Use the following guidance material to complete the veterinary medicines risk technical assessment report template.
The guidance material is intended for use by APVMA External Scientific Reviewers only.
A link to the relevant guidance material for each section is also available at the start of each section in the report template.
Part 2: Chemistry and manufacture of the immunobiological active and product:
- GMP status of the manufacturing facility
- Formulation or composition of product
- Containers
- Manufacturing process of the final product
- Production, control and testing of starting materials
- In-process control tests during production
- Control tests on the final product
- Consistency of production
- Stability of the finished product
- Conclusions on chemistry (quality) and manufacturing
Part 6—Occupational health and safety
- Efficacy
- Safety
Overall conclusions on the application
Outstanding points on chemistry, manufacturing, efficacy and safety
How to return your completed report
Executive summary
In the executive summary, provide an overview of:
- the type of information provided (and relied on), and
- its suitability or relevance to the making of a positive or negative recommendation (two pages maximum).
The executive summary should only be prepared when all the application data and/or relevant information has been assessed in light of all scientific, regulatory and legislative requirements pertaining to the application.
A final position or recommendation should also form part of the executive summary.
As a guide, the executive summary should address:
- any critical deficiencies in the chemistry/manufacturing steps used in the production of the immunobiological including validation studies (eg inactivation), starting materials (eg risk from extraneous agents), in-process or final product assays, consistency of production and stability
- any significant risks identified from assessment of the critical laboratory/pen or field safety trials, for example significant local and/or systemic reactions in the target animal(s), risk of shed/spread to in-contact species, risk of recombination with field strains, risk to the user of the immunobiological, potential residues to consumers
- if the efficacy claims are fully supported by assessment of the critical laboratory/pen and field study data:
- has the applicant established an onset of immunity (OOI), duration of immunity (DOI)?
- have the studies supported the minimum age to be vaccinated and the various categories of animals (pregnant)?
- for in vivo studies and tests the Expert may comment on any 3Rs issues of concerns
- if the label particulars are consistent with the intended use of the product and the warnings and constraints are appropriate to ensure the safety of treated animals, users of the product, consumers of meat and dairy products from treated animals and the environment
- if there are any potential trade issues.
Part 1:
Application overview
The purpose of the application overview is to provide a brief outline of the application and to lead Risk Managers/Delegates through an application. The overview should contain general information on the product, and a summary of all data in the application.
More information will need to be included depending on the specificities of each product, for example active substances derived through biotechnology, non-standard manufacturing processes, novel QC methods to control quality steps, novel starting materials (adjuvants and/or excipients), presentations or delivery systems etc. For novel products attention should be given to the novel areas of the product, whether it is in the development, manufacture, testing or packaging stage.
If the immunobiological is a genetically modified organism (GMO) if should be confirmed that the application included a copy of the license issued by the Office of the Gene Technology Regulator (OGTR).
If biological raw materials of animal origin are imported, you should comment on whether a copy of the import permit has been provided otherwise it should become a non-standard condition of the registration.
For in vivo studies and tests, any 3Rs issues of concern should be highlighted. Comment is particularly relevant regarding in vivo challenge tests for potency or the use of animal models to demonstrate the absence of virulence/toxicity.
Give a critical summary of the development of the active substance(s), for example why the particular strain(s) was chosen and its relevance to the field situation in Australia.
Provide details on the proof of concept and the mechanism of action of the biological active substance to trigger the intended immune response and its relevance in the pathogenesis of the disease. Give the rationale for combined products where there is more than one active ingredient in the final formulation.
Explain briefly how the biological characteristics of the seed materials have been taken into consideration and how they are relevant to the development of the active ingredient in the finished product, for example for gene deleted vaccines the rationale for the development of a vaccine that enables a diagnostic test to differentiate between infected and vaccinated animals (DIVA).
Give a critical summary of the rationale for the development of the product and the significant process validation and developmental clinical studies that led to the choice of the final formulation.
Briefly summarise the qualitative and quantitative particulars of the active ingredient (antigen) concentration where relevant: target titre, minimum protective titre, minimum release titre, maximum release titre.
Choice of adjuvants and excipients which are either critical to the development of the finished product should be mentioned here together with their function. Briefly explain the container-closure system selected.
Choice of any preservative(s) should be described with comment on the suitability of the preservative for the formulation.
Immunobiological properties
The purpose of this section is to provide an overview of the diseases and/or conditions that the immunobiological is designed to treat, prevent or detect. Details on the nature of the immune response and any correlation of an immunological marker with protection should be described if used by the applicant for assessing protection in the critical efficacy studies.
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.
The categories of animals to be treated/vaccinated should be described especially if the product is intended for pregnant or very young animals where maternally derived antibodies may be an issue. A detailed assessment should be undertaken in the relevant section of the efficacy study reports.
The Expert should also provide information on efficacy claims including the onset and duration of immunity and whether the claims are considered relevant for the proposed pattern of use in the field.
Clinical particulars
Clinical particulars from the proposed label should be summarised in this section to include:
- target species
- efficacy claims
- contraindications
- undesirable effects (with reference to frequency and seriousness)
- any precautions for use
- dosage and method of administration
- overdose
- 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.
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.
If the product has previously been evaluated, you should provide full details of the outcome if known, along with details of the overseas approved use pattern (host species, claims, directions for use and withholding periods), including any use restrictions.
