Institute for State Control of Veterinary Biologicals and Medicines Ústav pro státní kontrolu veterinárních biopreparátů a léčiv

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1 Institute for State Control of Veterinary Biologicals and Medicines Ústav pro státní kontrolu veterinárních biopreparátů a léčiv Ústav pro státní kontrolu veterinárních biopreparátů a léčiv Hudcova BRNO Czech Republic uskvbl@uskvbl.cz MUTUAL RECOGNITION PROCEDURE FOR A VETERINARY MEDICINAL PRODUCT BioBos IBR marker inact, suspension for injection for cattle

2 MODULE 1 PRODUCT SUMMARY EU Procedure number Name, strength and pharmaceutical form Applicant Active substance(s) ATCvetcode Target species Indication for use BioBos IBR marker inact, suspension for injection for cattle a.s. Komenského Ivanovice na Hané Czech Republic Bovine Herpesvirus type 1(BHV-1) inactivated (strain Bio-27: IBR ge-) QI02AA03 Cattle For active immunization of cattle to reduce intensity and duration of the clinical signs caused by infection with BHV-1 (IBR) virus and to reduce excretion of the field virus. MODULE 2 The Summary of Product Characteristics (SPC) for this product is available on the Heads of Veterinary Medicines Agencies website ( 2/10

3 MODULE 3 PUBLIC ASSESSMENT REPORT Legal basis of original application Date of completion of the original mutual recognition procedure Date product first authorised in the Reference Member State (MRP only) Concerned Member States for original procedure Mutual Recognition application in accordance with Article 31 of Directive 2001/82/EC as amended. 20/12/ /02/2013 BG, EE, HU, LT, LV, PL, RO, SI, SK I. SCIENTIFIC OVERVIEW The vaccine BioBos IBR marker inact is an inactivated and adjuvanted monovalent vaccine which is intended for active immunization of cattle to reduce the intensity and duration of the clinical signs caused by infection with BHV-1 (IBR) virus and to reduce the excretion of the field virus. Active immunity starts 3 weeks after the basic vaccination and persists for 6 months after the basic vaccination. The recommended vaccination scheme is vaccination cattle from the age of 3 months onwards with two applications of 2 ml vaccine at an interval of 3 weeks. Administration route is intramuscular injection. The withdrawal period is zero days. Stability data, which support the proposed shelf-life of 2 years, have been provided. The product is produced and controlled using validated methods and tests, which ensure the consistency of the product released on the market. It has been shown that the product can be safely used in the target species; the reactions observed are indicated in the SPC. The product is safe for the user and for the environment, when used as recommended. Suitable warnings and precautions are indicated in the SPC. The efficacy of the product was demonstrated according to the claims made in the SPC. The overall risk/benefit analysis is in favour of granting a marketing authorisation. 3/10

4 II. QUALITY ASPECTS A. Composition Composition: One vaccination dose (2 ml) contains : Active substance: Bovine herpesvirus type 1 (BHV-1) inactivated, strain Bio-27: IBR ge - RP 1* *) RP = Relative potency (ELISA test) compared with the reference serum obtained after vaccination of the guinea pigs with the vaccine batch that has successfully passed the challenge test in the target species. Adjuvants: Aluminium hydroxide, hydrated for adsorption Quillaja saponin (Quil A) Excipiens: Thiomersal The vaccine is presented in: Glass vials, hydrolytic class, type I (Ph.Eur.): 10 ml vial with 10 ml. Glass vials, hydrolytic class, type II (Ph.Eur.): 50 ml vial with 50 ml or 100 vial with 100 ml. Plastic vials (HDPE): 60 ml vial with 50 ml or 120 ml vial with 100 ml. Vials are hermetically closed with the rubber stoppers, sealed with the aluminium caps and placed in a cardboard or plastic box. Package leaflet is included in each package. Package size: Plastic boxes: 10 x 5 doses (10 x 10 ml) Cardboard boxes: 1 x 5 doses (1 x 10 ml), 1 x 25 doses (1 x 50 ml), 1 x 50 doses (1 x 100 ml) The particulars of the containers and controls performed are provided and conform to the regulation of monographs and of the European Pharmacopoeia. The choice of the vaccine strains, of the vaccine composition, adjuvant, inactivating agent, preservative, of the dose volume and vaccination schedule are justified. The inactivation process and the detection limit of the control of inactivation are correctly validated. The product is an established pharmaceutical form and its development is adequately described in accordance with the relevant European guidelines. 4/10

