non-medicinal products, veterinary technical devices and biocides Activity of the Inspection Section in GMP Inspections Inspekce SDP Department of market control, dispensing and usage Pharmacovigilance department Activity of the ISCVBM testing laboratory Official Control Laboratory of veterinary medicines Legal Agenda Department of informatics, ISCVBM Bulletin, providing of information, Supervision of Advertising Economic and operating sphere Economic and operating sphere Incomes Financing of capital reproduction Budgetary resources not expended Research and development projects

5 10.6 Foreign and domestic business trips Assets Membership in international organizations Employees Fire prevention and safety of work Conclusion Abbreviations

6 1. Introduction Insitute for State Control of Veterinary Biologicals and Medicines hereby presents the Annual Report which summarizes results of activities of the Institute in the year 2014 and outlines priorities for the Istitute in the upcoming period. As regards the themes solved by the Institute during 2014, this period can be described as proceeding in activities in the field of antimicrobial resistance, intensive incorporation of the Institute into the international marketing authorisation procedures, development of cooperation with other medicinal agencies in the neighbouring countries as well as preparation for better information service, through which the Institutes aims to ensure the most accessible information on authorised veterinary medicinal products. By means of contract concluded with the Austrian agency the Istitute commenced active cooperation with the aim to cooperate on authroisation procedures and development of profesional capacities for assessment of medicinal products. This cooperation also contributed to the increased number of centralised applications in which the Institute was actively incorporated. Another significant field in which the activity of he Institute strenghtened significatntly was also its position as a reference member state in the international marketing autorisation procedures, where most of the applications represent application by the domestoc pharmaceutical industry. The Institute also responded to needs of supervisory activities and strenghtened activities in the field of official batch release of imunological veterinary medicinal products. The Institue indentified areas in which it is necessary to develop professional capacity of activities representing for instance bacteriophages and derivative products, procucts based on monoclonal antibodies, cytokines / immunomodulators, products based on stem cells. At the same time the Institute makes effort to create conditions in these areas to enable the products placing on market. The activity of working group for antimicrobials at MA becomes very satisfactory, with the most important shift can be seen in agreement to commence the monitoring programme of resistance in targeted pathogenes, which will be implemented in a pilot stage during In the field of inspection it is necesary to state that the area of maufacture of veterinary medicinal products and inspection of manufacturing practice is stabilized. Both in this area, the Institute is active in the international sphere - PIC/S, JAP (Joint Audit Programme) where the main aim of these international activities is to facilitate placing of product of domestic pharmaceutical inustry on markets within the EU countries and in third countries. In the area of good manufacturing practice there is a significant shifting to the concept of so called consistent maufacture and the Institute thoroughly monitores development in theis area and prepares in cooperation with domestic manufacturers its implementation. Both the area of veterinary medicinal products distribution and sales of selected veterinary medicinal products. I believe, that implementation of sales of selected medicinal products in the veterinary sphere brought activation of veterinary market towards the breeders resulting in benefit for all concerned participants breeders, veterinary practicioners and pharmaceutical companies. 6

7 From the inspection view, the most issuable area in 2014 was internet trade and illegal import of medicinal products into the Czech Republic. Therefore inspection of internet trade was preferred area in terms of inspection activities. In terms of laboratory control activity the main instrument for quality control of veterinary medicinal products is represented by well-established market surveillance system based on risk evaluation for veterinary medicinal products placed on the Czech market. Importance of official control is supported by regular findings of results beyond authorised specifications. In terms of monitoring, the range of analytical methods (analytes, matrices) is specified by the State Veterinary Administration and further by communication with relevant european reference laboratories. In conclusion of this introduction I would like to express my thanks for excellent cooperation and support from the Ministry of Agriculture, State Veterinary Administration and other partners of the Institute in the field of state administration, as well as to regulated subjects marketing authorisation holders, manufacturers and other entities. My endeavour is that Institute for State Control of Veterinary Biologicals and Medicines fulfils its mission in full and in a way to contribute to maximum development of professional activity, with minimalization of administrative impacts, thus bringing the maximum effect for those using the results of Institute s activities. Prof. MVDr. Alfred Hera, CSc. 7

8 2. Quality assurance system Also in 2014 the Institute proceeded with implementation of quality assurance system in all areas of its activitiy. Regular visit of the Czech Institute for Accreditation in the Institute confirmed ability of the Institute to fulfill its obligations resulting from the accreditation. Further to amendments of legislation, revision of many internal controlled documents was carried out. In March 2014 there took place a third round of visit of auditors from other medicinal agencies within the scope of BEMA project (Benchmarking Exercise of Medicines Authorities BEMA III. Results of mentioned visit confirmed that quality assurance system capability of the Institute ensures performance of activities according to specified requests and in comparable professional level with other well-established agencies within the EU countries. 8

9 3. Activitiy and cooperation with national, European and other international institutions 3.1 Preparation and comments on legislation In 2014 a preparation for amendment of act on veterinary care and amendment on act on medicines was initiated. Concurrently, works on future wording of delegation legislation were initiated. The Institute was actively engaged in amendment procedures of two drafts of EU regulations submitted by the EU Commission, resp. draft of regulation for veterinary medicinal products and regulation for medicated feed. In this relation the Institute prepared several opinions and drafts both for discussions of working groups, Czech EU parliamentary members and for EC Secretariat. In case of draft for medicated feed, a relatively direct course of further discussion of legislation draft is expected, whilst in the field of medicinal products difficult discussions are expected. 3.2 Ministry of Agriculture, State Veterinary Administration and other partners of the Institute in the CR Ministry of Agriculture MZe and ISCVBM activitiy within the scope of Working group for antimicrobials With regard to increase of both international and national importance of antimicrobial resistance issue first meeting of a core coordinating group (June 2013) and further meeting of Working group for antimicrobials at MZe (September 25, 2013). One of the tasks of this WG is apart from setting of exact rules and priorities of antimicrobial policy within Mze is also cooperation with CKS NAP and thus with human area to create update Action plan targeted to antimicrobials for the Czech Republic. This group shloud deal with the AMR problems in the resort of agriculture for a long term period on a conceptually basis, therefore discussion of the group was focused on priorities to solution and progressive definition of specific tasks and responsibiities. In 2014 the meeting of PSA took place in June and September. Several main tasks resulted from meetings, with the following two key tasks: 1) Comencement of monitoring of sensitivity and resistance of targeted pathogenes (year 2015), with SVS and NRL AMR as referees in cooperation with VÚVeL (suply of boards for assessment of MIC, analyses of results) and SVÚ (Praha, Jihlava, Olomouc testing), ÚSKVBL (information on authorised VLP). 2) Appeal to associations of breeders: cattle, poultry, pigs to present indications in which te atimicrobials are highly consumed, with te highest frequency, with impact to economy and therefore they would be convenient for settin of recommended treatment procedures. Cross Compliance Checks of obligations of farm animal breeders producing animal products for human consumption, which comprise also requirement of Cross-Compliance Inspection SMR 10: prohibition of use of some substances with hormonal and thyreostatic effect and betasympathomimetics in animal farms (Directive 96/22/EC) are managed based on risk analysis by SVA CR. The inspections are carried out by Regional veterinary administrations, the inspectors from the Institute take part in selected inspection within the frame of 9

10 methodical cooperation. No requirement for cross-compliance inspection was applied from SVA CR Committee for GMO at MZe CR In 2014 the Institute appointed on employee for work in the Committee. The work consisted in assessment and elaboration of expert positions to submitted applications for granting of approvals to contained use of GMO or releasingt of GMO to environment or market, according to the Act No. 78/2004 Coll on handling with GMO and genetic products. Within the territory of CR only the GM corn has been approved for crop, total area under GM corn crops was ha with the larest areas in Central Bohemia Region. Compared to previous year the croped area decreased by 806 ha and the number of producers decrease as well (from 31 to 18). In relation to amendments of legislation in the frame of amendment of the Act No. 252/1997 Coll., on agriculture, as of January 2015 the Authority for preliminary control of data reported at producers in terrain. The new authority for control is The State Agricultural Intervention Fund. Other procedures have been still carried yout by ÚKZUZ (selection of localities, analysis of data reported). This change resulted in update od material Organisation and cultivation of GM crops in CR. At present discussion continues on the Regulation No. 2001/18/ES, as regards the possibility for the member states to ban or restrict production of GMO, that are approved with the EU, on their territory. In 2014 here was one positive finding of GM papaya in the supplise from Thailand. At te same time there was found presence of GMO rice Bt63 and GMO Bacillus subtilis, that are part of additives to feeding mixtures. Presumably this relates to supplies from China. Quality, safety and efficacy of genetically modified veterinary medicinal products has further been assessed by EMA in a procedure of so called centralised authorisation procedure. In 2014, within this authorisation procedure the Institute participated in assessment of GM vaccine for poultry. It is the life vaccine, which stimulates active immunity against Mark disease and infectious laryngotracheitis of poultry. For possible need of identification of genetic modification in medicines it could be further used SVI in Jihlava. The Committee meeting took place in November 28, State Veterinary Administration and Regional Veterinary Administration Cooperation with State Veterinary Administration and Regional Veterinary Administrations continued in 2013 in the field of planning and providing of monitoring of extraneous substances. Results are presented in Chapter Planned monitoring. Further activities continued in the field of cooperation among inspectors in solving of above limits findings, in the field of medicated feed it was namely cooperation in creation and update of on-line form for transmission of information from legislation for edicated feed to information systém of SVS, antibiotic policy and in other areas. 10