Part 2: Chemistry and manufacture of the immunobiological active and product
The following guidance material for Part 2 indicates the type of information and level of detail that should be included in the quality section of the report for applications and variations to ensure consistency of APVMA report format and style, but it is not exhaustive.
More information may need to be included depending on the nature of the product, for example active substances derived through biotechnology, non-standard manufacturing processes, novel QC methods to control quality steps, novel starting materials (adjuvants and/or excipients), presentations or delivery systems etc. For novel products, attention should be given to the novel areas of the product, whether it is in the development, manufacture, testing or packaging.
In general, the Expert should confirm compliance with the relevant regulatory standards Ph.Eur, BP, USP and Guidelines (VICH, EMA) or comment on the appropriateness and relevance of in-house methods and the proposed specifications. If non-immunobiological standards and Guidelines relevant to other products, for example human biologicals or veterinary pharmaceuticals, are applied to the assessment this should be noted and the weight of expectation in the level of compliance indicated.
Any shortcomings, omissions or deviations from the Ph.Eur or Directive should be highlighted and the rational for acceptance explained and justified.
GMP status of the manufacturing facility
Comment should be provided on whether it is considered that the product is manufactured to a standard comparable with the Australian Code of Good Manufacturing Practice for Veterinary Products (APVMA GMP).
For Australian manufacturers, compliance is by provision of an appropriate APVMA manufacturer’s license. For products manufactured overseas, you should supply evidence of compliance with good manufacturing practice, for example EUDRA GMP Certificate.
Formulation or composition of product
Mention the compositions of the product, specifying the activity/strength (potency/titre) of the active substance and the concentration of the adjuvant(s) (if relevant) and listing the excipients, indicating in general terms their function in the formulation, for example adjuvant, preservative, excipient. Comment may be necessary whether or not the use of a preservative and colourants is justified.
If there are any formulation overages (for antigen stability and/or volume), state what they are and whether justified or not. Provide details of the solvent/diluent and its composition and where relevant details for any antigen, adjuvant and excipient included in the solvent/diluent.
Containers
Add a brief description of the primary (immediate) packaging (including its closure), including information on the quantity of product contained in each container.
Include brief reference to the specifications of the immediate container (and closure), for example whether the immediate packaging complies with the relevant Ph. Eur./BP/USP. If the primary containers/stoppers are sterilised give brief details and refer to provided validation reports.
Include comment confirming whether certificates of analysis have been supplied demonstrating compliance with the proposed specifications.
If any administration device is supplied with the product then brief details should be included here on its design, quality, performance data and the adequacy of its specifications.
Manufacturing process of the final product
Details of production of the active ingredient from seed material through to active ingredient/bulk antigen should be included in this section.
Include a brief description of the method of manufacture highlighting any critical steps, for example inactivation process for inactivated vaccines, blending and filling processes and stating whether they are adequately controlled.
Discuss the adequacy of the validation data of specific manufacturing steps (including hold times) and any justification related to the production process, for example in relation to the manufacturer’s experience with the specific process. Include details of whether or not the validation studies were performed on full production-scale batches or pilot batches at each proposed manufacturing site.
Provide manufacturing details of any diluent included with the product identifying any critical steps and the adequacy of any in process controls.
Novel manufacturing processes may require more detail including comment whether justified or not. Reference to critical or novel process validation steps should be described and comment provided on the suitability of the validation studies, for example purification, or other critical process steps as appropriate.
Include reference to manufacturing steps for other substances used during manufacture (eg adjuvants) including the specifications to ensure a homogenous and consistent starting material.
Production, control and testing of starting materials
All components and substances used in the manufacture of the product should have the relevant information as per Ph.Eur, BP, USP or 9 CFR and the information should be presented below in the relevant sections.
Any shortcomings, omissions or deviations from the Ph.Eur, BP, USP or 9 CFR or VICH and EMA GLs should be highlighted and the rational for acceptance explained and justified.
If biological raw materials of animal origin are imported, you should comment on whether a copy of the import permit has been provided otherwise it should become a non-standard condition of the registration.
Starting materials listed in pharmacopoeias
All starting materials listed in a pharmacopoeia should be presented with an indication as to which pharmacopeia they are listed under and if they are compliant. Include a phrase or sentence confirming whether the proposed specifications are in accordance with the Ph.Eur, BP, USP or 9 CFR or not and if certificates of analysis have been supplied.
The function of the material should be described, its method of identification and any particular issues of note, for example storage period/stability.
Starting materials not listed in pharmacopoeias
Starting materials of biological origin
All starting materials of biological origin not listed in a pharmacopoeia, for example master and working cell seeds, viral bacterial or other microbial/parasite seeds and other starting materials of biological origin such as bovine serum, trypsin, lactose, peptides and recombinant products should be presented here.
Include a brief description of the material, the species of origin and geographical region from which it is sourced. The function of the material should be described.
For seed materials include a brief summary of the species of origin, history and geographical origin. Include details of method of preparation of the Master and Working Seeds including the cell cultures and the master and working seeds involved.
Include details of the tests on Master Seed Viruses/Master Bacterial Seeds (MSV/MBS), Working Seed Viruses/Working Bacterial Seeds (WSV/WBS) and Master Cell Seeds/Working Cell Seeds (MCS/WCS) including compliance with the relevant monographs or GLs as per Ph.Eur, BP, USP or 9 CFR or VICH/EMA GLs and whether any specific issues were identified.