5 B. Method of Preparation of the Product The product is manufactured fully in accordance with the principles of good manufacturing practice from a licensed manufacturing site. A corresponding manufacturing licence and GMP certificates are provided. Process validation data on the product have been presented in accordance with the relevant European guidelines. The product is manufactured in accordance with the European Pharmacopoeia and relevant European guidelines. C. Control of Starting Materials Starting materials of non-biological origin used in production comply with indicated pharmacopoeia monographs. Biological starting materials used are in compliance with the relevant Ph. Eur. Monographs and guidelines and are appropriately screened and appropriately treated for the absence of extraneous agents according to the Ph. Eur monographs. The master and working seeds have been produced according to the Seed Lot System as described in the relevant guideline and satisfactorily tested according to current Europea requirements. Specific Measures concerning the Prevention of the Transmission of Animal Spongiform Encephalopathies Scientific data and/or certificates of suitability issued by the EDQM have been provided and compliance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products has been satisfactorily demonstrated. D. Control tests during production The tests performed during production (continuous microscopic control of cells, IBR ge- virus titre before inactivation, inactivation, titre of IBR ge- virus after inactivation, sterility test, ph determination, thiomersal, alumina) are described in detail and the results of 3 consecutive runs, conforming to the specifications, are provided.. E. Control Tests on the Finished Product The tests performed on the final product conform to the relevant requirements; any deviation from these requirements is justified. Relevant validations are provided. The tests include in particular: - appearance - user volume test 5/10

6 - sterility - identity - potency - ph value - airtightness - thiomersal content - alumina content The demonstration of the batch to batch consistency is based on the results of 3 batches produced according to the method described in the dossier. F. Batch to batch consistency The consistency of production has been demonstrated and the results of 3 consecutive runs, conforming to the specifications, are provided. G. Stability Stability data on the active substances have been provided in accordance with applicable European guidelines, demonstrating the stability of the active substance. The shelf life of non-inactivated IBR antigen (live virus) is 12 months at a temperature of -50 C or lower. Inactivated IBR virus may be stored for 3 months at 2-8 C or for 12 months at a temperature of -20 C or lower. During the manufacturing process of BioBos IBR marker inact. in the bulk vaccine may be stored for up to 4 weeks at 2-8 C. The stability of the bulk vaccine stored in this way was verified by stability data on the finished product. Stability data on the finished product have been provided in accordance with applicable European guidelines, demonstrating the stability of the product throughout its shelf life (2 years) when stored under the approved conditions (2-8 C). The BioBos IBR marker inact.vaccine is filled into multidose containers. The period during which the vaccine is consumed in veterinary practice by administration to the target species is referred to as shelf life after first opening and was verified. The shelf life after first opening of the vaccine is 10 hours at 2-8 C. III. SAFETY The vaccine is recommended for cattle from the age of 3 months onwards for 2 doses intramuscular administration at an interval of 3 weeks. Safety clinical findings have been based on the recommended vaccination scheme. Laboratory trials Safety studies have been performed with a vaccine batch (containing maximum content of the antigen) produced according the described production process. 6/10