11 3.2.3 State Institute for Drug Control Close cooperation continued with State Institute for Drug Control in all levels. Joint inspections were carried out in GMP, GDP as well as GLP, see Chapter 6 for details Activity of Inspection Section. Representatives of the Institute took part in trainings held by SIDC, information were interchanged between the authoristaion departments of institutes, there was cooperation in translations of revisions of Guidelines for GMP as well as in the field of laboratory analyses CISTA Testing of one feed mixture (chlortetracycylin) was carried out in laboratories of the ISCVBM based on agreement between ISCVBM and CISTA in the field of inspection of cross contamination of feed mixtures. Cooperation between CISTA and Institute proceeded during inspection of follow-up contamination of FM (feed mixture, commenced in 2010) after production of medicated feed sample withdrawal by CISTA, laboratory analyses in CISTA and ISCVBM, hand-over of results from analysis, mututal consultations on results from analyses (including hand-over of causes found during inspection activities to final investigation of the responsible authority) consultations concerning evaluation of cross contamination of FM with medicines. Further, meeting on the level of head representatives of ISCVM and CISTA was held to discuss Draft Regulation of European Parliament and Council on production, marketing and usage of medicated feed and cancellation of Regulation No. 90/167/EHS Ministry of Health zdravotnictví Pharmacopoeia Committee activity of the Institute for Pharmacopoeia in 2014 In 2014 the ISCVBM further participated in activity of pharmacopoeia according to task stipulated in the Act on Pharmaceuticals. Among the main tasks there was participation of Pharmacopoeia Committee of MZ CR (prof. MVDr. A.Hera, CSc. Vice-chairman, MVDr. Jeřábková Jana, Ph.D. member and Jaroslav Maxa, PharmDr., Ph.D. member), activity of Section for veterinary immunologicals and pharmaceuticals and activity in groups of experts of European Pharmacopoeia Commission (MVDr.Jana Jeřábková and Jaroslav Maxa, PharmDr., PhD ). In 2013 employees of ISCVBM participated similarly to previous years in the work on preparation of the Pharmacopoeia Bohemica Appendix This work consisted mainly of translations of revised articles and sections of pharmacopoeia for the european part (this part will include texts corresponding to European Pharmacopoeia - Appendices 8.3. to 8.5.) and of preparation of national part, which includes updated list of doses for animals of some of the medical substances used in veterinary practice. Pharmacopoeia activity was arranged and coordinated at ISCVBM by the Section of veterinary immunologicals and medicines of the Pharmacopoeia Commission of MZ CR, whose official administration place is in ISCVBM. The Institute ensured its work through the Department of Pharmacopoeia lead by Dr. Jana Jeřábková. In 2014 there were eleven employees of ISCVBM working in the Department of veterinary immunologicals and medicines of the Pharmacopoeia Committee at MZ CR and five other members from other work places, which was 16 members in total within this Committee. MVDr. Jana Jeřábková, PhD. and Jaroslav Maxa, PharmDr., PhD. actively took part in this Committee as a members of groups of experts of the Pharmacopoeia Commission, including participation on meetings in Strasbourg. 11

12 3.2.6 Expert Committee for Experimental Animals Protection In 2014 the Expert Committee consisted of five members and ensured operation of user establishment in accordance with legislation requests and needs of the Istitute. Professional treatment was ensured only by workers qualified according to the Article17 of the Act. No. 246/1992 Sb. in number of 10 workers and further with 4 keepers, that completed the training for laboratory assistants, technicians and keepers. The Committee carried out continual inspection activity within the frame of experiments, i.e. ensuring required level of animal welfare and other specified activities resulted from the Act. Also the activity in operation of the facility was carried out by trained workers in extra-work days according the time-schedule. Summary Report for the Ministry of Ariculture was elaborated including statistical tables from evaluated year. On November 5, 2014 the KVS SVS pro Jihomoravský kraj carried out inspection of the facility and related activities with no negative finding. Disposal of contaminated materials from the facility is carried out based on contracts by the companies Agris s.r.o. Medlov and SITA Brno. Number of used experimental animals in 2014 was higher than in previous year - see table due ti preparation of CVS rabbies virus for determination of IU in the rabbies vaccine, te maufacture of which was approved in the Project of experiments No. 8/2012. Also the international comparisation study was carried out by EDQM BSP 128. Following table presents numbers of laboratory animals used also in previous years. Numbers of laboratory animals used in the animal testing facility of the ISCVBM Mouse Guinea pig Poultry Total With respect to new legislation requests resulting from the amendment of the Act No. 246/1992 Coll, as of the January 1, 2015 the Certification according to the Article 17 is no more valid and thus no work with laboratory animals will be approved. For this reason the appointed employees completed training according to 15d, subsections 3 and 4 or 15e subsection 1 and 2 of amendment to the act with new valid certificates. In December 2014 a new expert committee was appointed Other national cooperating institutions Cooperation continued with the Veterinary Research Institute (VÚVeL) within the scope of joint grant project of both workplaces, which is focused to determine sensitivity and resistence profiles by means of micro dilution method at pathogenes insulated from the clinic of diseased animals Development and production of veterinary sets for determination of MIC antimicrobial substances by a standardized micro dilution method and a new concept of evaluation of effectivity of antimicrobial substances by MPC determination. In 2014 the cooperation with VFU proceeded. It consisted in participation of VFU workplace (microiology) within the frame of post-authorisation monitoring of sensitivity and resistance to florphenicols in Aeromonas salmonicida isolates originated from farm breedings of salmons. To obtain results within the CR also the AMR NRL participated in the post-authorisation monitoring. Cooperation with KVL proceeded as well. Representatives of ÚSKVBL met with representatives of KVL in March with discussions concerning preparation of international conference CEVC, which was held in April 2014 in Brno and discussions on antimicrobial use problems. 12

13 The inspection section cooperated with KVL in supervisory control of unauthorised purchaser of VMP and investigation of several initiations from KVL of unauthorised sales of VMP. 3.3 Institutions of the EU and other foreign partners European Medicines Agency (EMA) Activity in the Committee for Veterinary Medicinal Products (CVMP) and its Working Parties Committee for Veterinary Medicinal Products In 2014 representative of ISCVBM participated in 11 regular meetings of Committee for Veterinary Medicinal Products (CVMP).. By means of agreed cooperatiion conclusion of contract for cooperation the Institute actively participated in 2014 as a co-raporteur in assessment of two products in centralised authorisation procedure. Further the Institute actively participated in CVMP working group for scientific advisory (Scientific Advice WP), where the representative of the Institute was appointed to elaborate one statement in the field of maximum residual limits. Among the most inportant activities, that were solved by the Committee in 2014, there were questions relating to protection of environment and namely the question of so called PBT compounds, i.e. substances bringing the specific risks for environment (so called persistent, bioaccumulative and txic compounds), further the Comittee intensively discussed questions connected with antimicrobial resistance. The most important position of the Committee is position to questions of European Commission in the field of antimicrobial resistance, which prevails the importance of question of marketing authorisation of veterinary medicines. This issue will be taken into account by the European Commission during the process of amendment of legislation for usage of veterinary medicines. Joint working party for quality of human and veterinary medicinal products Joint CHMP/CVMP Quality working party (QWP) Joint CHMP/CVMP working party dealing with quality of human and veterinary medicines (QWP) met four times in 2013 (from that one meeting was shared with GMDP IWG working party and one meeting with representatives of industry). Within the scope of the party there were discussed revisions of current guidelines relating to quality of medicines, elaboration of new guidelines, questions and answers for industry. At the same time QWP collaborates with EDQM (within the scope of elaboration and revisions of European Pharmacopoeia (Ph. Eur.) monographies, general texts and certification procedure (CEP) of manufacturers of medical substances QWP group also actively participates in elaboration and revisions of guidelines ICH and VICH. The agenda also contains solving of questions relating to quality of particular human and veterinary medical products authorised by all kinds of procedures (MRP, DCP, CP, NP).. Namely following points from the field of veterinary medicines were subject of QWP agenda: - Revision of guidelines concerning manufacture of final medicinal product forms, chemistry of medicinal substances and choice of sterilisation procedure 13

