Báo cáo Nghiên cứu khoa học Diagnosis and control of diarrhoea in suckling pigs: Vaccine produced and efficacy tested

1 Ministry of Agriculture & Rural Development CARD Project Progress Report 001/04VIE Diagnosis and control of diarrhoea in suckling pigs MILESTONE 5: Vaccine produced and efficacy tested 2 Table of Contents 1. INSTITUTE INFORMATION ...........................................................................................................................3 2. PROJECT ABSTRACT ......................................................................................................................................4 3. MS ACHIEVEMENTS.......................................................................................................................................4 4. CONCLUSION ...................................................................................................................................................8 APPENDIX ONE:..........................................................................................................................................................9 3 1. Institute Information Project Name Diagnosis and control of diarrhoea in suckling pigs Vietnamese Institution National Institute of Veterinary Research (NIVR) Vietnamese Project Team Leader Dr. Cu Huu Phu Australian Organisation The University of Queensland/Victorian Department of Primary Industry Australian Personnel Dr Darren Trott, Dr Ian Wilkie, Dr Tony Fahy Date commenced April 13th 2005 Completion date (original) January 2007 Completion date (revised) April 2008 Reporting period March 2006-March 2008 Contact Officer(s) In Australia: Team Leader Name: Dr Darren Trott Telephone: 617 336 52985 Position: Associate Professor of Veterinary Science Fax: 617 336 51355 Organisation School of Veterinary Science The University of Qld Email: d.trott@uq.edu.au In Australia: Administrative contact Name: Melissa Anderson Telephone: 61 7 33652651 Position: Manager Research Projects Office Fax: 61 7 33651188 Organisation School of Land and Food The University of Qld Email: In Vietnam Name: Dr Do Ngoc Thuy Telephone: 84 4 8693923 Position: Head of Bacteriology Department Fax: 84 4 8694082 Organisation NIVR Email: 4 2. Project Abstract This project is designed to improve the productivity of smallholder pig farmers in Vietnam through improved health management, particularly of piglets during the pre-weaning period. Additional to the health management plan the project will develop and implement appropriate rapid diagnostic tests for the principal causes of pre-weaning diarrhoea to improve speed and accuracy of laboratory diagnosis. The third part of the project seeks to improve the production and efficacy of a locally-manufactured E. coli vaccine for the control and prevention of neonatal colibacillosis. In this phase, the E. coli vaccine, based on three major strains identified and characterized by Dr Do Ngoc Thuy during her PhD studies, was tested for safety and efficacy and is now being produced by the National Institute of Veterinary Research. The vaccine is currently being used in a related CARD project (A blueprint for smallholder pig production XXXX) . 3. MS achievements This report documents progress on the following deliverables for MS 5 (linked to the project logframe objective 1: Production and testing of locally produced E. coli vaccine): 1. Vaccine strains characterized. 2. Combined vaccine produced and available. 3. Efficacy testing completed, results analysed and reported. 4. Analysis of benefit:cost of local vaccine production 5. Strategies and pathways for commercial vaccine production and distribution Evidence: 1) Vaccine strains characterized: This is extensively detailed in Appendix 1 of the recently submitted MS 3 and MS 6 report. The vaccine Master Seed (50 x 1ml vials of each of the three vaccine strains in Brain Heart Infusion broth plus 12% glycerol) is held in a -80oC freezer at NIVR. Backup freeze dried cultures are also held at NIVR in case of a catastrophic freezer failure (if the -80oC freezer breaks down, the strains can be held at - 20oC for a short duration). Each time the vaccine is prepared according to the protocol outlined in Appendix 2 of the MS 3 and MS 6 report, a new vial of the Master Seed is subcultured and checked for purity. This then becomes the Working Seed for vaccine preparation, with the number of subcultures kept to an absolute minimum and culture conditions used for maximum fimbriae expression. Backup cultures are also held at The AQIS approved laboratory of The University of Queensland School of Veterinary Science (Managed by Associate Professor Darren Trott) and the OIE E. coli reference laboratory at The University of Montreal (managed by Prof John Fairbrother). 