This content is current only at the time of printing. This document was printed on 26 January 2020. A current copy is located at https://apvma.gov.au/node/1041
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Guideline for the registration of new veterinary vaccines
- 1. Introduction
- 2. Part 1—Application overview
- 3. Part 2—Chemistry and manufacture
- 4. Part 3— Toxicology
- 5. Part 4—Metabolism and kinetics
- 6. Part 5—Residues and trade
- 7. Part 6—Occupational health and safety
- 8. Part 7—Environment
- 9. Part 8—Efficacy and target animal safety
- 10. Part 9—Non-food trade
- 11. Part 10—Special data: genetically modified organisms
- 12. References
This guideline describes the minimum data that you are expected to provide in support of an application to register a new veterinary vaccine and the format in which you should present this information. In all, there are 10 data dossiers you should consider submitting:
- Part 1 Application overview
- Part 2 Chemistry and manufacturing
- Part 3 Toxicology
- Part 4 Metabolism and kinetics
- Part 5 Residues and trade
- Part 6 Occupational health and safety
- Part 7 Environment
- Part 8 Efficacy and safety
- Part 9 Other trade aspects
- Part 10 Special data.
You should read this guideline in conjunction with other relevant data guidelines on the APVMA website, guidelines provided by overseas regulatory authorities and international pharmacopoeia. Those documents provide specific guidance on the conduct of various types of tests or trials that may be followed to support an application for registration of a new veterinary vaccine.
The APVMA generally accepts data generated by tests that have been conducted according to monographs in the most recent editions of the European pharmacopeia (EP), British pharmacopeia (BP), US pharmacopeia (USP) and United States Code of Federal Regulations (9CFR).
1.1. Definition of veterinary vaccines
Veterinary vaccines are products that when administered to the host, provide, induce or change an immune response to a target chemical or biological entity.
New veterinary vaccines are generally exempt from toxicology and occupational health and safety (OHS) assessments, except in the case of new adjuvants or other excipients of OHS concern. Toxicology and OHS assessments may be relevant for aerosolised vaccines.
1.2. Autogenous vaccines
Autogenous vaccines are excluded from these guidelines because they are normally not registered. The APVMA has issued a number of permits for their manufacture, supply and use.
1.3. Imported biological constituents
You are expected to submit a permit to import biological products as part of your application, if the vaccine includes any imported material(s) of biological source used at any stage of production of the vaccine. However, we may register a veterinary vaccine without a permit by imposing conditions of use and supply on the product. Although the vaccine would have been registered, the manufacturer would be unable to supply it without first obtaining a permit.
1.4. Expert reports
You may provide expert reports to support your application for registration of a veterinary vaccine. You should provide a brief resumé for each expert and state their professional relationship to you. However, we will only consider such reports as supportive material and they will not replace the relevance of pivotal studies.
2. Part 1—Application overview
You should provide supportive data for each of the elements described below. If you do not provide data for one or more elements, you should submit a valid scientific argument explaining why as part of the application overview.
The purpose of the application overview is to provide a brief outline of the application and to lead reviewers through an application. The overview should contain other general information on the product, and a summary of all data in the application.
The executive summary within the overview should include the reasons for the application. For a new product, this should include whether the product contains a new active constituent and scientific argument for registration of the product. The argument should outline the importance, prevalence and (if applicable) the regional distribution of the disease, pest, and/or problem the product is intended to control, plus the economic and/or technical advantages of the product.
You should also provide a summary of the detailed information on the product characteristics. The information should include the immunobiological properties and the clinical particulars of the product.
2.1. Immunological properties
Immunological properties are the diseases and/or conditions that the product is designed to treat, prevent or detect and the type of immune response and correlation with protection.
If the type of response has not been determined, you should provide a general summary of what is known about the infectious agent and the type of responses that are likely to be effective in conferring protection. You should also provide information on efficacy claims and the duration of immunity.
2.2. Clinical particulars
Clinical particulars include:
- target species
- indications for use
- undesirable effects (with reference to frequency and seriousness)
- precautions for use
- dosage and method of administration
- special warnings for each target species
- major and minor incompatibilities (if appropriate)
- withholding periods
- special precautions for the user/administrator of the product
- first aid instructions
- safety directions.
2.3. Registration status overseas
You should provide details of any known current or previous applications or approvals in other countries for products containing the same formulation in the application overview. If the product has previously been evaluated, you should provide full details of the outcome, along with details of the overseas-approved use pattern (host species, claims, directions for use and withholding periods), including any use restrictions.
Where available, you should provide overseas evaluation reports.
You should also provide any other information relevant to the proposed application; for example, approvals for other formulations containing the same active constituents.
3. Part 2—Chemistry and manufacture
3.1. GMP status of the manufacturing facility
You should provide evidence that the product is manufactured to a standard comparable with the Australian Code of Good Manufacturing Practice for Veterinary Products. For Australian manufacturers, compliance is by provision of an appropriate APVMA manufacturer’s licence. For products manufactured overseas, you should supply evidence of compliance with good manufacturing practice.
3.2. Formulation or composition of product
You should supply the following information on the formulation or composition of the product:
- active constituent(s)—including maximum and minimum release titres and end-of-shelf-life titre
- excipients—including diluent, preservatives, stabilisers, emulsifiers, colouring matter and markers
- reference to standards (where applicable)
- function of each constituent
- quantity of each constituent in the formulation—this should be expressed in appropriate units (eg TCID50, mL, mg).
You should supply the specifications for the immediate container, and stoppers and closures (including acceptable tolerances) as well as the method for opening and closing.
You will need to demonstrate that the material used for the immediate container is compatible with the type of product. The choice of material should take into consideration the potential for toxicity, because some materials are known to have the potential to leach and/or react with the product and produce substances that can be toxic to the target species.
3.4. Manufacturing process of the final product
You should provide a flow chart of the manufacturing process, showing each step from production of the active constituent to formulation of the final product in final containers, including any critical in-process control testing steps.