14 - Development of guideline for control of genotoxic impurities in chemical medicinal substances and derived medicinal product forms (in cooperation with safety working group, SWPv) - Development of guideline for intramammar products (in cooperation with efficacy working group, EWP) - Draft revision guideline VICH GL3 from industry (conception to incorporate climate zones III and IVb) - Definition of medicinal substances as drugs for maufacture of final medicinal product forms (medicinal substances in mixture with excipient) - in-vivo/in-vitro correlation of solid medicinal product forms based on disollution analyses, limits for routine tests of dissolution of commercial batches - definition of input drugs for manufature of medicinal substances and its control - specific questions of quality control of specific authorisation applications - QP declaration template of GMP for manufacture of medicinal substances - Limits of unspecified imuprities in medicinal substances for human and veterinary use versus veterinary use only - GMP question for sterilisation of primary package used during aseptic manufacture of medicinal product forms Safety Working Party Safety Working Party CVMP Following the agenda from the previous period there were 4 meetings of the working group carried out during The meetings were focused on safety issues of VMP from the perspective of user, from the perspective of safety for target species of animals as well as for safety of residues. Working group has continued in the field of preparation of guidelines for VMP marketing authorisation, prepared opinions for CVMP and discussed the professional topics of given issue. The group worked on preparation on proceedings to following assessment Description and evaluation of maximum residual limits for biocides Adjustment of exposure limits during identification of risk in manufacture of various medicinal products in common identical equipment Access to residual values that are under the limits of quantification Tests of genotoxicity of impurities in active substances (VICH) Evaluation of residual studies in honey (VICH guideline) Evaluation of genotoxicity according to VICH guideline GL23(R) Risks for underground water (together with ERA WP) Methods for evaluation of safety of usage and safety of user during usage of topically administered veterinary medicinal products Other discussed issues were: Clarification of used guidelines and approaches for CVMP EMA EFSA common evaluation concerning preparation of RPA Implementation of 3R principles Alternative reference linits and evaluation of exposition (TTC, ArfD) Acute risk for determination of safety for consumer and residue in place of VMP application Guideline for determination of withdrawal period for milk (and relevant part of guideline for SPC texts) Draft VICH guideline for for specification of depletion studies of residues in aqua species 14

15 Wording and requirements of other valid guidelines being used in evaluation of residues, that had been established earlier, have been harmonised according to rules in GL VICH guidelines. At the same time details for meeting of CCRVDF were prepared including data for EU position at mentioned meeting. Possibility for use of EOGRTS (Extended One Generation Reproductive Toxicity Study) was evaluated, instead of two-generation study being used at present, thus within the frame of 3R project. Working group for efficacy of veterinary medicines Efficacy Working Party The party works on establishment of new guidelines for evidence of efficacy, its comments and implementation. The party cooperates with other parties on common topics. EWP met four times during 2014 on two-days meetings, where the following actual issues were solved: Revised guidelines: - Guideline for evaluation of products with fixed combination (EMEA/CVMP/83804/2005) document of questions and answers (EMA/CVMP/EWP/325284/211-Rev.1). Document came into force in May Consideration of benefit and risk of fixed combinations multi proffessional guideline, draft 4 in discussion - Revision of EWP guidelines with respect to 3Rs rules (EMA/CHMP/CVMP/JEG - 3Rs/450091/2012) - Management of efficacy studies for intramammar products in cattle, multi proffessional guideline 2nd public consultation. - Management of efficacy studies on non steroid antiinflammable products. Document came into force in January Documented efficacy of veterinary medicinal products containing antimicrobial substances - multi proffessional guideline (EWP, SAGAM). has not been finished yet, public consultation in February Documented efficacy of veterinary medicinal products containing antimicrobial substances - document of questions and answers draft 4 in discussion. - Evaluation of better taste of peroral products. Document came into force in July Testing and evaluation of efficacy of antiparasitic substances for treatment and prevention of tick and flea infestation in dogs and cats: has not been finished. - VICH guideline on requirements for evidencing of bioequivalence multi- professional guideline (EWP, QWP, SWP) has not been finished yet. - SPC for anthelmintic products (EMEA/CVMP/EWP/170208/2005), Anthelmintic resistence. Has not been finished yet. Revision of following guidelines was suggested: - Efficacy evaluation of anthelmintics: general requirements - Efficacy evaluation of anthelmintics: specific recommendation for pigs - Efficacy evaluation of anthelmintics: specific recommendation for cattle - Efficacy evaluation of anthelmintics: specific recommendation for sheeps - Efficacy evaluation of anthelmintics: specific recommendation for goats - Efficacy evaluation of anthelmintics: specific recommendation for horses - Efficacy evaluation of anthelmintics: specific recommendation for dogs - Efficacy evaluation of anthelmintics: specific recommendation for cats - Efficacy evaluation of anthelmintics: specific recommendation for poultry - Efficacy evidence of ectoparasitics 15

16 Working group for Immunological veterinary medicinal products Immunological Working Party (IWP) Immunological working party met three times in The main task of this working party was namely preparation of several guidelines for evaluation and marketing authorisation of immunological veterinary medicinal products and preparation of statements with relation to current issues, for instance evaluation of risk of occurence of RD 114 virus in veterinary medicinal products as well as several years work on guideline for testing of foreign agens. The following current issues were solved at IWP meetings during 2014: - Work proceeded on guideline Table of foreign agens, - Guideline specifying change or addition of strains in vaccines against horse flu was reviewed and finished, - Work proceeded on guideline replacement of cell lines used for manufacture of immunological veterinary medicinal products, - Work proceeded in preparation of Reflection paper : consideration of risk connected with usage of unauthorised veterinary vaccines in case of urgent need, - Work proceeded in preparation of Reflection paper : using of heat treatment for inactivation of RD 114 retrovirus in life immunological veterinary medicinal products - Risk management strategy document was finalised with respect to occurence of RD 114 retrovirus in veterinary products - Disscussion was held on the need for guideline Statistical principles for clinical tests of veterinary immunological medicinal products - Discussiona was held on the need for guideline regarding requirements for authorisation documents for immunological medicinal products against cancer of dogs and cats - Preparation was commenced of workshop concerning technical requirements for authorisation of vaccines in the EU common EMA /HMA workshop. Pharmacovigilance working party - CVMP During 2014 there were 6 meetings of working group for pharmacovigilance. During the previous years new procedure for products approved in centralised procedure had been implemented and stabilised - continuous inspection of centrally approved products, namely evaluation of new reports and current knowledge. Activity is supported with SOP on safety monitoring of centrally authorised products SOP/V/4032. In 2014 this issue was supported with draft flowchart for evaluation of PSURs in centrally approved products. The working group focused on the question of signal detection. In the previous year the fudamental document PhV surveillance and signal detection of veterinary medicinal products, was accepted, which was extended in 2014 with draft Recommendation on PhV surveillance and signal detection on veterinary medicinal products, suggesting procedure within the frame of Signal Management Process (signal detection, signal priorisation, signal validation, signal evaluation, recommendation for action). During the course of the year the guideline Best practice for using EudraVigilance Veterinary (EVVet) datawarehouse queries and the veterinary PhV surveillance database for SOP/V/4032 (EXT/281663/2013), was submitted and discussed, incorporating a short description of procedure in case of application of EMA for signal detection analysis destined for rapporteur in using the EudraVigilance Veterinary. Revision was carried out in material Guidance notes on the use of VeDDRA terminology for reporting suspected adverse reactions in animals and humans (EMA/CVMP/PhVWP/288284/ Rev.7). Some issues have been persisting in evaluation of adverse effects according to used terminology (Coding). 16