2) Combined vaccine produced and available: This is extensively detailed in Appendix 2 in the recently submitted MS 3 and MS 6 report. It should be remembered that currently the vaccine is unregistered and as such, it has only been produced in small amounts for the Northern herds that took part in the initial surveys in 2005/2006 and for the central provinces of Quang Tri and Thua Thien Hue, as part of the fulfilment of the 004/05VIE 5 project. Thus far, no vaccine reactions, ill-health or poor efficacy have been reported, though it must be remembered that no samples for piglets with diarrhoea in the first week of life have been obtained from vaccinated herds to 100% confirm efficacy (this will be conducted in the field trial to be held in Central Vietnam on test and control farms). Anecdotal reports from Northern herds and from Central Vietnam suggest that the vaccine achieves excellent protection from neonatal diarrhoea during the first week of life, however again this has not been substantiated in a controlled trial. Vaccine production records from NIVR are as follows: Record of vaccine production 2006 Testing Bach No. No. of doses Safety Sterility Note (vaccinated province) 1 205 X X Thai Binh 2 576 X X Thai Binh, Hai Phong 3 1.008 X X Thai Binh, Ha Tay, Hai Phong, Thai Nguyen 2007 Testing Bach No. No. of doses Safety Sterility Note (vaccinated province) 1 300 X X Hai Duong, Phu Tho 2 807 X X Thai Binh, Thai Nguyen 3 2015 X X Hai Phong, Ha Tay, Ninh Binh, Phu Tho, Vinh Phuc 2008 Testing Bach No. No. of doses Safety Sterility Note (vaccinated province) 1 407 X X Ha Tay 2 986 X X Thai Binh, Hai Phong 3 2010 X X Phu Tho, Vinh Phuc, Hai Phong, Hai Duong, Hue, Quang Tri 4 1786 X X Thai Nguyen, Vinh Phuc, Hai Phong 6 2009 Testing Bach No. No. of doses Safety Sterility Note (vaccinated province) 1 820 X X Hue, Quang Tri 3) Efficacy testing completed, results analysed and reported: A full report on the efficacy testing of the vaccine in small scale trials, in terms of protection afforded to neonatal piglets, safety of the vaccine and comparison with existing commercial vaccines for induction of specific protective antibody levels was detailed in Appendix 3 of the MS 3 and 6 report. Experiments involving live animals are expensive and we believe that the testing undertaken thus far for 001/04VIE satisfies this deliverable. As part of 004/05VIE, we plan to conduct a field trial in Central Vietnam encorporating a study of the major causes of pre-weaning diarrhoea in test demonstration and control farms. As such progress on this deliverable will be reported in the project validation and final reports for 004/05VIE in early 2010. 4) Analysis of benefit:cost of local vaccine production: A detailed benefit:cost analysis of the local vaccine vs imported vaccine vs treatment only vs no treatment is provided below. Table 1: Benefit:cost analysis of locally produced NIVR E. coli vaccine vs imported commercial vaccines (price comparison). Vaccine Characteristics Pfizer Litterguard Intervet EcoVac NIVR Vaccine Type of vaccine Killed whole cell plus toxoid Killed whole cell Killed whole cell Components (Fimbriae) F4, F5, F6, F41 (also Clostridium toxin) F4, F5, F6, F41 F4, F5, O8 F19 (3 strains)* Cost per dose (Dong) 20,000 VND 20,000 VND 4,000 VND *To date, only three fimbrial types have been identified in neonatal piglets with colibacillosis in Vietnam, F4, F5 and the new F19 antigen. It is difficult to estimate the direct costs resulting from mortality and stunted growth of smallholder piglets due to neonatal colibacillosis. In many cases, the disease occurs so rapidly that neonatal piglets are found dead or in a severe state with dehydration, metabolic acidosis and profuse, watery diarrhoea. Based on current 2009 prices for weaner Mong Cai piglets (and not including the fact that in 004/05VIE, we are trying to organize a breeders collective, providing breeder Mong Cai weaners to other farmers at much higher prices), the following scenarios provide some estimate of benefit:cost. 7 Scenario 1: Farmer does not use any vaccine for neonatal colibacillosis and the litter dies or their health is severely compromised: Costs of doing nothing (loss of all pigs): Average price per weaner: 70,000-80,000 VND (for fattening); 160,000 VND (for breeder) Average litter size weaned: 10 Estimated loss: 700,000-1,600,000 VND per litter (not including costs of maintaining sow until next pregnancy). Scenario 2: Successful treatment of sick piglets Costs of medication (fluids and electrolytes, antimicrobials): - Note most smallholder farmers are using fluoroquinolones which are banned in Australia for the treatment of food-producing animals (and no withholding periods in Vietnam). This has an important public health impact that will need to be addressed in the future as fluoroquinolones are important drugs in human medicine and resistance is growing. Cost per treatment: Antimicrobials: 6,000 VND per pig Electrolytes: 10,000 VND per pig Labour/syringes: 5,000 VND per pig Reduced growth rates of sick pigs: 20,000 VND per pig Total cost: 41,000 VND per pig Number of pigs weaned = 8 (assuming that two pigs die despite treatment) Total costs: 410,000 VND Scenario 3: Pfizer Litterguard used to prevent neonatal colibacillosis. 