The importation of some commodities is, by law, subject to the biosecurity conditions outlined in the departments Biosecurity Import Conditions (BICON) system. Some commodities are only allowed into Australia upon the granting of an import permit from the department. If the Starting Materials are imported comment on whether an appropriate Import Permit has been granted by the Australian Department of Agriculture. This is a prerequisite for the import of live and inactivated vaccines and should accompany the application of form a non-standard condition for registration.
Further details for testing and import of veterinary vaccines can be found on the Department of Agriculture's website.
A summary of the tests conducted for identity, extraneous agents, purity, sterility, absence of mycoplasma and retroviruses should also be included. Storage conditions should be briefly indicated. For live attenuated vaccines, proof of stability of the attenuation characteristics of the seed has to be given (see 'Safety').
Comment on the in-house control tests implemented to ensure the quality and consistency of the starting material and their specifications. Include comment on whether a certificate of analysis (where relevant) has been included and complies with the in-house specifications. Comment on the source of the starting material and any significant processing and/or testing to remove the risk of extraneous agents.
For genetically engineered starting materials, include information on any added or deleted genes, biological properties, gene expression and genetic stability of the final construct. This information shall include details such as the description of the starting cells or strains, the construction of the expression vector, control of the inserted sequences, details of the plasmid vector if applicable.
Any adjuvant or ‘novel’ excipient should be clearly mentioned here if of biological origin.
Any starting materials of human and/or animal origin that may carry risk of transmitting animal spongiform encephalopathy agents should be identified here and reference included how the applicant, for example, demonstrated Transmissible Spongiform Encephalopathy (TSE) compliance for each by TSE certification and/or via scientific documentation.
Comment should be made on the overall TSE risk assessment for the product taking account of all the starting materials and the intended use of the product in the target species. Where necessary highlight any specific TSE issues that were addressed in relation to the application that may be considered high-risk, for example ruminant derived starting material used to prepare ruminant vaccine.
Starting materials of non-biological origin
All starting materials of non-biological origin not listed in Ph.Eur, BP, USP or 9 CFR should be mentioned here with information on their specifications and whether they conform to their certificate of analysis and if the presented documentation is adequate to be considered acceptable or not.
In-house preparation of media and solutions consisting of several components
Culture media consisting of several components used for production of an active substance shall be regarded as one starting material. All components shall be described in the previous sections but details of the complete formulation included here.
State if there are any risk that might be posed by the use of media and solutions.
In-process control tests during production
This section should include details of the control tests performed at the various stage of the manufacturing process and their validation commencing at the control tests performed on the production seed through to any tests conducted on the bulk active ingredient.
Include a brief overview of any control tests (and respective limits, if relevant) conducted during intermediate stages of the manufacturing process with comment on their validation, necessity and suitability to control consistency and homogeneity of production, for example antigen content, sterility and CPE. In line with Ph.Eur, BP, USP or 9 CFR tests relevant to this section also include inactivation controls, detoxification, physical tests, chemical tests, pH, etc.
Control tests on the final product
This section includes tests on the final filled product and/or bulk formulated vaccine where appropriate and justified.
In general, give the objectives of the test with a reference to Ph.Eur, BP, USP or 9 CFR if relevant, or the reference to any internal test method or standard), and a short description of the proposed test.
State whether the proposed specifications/limits for each control test are justified and whether they provide a satisfactory confirmation of the quality of the product. Include details of whether the control test is performed on the final product or bulk and whether the approach is acceptable or not.
Comment in particular, on the tests to identify and quantify the active substance in the final product.
Give brief information on the batch potency test including reference to validation studies provided and studies used for determination of release and/or end-of shelf life specifications. State whether the limits have been adequately justified.
State if all the analytical methods are well described, if any are Ph.Eur, BP, USP or 9 CFR methods if appropriately validated in accordance with current guidance (EU GLs or VICH GLs 1 and 2 [Validation of Analytical procedures] and VICH GL 40 [Test procedures and acceptance criteria for new biotechnological/biological veterinary medicinal products]).
General characteristics of the finished product: List of tests performed, and confirm compliance with the specifications. Examples of tests provided here include appearance, volume, pH, viscosity etc.
Identification of the active ingredient(s): A brief description of the method used to confirm the identity of the active ingredient. Confirmation that the methods used to identify the strains/serotypes of the active ingredients are suitable. For GMO active ingredients include a brief description of the method of identification including techniques for the identification and detection of the inserted sequence and vector.
Batch titre or potency: A brief description of the potency test should be provided. Validation is reliable to guarantee the minimal level shown to be efficacious in the critical efficacy studies in Part 4 and that release specifications are justified. Confirm that that the test is able to detect a sub-potent batch and the appropriateness of the test to ensure consistency of production.
Identification and assay of the adjuvants: A brief description of the methods used to confirm the identity and quantity of the adjuvant where relevant.
Identification and assay of each of the excipients: A brief description of the methods used to confirm the identity of the excipient where relevant.
Sterility and purity tests: List the tests performed that confirm the sterility and purity of the finished product. Include reference to the Ph.Eur, BP or 9 CFR for sterility, purity and mycoplasma.
Residual humidity (if relevant): Each batch of lyophilised product shall be tested for residual humidity according to Ph.Eur, BP, USP or 9 CFR.
Consistency of production
Batch analyses results from at least two consecutive batches of active substance and finished product should be summarised with comment on whether they confirm consistency and uniformity of the product.
Comment on whether pilot or industrial scale batches have been used to demonstrate consistency and highlight any deviations from the proposed method of production for routine batches.