17 Within the frame of its discussions or in so called Non-Urgent Information (NUI) the working group solved several individual cases, i.e. residues findings after using of veterinary medicinal products in products of animal origin, professional doscussion on dispensing (prescription only medicines versus over-the-counter medicines) contamination of immunological preparate, investigation of increased mortality of pigs in relation with potential increased virulence of immunological preparate, investigation of insufficient efficacy of product in relation to potential speed and quality of product dilution prior to its administration. In the second half of 2014, the issue came to the foreground on new veterinary legislation and member states could become aquainted with draft Regulation of the European Parliament and of the Council on veterinary medicinal products. During the year 2015 there has been scheduled 6 meetings of working group for pharmacovigilance. Working group for pharmacovigilance inspections The field of pharmacovigilance inspections was focused mainly on human part, however the EC seeks for similar legislation both for the human and veterinary field, though the field of animal diseases is highly different. In relation with evaluation and inspection planning there was submitted draft of evaluation table for risk evaluation in the frame of pharmacovigilance system of holder and its possible enslistment to inspection plan Risk-based programme for routine PhV inspections (EMA/INS/PhV/159005/2014). It is a supporting draft systém for pharmacovigilance assessors and inspectors mainly in the level of national agencies. From October 13 to 15, 2014 there was training organised by EMA in Roma (Italy) with a subject of pharmacovigilance inspections. In total there were 100 participants from 25 countries, including guests from Japan, Canada, Egypt ad Ghana. The training included bot human and veterinary field of pharmacovigilance inspections and was outlined as a complex of common presentations and discussions followed by further separated workshops for human and veterinary sphere. The training obtained positive assessment both from participants and lecturers. There are 4 meetings of pharmacovigilance inspections working party planned for Consultative Group on Veterinary Pharmacovigilance Systems (ex-evvet JIG) In 2014 there were 3 meetings (virtual meeting) of above mentioned working group. The meetings are organised in two parts (with and without presence of IFAH-Europe representatives). By the end of 2014 the EVVeT Database contained 80 thousand reports on adverse effects occured in EHP and 50 thousand reports on adverse effects outside EHP (so called third countries reports) reports out of the total number of reports relate to adverse effects in human after administration of VMP in animal. EVVET 3 project was stopped in January 2013 by financial reason (project conducted from 2010). The aim of this project was to conform the EVVeT databese with VICH guidelines on pharmacovigilance (GL42, GL30, GL24, GL35) and obtain convenient tools for supervision and management of pharmacovigilance data. In 2014 proceeding of works was influeced by new draft of Decision on VMP, which was announced by EC in Ocober In 2015 there are 4 meetings planned of this working group (virtual meeting). Working Group of inspectors of GMP and GDP (Good Manufacuring and Distribution Practice Inspectors Working Group GMDP IWG) Withing the frame of harmonisation of procedures and approaches in the field of inspections in manufacturers of medicines the GMP and GDP inspectors working group is organized by (GMDP IWG). During the year 2014 four meetings of this group took place. The members of this group are representatives of inspectorates from the EU/EEA countries, the observers are 17

18 representatives from EDQM, countries acceding EU and third countries with concluded agrrement on mutual recognition of certificates and results of inspections (MRA). During the regular meetings the new and revised chapters and amendments of guidelines on good manufacturing practice, documents relating to MRA, impact of new legislation on the sphere of active ingredient manufacturers, documents on harmonisations of inspection procedures and the sphere of cooperation with other working groups even with another organisations as a PIC/S, EDQM, PDA, ISPE are discussed, with additional new part from 2009 concerning guidelines and inspection procedures in the sphere of good distribution practice. In 2014 there were discussed namely revisions of chapters 3, 5, 6, 8 of Guidelines for GMP, Supplements 15, 16, 17, 19 of Guidelines for GMP. On the European Commission webpages Eudralex Volume IV Good Manufacturing Practice Guidelines there were in 2014 presented following amendments of chapters in part I of Guidelines for Goord Manufacturing Practice: Chapter 2 Workers (validity from Feb 16, 2014), Chapter 3 Premises and Equipment (validity from Mar 1, 2015), Chapter 5 Manufacture (validity from Mar 1, 2015), Chapter 6 Quality Control (validity from Oct 1, 2014), Chapter 8 Complaints and Withdrawal (validity from Mar 1, 2015); further it was variation in item 1.2., Part II of the Guidelines for Goord Manufacturing Practice. Public consideration of amendments was held to revision of Supplement 15 of Guidelines for Good Manufacturing Practice Qualification and validation and Supplement 16 of Guidelines for GMP Approval by qualified person and release of batch. Also the document Compilation of Community Procedures on Inspections and Exchange of Information (October 2014) was revised, which incorporated revised EU formats and procedures ( Guidance on the occasions when it is appropriate for competent authorities to conduct inspections at the premises of manufacturers, importers and distributors of active substances and manufacturers or importers of excipients used as starting materials sphere of human medicinal products; Procedure for dealing with serious GMP non-compliance requiring co-ordinated measures to protect public or animal health ; Interpretation of the Union Format for GMP certificate ). In 2014 the working group discussed also the issue of water manufacture for injections, inspections of equipment for radiation sterilisation, sterilisation of primary packing materials used in aseptic manufacturing process and others. Some topics were discussed commonly with wotking group for quality of human and veterinary medicinal products (QWP). Further topics were maintaining of equivalence between the competent authorities and revision of this procedure. In this relation EMA held trainig in cooperation with PIC/S for auditors within the frame of JAP Programme, with participaton of ISCVBM representative. Working group for evaluation of environmental impact assessment Enviromental risk assesment working group Working group for assessment of environmental risks (Environmental risk assessment working group, ERA WP) is involved in negative influences of veterinary products and medicines to nontargeted organisms in environment and other environmental risks represented by persistence etc. The group prepares documents for CVMP (guidelines implementation documents, expertises etc.), supporting legislation and contributing to rational evaluation of veterinary medicines impact to living environment. In addition to activities for CVMP, the group works on harmonisation of approaches with other groups of simmilar specialization within the scope of multinational organizations namely DG SANCO, ECHA (legislative REACH), OECD, SETAC and others. In 2014 ERA WG met three times (January, June, October). Current issues mentioned below were solved on these meetings (meantime also communication and negotiations with work on texts editation were carried out): - Ivermectin and its environmental risks work on review for risk-benefits evaluation was finalized on the CVMP level. Document was approved by CVMP and subitted to external 18

19 consultations. Ivermectin antiparasitics in geeral represent significant problem for environment with respect to many hazardous characteristics. This activity should contribute to complex assessment and decision on environmental risk management of ivermectin (as well as in complete group of medicinal products). - Risks of PBT medicines (persistent, bioaccumulative and toxic substaces). Based on horizontal legislation and global agreements it is ecessary to minimize risks of substances with PBT characteristics in environment. ERAWP prepared basic data for CVMP summarising problems and harmonising with other legislation (REACH, pesticides). The problem is under solution due to impacts not yet determined and subsatntial complexity. - Risks of veterinary medicines for underground water represents objectively and formally complex problem, which was discussed not only from the ERA, WP view but also in coordination with experts for human safety (in gestion of CVMP Safety WP, problems of underroun water utilization). After previous discussions in CVMP there were discussed specific partial steps for finalization. - Antimicrobial resistance preparation of dcument continued (Reflection paper on antibiotic resistance in the environmental risk assessment of antibiotics), which would present sufficient material for CVMP to assess relevant regulatory steps in future. - In the course of the year ERAWP organized practically-focused training for pro assessors (assessor training), which was apart from general focus on practical skill in assessment of environmental risks according to existing recommendation and binding procedures orientated mainly to problematic issues represented by environmental fate studies of VMP or utilization and implementation of models in ERA evaluation (i.e. FOCUS model). Other activities of the Institute within the frame of medical agency QRD Working group of the Quality Review of Documents (QRD) consists of representatives of the national agencies of EU member states, representatives of European Commission and representatives of European Medicines Agency. The main aim of this group is to ensure comprehensibility, conformity and accuracy of information on medicinal products (summary of product characteristics - SPC, package leaflet and labelling) and its translation, that are enclosed to opinions of the committees and decision of European Commission. Furthermore the group controls conformity of all information presented on medicinal products with requirements of EU legislation. In 2014 all SPC, PL and labelling translations for VMP whose marketing authorisation or extensions of marketing authorisation expired during this year were revised. Also in cases of approved variations and renewals of registration (also IB texts reviewed ad hoc) where changes have been made in texts the accuracy was checked. During the first half a year there were revised texts to 10 new marketing authorisations, to 2 extensions of marketing authorisation, to 9 marketing authorisation renewals, to 2 variations of type II, to 3 variations of type IB and to 2 year revaluations of marketing authorisation and to 2 referals. In the second half of 2014 texts to 6 new marketing authorisations were checked, 4 marketing authorisation were extended, 3 variations of type II, 1 variation of type IB and 2 year revaluations. 19