20,000 VND x 2 doses Labour: 5,000 VND per injection Total costs: 50,000 VND per litter Scenario 4: NIVR E. coli vaccine 4,000 VND x 2 doses Labour: 5,000 VND per injection Total costs: 18,000 VND per litter Cost-benefit analysis based on minimum price for pig sales based on a littersize of 10 piglets weaned. Summary Do nothing Treatment Pfizer Littergard NIVR Vaccine Costs 700,000 328,000 50,000 18,000 Income nil 560,000* 700,000 700,000 Profit/loss -700,000 232,000 650,000 688,000 *Assuming that two piglets die per litter despite treatment. 8 5) Strategies and pathways for commercial vaccine production and distribution. This has proven to be the most difficult deliverable to negotiate. NIVR continues to produce the vaccine for research purposes, as attested by the vaccine records, but registration requires a detailed document to be submitted to the Department of Animal Health (Appendix ONE with this report). Most of the requirements for registration, including safety and efficacy have been met by the current project, with the final trial in central Vietnam providing necessary field efficacy data. NIVR Bacteriology Laboratory is not experienced in the commercialization of its discoveries, therefore we suggest partnership between the two major local vaccine manufacturers that hold GMP/GLP licenses, NAVETCO (for the south of Vietnam) and the National Veterinary Factory (for the north) to complete the registration dossier. Prior to this occurring however, we advise that the project hire a patent attorney to assist Dr Do Ngoc Thuy, the inventor of the vaccine to lodge a patent application with the Office of Intellectual Property of Vietnam within the Ministry of Science and Technology. Once this is obtained, negotiations may be commenced whereby the level of royalties returning to the sole inventor and the NIVR laboratory are clearly indicated. The assistance of the CARD programme management team is also requested to foster negotiations with the Department of Animal Health and other major stakeholders. This will ensure that delays are kept to a minimum and that the vaccine becomes readily available for use by smallholder farmers. Such a strategy towards commercialization could also be used for other NIVR vaccines, such as the NIVR oedema disease vaccine that has excellent efficacy but is currently unregistered. Oedema disease is also a major problem faced by smallholder farmers. 4. Conclusion The deliverables for MS 5 have been achieved within the project logframe. Given the success of the final field trial in central Vietnam, we anticipate that it will be a further 12 months before the vaccine becomes available. NIVR will continue to supply small batches of the vaccine for research purposes, particularly in the extension projects planned for 2010 in central Vietnam and to confirm the continued safety and efficacy of the product. 9 APPENDIX: GUIDELINES FOR REGISTRATION OF VETERINARY MEDICINES IN VIETNAM MINISTRY OF AGRICULTURE AND RURAL DEVELOPMENT DEPARTMENT OF ANIMAL HEALTH SOCIALIST REPUBLIC OF VIETNAM Independence-Freedom-Happiness No: 788 /TY-QLT Hanoi, 05 December 2003 GUIDANCE ON THE REGISTRATION PROCEDURES FOR OBTAINMENT, MODIFICATION AND RENEWAL OF MARKETING AUTHORIZATIONS OF VETERINARY MEDICINAL PRODUCTS IN VIETNAM Pursuant to “the Regulation on the Implementation of the Ordinance on Veterinary Services”, “the Rule on Veterinary Medicine Management” issued under Governmental Decree 93/CP dated on 27 November 1993. Pursuant to "Promulgation of the Regulation on the Procedures for Registering Veterinary Drug Manufacture, Trade, Trial, Quality Control and Micro-organism Strains used by the Veterinary Services" issued under Decision No.194 NN-TY/QĐ dated on 31 December, 1994 of the Minister of Agriculture and Food industry; Pursuant to "Decision No.89/2003/BNN-QĐ dated on 04 September, 2003 of the Minister of Agriculture and Rural Development function, responsible, rights and structure of DAH; In order to improve the quality of the management of veterinary medicinal products, to protect efficiently the animal production, to ensure the hygiene and the safety of foods for consumers, to favour the integration into ASEAN, the DAH has adopted this guidance on the registration procedures for obtainment, modification and