Stability of the finished product
Include sections on the stability of:
- active substance, ie final bulk antigen before formulating as bulk vaccine.
Bulk vaccine prior to formulation if applicable:
- final product including active ingredient(s) in final filled container in its final state
- the associated solvent/diluent.
Comment on whether or not appropriate controls were used at the appropriate time points to establish the stability of the active substance, final product and in-use stability.
In general, for active ingredient and final product, summarise the stability studies and significant findings. State conditions (storage at xx°C, container material) used, number of batches that had been produced, batch sizes (whether pilot scale/production scale) and immediate packaging material.
For final product comment on the bracketing design (testing smallest and largest container).
The description should be concise and normally not more than a short paragraph. No tables of stability study results to be included. Briefly discuss the stability results and any out of specifications results and mention the conclusions in this respect. Any shortcomings/omissions should be highlighted and justified.
If a preservative is included in the product include details of the preservative efficacy studies at the end of shelf life and comment on whether the test method and specifications complies with Ph.Eur, BP or 9 CFR requirements.
If an in-use period is proposed for the final product, a comment on the stability data supporting the in-use period should be made in this section.
Stability of the diluent/solvent. The stability studies of the diluent/solvent should be confirmed, and where the diluent/solvent includes an active component the full spectrum of observations as described above should be applied.
Conclusions on chemistry (quality) and manufacturing
Summarise briefly the conclusions in respect to the compliance with APVMA, Ph.Eur, BP or 9 CFR, EMA GL and VICH requirements and Guidelines for production and testing of Active and Veterinary Product.
Confirm compliance with the relevant APVMA, Ph.Eur, BP or 9 CFR, EMA GL and VICH requirements and Guidelines highlighting the adequacy and completeness of the data provided in general (without giving details of studies) with any shortcomings/omissions highlighted and justified and the conclusions drawn.
Comment on the sites for manufacture and testing and whether they comply with APVMA standards for Good Manufacturing Practice (GMP).
Comment of critical areas including, the shelf-life of the active ingredient and final product, the appropriateness of the manufacturing method and in-process and final product controls, the selection and testing of starting materials, including adjuvants, excipients and preservatives (where applicable) identifying any deficiencies and explaining the criteria for acceptance where there are gaps in the data or compliance with APVMA, Ph.Eur, BP or 9 CFR, EMA GL and VICH requirements and guidelines.
Part 5: Residues and trade
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.
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 the implications for trade and where a persistent local tissue reaction may occur following injection, consideration should be given to establishing a withholding period or carcass disposal statement on the label.
Part 5B: Trade
If the veterinary vaccine is used in food-producing animals, comment should be given on the potential of the product to affect trade. You should also address trade issues relating to the use of genetically modified organisms.
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.
Part 6: Occupational health and safety
If the Expert is requested to comment of Occupational Health and Safety, they should address potential occupational health and safety risks associated with the manufacture and use of the product. This may include safety instructions, use of personal protective equipment, first aid instructions, information for medical practitioners.
Provide an overview of the assessment of the hazard presented by the product to the users, as presented by the applicant, highlighting significant findings/shortcomings/omissions.
Briefly outline any inherent toxicity (including immunological/ pharmacological effects if relevant), exposure (worst- case scenarios), mention any relevant studies submitted and whether there is a risk arising.
If different exposure scenarios are to be considered, briefly describe the exposure scenarios with the conclusions on the risk characterisation and discuss resulting risk management proposals, where appropriate.
Part 7: Environment
Provide an assessment 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.
Environmental risk assessment (ERA)
The Expert should provide a brief overview of the ERA, highlighting significant findings/shortcomings/omissions. If any of the issues are considered key, then it may be appropriate to describe these in a little more detail. The ERA for an immunological must address the risks arising from each of the components of the product, not just from live organisms in vaccines.
If the immunobiological is a genetically modified organism (GMO) if should be confirmed that the application included a copy of the license issued by the Office of the Gene Technology Regulator (OGTR). Further consultation may be required with the various Competent Authorities responsible for GMOs and the Expert should highlight any issues that may be of importance for registration of the product.
For live recombinant vector vaccines (GMOs) special considerations should be highlighted in the report:
- identification of the characteristics of the recipient organism, which are relevant to the assessment of the GMO in question
- identification of any known risks to human health and the environment resulting from the release into the environment of the recipient non-modified organism
- assessment of whether the genetic modification has been characterised sufficiently for the purpose of evaluating any risks to human health and the environment
- description of the result of the genetic modification in the modified organism
- genetic <and phenotypical> stability
- reversion to virulence
- estimation of the likelihood (probability and frequency)of recombination event between the vaccine virus strain and the field strain
- identification of any new risks to human health and the environment that may arise from the release of the GMO in question as compared to the release of the corresponding non-modified organism based on the environmental risk assessment
- a conclusion on whether the GMO in question should be placed on the market and under which conditions, should be provided. These conditions should be specified if applicable. The conclusion should clearly address the use proposed and the risk management (eg if appropriately reflected in the label). In the case that it has been concluded that the GMOs should not be placed on the market, a brief justification should be provided and should be copied in the overall conclusions
- for DNA plasmid vaccines, the risk of integration of the plasmid into the genome of vaccinated animals should be evaluated, in particular for food-producing species.
Part 8: Efficacy and safety
Efficacy
Introduction
The Expert should provide an introduction of the various elements of the efficacy section of the product under consideration should be presented, in order to understand the approach taken, without repeating the general description of the product.