20 ESVAC (European Surveillance on Veterinary Antimicrobial Consumption) ESVAC project coordinated by European Medicines Agency which was launched in 2009 was continuing in The Czech Republic through the representative of ISCVBM, further participated on further proceeding and development of project. In February 2014 an annual meeting took place, which was attended by all EU member states, Norway and Switzerland. Mainly questions regardig submission of data from 2012 and its harmonised evaluation with publication were discussed. CR prepared presentation (Use of sales data for CIAs at national level, example from CZ, L. Pokludová), which showed results from work within the frame of targeted inspections focused on veterinary surgeons with the highest number of prescriptions of antimicrobials with limited indication (CIA = Critically Important Antimicrobials). Public discussions were also attended by representatives of EC, FVE, pharmaceutical industry and other bodies, for whom information on consumptions of veterinary antimicrobials are substantial. During 2014 elaboration of report analysing development of consumptions of veterinary antimicrobials was carried out (resp. veterinary antimicrobials sale) in connection with analysis of population condition of livestock in 26 EU states including EEA states (+ Switzerland) whose requested data were available. Publication is available on EMA website: (fourth ESVAC report). The report informs on sale territories and trends in relation with population of farma animals, with evidence of analyses for individual member states, groups of antimicrobials with comments on critically important molecules. There is also bried specification of consumption condition in pills for animals as pets (dogs and cats). Project is still designed on uniform templates for data collection so that this information could be further analysed in details, which would result in obtaining the most credible and comparable data within the frame of EU member states, so that a long term trend could be evaluated in future and risk analysis conducted with relation to antimicrobial substances usage in animals, namely with impact on occurrence and development of resistance. In 2014 also work of two restricted working groups continued Ad hoc WG on unit of measurement and Ad hoc WG on collecting data by species, CR was not a member of these subgroups (it was not addressed for nomination number of members was limited). Nevertheless, CR has become a member of Ad-hoc ESVAC expert group to provide advice on surveillance on sales of veterinary antimicrobial agents (Ad hoc expert subgroup focused on harmonisation of primary data collection, which meets (mostly in form of Adobe meetings and 1 per year personally) to discuss future aims of project, data publication and targeting of analyses. Documents from these meetings were circulated internally via electronic mail and commented in meeting in February Also request for filling of templates on data on sales in 2013 was announced. ÚSKVBL provided this data for validation by EMA. Further meeting of the group was announced (February/March 2015). Similarly to previous year, Dr. Pokludová was charged with coordination of cooperation within the ESVAC project, filling of data to standard ESVAC templates and communication with EMA team in the field of antimicrobial consumption surveillance, who at the same time presents the data on consumption on national and international levels. Input data on consumption, its collection, presentation to public through ÚSKVBL Bulletin and other compilation in ESVAC are ensured similarly to previous years by experts from Inspection section MVDr. L. Koutecká CSc. and D. Dorn. In 2014 CR participated in two other partial projects: 1) Provision of source data on dosage of antimicrobials from SPC of veterinary medicinal products authorised in CR (Project of determination of measurement units: calcuuulllation of defined daily doses in animals and defined doses per one treatment course in animals). Total of 9 countries participated in this project including CR. 20

21 2) Test stage of project for data collection on animal farms for the year 2014 the tests were carried out in pig farms from birth to feed (5 farms). The aim of the project was to setup the template for data collection, find out the total time, financial and personal demand. Total of 10 countries participated in this project incuding CR. The project was carried out in cooperation with section of inspection and marketing authorisation as well as with veterinary surgeons of mentioned farms in terrain. In future years the pilot stages shouold follow on approved templates for pigs (2015), poultry hen broiler (2016), cattle calves (2017) European Commission Standing Committee on veterinary Medicinal Products In 2014 four meetings of Standing Committee for Veterinary Medicinal Products were convened. On this meeting the Committee discussed implementing decission of Commission by which the Annex to Directive (EU) No. 37/2010 on pharmacologically active substaces and its classification according to maximum residual limits in food of animal origin regarding barium selenate and lasalocid. Further the Commissio presented to the Standing Committee forms prepared for survey of current course of MRL evaluation and its relevance, which had been sent to applicats (companies, member states, Commission) and other participants in the process. Results from survey and analyses will be published in report for Parliament and Council. The Committee repeatedly discussed issue on substances administered by injection and evaluation of potential residues in the point of injection. The Committee decided on post-referal implementing Decision of Commission regarding the Fiprex products. The Committee members were informed on new draft of legislation for veterinary medicinal products. The Committee members have become aquainted in meetings with proceeding in actions relating to antimicrobial resistance. Working group for resistence on antimicrobials (Working group on AMR) In 2014 this working group arranged two meetings (February 2014 and December 2014). On February meeting of this group there was presented information on EC plan to fulfilment of EC Action plan published in November 2011, information on proceeding in ESVAC project, inormation on monitoring in zoonotic and indicator bacterias Decision 2013/652/EU on harmonised monitoring of AMR (in force from January 1, 2014) and technical information on AMR monitoring, new moitoring of ESBL, AmpC and carbapenemases, collecting and elaboration of data (EFSA). Further, on February meeting there was presented information from projects within the human medicine (ECDC, EARS- net and ESAC-net) and information on international projects. Also in 2014 there was meeting of Prudent use of antimicrobials group, where Mgr. Pokludova as a representative of ISCVBM presented and defended statements on behalf of CR in RESTRICTED WORKING GROUP ON ANTIMICROBIAL RESISTANCE (PRUDENT USE OF ANTIMICROBIALS) SANCO/G4 Guidelines on the prudent use of antimicrobials in veterinary medicine. The group met in April on workshop in Brussels to discuss repeatedly modified versions of document concerning particular steps and measures targeting to maximum prudent use of antimicrobials within the EU member states (see above). On the contrary to presumed, it was not possible to finalize the document in 2014 due to the high amount of comments and amendments (over 30 subjects and comments). Finalization was postponed to Further meeting of Working group on AMR is expected in March 2015, where another version of Guideline shall be submitted with finalization assumed by EC in half of

22 European Council Working groups of Council Working group for veterinary experts (animal health) F. 21.B Regulation of EP and Council amending Regulation (EC) No. 726/2004, laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency Regulation of EP and Council on veteriary medicinal products, documents: 13289/14 + ADD 1 + ADD 2 + ADD 3 Working group for agricultural issues (feeds for animals): F 17. b Proposal for a Regulation of the European Parliament and of the Council on manufacture, placing on the market and use of medicated feed and repealing Council Directive No. 90/167/EEC, documents: 13196/14 + ADD1 + ADD2 + ADD3, revision of rules for medicated feed (further MK) has been prepared from EC side for a long term (2009). Current proposal shall replace Directive No. 90/167/EEC. Within the department of MA the Institute assumed a gestion to discussed proposals of legislation in the field of legislation for veterinary medicinal products and medicated feed. ISCVBM worked out positions to both of mentioned proposals. ISCVBM experts regularly take part in all meetings of Council WG. ISCVBM cooperates in gestion with MA regarding amending of Regulation No. 726/2004. Proposals of new legislation were released for publishing by the European Commission in September Meetings of working groups of the Council took part in October and November Many member states (including CR) presented fundamental reservations. In addition to elaboration of frame positions and participation in Council WG the Institute communicated with deputy chairman of ENVI Committee EP (RNDr. Poc) to discuss amendments within the frame of AGRI com EP aas well as with representative of AGRI Committee (shadow rapp for VMP proposal, JUDr. S. Polčák) to propose report for ENVI Committee EP). ÚSKVBL also discussed given issues within the HMA (Heads of Medicines Agnecies), with active participation in preparation of official letter adressed to EP Institutions ensuring cooperation of member states Veterinary Coordination Group for Mutual Recognition and Decentralized Procedures (CMDv) The Veterinary Coordination Group for Mutual Recognition (MRP) and Decentralized Procedures (DCP) is a working group established for regulation and legislative and professional coordination of interational authorisation procedures MRP/DCP. CMDv took up its activity in 2005, directly following the activity of preceding group of the same character - WMRFG (Veterinary Mutual Recognition Facilitation Group) which had been working since CMDv working group meets 11 times per year (every month excluding August) in the premises of EMA, in London, United Kingdom. The meetings are attended by appointed members of competent national medicines agencies of the EU member states, with appointment for 3 years 22