You should also present a detailed description of each process step in the flow chart—for example, amplification/culture, harvesting, purification, inactivation procedures, blending, adjuvanting, bulk antigen storage, filling and lyophilisation, as relevant.
3.5. Production, control and testing of starting materials
Starting materials mean all components used in the production of the veterinary vaccine. The EP, BP, USP or CFR requirements, where appropriate monographs exist, should apply to all substances in the product. We will consider references to other compendial standards on their merits.
You should provide documentation from suppliers, such as certificates of analysis and/or raw material specifications, in an annex to this part of the application dossier.
3.5.1. Raw materials
You should provide detailed information of specifications and functions of all raw materials. If biological raw materials of animal origin are imported, a copy of the import permit (if available) and the manufacturer’s specifications will suffice.
Where appropriate, you should indicate the methods used to determine that starting materials of biological origin are free from contaminants.
Materials from defined and reliable sources should be used. The specification should note the manufacturer(s) and origin of the raw material.
3.5.2. Starting materials listed in a pharmacopoeia
You should provide:
- the name and code identifying the starting material
- the title of the monograph and year of publication, preferably together with a copy of the monograph
- certificate(s) of analysis.
3.5.3. Starting materials of non-biological origin, not listed in a pharmacopoeia
You should provide:
- the name(s) of each starting material (trade name, scientific synonyms)
- description and function
- material specification (identification and purity)
- controls and tests performed on the starting material and/or certificate(s) of analysis.
3.5.4. Starting materials of biological origin not listed in a pharmacopoeia
You should provide:
- the name(s) of the starting material (trade name, scientific synonyms)
- description and function of the starting material
- material specifications (identification and purity)
- controls and tests performed on the starting material and/or certificate(s) of analysis.
Where applicable, you should provide evidence that imported biological materials of animal origin used in the manufacture of the master seed are free from agents that cause transmissible spongiform encephalopathies. Provision of a current import permit will suffice.
3.5.5. Genetically modified starting materials
Genetically modified organisms require a licence issued by the Office of the Gene Technology Regulator (OGTR) before we can consider your application.
For products based on biotechnology where genetic engineering occurred in Australia, you should contact the OGTR before submitting your application to the APVMA.
3.5.6. Master seed organism
Whenever possible, veterinary vaccines production should be based on a seed lot system and on established cell banks. Each master seed lot should be assigned a specific code description for identification purposes.
For production of veterinary vaccine carried out in animals, the origin, general health and immune status of the producing animals should be verified. Defined pools of source materials should be used.
A record of the origin, date of isolation, storage conditions and passage history of all seed materials (for example, virus, bacteria, fungi, protozoa and rickettsia), including purification and characterisation procedures and substrates used, should be provided.
Characterisation of the microorganism should include as a minimum:
- the genus and species
Information on the biological characteristics of the master seed should include information on growth characteristics and environmental distribution.
You should provide details of studies and tests carried out to demonstrate purity, identity, target animal safety/pathogenicity, and target animal immunogenicity of the master seed lot. You should include a brief description of the methods for identifying each strain by biochemical, serological and morphological characteristics and distinguishing it as far as possible from related strains. You should also describe the method for determining the purity of the strain.
You should also demonstrate that the master seed is free from extraneous agents. Tests to demonstrate that the master seed lot is pure and free from extraneous agents should be performed as per EP, BP, USP or 9CFR, where monographs exist. For live attenuated veterinary vaccines, you should provide proof of the genetic and phenotypic stability of the attenuation characteristics of the seed.
The minimum and maximum number of passage levels from master seed to production level should be specified and should not exceed five unless justified by data. You should specify and appropriately document the methods, substrates used, testing and storage of seed lots and seed passages.
You should also demonstrate that the characteristics of the seed material (for example, dissociation or antigenicity) are not changed by these subcultures. You should document the conditions under which each seed lot is stored and provide a release specification of the master seed organism.
3.5.7. Working seed organism
You should provide the method of preparation and description of the working seed lot. The description should include the range of passage levels to be used for production, controls applied, tests carried out on working seed lot and storage conditions.
You should provide a release specification for the working seed organism.
3.5.8. Cell substrate/production medium
There are essentially three classes of cell substrate/production medium:
- live animal culture; eg specific pathogen–free (SPF) eggs, chickens, cattle
- tissue culture (continuous cell lines or primary cells)
- microbiological media.
If the cell substrate/production medium consists of SPF eggs, primary SPF chicken cells or SPF chickens, you should demonstrate compliance with EP, BP or 9CFR. You should also provide the following information:
- the source of SPF eggs or chickens or other animals
- SPF status of source flock/herd
- test monitoring procedures and specification
- disease prevention protocols; eg isolation, vaccination
- disease/agent monitoring procedures and testing specification.
If the cell substrate/production medium consists of tissue culture substrates (continuous cell lines), you should provide the following information:
- source of the master cell seed
- treatment of the master cell seed since origin
- seed lot system
- designation/identification of master cell seed
- details of master cell seed testing method and results to demonstrate sterility, freedom from extraneous agents and freedom from specific adventitious virus contamination, including Type C in particular agents covered by the tests applied. You should give particular attention to the potential for contamination with bluetongue, pestivirus, porcine parvovirus, rabies virus, and prion agents of transmissible spongiform encephalopathies
- an import permit where appropriate
- proof of freedom from mycoplasma (where applicable)
- evidence that master cell seed tests comply with EP, BP USP or 9CFR (where applicable).
If the cell substrate/production medium consists of microbiological media, you should provide the following information:
- name of the medium and composition
- raw material specifications, including any tests required for freedom from specific agents such as pestivirus, and prion agents of transmissible spongiform encephalopathies
- an import permit where appropriate
- a description of the method of preparation and sterilisation under the heading ‘Media preparation’.
Other types of products for which guidelines are yet to be developed include products produced in animals or plants by chemical synthesis (chemical conjugates) and those produced by other methods (for example, nematodes). In all cases, you should provide full details of the cell substrate/production medium.