If there are several target animal species/indications/pharmaceutical forms, data for these species should always be presented in the same species/indication/pharmaceutical form order.
Comment on whether there are specific Ph. Eur. monographs that the applicant needs to respect.
Comment on batches used in the study (routine production scale or pilot) and whether the content of the doses used was the minimum recommended.
Challenge model
The Expert should provide here a brief description of the validity of the challenge model, ie origin, epidemiological relevance of the challenge strain(s), titre, route and comment whether it was appropriate for the purpose of the efficacy studies.
The conditions under which the challenge is carried out in the laboratory trials/pen studies should, as far as reasonably practicable, mimic the natural conditions for infection, for example with regard to the route of administration of the challenge and development of clinical signs.
Describe here the model used and its justification and any studies or tests that have taken place to confirm its validity. If there are any concerns describe them briefly and how they may affect the outcome of the efficacy studies.
Efficacy parameters and tests
The Expert should provide brief information on the efficacy parameters and the selected tests to evaluate them.
Comment whether they are appropriate for this purpose, if they have been adequately validated and the eligibility of the selected tests for assessment of the efficacy of the vaccine.
Dose determination
Summarise the justification provided by the applicant for the recommended dose and any dose confirmation studies conducted.
Efficacy laboratory trials/pen studies
In this section the Expert should provide an overview of the laboratory trials/pen studies efficacy data package submitted in support of the registration of the immunobiological product providing a high level summary of the applicants strategy for demonstrating the efficacy of the immunobiological product.
The Expert should provide detailed description of the critical studies conducted to support the efficacy of the product in the following sections of the report template completing the summary tables for each critical study. These should be controlled studies including untreated control animals.
Other trials (supportive/pilot/exploratory etc) should only be briefly summarised. The Expert should indicate why studies could not be considered relevant (eg inappropriate study design, dose, etc).
Efficacy should be demonstrated for each category of each species (eg youngest, pregnant) recommended for vaccination, by each recommended route of administration and using the proposed schedule of vaccination (primary and booster).
The Expert should comment on the study results for the efficacy parameters and relate these results to the efficacy claims.
Comment on the reliability of results in consideration of the quality of the study. Highlight clearly those outstanding issues, which are of pivotal importance for determining whether the study brings evidence for an effect that can be regarded clinically relevant (major outstanding issues).
Ensure that clear information on results and conclusions are provided for each study.
The Expert should also complete a high-level summary table in 'Overall conclusion on efficacy' capturing the key studies that established the efficacy claims for the immunobiological product.
Onset of immunity
Any efficacy claims regarding onset and duration of protection should be supported by data from the efficacy studies. A discussion of the studies and the influence of passive acquired and maternally derived antibodies on the efficacy of the vaccine should be included if relevant. The onset of immunity should be established after the primary vaccination schedule by a suitable immune marker or from the results of a challenge study.
Use the example study summary table below to describe the detail of the study.
|
Reference and study title Include the dossier reference (study title as it appears on the front of the study summary) |
|
|---|---|
|
Objectives |
Specific objectives/aims of the study |
|
Trial design |
Randomised/blinded/placebo or active-controlled/superiority/non-inferiority |
|
Compliance with regulatory guidelines |
Ph.Eur/BP or 9 CFR product specific monographs
For safety studies comment on compliance with minimum safety requirements, VICH GL 44 Target Animal Safety (TAS) for veterinary inactivated and live vaccines and any specific Ph.Eur, BP or 9 CFR monograph requirements, which are applicable to the product |
|
Animals |
Species, sex, physiological status (with or without MDA, conventional/SPF, laying/broilers, fattening/piglets/sows, pregnant/non pregnant etc), age, allocation (randomly or not, number of groups, number of animals in each group etc) |
|
Animal status on inclusion |
Eligibility (disease status) |
| Vaccine | Name, active substance, pilot batch, commercial batch, titre (if not minimum, which justification is provided) |
| Control product/placebo |
Nominal dose rate/vaccination regimen
Method of administration |
|
Vaccination scheme |
Primary/booster vaccination schedule according to label? |
|
Challenge |
Strain, titre, route of administration |
|
Efficacy parameters |
State clearly the efficacy parameters used to investigate proposed claims |
|
Statistical method |
Which test(s) and why they were chosen, relevant parameters |
| Results | For each efficacy parameter, please provide a summary of the results for each group, P-value, and its precision (95% CI). State results in absolute numbers where possible, in addition to %. Preferably in the same order than listed above |
| Appropriateness of trial/experimental design | Notes of what is required can be found under the study types |
| Discussion | This should take account of the aims of the study and address the efficacy and safety of the test product |
|
Conclusions |
|
Duration of immunity
Use the example study summary table to describe the detail of the study.
The Expert should describe the design of the pivotal duration of immunity studies under laboratory/pen conditions, with clear information about the duration of protection (interval between administration of vaccine and observed protection against challenge) and whether it is from the basic vaccination scheme (primary vaccination schedule) or from the re-vaccination scheme (booster schedule).
Describe how protection has been investigated, ie based on challenge or on surrogate to protection (serology correlated to protection).
Comment on whether it covers the active or passive immunity or both, basic dose tested, the batches used (pilot, routine), duration of the tests, conditions, etc. The validity of the study model should be commented upon and the results evaluated in relation to the recommended use of the final product.
Duration of immunity allows either to justify the vaccination scheme (in particular the time of booster); if no booster vaccination is foreseen, it should normally cover the period at risk; any deviation to this should be commented on by the Expert.