7 The safety of the administration of one dose and the repeated administration of one dose in the target animal is demonstrated in controlled laboratory study which in total included 8 vaccinates animals (8 animals free of antibodies, aged 2-3 months). The investigation was performed according to the recommendations of Directive 2001/82/EC as amended and the relevant guidelines. The safety study demonstrates that the administration of one dose and the repeated administration of one dose can be considered to be safe, when used in accordance with the recommended vaccination schedule. The observed reactions are reflected in the relevant SPC and package leaflet sections. Hypersensitive reactions may occur in connection with the performed vaccination. In such cases an appropriate symptomatic treatment should be administered. Vaccine contains adjuvant which can cause transient local swelling of the size up to 2 cm in diameter. This swelling disappears within 4 days after vaccination. Examination of reproductive performance Vaccine can be used during pregnancy and lactation. Therefore, a special study was conducted in which rectal temperatures were measured and systemic and local reactions were evaluated after administration of the vaccine to pregnant animals. The trial was conducted on 24 cows (8 cows in each trimester of pregnancy). The effect of vaccination on the course of pregnancy and on newborn calves was also monitored. There are no data suggesting that this product might adversely affect the immune system of the vaccinated animal or its progeny therefore a specific study was not carried out. The vaccine is inactivated and thus the specific tests to be performed for live vaccines are not applicable. The vaccine contains the adjuvant substances Quil A and hydrated aluminium hydroxide, their concentrations in a single vaccine dose are so low that they pose no serious risk to the user. The vaccine contains thiomersal as preservative. Thiomersal does not pose any significant risk to consumers. Thiomersal is included in the list of allowed pharmacologically active substances presented in the Annex (Annex - Pharmacologically active substances and their classification in relation to MRL) to Commission Regulation No. 37/2010, without necessity to set MRLs for food animals. According to the Commission for Veterinary Medicinal Products (EMEA/MRL/140/96), it is not necessary to establish a MRL for thiomersal used as a preservative in multi-dose vaccines, in concentrations not exceeding 0.02%. Beta-propiolactone used as inactivating agent does not pose any significant risk to consumers. For these reasons, the determination of residues in animal tissues after administration of BioBos IBR marker inact. was not performed. No specific assessment of the interaction of this product with other medicinal product was made. Therefore, an appropriate warning in the SPC is included. Field studies Combined safety and efficacy field trial was performed on target animals. Vaccination was carried out on three cattle farms where animals of the youngest age recommended for vaccination and pregnant animals were vaccinated. Twenty pregnant animals and ten calves from 3 months of age were vaccinated in each herd. The vaccine was administered in accordance with the procedure recommended in the draft 7/10

8 package leaflet. The control groups vaccinated and revaccinated with Rispoval IBR - Marker inactivatum (comparator product), were included in the study. Milk yield was monitored in connection with the performed vaccination in 10 vaccinated cows on one farm. Simultaneously, a control group of 10 unvaccinated cows was formed. Average milk yield of the groups was compared in the period before and after vaccination and between the groups. The safety and efficacy of the vaccine in the field has been demonstrated. The results from field trials reflect those observed in laboratory trials. Ecotoxicity The applicant provided a first phase environmental risk assessment in compliance with the relevant guideline which showed that no further assessment is required. The conclusions of the environmental risk assessment as presented by the applicant, that there is a negligible risk to the environment associated with use of the vaccine, are accepted. The applicant has included the standard disposal statement for inactivated vaccines on the product literature and this is considered acceptable. IV. EFFICACY All experiments conducted with BioBos IBR marker inact. in laboratory and field conditions were designed to meet the requirements of the relevant veterinary legislation, including European Directive 2001/82/EC, as amended (2009/9/ES). The clinical evaluation was carried out in accordance with Act No. 378/2007 Coll., as amended, and Decree No. 226/2008 Coll., according to the Experiment Project approved by the Central Commission for Animal Welfare, and on the basis of the permission of clinical evaluation of the medicinal product issued by the Institute for State Control of Veterinary Biologicals and Medicaments in Brno. All studies on the target species, which were used to evaluate the efficacy of the vaccine BioBos IBR marker inact., were conducted by a.s., Ivanovice na Hané in the territory of the Czech Republic. The tests included challenge and serological tests on animals. Animals of private keepers were included in the studies. For verify the efficacy of developed vaccine in target animals were used two batches: batch with the minimum antigen content proposed for common production batches and sublimit batch with 10% of antigen content against the consider minimum antigen content. The chalenge virus was isolated from the nasal swab of a clinically ill calf with respiratory disease of a herd in the Czech Republic in the year Laboratory Trials The efficacy of the product has been demonstrated in laboratory studies in accordance with the relevant requirements. Onset of immunity The study focuses on the onset of immunity in animals against infectious bovine rhinotracheitis and was conducted according to the EP monograph 6.0, 01/2008: 0696 Article Immunogenicity (for live vaccine against IBR). The study enrolled 10 vaccinated calves and 2 control calves free of antibodies against IBR aged 2-3 months. The tested vaccines (100% and 10%) were administered to the animals intramuscularly, at a recommended dose, in accordance with the vaccination schedule. The animals were 8/10