3.5.9. Media preparation
You should provide a detailed description of the methods of preparation and sterilisation of all media used in such a way that they become ingredients of the product. You should include the controls applied, the testing carried out and the certificates of analysis of ready-to-use media.
3.6. In-process control tests during production
You should describe all critical analytical test procedures in sufficient detail to enable the procedures to be assessed. Procedures should be validated where appropriate and you should provide the results of validation studies on all key procedures as identified by the manufacturer.
Where applicable, you should use current pharmacopoeial monographs. You should give copies of the pharmacopoeial monographs, specifications and certificates in an annex to this part of the application dossier.
With a view to verifying the consistency of the production process and the final product, you should provide a flow chart of the production process showing the stages at which critical in-process control tests are carried out. This may be cross-referenced to the section headed ‘Manufacturing process of the final product’ if the flow chart is provided there.
You should provide information on critical tests performed for each control stage, as follows:
- title and company test code
- timing and frequency
- function of test
- a brief description of the test (a more detailed description should be given as an annex to Part 2 with details and results of the validation studies as appropriate). The detailed description should contain sufficient information to enable us to assess the adequacy of the test method and (if applicable) whether it is consistent with the cited monograph. You may provide a copy of the test procedure document as the detailed description, but this is not compulsory.
You should only provide details of tests that are considered critical to allow the manufacturing process to continue to the next stage.
You should provide in detail the assay methodology for detoxified or inactivated immunobiological products and the limit of detection specified. This may be cross-referenced to the section headed ‘Manufacturing process of the final product’ if the assay methodology is provided there.
You should show that each pilot production batch has been appropriately detoxified or inactivated using relevant test standards wherever available. You should provide kinetics of inactivation or detoxification.
3.7. Control tests on the final product
You should provide detailed information on final product tests performed on each batch, including the batch release specification. This should include as appropriate:
- identification assay for active ingredients
- identification assay for adjuvants
- moisture (as required)
- safety when required
- extraneous agents including mycoplasmas.
For each test, you should provide information on:
- title and company test code (specify monographs where appropriate)
- timing and frequency
- function of the test
- brief description of the test—you should give a detailed description as an annex to Part 2 with details and results of the validation studies where appropriate. The detailed description should contain sufficient information to enable us to assess the adequacy of the test method and (if applicable) whether it is consistent with the cited monograph. You may provide a copy of the test procedure document as the detailed description, but this is not compulsory.)
- the fate of material that has failed the test (for example, any re-test provisions).
The batch release specification should indicate the following:
- provision for identification of the batch undergoing testing and the test date
- the name of each test
- the company test code
- limits of acceptance of results.
3.8. Summary of test results from two consecutive pre-registration batches
You should provide a summary of results of tests on at least two preferably consecutive batches of finished product to support your application for registration of the product.
These batches may be pilot or production batches. If they are pilot batches, they should be representative of production batches.
3.9. Stability of the finished product
The storage shelf lives of conventional vaccine products may vary from days to several years. Therefore, it is difficult to provide uniform guidelines regarding the stability study duration and testing frequency that would apply to all types of conventional vaccine products. However, with only a few exceptions, the shelf lives for existing products and potential future products will be within the range of six months to five years. Therefore, this guidance is based on expected shelf lives in that range.
When shelf lives of less than one year are expected, real-time/real-temperature stability studies should be conducted approximately monthly during the first three months and at three-month intervals thereafter, so as to generate multiple measurements (a minimum of five tests three months apart) for the purpose of assessment.
For products with expected shelf lives of greater than one year, the studies should be conducted every three to four months during the first year of storage, every six months during the second year, and annually thereafter.
While the testing intervals described above are appropriate in the pre-registration stage, reduced testing may be appropriate after approval or licensing/registration where data are available that suggest adequate stability.
While not mandatory, stability testing (at least potency/titre) should be conducted to three months past the claimed shelf life.
You should provide a summary of the proposed shelf life, storage conditions and justification for the proposed shelf life. Real-time studies should be carried out on the final finished product in the marketed container. If there are insufficient real-time stability data to support the proposed shelf life of the product, you should provide a stability testing protocol and timetable for testing the product with the application dossier.
You should supply information for at least three batches as follows:
- a description of the product packaging during testing
- a description of storage conditions (for example, temperature ranges)
- a brief description of each test (a detailed description to be given as an annex to Part 2, if this information has not been provided earlier). The tests should include (as appropriate) physical, chemical, biological and microbiological aspects of the product, and should indicate those tests claimed to be critical stability indicating measures
- for multi-dose, not-for-immediate-use formulations, preservative efficacy testing should be conducted to validate inclusion of the preservative chosen. The tests should be consistent with those indicated on the batch release specification. A test for sterility and safety (where included on the batch release specification) should be conducted at the final time point of the stability test protocol
- a table of results with batch number, date of manufacture, dates of testing and storage conditions.
The results of the stability testing should be consistent with and confirm the minimum release titre and end-of-shelf-life specifications for the product.
You should consider submitting additional information for products containing one or more ingredients that are recognised to be inherently unstable.
You should provide information on the effect of external influences—such as sunlight and heat—on the stability of the product when in use.
Each antigen or active ingredient in a multivalent vaccine should be tested. Stability data for a multivalent formulation may be extrapolated to formulations of lower valency provided that:
- the quantity of each antigen, adjuvant and excipients of each multivalent vaccine under consideration is identical
- the market packaging and recommended storage conditions are also identical.
If any of these parameters vary, you should provide separate stability data for each formulation.
The continued integrity of products in multi-dose containers after the first opening is an important quality issue. The repeated opening and closing of a multi-dose container may pose a risk to its content with regard to microbiological contamination, proliferation and/or physicochemical degradation once the closure system has been breached. You should present in-use stability data to determine an in-use shelf life for inactivated and live multi-dose vaccines after first broaching the cap. Any unused product or waste material should be disposed after the in-use shelf life has expired. This also applies to not-for-immediate-use products that may or may not require reconstitution or dilution before use.