renewal of marketing authorizations of veterinary medicinal products in Viet Nam as follows: I/ REGISTRATION FOR OBTAINMENT OF MARKETING AUTHORIZATIONS OF VETERINARY MEDICINAL PRODUCTS. Registered dossier for obtainment of marketing authorizations of veterinary medicinal product must be prepared in three copies, made clearly of A 4 size pages and right order of parts: One copy is submitted to the DAH One copy is submitted to the control institutions (content includes qualitative standards and methods of quality control) One copy is kept by the applicant 1. Content of the dossier: One registered dossier for marketing authorizations including 8 parts: (DRAFT OF TRANSLATION) 10 Part 1: Cover page (Form 1), table of content (Form 2) Part 2: Registration application form (form 3) Part 3: Summary of product characteristics (SPC, Form 4) Part 4: Label of VMP Part 5: Technical information on the quality of the VMP Part 6: Technical information on the safety and on the efficacy of the VMP. Part 7: Certificates of GMP, ISO, etc. The copy must be verified by the competent institution. Part 8: Any other relevant documents (certificates of manufactures and government laboratories for quality control of VMPs, results of trials, etc). Registered dossier for imported VMPs must be written in Vietnamese or English. The SPC must be written in Vietnamese. 1.1. The cover page and table of content registered dossier: 1.1.1. The cover page must include (Form 1): + The purpose of the application: for marketing authorization + The name of the applicant + The name of the VMP for registration. 1.1.2. Table of content registered dossier (Form 2): Parts of dossiers must be in right order with page numbers. 1.2. Registration application form: The registration application form must contain following contents: - Name and full address of the applicant - Name of the VMP - Pharmaceutical form of the VMP - Complete qualitative and quantitative composition of the VMP - All the different packagings - Therapeutic claims and dosages for each target animals - Withdrawal times for meat, milk and eggs if applicable - For import VMPs must have: The MA from the country of origin, other countries (if available); Certificate of GMP. The copies must be verified by the competent institutions. 1.3. Summary of product characteristics (SPC): The SPC is a document containing all the key information on a given VMP submitted to the MA procedure. At the end of this procedure, the DAH will check this information that is in compliance with the content of then MA and with the conditions of use of the VMP accepted in the MA. If it is not the case, DAH will ask the applicant to modify the SPC accordingly the national and international standards. 11 Once approved by the DAH, the SPC becomes an official document, attached to the MA, which provides the technical basis for the content of labels and package inserts. 1.3.1. Name of the VMP: Names of VMPs must be original names and not generic names, not copy of names that have patents. They are chosen so that they do not lead to any confusion with regard to the nature, the composition and the therapeutic effects of the VMP of concern. Names of the components of the VMP, active substances and excipients, must be the international common names. For components that originate animals, plants, minerals must be written in common names and scientific names in Latin. 1.3.2. Pharmaceutical form of VMP 1.3.3. Route of administration 1.3.4. Qualitative and quantitative composition 1.3.5. Pharmacological properties: - Pharmacodynamics - Pharmacokinetics 1.3.6. Therapeutic claims - Target animal species (names of animal species must be written specifically. Example: cattle, pig, poultry, etc). - Therapeutic claims - Dosages for each therapeutic claim and animal species 1.3.7. Specific warnings regarding the use of the VMP in the target animals - Specific cautions for use - Possible interactions with other VMPs, types of interactions - Unwanted side effects in case of use according to the recommended dosage. - Unwanted side effects in case of over dosage - Information about the use in pregnant, lactating and laying animals - Contraindications 1.3.8. Specific warnings regarding persons administrating the VMP to animals 1.3.9. Withdrawal times 1.3.10. Pharmaceutical information: - Expiry date of the VMP: + Before the opening of the primary packaging + If applicable, after: the opening of the primary packaging reconstitution of the VMP. - Special conditions for storage - Description of the nature and of the content of the primary packaging - Special indications, if applicable, for the elimination of the part of the VMP which has not been used. 12 1.3.11. Name and full address of the applicant and, if different, of the manufacturer of