23 period, further there are representatives of EMA and EC. One member of the European Union member states is appointed for a three years period as a chairman of this working group. CMDv group is formed from EEC countries and its activity is focused on following themes at international level of the EU: Individual VMP authorised by procedures MRP/DCP Negotiation on applications according to relevant legislation Elaboration and revision of relevant SOP of marketing authorisation procedures Harmonization of conditions, instructions and requirements in EU member states Reduction of national requirements Current questions and reminders from national agencies Current questions and reminders from pharmaceutical industry Among the main questions solved and discussed at CMDv group meetings in 2014 were: Revision of VET legislation Improvement of DCP proceedings Packaging of Obaly VMP/Pictograms Autogennous vaccines Classification of Borderline products Standard validation checklist / extension of authorisation Reduction of national requirements to authorisation procedures Blue-box requirements/additional national requests CESP Platform /Electronic applications Workshop variations of authorisation by Worksharing ASMF Worksharing /Pilot stage Update of requirements for el. applications Pharmacovigilance/ DDPS Instructions Updating of relevant CMDv guidelines Updating of CTS system According to needs to solve relevant business matters there are ad-hoc working subgroups established and terminated as a part of the CMDv group according to the needs for solving the relevant issues. CMDv group cooperates with oter working institutions and groups: EMA,EK, HMA,CVMP,CMDh,QRD,QWP,SWP,EWP,PhVWP-V,IWP, IFAH-EUROPE,EGGVP,AVC,TIGes Vet. In 2014 the EU presidency countries were member states Greece and Italy. These countrie ensured tasks connected with position of presidency country according to work content of CMDv group incuding Presidential working meetings. HMA In 2014 there was launched a common project of HMA and EMA system for professional traiing of assessors from medicines agencies.the system shall significantly facilitate access of individual medicines agencies to possibility of training of assessors and inckludes also possibility to finance the training. 23

24 HMA further proceeded in development of IT field, which represents one of the main agenda for future role of HMA HMA has been preparing an IT strategy in cooperation with EMA. HMA has been developing its web page together with implementation of new functions, the CTS system for coordination of international authorisation procedures managed by BfARM german agency has been developed as well. Budgets for common project are approved by HMA on a regular basis. Other fields with HMA active role are pharmacovigilance, issues connected with implementation of current legislation, internatuonal cooperation, inspection and surveillance questions etc. HMA V Work group for resistance to antimicrobials In 2010 working group was established for antimicrobial resistence, with a leadership by United Kingdom. Other countries entered to activity of the group - France, Spain, Ireland, Sweden, Deutschland and Czech Republic. During 2014 the document HMA-V Action plan of the antimicrobial issues was amended (original publishing in 2011). The group further worked on specific tasks to fulfill the Action plan of HMA for antimicrobial resistance. CR has become a referee for one of the items from the Action plan dedicated to finding of prescription customs of veterinary surgeons. With significant support from UK and after elaboration of more than 3000 responses of veterinary surgeons accross the EU the FVE central office (Federation of veterinary surgeons in Europe) evaluated results from survey (Federace veterinárních lékařů Evropy). In cooperation with FVE, UK and CR two publications were prepared on results from questionnaire among veterinary surgeons in selected EU countries (including CR) in professional journal Veterinary Records. The first one has been published: N. De Briyne, J. Atkinson, L. Pokludová, S. P. Borriello, S. Price: Factors influencing antibiotic prescribing habits and use of sensitivity testing amongst veterinarians in Europe, Veterinary Record, Vet Rec Sep 25 doi: /vr The second publication (Survey on antibiotics most commonly used to treat animals in Europe De Briyne, Atkinson, Pokludová, Borriello) is expected to be released to print in the first quarter of The results were also presented in form of posters at many interational events. Working group for law enforcement (Working Group of Enforcement Officers) The Institute was continuing in activity within the mentioned working group under HMA, within the scope of which there is also a specific veterinary group with the aim to exchange experiences and information on illegal activities relating to veterinary medicines. In 2014 the working group met two times within the scope of Greece (Vienna, Austria) and Italian (Roma) presidency Other institutions EDQM In 2014 as a members of the Expert Group of the European Pharmacopoeia Committee actively participated MVDr. Jana Jeřábková, Ph.D., MVDr. Radka Smítalová, Ph.D. and Jaroslav Maxa, PharmDr., PhD. MVDr. Jana Jeřábková, Ph.D. and MVDr. Radka Smítalová, Ph.D. ensure namely the agenda of immunological veterinary medicinal products. Jaroslav Maxa, PharmDr., PhD, ensures activities relating to work on monographs of antibiotics and synthetical chemical medicines. 24

25 Within the scope of activity of European Pharmacopoeia Dr. Jeřábková, PhD. and Dr. Radka Smítalová, PhD., members of Group 15V (group of experts for veterinary vaccines and immune serum) took part in three workshops in Workshops of 15V group discussed current issue on elaboration of new articles and revisions of current articles of the European Pharmacopoeia. Following articles were elaborated in 2014: - Revision of general article Vaccines for veterinary use - Revision of Chapter Avian viruse vaccines: tests of foreign agens in inoculum - Revision of Chapter Avian life virus vaccines: tests of foreign agens in final product batches - Revision of Chapter Cell cultures for manufacture of veterinary vaccines - Revision of Chaptery Substances of animal origin for manufacture of veterinary vaccines - New Chapter Healthy chicken flocks for manufacture of inactivated vaccines for poultry with follow-up revision of monographs for inactivated vaccines for poultry - New monography Vaccine against borreliosis in dogs - Works on guideline on foreign agents testing in common cooperation with working group CVMP-IWP práce na pokynu o testování cizích agens On behalf of the Expert Group 7 (Group of antimicrobials) of the European Pharmacopoeia Committee Dr. Maxa took part in two meetings in During the year 2014 the group continued in work on revisions of monographs of penicilin and tetracycline antibiotics, erythomycines etc. Revisions of doxycyclini hyclas and doxycylini monohydrate were finalized. Revised monography on demeclocycline HCl, with participation of laboratory from our Institute, was approved by the Commission. Based on the results of analysis of batches carried out in the laboratory of the Institute the revisions of monographs of tylosine, tylosine tarttrate and tylosine phosphate concentrated solution and tylosine phpsphate, which were published in Pharmaeuropa Comments of national authorities and manufacturers were discussed and implemented into the final version. Laboratory verification was carried out on the new method for impurities of tetracycline hydrochlorid. Further, Dr. Maxa nad the laboratory participated on colaborative studies od standards: pig insulin, lithium-clavulanate, levothyroxine, polymyxine B sulphate, procainbenzylpeniciline. Within the scope of Expert Group 10A (chemical substances) Dr. Maxa took part in three meetings in In Pharmeuropa There was published monography of albendazole, the revision of which had been elaborated in the laboratory of the Institute. The laboratory developed and validated also HPLC method for determination of indometacine content for its monography. From the new monographs the group worked for instance on zolmitriptane, bupivakaine, naratriptane HCl, dexamfetamin sulphate, ropivakainu HCl etc. Revisions of several other monographs were carried out, e.g. flupentixole chloride, desloratidine, hydroxycarbamide, xylazine etc. Pharmaceutical Inspection Convention/Scheme (PIC/S) The Institute has been PIC/S member since The contribution of membership is partly access to seminars and trainings for inspectors on required level and partly increase of the international reputation of Institute and recognition of results of its inspections also by the authorities outside EU/EEA and thus simplification of the Czech industry access to these markets. In terms of PIC/S membership the Institute has been participating in preparation of guidelines within the PIC/S and in the harmonisation of inspection procedures. Inconsiderable contribution is the possibility to take part in highly professional seminars and obtaining of 25