You should submit data for single-dose or single-application products requiring reconstitution or dilution to support the proposed shelf life for the reconstituted product, if not used within 30 minutes of reconstitution.
4. Part 3— Toxicology
Toxicity data are not normally relevant for veterinary vaccines but may be relevant where a novel active constituent, novel adjuvants and/or excipients are used. You should submit data for toxicology assessment if Poisons Schedules classification is necessary.
5. Part 4—Metabolism and kinetics
See Part 5A.
6. Part 5—Residues and trade
6.1. Part 5A—Residues
Residues data are not normally required for veterinary vaccines, but may be required in some circumstances where novel adjuvants and/or excipients are used in vaccines administered to food-producing animals.
You should consider the possibility of any residues remaining in food. You should provide precise identification of the substance or product concerned. This includes:
- international non-proprietary name (INN)
- International Union of Pure and Applied Chemistry (IUPAC) name
- Chemical Abstracts Service (CAS) name and number
- classification (therapeutic, pharmacological)
- material safety data sheet
- other relevant information.
For most veterinary vaccines, the establishment of a withholding period is relevant only with respect to a product that contains live zoonotic organisms, novel adjuvants and preservatives. You should provide justification for a nil withholding period.
In consideration of implications for trade and where a persistent local tissue reaction may occur following injection, you should include a withholding period or carcass disposal statement on the label.
6.2. Part 5B—Trade
If the veterinary vaccine is used in food-producing animals, you should comment on the potential of the product to affect trade. You should also address trade issues relating to the use of genetically modified organisms.
You should also address the potential for a veterinary vaccine to mask or interfere with diagnosis or monitoring of outbreaks of the disease against which it is directed, and any implications of its use in maintenance of Australia’s specific disease-free status.
Veterinary vaccines containing antigenic components for diseases that are not known to occur in Australia not only have the potential to mask or interfere with diagnosis in the case of an outbreak of that disease, but may also severely compromise Australia’s disease-free status. Therefore, this type of product will not usually be granted registration.
7. Part 6—Occupational health and safety
In your application, you should address potential occupational health and safety risks associated with the manufacture and use of the product. This may include any or all of the following:
- safety instructions
- use of personal protective equipment
- first aid instructions
- information for medical practitioners.
8. Part 7—Environment
You should provide information on the extent of exposure of the product, its active constituents or relevant metabolites to the environment, and proposed disposal methods for unused or waste product.
9. Part 8—Efficacy and target animal safety
Efficacy of a vaccine means induction of immunity to provide protection against a specified disease. The nature, degree, onset and duration of immunity are the main parameters of the protection. All claims for the efficacy of vaccines, including the duration of protection and the administration schedules, should be fully supported by data from specific laboratory trials and field studies.
In the first instance, you should demonstrate the efficacy and safety of veterinary vaccines by experiments under laboratory conditions. You should describe precisely all laboratory/pen and field trials. Unless otherwise justified, you should supplement the results from laboratory/pen trials with data from field/clinical trials measuring clinical endpoints. Under some circumstances, such as where an acceptable laboratory challenge model is not available, field efficacy trials alone may be acceptable.
Efficacy data should be generated in Australia for the registration of all veterinary vaccines intended for use in food-producing animal species, unless you can provide strong scientific argument that overseas data are applicable to Australia’s climatic conditions, genetic stocks and farm management practices.
The acceptance of such argument will be at the discretion of the APVMA.
Australian efficacy data may also be relevant for non-food-producing animals where it is necessary to confirm efficacy because of any potential for differences in the strain types and virulence of disease-causing microorganisms.
There are two main reasons for conducting field trials on veterinary vaccines:
- confirmation that the efficacy and safety of a product demonstrated in laboratory studies is reflected in field conditions
- on a large scale, investigation of aspects of efficacy that cannot be studied sufficiently well in the target animals under laboratory conditions. Examples of this are:
- diseases where a suitable experimental infection model does not exist
- diseases with more than one causal agent
- cases where special husbandry facilities are involved (for example, drinking water vaccines for poultry, water qualities and temperatures for fish vaccines)
- diseases where environmental factors play a major role in the aetiology.
9.1. Supportive data for efficacy and safety of the vaccine in the target species
The number of animals and/or groups used in a trial should be sufficient to enable the trial results to be evaluated for statistical significance.
In general, the animals to be used should be susceptible to the disease(s) against which the vaccine is being evaluated. Where available, and if appropriate to the study, specific pathogen–free animals should be used.
The effect of factors such as age, bodyweight, gender and maternal antibodies should be addressed in the trial design and analysis of results.
The product used in the trial should have a titre which is the end-of-shelf-life titre or lower, under the recommended conditions of use.
For veterinary vaccines that contain genetically modified organisms, you should consult the OGTR before the trial begins, irrespective of whether the trial would be conducted under contained conditions or in the field.
Clinical and field trials should be conducted in a manner consistent with the principles of good clinical practice. You may seek advice from the APVMA on trial protocols by lodging an application for technical assessment.
If Australian data are to be generated through field trials, such trials should be conducted under a research permit.
You should consider conducting the following trials in support of efficacy and safety claims:
- pen/laboratory trials
- clinical/field trials.
9.1.1. Pen/laboratory trials
220.127.116.11. Efficacy trials
- establishment of minimum protective dose and vaccination schedule
- confirmation of protection against challenge in each target species and representatives of each class of target animal
- influence of passively acquired and/or maternally derived antibodies on efficacy, if appropriate
- onset of immunity
- duration of protection
- timing of, and response to, booster vaccination
- compatibility with other treatments (vaccines) administered within seven days of administering the product under evaluation.
18.104.22.168. Safety studies
- single-dose studies
- repeat single-dose studies (where applicable)
- overdose studies (10× for live vaccines, 2× for inactivated vaccines)
- immunological effects
- reproductive effects (where appropriate)
- compatibility with other known products administered within seven days of administering the product under evaluation.