the VMP. 1.4. Label: Labels of VMPs must satisfy the requirements at the Circular letter No. 75/2000/TT- BNN-KHCN dated on 17 July, 2000 of the Minister of Agriculture and Rural Development and the regulation on writing labels of goods of the government which was issued at Decision No. 178/1999/QĐ-TTg dated 31 August 1999 of Primer Minister. Draft labels, submitted with the registration dossier. For import VMP, the labels must be written in Vietnamese and enclosed with the registration dossier. The information on the labels which must be in compliance with the content of draft SPC proposed by the applicant to DAH, containing following contents: + Name of the VMP + Pharmaceutical form + Route of administration + Qualitative and quantitative composition in active substances + Therapeutic claims for each of the target animals + Dosage for each of the target animals + Contraindications + Expiry date (month and year) + Withdrawal times + Name and address of the manufacture 1.5. Technical information on the quality of the VMP 1.5.1. Manufacturing process The manufacturing process must be described with enough precision to indicate any possible contamination of the VMP with by products. 1.5.2. Quality standards and analytical methods Quality standards for the components, active substances and excipienst, of a VMP must comply with the specifications of monographs of internationally recognised Pharmacopoeia. When such a monograph does not exist, the applicant must provide a monograph of a similar quality. Quality standards for the finished VMP must be established by the applicant and must comply with the current quality standards usually accepted at the international level. The variation between the concentrations of any active substance found during the quality control of a VMP must not exceed plus or minus 10% with regard to the announced quantity (90 % - 110 %). The variation of volume/weight of finished products must not exceed plus or minus 5% with regard to the announced quantity (95 % - 105 %). Analytical methods provided by the applicant must be: + In line with the scientific technology used in this domain. + Reasonably validated with regard to the recognised ISO standards. + Clearly described so that they can be handled by the official laboratories in charge of the quality control of VMPs. 13 Samples of VMP and, on request from the DAH, of relevant active substances have to be provided to these official laboratories for them to carry out, qualitatively and quantitatively, the control of the active substances of VMPs. 1.5.3. Certificates of analysis: a/ Certificates of analysis of the manufacturers: The manufactures themselves must totally be responsible of the quality of VMPs, they have also be responsible of the implementation of the quality control of their VMPs. These controls can be made by the applicant itself or by an external laboratory under contract with the applicant. The certificates analysis, made before the submission of the MA dossier to the DAH, must be provided in this section. b/ Certificates of analysis of the government laboratories. The DAH has requested the applicant to send samples of VMPs or any other relevant substances (if request able) to the government laboratories, let these laboratories implement quality control of VMPs. During the MA procedure, official laboratories of the DAH can carry out, possibly on a random basis, additional controls of the qualitative and quantitative composition of VMPs. They have to send their results to the DDM/DAH in due time. 1.5.4. Expiry date: The applicant has to provide the DAH with the data supporting the duration of the stability of the VMP of concern and supporting the proposed expiry date. Criteria to be taken into account for these stability studies must be the quantitative composition of the active substances of the VMP. Quality standards to be met in order to assess the stability of VMPs should be based on a variation of less than 10% with regard to the announced amount (90% - 110%). Methods used for this purpose must be those which are used for the quality control of finished VMPs. 1.6. Technical information on the safety and on the efficacy of the VMP: The applicant is totally responsible for: - Safety of its VMPs with regard to the animal health, consumer health, users of this VMP and environment. - Efficacy of its VMP for all the intended target animal species. Dossiers must provide the DAH with all the relevant information in these two domains. Case of generic VMPs, it is possible for the applicants have not to provide the DAH with all these data about the safety and the efficacy of VMPs for those generic VMPs. II/ PROCEDURE CONCERNING THE VARIATION OF MAS: As a MA of a VMP is granted for a several years, it is usual that, during this period of time, a significant number of changes, administrative and technical, occurs which impacts the quality, the safety, the efficacy and the management of this VMP. Therefore, the applicant must ask for permissions from the DAD for any kind of modification, administrative and technical, concerning this VMP that is licensed. 