For duration of immunity studies under field conditions, the relevant study should be described under the section for Field trials. Relevant EMA note for guidance on duration of protection achieved by veterinary vaccines (EMEA/CVMP/682/99) should be taken into consideration.
Maternally derived antibodies (MDA)
Use the example study summary table to describe the detail of the study.
If vaccination is recommended in animals at an age at which maternally acquired immunity may still be present and may interfere with active immunity development, describe here any studies performed to determine whether such interference occurs.
If interference occurs comment on how the applicant addresses it.
Comment whether, batches containing the minimum active content were used and if not the justification.
Describe here any data presented from scientific publications or from field trials relevant to MDA interference investigations.
Interactions with other immunobiologicals
Use the example study summary table to describe the detail of the study.
The Expert should document whether interactions with other vaccines/immunobiologicals that may be used concomitantly have been investigated.
The efficacy aspects of any studies presented in support of compatibility claims should be summarised and concluded on.
The Expert should conclude on the acceptability of any proposed compatible claims for the veterinary products. It should be noted that this should also involve assessment of whether the efficacy of the (authorised) product for which compatibility is claimed is affected by concurrent or simultaneous use with the vaccine(s)/immunobiological(s) under evaluation.
Field trials
The results from the pivotal laboratory trials/pen studies should be supplemented with data from field trials. In cases where laboratory trials/pen studies cannot be supportive of efficacy, the performance of field 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 a strong scientific argument is provided that overseas data are applicable to Australia’s climatic conditions, genetic stocks and farm management practices.
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.
The Expert should indicate the location, briefly summarise the protocol (trial design, numbers, monitoring, vaccination schedule, whether a natural challenge was observed) and the outcome for different indications, target species, species subcategory and product used (pilot, industrial batch, reflective of proposed min/max specifications).
Modifications to the study summary above may be required depending on the type of product and study design. Information is necessary with regard to, for example the objectives, study design, sites (country[ies]), study population (number of study animals, age, sex, disease condition, high number of animals excluded or lost to follow up during the study etc), investigational and control treatments, efficacy parameters, and statistical methods used to evaluate the results for the endpoint.
Add information on major deviations from the study protocol.
Introduce the results of the efficacy parameters, as applicable to support proposed claims.
Evidence (or lack) of significant interactions with concomitantly administered products should be reported.
Comment on the validity of the study design for investigating the proposed claims (product and dose regimen) for the intended indication, including an evaluation of the appropriateness of the statistical methods used. Indicate if the study complies with the VICH GCP-guideline.
Comment if there was sufficient exposure to the field pathogen(s) or whether a natural disease outbreaks occurred during the field trial, to enable conclusions to be drawn regarding efficacy under field conditions.
Comment on the study results for the efficacy parameters (size of treatment effect and confidence interval) and relate these results to the primary objective.
Comment on the reliability of results in consideration of the quality of the study. Highlight clearly those outstanding issues that are of pivotal importance for determining whether the study brings evidence for an effect that can be regarded clinically relevant (major outstanding issues). Ensure that clear information on results and conclusions are included.
Conclude briefly on the study by indicating whether it fulfilled its objectives, at least the primary objective, and whether the study therefore provides solid/partial/strong/weak/no evidence for the effectiveness of the product.
The Expert should present each study in a table using the example summary of field trials table below.
|
Reference and study title Include the dossier reference (study title as it appears on the front of the study summary) |
|
|---|---|
|
Objectives |
Specific objectives/aims of the study |
|
Study design |
Randomised/blinded/placebo or active-controlled/superiority/non-inferiority
Efficacy or efficacy and safety |
|
Study sites |
Setting/location, single/multi-centre |
|
Compliance with regulatory guidelines |
GCP |
|
Animals |
Species, sex, physiological status (with or without MDA, conventional/SPF, laying/broilers, fattening/piglets/sows, pregnant/non pregnant etc), age, allocation (randomly or not, how many groups, number of animals in each group, etc) |
|
Animal status on inclusion |
Eligibility (disease status) |
| Vaccine |
Name, active substance, pilot batch, commercial batch
Minimum, standard or maximum potency batches |
| Control product/placebo |
Nominal dose rate/regimen
Method of administration |
|
Vaccination scheme |
Primary/booster vaccination schedule according to label? |
|
Natural challenge |
Comment if there was sufficient exposure to the field pathogen(s) or whether a natural disease outbreaks occurred during the field trial, to enable conclusions to be drawn regarding efficacy under field conditions
If animals were removed from the field and challenged under laboratory/pen conditions this should be described in detail and comment made on the relevance of the challenge model, the immune status of animals and the relevance of the study to support the claims for efficacy |
|
Efficacy parameters |
State clearly the efficacy parameters used to investigate proposed claims |
|
Statistical method |
Which test(s) and why they were chosen |
|
Results |
|
|
Efficacy parameters |
For each efficacy parameter, please provide a summary of the results for each group. P-value and its precision (95% CI). State results in absolute numbers where possible, in addition to % |
|
Discussion |
|
| Deviations | Add information on major deviations from the study protocol |
| Interactions | Evidence (or lack) of significant interactions with concomitantly administered products should be reported |
|
Discussion |
Summarise the results. This should take account of the aims of the study and address the efficacy (and safety if relevant) of the test product
Comment if there was sufficient exposure to the field pathogen(s) or whether a natural disease outbreaks occurred during the field trial, to enable conclusions to be drawn regarding efficacy under field conditions
Comment on the study results for the efficacy parameters (size of treatment effect and confidence interval) and relate these results to the primary objective
Comment on the reliability of results in consideration of the quality of the study
Highlight clearly those outstanding issues that are of pivotal importance for determining whether the study brings evidence for an effect that can be regarded clinically relevant (major outstanding issues) |
| Conclusions | Conclude briefly on the study by indicating whether it fulfilled its objectives, at least the primary objective, and whether the study therefore provides solid/partial/strong/weak/no evidence for the effectiveness of the product |
Conclusion on field trials
Finally, provide an overall conclusion on the field trials summarising the strength of support of all the field trials together provide for the proposed claims, but also any major outstanding issues.