For live vaccines, also include:
- spread to non-vaccinates
- spread to non-target animals
- dissemination in the host
- reversion to virulence
It would be preferable to undertake the above studies under controlled laboratory conditions. However, where a suitable laboratory challenge model or marker of protection is not available, or for other justifiable reasons, you may need to rely on large-scale, well-planned field trials for some or all of these studies.
Field trials will usually supplement the data generated from laboratory studies.
9.1.2. Clinical/field trials
Field trials can serve two purposes:
- they can be used to demonstrate safety and efficacy of commercially-produced batches of vaccine where safety and efficacy have been determined by pen studies (using product at the end-of-shelf-life titre or lower under the recommended conditions of use)
- they can be used as a method of determining safety and/or efficacy of a product where it is not possible or practical to undertake appropriate pen studies. In this case, field efficacy studies should be undertaken using product at the end-of-shelf-life titre or lower under the recommended conditions of use. Field safety studies should be undertaken using product at the maximum release titre.
22.214.171.124. Efficacy and safety trials
The trials should:
- use the recommended dose and vaccination schedule as per proposed label instructions, using product that is at, or close to, the proposed end-of-shelf-life titre
- use representative batches manufactured using procedures outlined in the dossier
- replicate the proposed major uses of the product (route, method, administration schedule, target species including the most sensitive class or members of the target species)
- for animals kept under extensive or pastoral conditions, use a minimum of three sites, encompassing different husbandry practices and environments
- for intensively reared animals, use a minimum of two sites.
The dossier should document any adverse reactions.
These studies should be well planned, controlled, monitored and carried out under conditions where endemic disease is known to occur and challenge rates would be expected to mimic those seen commonly in the field.
You should fully describe and validate all techniques involved, where necessary. You should report all results, whether favourable or not, and you should also present statistical analysis, if appropriate to a particular study.
You should provide detailed discussion and conclusions, based on the results of the pen/laboratory studies and clinical/field trials.
126.96.36.199. Animal welfare
Special care should be taken with the trial protocol in order to respect the welfare of animals used in the trials.
You should obtain the approval of a properly constituted animal ethics committee prior to the commencement of any trial conducted in Australia. If you have not yet received such approval, you should state in your application when you expect to receive approval. You should submit the approval to us before the trial begins.
9.2. Guidelines for trials to generate efficacy and safety data
9.2.1. Parameters of efficacy trials
You should clearly define in the study protocol the parameters to be measured in efficacy trials and give justification in relation to the indications and specific claims for the vaccine. Conversely, you should give justification for not measuring parameters that are usually related to the disease concerned.
Three types of parameters exist:
- clinical parameters (for example, mortality, morbidity, lesions, weight gain, epizootiological impact)
- indicators of immune response to vaccination (for example, serological response). For an indicator to be acceptable as a correlate of vaccine efficacy, you should show that a sufficient qualitative and quantitative correlation exists between the indicator measured and the claimed protection in the target species. Where claims are made for a specific age, breed, category or class of animal, you should provide supporting data
- indicators of infection (for example, viraemia, organism shedding) or transmission (for example, serological response).
If they are relevant and available, you should use test methods that can differentiate naturally infected animals from vaccinated animals.
9.2.2. Controls and trial design
Unless otherwise justified, the efficacy trial should compare a group of vaccinated animals with an equivalent group of unvaccinated or placebo-vaccinated controls.
In some circumstances, unvaccinated or placebo-vaccinated groups cannot be used, for management, animal welfare or other reasons. In such circumstances, you should explain the reasons, and you may use a comparison with animals vaccinated with a reference product if available.
For modified live vaccines whose vaccine agent(s) may potentially spread, it may be appropriate to separate vaccinates from controls. In such cases, separate housing of the two groups would be justified.
You should justify the selection and utilisation of the controls. The study protocol should indicate what purpose the control group serves. Some examples include:
- evidence that exposure to infection took place (unvaccinated controls)
- evidence of the test product’s efficacy in comparison with a registered reference product with the same indications for use (reference product as control)
- provide evidence that exposure to infection took place
- historical comparison (where whole herd or whole flock vaccination is required and comparisons are with historic data on the same site)
- provide evidence that exposure to infection took place.
For such comparisons to be valid:
- with the exception of historical comparisons, the controls and vaccinated animals should be of a similar age, sex and weight, and preferably be investigated at the same time
- the experimental animals should be allocated at random to their groups. Where whole herds or flocks are to be compared, they should be matched as closely as possible according to a set of characters defined in the trial protocol
- the environment in which the two groups of animals are housed or otherwise managed should be as equivalent as possible (ie same farm/barn/batch) or at least as similar as possible (eg same farm/different barn/same batch).
The challenge infection or exposure should be as similar as possible in the two groups of animals. This will not be the case if cohorts consist exclusively of vaccinated animals or controls. In this case, replicates of the trials under the same or matched conditions may be appropriate, using randomised groups or a number of different sites. You should consider the implications for the incidence of infection (infection rate) of running vaccinated and unvaccinated controls together when designing a trial.
The use of historical data for control purposes may be acceptable, but where such data are used, they should have been shown to be well documented and consistent over a representative length of time. Use of historical data usually requires trials to be undertaken on a number of sites.
When investigating a combined vaccine, the control group may comprise animals vaccinated with a product formulated to contain all the components of the vaccine except the component under study. You should submit data to support efficacy of each component in the multivalent/combined vaccines for which you are seeking registration. You should generate the data using the formulation or particular combination for which you are seeking registration.
Ideally, the trials should be double blind and placebo-controlled, but this is often difficult to achieve in practice.
The need for placebo controls depends on the study plan. If the parameter to be measured is a subjective one (for example, coughing), the trial should be conducted in a blind manner and either placebo controls should be included, or the person who measures this parameter should have no information on the details of the vaccination.