26 many contacts to GMP inspectors. In 2014 representatives of ISCVBM took part in two PIC/S Committees + PIC/S lectures with theme Dedicated facilities (May Geneve, October Paris). In 2013 the new structure within the frame of PIC/S was implemented. One employee of the Institute is a member of working group - Compliance Sub Committee, dealing with coordination and survey of evaluation proceeding in acceding agencies, reviewing of reports and recommendations from evaluation, monitoring of correctional measures. This group commenced its activity on January 1, During the year 2014 there were 3 meetings by means of teleconferences. Main discussed items on the level of PIC/S in 2014: established working groups for harmonization and classification of shortcomings in the sphere of good manufacturing practice; working group for revision of Supplement No.1 of Guidelines for good manufacturing practice; revised version of PIC/S GMP Guide (incorporating revised supplements 2 and 14) and revised PIC/S Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments ; approved new PIC/S GDP Guide, changes discussed in document Guidance Document on Foreign Inspections. At present, following documents are revised: Guidelines on the formalised risk assessment for ascertaining the appropriate Good Manufacturing Practice for excipients of medicinal products for human use, Guidelines on the principles of Good Distribution Practices for active substances for medicinal products for human use, Procedure for handling falsification in the context of GMP/GDP compliance. Audit Checklist was revised, preparation of documents Guideline on Audit Checklist, and PIC/S Accession Guideline is carried out.. In 2014 corrective measures of new PIC/S members were evaluated as well as new applications for access to PIC/S. Within the scope of JVP (Joint Visit Programme) one employee of the Institute joined the veterinary group consisting of Belgium and France authorities (period ). One common inspectin was carried out in 2014 in France at manufacturer of sterile pharmaceuticals, further two common inspections are planed for 2015 in Belgium and in the Czech Republic. Seminars 3.4.Activity of the Institute in Relation to Regulated Subjects By means of its affiliate at Czech Association for medical technique the Institute in 2014 organized two seminars, one for distributors (April 2014) and one for qualified persons and managers in manufature of medicated feed (May 2014). On the seminars there were negotiated issues in the sphere of veterinary medicines regulation in CR and EU, information on Amendment to the Act on Pharmaceuticals, pharmacovigilance, ways of announcement, role of distributor, addictive substances, distribution of unauthorised VMP, GDP certificates, guidelines for SDP-EU, shrotcomings at distributors. One seminar for workers in distribution of medicated feed was prepared with themes concerning activity of SVA in the field of usage of medicines, issue of veterinary prescription for feed medication, proceeding of CISTA during inspection of cross-contamination of feed, validation of manufacturing equipment for medicated feed in terms of cross-contamination, pharmacovigilance in the field of medicated feed. Lecturers from the Institute were accompanied by MVDr. M. Bleierová from SVA and Ing. J. Fiala, Ph.D., from CISTA. 26

27 Guidelines During 2014, 5 guidelines were issued by the Institute according to needs and terms relating from the Act on Pharmaceuticals.. Generaly valid guidelines No. Name Valid from Substitutes Ammends UST-1/2011 Rev. 1 Recommended procedure for advertising of VMP the sales of which is under prescription, into the professional journals and publications UST-1/2011 Guidelines for authorisation of veterinary medicinal products No. Name Valid from Substitutes Ammends REG-3/2009 Rev. 2 Guidelines in the GMP Templates for preparation of draft texts of SPC, leaflets information and packaging marks on veterinary medicinal products REG-3/2009 Rev. 1 No. Name Valid from Substitutes Ammends INS/VYR- 01/2015 INS/VYR- 01/2014 Guidelines in the GDP Amendments of guidelines for GDP-Part I, Chapter 6, notification to changes in Chapters 3,5,8 and in Part II Guidelines for GMP during manufature of LL Amendments of guidelines for GMP-Part I, Chapter GMP Guidelines GMP Guidelines No. Name Valid from Substitutes Ammends INS/DIS- Guideline for marketers of INS/DIS- 04/2008/ selected VMP /2008 Rev

28 4 Agenda of the Institute Similarly to previous years, in 2013 the registry and forwarding office of the Institute registered documents by means of Magion records system software with interconnection to the Documentum system software. In total of ref. numbers evidenced Reference numbers relating to evidenced documents during the years

29 5 Activity of Section of marketing authorisation, registery of VTD and clinical evaluation 5.1 Marketing authorisation of VMP Incorporation of the CR to European Procedures of Marketing Authorisation, authorisation through national procedure, authorisation agenda For authorisation purposes of veterinary medicinal products the Czech Republic implemented authorisation procedures in relation to its character and taking into account relevant legislative standards. In 2014 veterinary medicinal products were approved by four basic types of authorisation procedures national procedure, mutual recognization procedure, decentralized procedure and centralized procedure. National procedure, mutual recognisation procedure and decentralized procedure were carried out in compliance with requirements of consolidated Directive of European Parliament and Board No. 2001/82/ES, as amended by the Directive 2004/28/ES and in case of centralised procedure of the Commonwealth in compliance with Regulation No. 726/2004. Tab. 5/1: Number of authorised VMP based on procedure type on the TYPE OF PROCEDURE TOTAL National procedure 858 Mutual recognition procedure by EU member states Decentralised procedure Centralizovaný postup EU TOTAL NUMBER OF AUTHORISED VMP IN CR 1738 Obr. 5/1: Percentual representation of marketing authorisation procedures in % 18% 49% vnitrostátní National procedure postup postup Mutual vzájemného recognition procedure uznávání decentralizovaný Decentralised procedure postup centralizovaný postup EU Centralised procedure 14% 29

30 Tab. 5/2: Summary of total number of submitted applications and cases when MAwas granted in 2014 Mutual Recognition Procedure and Decentralised Procedure 2014 Type of marketing authorisation Cathegory of VMP CR concerned member state (CMS) Submitted Applications Number of Applications Granted MA CR reference member state (RMS) Submitted Applications Granted MA Mutual Recognition Procedure First Use Mutual Recognition Procedure Repeated Use Mutual Recognition Procedure - decentralised procedure Renewal of marketing authorisation Variation Type IA Variation Type IB Variation Type II Pharmaceuticals Immunologicals Pharmaceuticals Immunologicals Pharmaceuticals Immunologicals Pharmaceuticals Immunologicals At variations to marketing authorisations, the numbers represent real number of submitted applications, not the real number of evaluated changes in application. 1 Pharmaceuticals Immunologicals Pharmaceuticals Immunologicals Pharmaceuticals Immunologicals In compliance with regulation of Directive No. (ES) 1234/2008 and ammendment No. (ES) 712/2012 it is possible to aggregate variations to marketing autorisation into one application so called formo f aggregation of Variations and distribution of work. The number mentioned in table for 2013 thus represents number of applications submitted, not the number of real variations of marketing authorisation processed. 30

31 VMP marketing authorisation with mutual recognition procedure and decentralized procedure a) MRP (Mutual Recognition Procedure - i.e. veterinary medicinal product authorised in national procedure at least in one of the EU member states is authorised to other EU member states) b) DCP (Decentralised Procedure i.e. veterinary medicinal product is athorised for the first time in selected EU member states at once) International authorisation procedures MRP and DCP represent significant position in the Czech Republic, enabling to obtain authorisation license for the medicinal product both of pharmaceutical and immunological character to be marketed on the Czech market. After the new authorisation procedure of the product there are folowing procedures during the product life cycle as the procedure of marketing authorisation renewal and large or small variation in authorisation documents od veterinary medicinal product. In MRP and DCP procedures during 2014 the Czech republic was both in position of RMS and in position of CMS (RMS Reference member state selected by the applicant for marketing authorisation to provide regulating, professional and coordinating activity, CMS Concerned member state selected by the applicant for marketing authorisation as a target state for marketing authorisation of given medicinal product). CR/RMS: In 2014 CR was in position of RMS in the field of new marketing authorisations in six DCP procedures and in four MRP procedures, in which immunological products significantly prevailed pharmaceutical products. In the field of marketing authorisation renewal CR was in position of RMS both in pharmaceutical and immunological products, where the number significantly increased in pharmaceutical products. In the field of variations to marketing authorisation CR took part in RMS role both at pharmaceutical and immunological products at variation type IA and IB, thus with higher number of products than in previous year. At variations type II there was the same situation as in previous year, there was no application for CR in the position of RMS. In 2014 CR was for the role of RMS both in MRP and DCP procedures by foreign and Czech companies. Though the number of applications for new MRP and DCP marketing authorisations has significantly increased from the side of the Czech companies, which enables the Czech companies to participate in marketing authorisation procedures on the European level with all relevant aspects. Also in 2014 the CR keeps its active position in the role of RMS among the EU member states and thus extends its coordinating, legislative and professional experience in the field of international marketing authorisation of veterinary medicinal products. CR/CMS: Numbers of applications for new marketing authorisation by MRP, where the Czech Republic was in position of CMS have decreased in pharmaceutical products received and increased in granted applications. In case of immunological products the number of received applications has increased and the number of granted applications has remained on the same level compared with previous years. Number of applications for new marketing authorisation by DCP at pharmaceutical products in case of received applications has 31