Overall conclusion on efficacy
The Expert should briefly summarise the findings conclusions/outcome of the laboratory/pen and field trials, highlighting the main findings/concerns.
A clear conclusion should be drawn on the data presented, indicating both the main strengths and the weaknesses of the application, and which claims have been supported by the data in the application.
If outstanding concerns remain, major concerns should be indicated and need for additional data highlighted.
If it is possible to address the objections by risk management measures (eg amending the label), this must be stated (eg rewording of an efficacy claim, addition of contraindications or special precautions for use).
In addition complete the following summary table for all efficacy laboratory trials/pen studies and field trials that support the claims for the immunobiological product.
|
Reference/study title: |
Animals |
Vaccine |
Vaccination scheme |
Trial design |
Results |
Conclusion |
Comment |
|---|---|---|---|---|---|---|---|
|
APVMA#: |
5 vaccinated dogs |
Minimum titre CPV 5 x 107 TCID50/ml per dose |
Vaccinated at 8 and 12 weeks of age |
Challenged with virulent CPV (5 x 1010 TCID50/ml) at 14 weeks of age
Monitored for D+, pyrexia, CPV excretion in faeces, serology, viraemia, LN depletion |
All vaccinated pups survived, no clinical signs but pyrexia and mild D+ on Day 2-4 post-challenge. No viraemia detected by PCR
|
Vaccination at 8 and 12 weeks protects pups at 2 weeks post-vaccination of primary course
|
Supports the OOI of 2 weeks post-primary vaccination schedule at 5 x 107 TCID50/ml per dose |
Safety
Safety introduction
As introduction the relevant elements pertinent to the safety assessment of the product under consideration should be presented, in order to understand the approach taken, without repeating the detailed general description of the product in Part 1.
A brief summary of key elements of the product should be included, for example type of vaccine (live, inactivated, etc), adjuvants, GMO or novel immunobiological.
If the vaccine is a live one reference can be made to the pathogenesis of the field strains, their impact on the targeted animals and specific points of concern, if applicable.
If a novel immunobiological, some additional information may be required to explain the applicant’s approach for demonstrating the safety.
Provide comment if there is a Ph.Eur, BP or 9 CFR monograph which is applicable to the product which specifies the requirements for safety testing—and if the European Pharmacopoeia (Ph. Eur.) chapter 5.2.6 have been followed.
Other trials (supportive/pilot/exploratory) should only be briefly summarised, if relevant.
The Expert should indicate why studies could not be considered relevant (eg inappropriate study design, dose, etc).
Experts should also comment on whether pen/lab studies were performed to GLP and if not whether they consider the level of QA satisfactory or not.
Laboratory trials/pen studies
In this section the Expert should provide an overview of the laboratory trials/pen studies safety data package submitted in support of the registration of the immunobiological product providing a high level summary of the Applicants strategy for demonstrating the safety of the immunobiological product.
The Expert should provide a detailed description of the critical studies conducted to support the safety of the product in the following sections of the report template completing the summary tables for each critical study. These should be controlled studies including untreated control animals.
Any shortcomings/omissions should be highlighted and justified.
If several studies and references have been provided, first summarise briefly how many studies were provided and separate these into pivotal and supportive. Experts should refer to the requirements outlined in VICH GL 44 Target Animal Safety (TAS) for veterinary inactivated and live vaccines.
Comment on the reliability of results in consideration of the quality of the study. Highlight clearly those outstanding issues, which are of pivotal importance for determining the safety of the immunobiological product (major outstanding issues).
Ensure that clear information on results and conclusions are provided for each study.
The Expert should also complete a high-level summary table in 'Overall conclusion on safety' capturing the key studies that established the safety of the immunobiological product.
Safety of the administration of the proposed dose
At a minimum include information taking into account the need to use the recommended maximum dose of immunobiological/vaccine (or (titre or potency) containing bacteria/virus at the least attenuated passage level and in the case of live vaccines containing maximum release titre.
Vaccination should be following the primary vaccination scheme by the recommended route(s) of administration, to an appropriate number of animals of each species and category for in which it is intended to be used, including animals of the minimum age (serological status where relevant) at the start of administration and pregnant animals, where appropriate.
Additionally, comment whether a pilot or production batch of the product containing the maximum release potency or, in the case where maximum release potency to be registered is not specified, then a justified multiple of the minimum release potency was used.
Finally, comment on compliance with minimum safety requirements and any specific Ph.Eur, BP or 9 CFR monograph requirements, which are applicable to the product applicable to the product.
Observations and examinations for signs of systemic and local reactions shall be described as well as where appropriate post-mortem macroscopic and microscopic examinations.
Results should be evaluated in a conclusion in relation to the safety of the administration of a recommended dose following the primary vaccination scheme.