9.2.3. Establishment of the minimum protective dose and vaccination schedule
The establishment of a minimum protective dose and vaccination schedule can be undertaken as a dose-response study or as a study to confirm that the chosen dose and vaccination schedule are efficacious in the target species. From this study, the end-of-shelf-life titre may be established. Allowance may need to be given for assay variation in setting the end of shelf life from the minimum protective dose.
You should justify the method for determining the minimum protective dose, particularly if a suitable laboratory challenge model or serological (or other) marker of protection is not available. It may be appropriate to use a pharmacopoeial ‘standard’ recommendation where that standard has a long history of satisfactory use.
You should demonstrate efficacy of each component of a combination vaccine following inoculation of the combination vaccine rather than from an evaluation of each component as a monovalent product. You should evaluate the potential for interference between the components, unless valid scientific argument is presented.
9.2.4. Field efficacy trials
Field trials should follow a study plan (trial protocol) that has been prepared before the trials begin. You should document and justify any variations to the study plan.
Field trials should include statistically significant numbers of animals to enable the results to be appropriately analysed. Wherever possible, field trials should be carried out on a number of sites to ensure that the evaluation covers representative animal houses/husbandry practices and environmental (geographical) differences.
Field trials should at least cover the proposed major uses of the vaccine. The vaccine should be administered by the route, method and vaccination schedule that will be recommended on the product label, and in the most relevant category of target species (age, weight, sex, etc.).
The vaccine dose used should be at antigen levels equivalent to, or lower than, those expected at the end of the product’s shelf life. The vaccine used in the trial should be taken from a batch or batches manufactured according to procedures described in the application for registration. The formulation of the product submitted for registration approval should be identical to that used in the efficacy trials.
You should note that the data generated from a field efficacy trial should support the proposed expiry or end-of-shelf-life titre and may form the basis for establishing the expiry titre or potency for the product in the absence of relevant laboratory data.
The antigen component of the product may be diluted to achieve an expiry titre or potency for the study. You should provide a complete description of the dilution process. You should clearly specify the titre or potency of the batches used for the trials. All adjuvants and excipients should be present in the same concentrations as in the proposed formulation,
Whenever possible, the field trial should include the challenge of animals that have been vaccinated using the vaccine under investigation, by exposure to natural infection. However, we recognise that a natural infection can neither be predicted nor standardised. It may not appear at the appropriate time and may be too weak or too low in incidence; in the case of multivalent vaccine testing, not all natural challenges may occur in the study timeframe.
In a field trial where productivity data are required to establish safety or efficacy (but not necessarily to make a claim for productivity gains), it may be appropriate to include large numbers of animals to obtain significant differences in some of the productivity parameters. In some intensive industries, it may be appropriate to replicate whole sheds of animals to obtain significant differences.
9.2.5. Reference product
The reference product and the vaccine under study should have the same efficacy claims. The level of efficacy of the reference product should be established by using a product currently registered in Australia.
When the vaccine under study is being compared with a reference product, a group of controls should be included whenever possible to establish exposure to infection. Even if this is not possible, you should present sufficient evidence that both products have a demonstrable beneficial effect rather than just comparing the results of the two groups of animals.
9.2.6. Exposure to infection
The trial results should supply clear evidence that the vaccinated animals and control animals have been exposed to the pathogen of interest. In principle, the level and timing of exposure should be the same in both groups of animals, but this may be difficult to achieve under field conditions.
Observations of signs of disease are rarely sufficient by themselves and wherever possible, clinical records should be supported by laboratory tests. In principle, the agent itself should be detected and identified.
In the case of live vaccines, whenever possible the isolated field strains should be differentiated from the vaccine strains. Depending on the agent and disease concerned, serology performed on a statistically significant number of animals may indicate exposure to infection. The serological method used should be validated and, in general, be the same as used in the laboratory trials.
The cause of any deaths or unexpected signs of disease related to the parameters being measured should be determined, unless otherwise justified. With poultry vaccines, standard poultry company procedures for diagnosis may be used to determine the cause of death.
If field challenge does not occur, there may be justification for challenging some of the vaccinated animals and controls under laboratory conditions to determine the level of protection achieved by field vaccination.
9.2.7. Intercurrent infections
In the trial design you should consider the potential for infection with intercurrent agents other than those under study. Such infections may influence the parameters being measured and thus affect the outcome of the trial. In some circumstances, their impact on the interpretation of trial results may be reduced considerably if vaccinated and control animals can be investigated at the same time and allocation of both groups of animals has been made at random.
9.2.8. Pre-existing antibodies
Pre-existing antibodies against the vaccine agents may be maternally derived, or be due to infection or vaccination.
If the indication or specific claims for the vaccine are related to efficacy in the presence of maternal antibodies, the trial protocol should include vaccination of animals with maternal antibody titres at the age of vaccination that normally occurs in the field.
Where pre-existing antibodies due to previous exposure to the agent being studied or a related agent are present, the trial may be acceptable if the immunological status of the vaccinated animals and controls at the time of vaccination is known, and a justification for their use is given. Unless justification can be provided, field trials should not be carried out in animals that have been previously vaccinated with products containing the same active substances as the vaccine under study.
9.2.9. Interactions with other products
If a product is recommended for administration in combination with or at the same time as another veterinary chemical product including a vaccine, you should demonstrate compatibility, efficacy and safety. You should declare any known interactions with other products.
9.2.10. Analysis and interpretation of field trial data
You should include all relevant field trial data in the dossier. Only data of valid field trials may support an application. You should give all relevant details of any incomplete or abandoned test or trial.
Reports of relevant individual field trials (including incomplete or abandoned trials) or trials at different geographic locations should be provided as individual study reports. Large, combined reports are more complex to navigate during the evaluation process. Also, individual reports make it easier for the reviewer to identify data not relied upon (for example, incomplete trials).
You should relate the analysis of field efficacy trial data to the indication and specific claims made for the vaccine and the parameters measured. You should relate the analysis of field safety trial data to the recommendations for the administration of the vaccine; that is, you should show that the vaccine is safe under the recommended pattern of use.