32 decreased and in case of granted applications has increased. In immunological products the numbers both of received and granted applications have increased compared with previous year. Also in 2014 the situation is similar to previous years when number of applications received for marketing authorisation of pharmaceutical products is several times higher than number of applications received for marketing authorisation of immunologicals and when marketing authorisation through DCP procedure prevail the authorisations by MRP. Number of applications for marketing authorisation renewal at pharmaceutical products has decreased, in case of granted applications the number has significantly increased. In immunologicals the numbers both of the received and granted applications remain on the same level. Number of applications for marketing authorisation variations type II in pharmaceutical products received has decreased, in case of granted applications the number has significantly increased. In immunological products the number of received applications has decreased and the number of granted applications remains on the same level. Number of applications for marketing authorisation variations type IA in pharmaceutical products has significantly increased both at received and granted applications. In immunological products the number has decreased both at received and granted applications. In marketing authorisation variations type 1B both at opharmaceutical and immunological products in received and granted applications the numbers have significantly increased. Marketing authorisation of veterinary medicinal products by national procedure Out of the total number of 1738 authorised veterinary medicinal products the national procedure still represents the highest number. By the Dec 31, 2014 the number of autorised products by national procedure reached 858 (890 in 2013) and by means of mutual recognition procedure and decentralized procedure it was 569 (489 in 2013) which shows that th number of international procedures is permanently increasing. This is supported by the fact, that in 2014 there were only 12 domestic procedures out of the 101 newly authorised products. Validity of the authorisation is determined to 5 years according to the Act on Pharmaceuticals. Further the holder of aurhorisation may apply for extension of authorisation. Once the authorisation has been extended it is then valid for unlimited period. Only by pharmacovigilance reasons the Institute can issue decision on extension of authorisation validity for 5 more years, however, the decision can be issued only once. Due to this fact ten number of authorised products according to the Act for unlimited period increases and number of applications for extension proportionately decreases. Procedures of authorisation extension of products that were authorised in past according to different rules have been terminated, which represents time demanding amendments of product documentation both from by holder and by the Institute. Threrefore the number of granted applications (34) prevails the number of received applications(18). In case that authorisation holder does not apply for extension, the validity expires. Another possibility to terminate the authorisation is upon the marketing authorisation holder application or upon the authority suspension. In 2014 there were 48 marketing authorisation terminated (out of the total number of authorised products by NP, MRP, DCP). 32

33 The highest number of domestic administrative procedures is represened by procedures for variation of authorisation. Applicants for domestic authorisation variations use the possibility to cummulate variations, where the applicant may apply for more variations in one application, in some cases for more registration numbers, which is enabled by amendment of the Act No. 378/2007 Sb., in direct consequence with directly applied Regulation of European Commission (EC) No. 1234/2008 as ammended by No. 712/2012 on evaluation of variations to marketing authorisation of human and veterinary medicinal products. Cathegorization of variations is determined in announcement of Commission C (2013) 2804 dated in May 16, 2013 Instructions for various cathegories of variations which enables flexibility of assessment. Another Regulation of European Commisssion (EC) No. 1234/2008 dated on November 24, 2008 on assessment of variations to marketing authorisations of human and veterinary medicinal products is used both for procedures determined in Chapters II, IIa, III and IV, and for the documentation which should be submitted within mentioned procedures. Due to the possibility of cummulation of variations into one application, to determine number of of applications for variation the Institute (since 2013) has been presenting the number of received applications instead of presenting real number of assessed variations in every application. In 2014 the number of applications for variation signifiantly icreased. The highest number is in applications for variation type IA, IA IN. In total during the year there was received 547 applications for variation and 610 applications type IA, IA IN were granted (including applications submitted before the end of previous year. In previous year there were 239 granted applications. The second highest number of applications were applications for variation type IB amounting to 189 with 134 granted applications in total. Nevertheless, it is necessary to mention, that thanks to the possibility of cummulation there was granted also considerable amount of variations of type IA, IA IN, resulting from the main variation IB. Total number of granted variations of type II, which could considerably ifluence quality, safety or efficacy in given medicinal product is 94. Also these applications related to main variation included other variations type IB, IA or IA IN, In case when during the course of marketing authorisation procedure the authorisation has been handed-over from original holder to the new one, there is applied another domestic procedure based on the application for transfer of authorisation. This domestic procedure is being applied both for the domestic autorised products and for te products authorised in MRP/DCP. However, in 2014 there was no such application. Another domestic procedure represented in the table is application for parallel import. This procedure is determined as a distribution of medicinal product from another member state into the Czech Republic, provided that marketing authorisation for this product has been grated in the Czech Republic and in the memer state and distribution is not ensured by the marketing authorisation holder in the Czech Republic or in cooperation with this holder. In 2014 there were 6 applications received and granted. 33

34 Tab. 5/3 : Summary of number of submitted applications and granted applications in 2014 by national procedure Type of marketing authorisation Cathegory of VMP Number of applications Submitted applications Granted applications* Marketing authorisation Renewal of marketing authorisation Marketing authorisation transfer Marketing authorisation withdrawal Parallel import Pharmaceuticals Immunologicals 5 2 Pharmaceuticals Immunologicals 5 17 Pharmaceuticals 0 0 Immunologicals 0 0 Pharmaceuticals Immunologicals 4 4 Pharmaceuticals 1 1 Immunologicals 5 5 Authorisation Variations represent number of submitted applications, not real number of assessed variations in one application 1 Authorisation variation type IA Authorisation variation type IB Authorisation variation type II Pharmaceuticals Immunologicals Pharmaceuticals Immunologicals Pharmaceuticals Immunologicals * Higher number of granted applications than number of applications submitted means, that in given year there were completed also applications submitted at the end of previous year. 1 In compliance with regulation of Directive No. (ES) 1234/2008 and ammendment No. (ES) 712/2012 it is possible to aggregate variations to marketing autorisation into one application so called form of aggregation of Variations and distribution of work. The number mentioned in table for 2013 thus represents number of applications submitted, not the number of real variations of marketing authorisation processed. 34

35 Tab. 5/4: Number of submitted and granted applications in 2014 in comparison with previous years Type Application for new marketing authorisation Application for renewal of marketing authorisation Year Submitted Applications Granted Applications Application for marketing authorisation variation (in 2014, as well as in 2013 number of variations to marketing authorisation represents number of applications submitted, not the real number of assessed variations incorporated in application,appart from previous years ) Application for marketing authorisation transfer 2014* 2013* Application for marketing authorisation withdrawal Application for discontinuance of administrative proceeding

36 Appeal against the MA decision Administrative corrections in the MA decisions Total * In compliance with regulation of Directive No. (ES) 1234/2008 and ammendment No. (ES) 712/2012 it is possible to aggregate variations to marketing autorisation into one application so called form of aggregation of Variations and distribution of work. The numbers mentioned in table for 2013 and 2014 thus represent numbers of applications submitted, not the number of real variations of marketing authorisation processed. In 2014 the Section of marketing authorisation, approval, registery and clinical trials received 1617 applications and grated 1603 applications. Compared to 2013, when the Institute for the first time accepted the systém of application calculation, thus without taking into account real numbers of variations assessed, the numbers of received and granted applications for variation were lower. In 2014 despite the new systém of application calculation there is considerable increase of received applications. In the 9 years period it is the highest number of received and granted applications. The amount of administrative load and proffesional work in the Section of marketing authorisation has increased. Summary of VMP authorised according to its character and way of dispensing On the date of Dec 31, 2014 in the Czech Republic were authorised 1738 veterinary medicinal products in total, from which there were 1326 pharmaceutical products and 412 immunological products. Percentual representation of veterinary medicinal products according to way of dispensing remains on the constant level. Veterinary edicinal products on prescription still represent nearly 90% from the total number of VMP, less amount these are OTC veterinary products and so called selected medicinal products without limitation to dispensing on prescription similarly to OTC medicines, which can be sold also by retailers of 36

37 selected medicinal products. At present, there are also veterinary medicinal products with various forms of dispensing (OTC or selected) based on the size of packaging. The last cathegory in terms of dispensing are veterinary products solely used by veterinary practicioner. Tab. 5/5: Summary of authorised VMP according to its character and way of dispensing and usage Type of VMP Total Prescription only VMP (RP) OTC VMP (VP) Selected VMP (VY) Solely used by veterinary practicioner (OV) Pharmaceutical products Immunological products Total Obr. 5/5-2: Percentual representation of authorised VMP according to way of dispensing and usage 89% 6% RP VP VY OV RP vázaná na předpis VP volně prodejná VY vyhrazená OV pouze pro použití vet. lékařem 1% 4% 5.2 Antibiotic policy Sphere of antimicrobial policy is distinguished with enormously high international activity namely in international context. ISCVBM and its experts actively participate in number of actions and projects within this sphere both at national and at international level. During 2014 active participation continued on meetings of Central coordination Group of National Antibiotic Program CKS NAP. Representative of ISCVBM (Prof. A. Hera) 37