2.1. Case of generic VMPs that has MAs: 14 a/ The DAH does not allow any variation of following contents: - Qualitative and quantitative composition in active substances - Pharmaceutical form - The target animal species - Therapeutic claims - Dosage for each of the target animals - Withdrawal times As the variation of these contents will cause lose of characteristics of generic VMPs. b/ The DAH just only allows following variations: - Name of the VMP - Name and address of the manufacture - Packaging - Form of label - Form, colour of VMPs, but these variations do not cause any variation of product quality. c/ All other variations, the applicant must inform the DAH. 2.2. Variations of MA for non-generic VMPs a/ In case it wants to amend one of following contents, the applicant must rewrite and submit a new dossier to the DAH: - Variation of Pharmaceutical form - Variation of administration route b/ In case it wants to amend one of following contents, the applicant must ask for permission from the DAH: - The name of the VMP - The qualitative and quantitative composition in active substances This variation should be limited to the deletion of one or more active substance(s) or to the replacement of one active substance by another one belonging to the same pharmacological group. - An additional therapeutical claim with the corresponding dosage - The extension of an approved therapeutical claim to another animal species with the corresponding dosage - An additional withdrawal time - The shortening of the duration of a withdrawal time - The extension of the expiry date - The manufacturer of the VM. c/ All other variations, the applicant must inform the DAH. III/ PROCEDURE CONCERNING THE RENEWAL OF MAs: 3.1. For first renewal cases: Before expiry date within 3 months, the applicant must submit the application for to the DAH with attachment of the MA and any variant of amended information (if available). 3.2. For second renewal cases and go on: Before expiry date within 3 months, the applicant must submit the application for to the DAH with attachment of dossier that contains contents at Part 1, Part 2, Part 3, Part 4 and Part 7 of main content 1 (content of registration dossier) of this 15 guidance and report on marketing of the VMP that would be renewal (Form 6). For import VMPs, the Certificate of GMP and MA are needed attachment. IV/ RECIPIENT AND ASSESSMENT OF REGISTRATION DOSSIERS FOR MARKETING AUTHORISATION: Registration dossiers must be sent to Division of Veterinary Medical Product Management of the Department of Animal Health, with address: No.15, 78 Lane, Giai Phong Street, Phuong Mai, Dong Da, Ha Noi. Tel: +84.4. 8687150 – 8696788; Fax: +84.4. 8691311 E-mail: dah.vn@fpt.vn - ty@mard.gov.vn - pqlt.ty@mard.gov.vn Assessment of registration dossiers will be regularly within from 15 to 50 monthly in March, June, September and December. The DAH prioritizes to assess: + Registration dossiers for VMPs which are produced by local GMP manufacturers. + Registration dossiers for essential VMPs, ingredients for production of VMPs that are needed for prevention and control of animal diseases in Viet Nam. In order to improve efficiently management of VMPs, especially on antibiotics, the DAH just only receive the registration dossiers for VMPs that contains only one or two antibiotics in maximum. The DAH recommends that manufacturers: 1/ Just only produce VMPs that only one antibiotic, especially on VMPs with form of solution and injectable. 2/ Should not use antibiotics that belongs to Fluoroquinolones, example: Eprofloxacin, Ciprofloxacin and Ofloxacin for their production of VMPs as these antibiotics are used for human medicine. V/ ENFORCEMENT: Any organizations or individuals carry out business that relates VMPs in Viet Nam must be comply with this regulation. This regulation will be replaced the regulations No. 730/TY-QLT dated 11/11/2002 and No. 447 TY/HD dated 15/7/2003 of the DAH. If there are any questions for implementation, please contact the administrator via address at Part IV. Recipients: - Manufacturers and companies carry out business that relates VMPs and ingredients for production of VMPs. - Representative Offices of Foreign Companies in Viet Nam. - MARD (for report) - Department of Science and Technology - Department of Agriculture - Provincial Sub-Departments of Animal Health - Keep at DDM and Administration DIRECTOR OF DEPARTMENT OF ANIMAL HEALTH Dr. Bui Quang Anh