You should give especially careful consideration to:
- the study plan
- the plan for analysis
- evaluation of the data
- the method of statistical evaluation
- randomisation of the various groups of animals
- the use of blinding in the study method
- the number of animals required, including eventual losses during the trial.
In the case of efficacy as judged by serology, the titres achieved in vaccinated animals used in field trials should not be significantly lower than those achieved in the laboratory trials.
In the case of a marker vaccine, you should pay special attention to properties of the marker.
9.2.11. Duration of protection
The duration of protection is the longest interval between the administration of a vaccine to target animals and loss of protection against challenge. The level of protection against challenge should be consistent with the label claim for the entire nominated duration of protection or revaccination interval.
Duration of protection studies should be conducted under well-controlled conditions. If the studies are very difficult to conduct under laboratory conditions, field trials only may be carried out. Since the duration of protection given by vaccination is being measured in the studies, the vaccinated target animals should not be exposed to intercurrent field infection which could boost natural immunity. For this reason, it is usually appropriate to maintain unvaccinated target animals in contact to act as sentinels in laboratory or field studies.
You may supplement the results from vaccination challenge trials conducted under laboratory conditions with data from well-controlled field studies. In field studies, target animals may be vaccinated in the field and undergo a natural challenge in the field or an experimental challenge under laboratory conditions.
The duration of protection achieved by vaccines is influenced by a number of factors such as:
- the characteristics of the causal agents of the disease
- the epizootiology of the infection
- the immunogenicity of the vaccines’ active substances
- the nature of the target animals’ immune response.
The duration of protection may be different for each category of vaccine and for the products within a category of vaccines, as a consequence of the particular properties of the products concerned.
In addition, the apparent duration of protection achieved under field conditions may not be consistent and may vary from that achievable under laboratory conditions because of a number of factors, such as episodic or occasional exposure to the infectious agent(s) and health condition and immunological status of the animals to be vaccinated.
In order to reduce the frequency of vaccination, we recommend that wherever possible, studies (endpoint studies) demonstrate the actual duration of protection provided. The duration of immunity to each antigen in a multivalent vaccine should be determined.
In some cases, one administration of a vaccine will provide protection for the natural or economical life of the vaccinated animals. In other cases, a primary vaccination course (usually two administrations) is required with a follow-up or booster vaccination.
Where the primary vaccination course involves more than one administration and/or a follow-up or booster vaccination is required, the level of protection afforded between administrations should be assessed.
Where there is no recommendation for more than one administration of a vaccine or for only a primary vaccination course, this implies lifelong protection. As the natural or economic life span of animals differs between species, and between categories of animals within a species, the claimed duration of protection should be specified and supported by adequate data.
In cases of seasonal diseases, it may be sufficient to demonstrate the duration of protection in the year after vaccination until the end of the natural occurrence of the disease, provided that the vaccination is undertaken at the appropriate time in respect of anticipated disease occurrence. Persistence of protection in subsequent years, with or without revaccination, should be addressed.
It is not possible to generalise about the minimum period for which a vaccine should be expected to provide protection. However, in all cases, the duration of protection should be relevant to the length of time during which an animal is likely to be at risk.
9.2.12. Duration of protection from the primary vaccination schedule
In some circumstances (for example, animal welfare grounds, scientific justification) where there is a strong correlation between a marker (such as serological response) and protection, evidence of protection from the marker alone may be acceptable.
188.8.131.52. Active immunity
The duration of protection provided by the primary vaccination schedule should usually be demonstrated by a challenge of vaccinated animals just before the recommended time for the start of revaccination.
184.108.40.206. Passive immunity in progeny
You should present data to support the duration of passive protection that is claimed for progeny from vaccinated parents. The duration of immunity should usually be demonstrated by challenging the progeny at the end of their claimed period of protection
9.2.13. Duration of protection from the revaccination schedule
The response to revaccination is best demonstrated by challenge trials at suitable times between the end of the schedule and the end of the claimed period of protection.
For an indicator to be acceptable, you should provide evidence to show that the indicator plays a substantial role in the protection of the target species and that there is a sufficient qualitative and quantitative relationship between the indicator and the target species’ protection against the disease concerned.
You should demonstrate via serological studies or other markers of protection that the level of response before revaccination or at the end of the protection period is consistent with the efficacy claims made for the product.
You may use the data generated for a multivalent vaccine to support the protection claimed for a vaccine containing fewer active constituents, provided the latter vaccine is manufactured according to the same process and has the same composition (with the exception of the deleted antigens), and provided no evidence exists of a negative or positive interference from the other active ingredients present in the multivalent vaccine.
9.2.14. Safety trials for veterinary vaccines
Safety trials should be conducted in the most sensitive class or members of the target species with the dosage that is recommended for use and preferably with the maximal titre or potency for which the application is made.
For live vaccines, the vaccine agents should be at the lowest attenuated passage level that will be present in the vaccine to be registered. You should note that the titre or potency of the batches used for safety testing, particularly the overdose studies, will form the basis for establishing the maximum release titre or potency for batch release.
The vaccine used for testing should be taken from a batch or batches produced according to the manufacturing process as described in the dossier. Once the maximum release titre has been established, we will not accept release of product batches with a higher titre or potency, unless you provide results of additional safety testing at the higher titre or potency.
You should state potential risks versus potential benefits from the use of the product. If the product contains live organisms, especially organisms that could be shed by vaccinated animals, you should evaluate the potential risks to unvaccinated animals, whether the same species or any other potentially exposed species. You should refer to BP, EP or 9CFR/USP monographs where they exist.
220.127.116.11. Laboratory tests
For each test, you should specify the title of the test with reference number, names of collaborators in the study, introduction and objective of the test or study, reference to the relevant EP, BP or 9CFR/USP monographs, start and end dates of the study (at least 14 days observation or as specified in the monograph), and a summary of study materials and methods, results, assessment criteria (for example, systemic and local reactions, rectal temperature, growth performance), discussion and conclusions.