9 challenged with IBR virus 21 days after the basic vaccination and observed for the presence of clinical signs and virus shedding (by nasal swabs). Moreover, blood samples were collected to determine the level of antibodies against IBR virus by serum neutralization test. Efficacy was evaluated by comparing the score of clinical signs of the disease and virus reisolation following challenge in groups vaccinated with 100% and 10% antigen content as compared with the control group of unvaccinated animals. It was verified that administration of 1 dose of BioBos IBR marker inact. in seronegative calves at the age of 2-3 months is effective for reduction of the intensity and duration of the clinical signs caused by infection with BHV-1 (IBR) virus and to reduce the excretion of the field virus. The indications for use and the information on onset of immunity are reflected in the relevant SPC and package leaflet sections. Duration of immunity The study enrolled 5 vaccinated calves and 2 control calves free of antibodies against IBR. The vaccine was administered to the animals at a recommended dose, in accordance with the vaccination schedule. The animals were challenged 6 months after the basic vaccination and observed for the presence of clinical symptoms. Moreover, blood samples were collected to determine the level of antibodies against IBR virus by serum neutralization test and nasal swabs were made to determine the virus titre. The efficacy of the vaccine BioBos IBR marker inact. with minimum potency was demonstrated satisfactory in the challenge test performed according to the monograph in EP 6.0, 01/2008:0696 Art Immunogenicity (of live vaccine against IBR) using two administrations at a 21-day interval, to calves 2-3 months old, free of maternal antibodies to IBR, with challenge made 6 months after the basic vaccination. The indications for use and the information on duration of immunity are reflected in the relevant SPC and package leaflet sections. The effect of booster vaccination in calves aged 3 months The study enrolled 5 vaccinated animals free of antibodies against IBR. The vaccine was administered to the animals at a recommended dose, in accordance with the vaccination schedule. Within the study, rectal temperatures, local and systemic reactions were monitored in animals after primary vaccination, revaccination and booster vaccination and the antibody response to BioBos IBR marker inact. was evaluated. Serological tests confirmed that after the booster vaccination there was a rise in the level of specific antibodies against IBR virus to a level comparable with or higher than the level of antibodies obtained after primary immunization, which passed successfully by challenge test. The positive effect of booster vaccination was demonstrated. Field studies Combined safety and efficacy field trial was performed on target animals. Vaccination was carried out on three cattle farms where animals of the youngest age recommended for vaccination and pregnant animals were vaccinated. 9/10

10 Methods of evaluation of efficacy: a) Evaluation of the product efficacy in animals of the minimum age recommended for vaccination b) Evaluation of the effect of passively acquired and maternal antibodies on the vaccination of calves c) Evaluation of efficacy of the product administered to pregnant cows The field testing demonstrated the satisfactory safety and efficacy of the vaccine BioBos IBR marker inact. The results obtained in field studies confirm laboratory trials findings. The field studies verify the efficacy of administration of the test product under field conditions included the youngest category of animals for which the vaccine is intended, i.e. i.e. calves from 3 months of age and pregnant animals. Simultaneously, the efficacy (seroconversion) of the vaccine was proved in the presence of colostral antibodies. The field study was demonstrated that vaccination has an effect in animals in the presence of maternal antibody. However, verifying the influence of maternal antibodies was not carried out according to the instruction of EMA/CVMP/IWP/439467/2007 (Reflection paper on the demonstration of possible impact of maternally derived antibodies on the vaccine efficacy in young animals) and therefore it cannot be considered sufficient. In addition, this information is reflected in the summary of product characteristics point 4.4: Efficacy has not been demonstrated in the presence of maternally derived antibodies. V. OVERALL CONCLUSION AND BENEFIT RISK ASSESSMENT The data submitted in the dossier demonstrate that when the product is used in accordance with the Summary of Product Characteristics, the risk benefit profile for the target species is favourable and the quality and safety of the product for humans and the environment is acceptable. 10/10