Tests should be repeated using each recommended route of administration. You should clearly specify the titre or potency of the batches used for testing.
The trial should normally compare a group of vaccinated animals with an equivalent group of unvaccinated or placebo controls. You should justify the choice of the controls. The control group should comprise animals against which the vaccinated animals can validly be compared.
You should describe in detail any adverse systemic and/or local reactions. You should provide observation records for each animal as an annex to the study report.
18.104.22.168. Field/single-dose effect
Each animal species and category, including animals of the minimum age at which the product is to be used, should be tested with a single dose taken from either a pilot or production batch. Unless for use in a single geographical region only, testing should be carried out on two significantly different geographical sites if geography may impact on product safety.
You should document adverse systemic and/or local reactions. Where appropriate, macroscopic and microscopic examination of the injection site should be carried out to determine if a recorded abscess is aseptic or secondary to a skin or product contaminant.
The safety studies should in the first instance verify the safety of the vaccine under field conditions after one administration of one dose of vaccine as well as after repeated administrations, depending on usage recommendations.
The single dose should also be used to investigate the possible systemic side effects of vaccination with the product. Examples of systemic effects include allergic reactions, mortality, anorexia, pyrexia, changes in behaviour, weight gain, feed conversion, carcass quality, milk/wool/fur production, egg production and hatchability of breeding eggs, and male and female fertility.
In the case of live vaccines, you should document the behaviour of the vaccine agents in animal populations. In terms of local reactions, you should monitor and record the size, duration and nature of any lesions appearing at the sites of injection.
22.214.171.124. Repeat administration of a single dose
Repeat administration of a single dose may be relevant to reveal any adverse events induced by repeated administration. You should determine the timing of the repeated dose, but the interval between repeated administrations should not be longer than that recommended for field use. This test would not be relevant in situations where the product is administered only once in a lifetime.
126.96.36.199. Overdose effects
An overdose safety assessment of inactivated and non-pathogenic live vaccines is not usually relevant. Unless we advise otherwise, overdose testing is relevant for live vaccines shown to retain residual pathogenicity. Using the recommended dose based on the maximum release titre, an overdose is usually 2× for inactivated vaccines or 10× for live vaccines, unless otherwise specified in the EP, BP or 9CFR/USP.
Both overdose and repeat administration studies should be carried out using the most sensitive classes or categories of the target species. Testing may be carried out as follows:
- rectal temperature monitoring for one to two days before vaccination, four hours after vaccination and thereafter twice daily through to four days (96 hours). If there is no evidence of rising temperatures, monitoring may then be discontinued. Body temperature measurement is not required for birds
- monitoring for signs of systemic or local site reaction through to 14 days unless otherwise stated in the EP, BP or 9CFR/USP monographs for specific antigen. Performance monitoring, including appetite and general disposition, should be carried out daily
- examination of injection sites at regular intervals during the 24 to 96 hours after administration (time intervals should be justified by the nature of the product under investigation). If significant lesions are still present at the end of 96 hours, observation should continue daily until lesions have subsided to an insignificant level
- careful examination of the administration site for signs of inflammation by inspection and palpation. The dimensions of palpable lesions should be recorded. The injection site should be checked on the final day of clinical observation and again at the time of slaughter, as appropriate.
Abnormalities detected in the above tests should (where possible) be thoroughly investigated to assess the likely incidence, aetiology or sequelae.
188.8.131.52. Reproductive performance
Examination of reproductive performance of breeding animals should be considered when data or scientific argument suggest that the starting material from which the vaccine is derived may be a risk factor. Laboratory safety studies are required unless an exclusion statement is included on the label, for example:
Use in pregnant females/breeding males is not recommended
Safety in pregnant females/breeding males has not been determined
These studies should involve at least one dose per test animal of a representative pilot or production batch, and at least eight test animals, and last for at least 14 days. The observation period will depend on the nature of the vaccine under test and may have to extend to beyond parturition.
In assessing the need for testing in future breeding animals, the potential effects of the vaccine on progeny, the potential for teratogenic and abortifacient effects, and the potential effects on reproductive performance of both sexes should be considered. If recommended for use in active breeding males, semen quality should be monitored, together with the potential for shedding of vaccine organisms into semen. If shedding is found, semen quality should be monitored. Pregnant animals should be tested in each of the specific periods of gestation recommended for use on the label. An exclusion statement should be included on the label for those gestation periods not tested.
If the vaccine is recommended for use in future breeding poultry, the study design should evaluate parameters relevant to the future use of the target birds.
You should submit laboratory and/or field safety studies to support the use of the vaccine in breeding animals. If you do not provide reproductive performance studies, you should clearly state the reasons.
184.108.40.206. Examination of immunological functions
Where the vaccine is known to affect, or could be expected to adversely affect, the immune response (for example, by immunosuppression, autoimmunity or hypersensitivity) of the animal vaccinated or of its progeny, suitable tests on their immunological function should be carried out. Alternatively, you should provide a rationale for no detrimental effect on immune response.
9.2.15. Special data requirements for live virus vaccines
You should provide data on spread of the vaccine strain to non-vaccinated and non-target animal species unless you can provide acceptable argument to show that this cannot happen. You should also provide data on dissemination in the vaccinated animal, including tests for the presence of virus in excretions and secretions, including eggs, milk, urine and faeces, where relevant.
You should also provide information on:
- the possibility of reversion to virulence in the case of attenuated strains
- the possibility of recombination or genomic reassortment.
9.2.16. Interactions with other products
You should substantiate claims that the vaccine can be administered simultaneously or in combination with other products. You should declare any known interactions with other products.
10. Part 9—Non-food trade
This data part is not relevant to veterinary vaccines.
11. Part 10—Special data: genetically modified organisms
Products that contain genetically modified organisms require a licence issued by the Office of the Gene Technology Regulator (OGTR).
You must submit a copy of the OTGR licence for field release to the APVMA before we can issue a trial permit. Where our trial requirements are met, we will issue a trial permit.