Use the following example study summary to describe each study.
|
Reference and study title Include the dossier reference (study title as it appears on the front of the study summary) |
|
|---|---|
| Objectives | Specific objectives/aims of the study, eg overdose safety study |
| Study design | Design of study, eg 10X overdose in minimum age animals |
| Study sites | Setting/location, single/multi-centre for field safety studies |
| Compliance with regulatory guidelines | GLP/VICH GL44 |
| Animals | Species, sex, physiological status (conventional/SPF, laying/broilers, fattening/piglets/sows, pregnant/non pregnant etc), age, allocation (randomly or not, how many groups, number of animals in each group, etc) |
| Animal status on inclusion | Eligibility (disease status) eg seronegative |
| Vaccine | Name, active substance, pilot batch, commercial batch titre |
| Control product/placebo | Method of administration |
| Vaccination scheme | Primary/booster vaccination schedule according to label? |
| Statistical method | Where applicable eg for field safety studies |
| Results | |
| Safety parameters | For each efficacy parameter, please provide a summary of the results for each group |
| Discussion | |
| Discussion | Highlight the all safety issues identified in the safety study and comment on whether or not a warning or statement is required on the label |
| Conclusions | Conclude briefly on the study by indicating whether it fulfilled its objectives |
Safety of the administration of an overdose
Use the example study summary table to describe the detail of the study.
Please note that this section is not applicable for inactivated vaccines under VICH GL44, as no overdose studies are required for this category of product. For a novel immunobiological, describe the applicant’s approach to addressing overdose safety requirements.
At a minimum include information taking into account the need to use the recommended route(s) of administration to an appropriate number of animals of the most sensitive category of the target species and serological status if relevant (eg whether there is a need to consider influence of maternally derived antibodies).
Comment on the dose administered and its justification (ie for live vaccine it is expected that a 10X dose of vaccine at the least attenuated passage level containing the maximum release titre for which the application is submitted shall be administered).
In the case where the maximum release titre to be registered is not specified, or if the vaccine is formulated at a fixed concentration of antigen and no minimum/maximum dose is applicable, the study should be conducted with a justifiable multiple of the minimum release titre.
Finally, comment on compliance with minimum safety requirements and any specific Ph.Eur, BP or 9 CFR monograph applicable to the product.
Observations and examinations for signs of systemic and local reactions shall be described and, where appropriate, post-mortem macroscopic and microscopic examinations.
Results should be evaluated in a conclusion in relation to the safety of the administration of an overdose dose following the primary vaccination scheme.
Safety of the repeated administration of the proposed dose
Use the example study summary table to describe the detail of the study.
The Expert should provide comment on the administration protocol and the level of dose administration. Include information taking into account the need for the vaccination schedule to include the primary vaccination regimen plus an additional dose via the recommended route of administration to animals of the most sensitive category of the target species.
Comment whether a pilot or production batch of the product containing the maximum release potency was used. If not comment whether an acceptable justification was provided (ie in the case where the maximum release potency to be registered is not specified, then a justified multiple of the minimum release potency can be used).
Comment if seronegative animals were used in case of live vaccines and if not whether reasonable alternatives were provided. In cases where seronegative animals are not reasonably available, alternatives should be justified.
Finally, comment on compliance with minimum safety requirements and any specific Ph.Eur, BP or 9 CFR monograph applicable to the product.
Observations and examinations for signs of systemic and local reactions in injection sites shall be described, where appropriate post-mortem macroscopic and microscopic examinations.
Comment on duration and frequency of examination taking into account that injection sites should be examined daily or at other justified intervals by inspection and palpation for a minimum of 14 days after each administration.
Results should be evaluated in a conclusion in relation to the safety of the administration of a recommended dose following at least one additional vaccination after the primary vaccination scheme.
Examination of reproductive performance
Use the example study summary table to describe the detail of the study.
Comment on whether the examination of reproductive safety was appropriate for the purpose of the study, ie use of the recommended dose according to the proposed vaccination scheme, by the recommended route(s) of administration to the groups of animals used (whether numbers were sufficient and if control groups were included) and whether a pilot or production batch was used.
Additionally, comment whether the observation period was appropriate to determine reproductive safety.
For vaccines recommended for use in pregnant animals comment whether the study(s) covered the periods of gestation recommended for use and whether the observation period was extended to parturition, to examine any harmful effects during gestation or on progeny.
Any additional studies to determine the effect(s) of semen, including shedding of the live organism in semen should be described in this section.
Comment on whether reproductive performance is also examined in field safety studies and if it is supportive and consistent with the results of the laboratory/pen studies.
If the reproductive safety studies are not performed, an exclusion statement must be included on the product information label, unless a scientific justification for absence of risk for use of the product in the breeding animal is provided.
In addition, since this section establishes the basis of the information on the label concerning use during pregnancy, lactation or lay, ensure that a relevant statement can be included on use during lactation, if applicable.
Summarise briefly and state whether the studies are adequate or not, to support the claims on the label. Depending on the results, consider potential contraindication in breeding, pregnant (consider the acceptability on use for the different stages of gestation) or lactating animals.
Examination of immunobiological functions
The Expert should provide a brief description of the tests on the immunological functions in cases where the product might adversely affect the immune response of the vaccinated animal or of its progeny.
Special requirements for live vaccines
The Expert should refer to the relevant guidelines including: VICH GL41 Target Animal Safety—Examination of Live Veterinary Vaccines in Target Animals for Absence of Reversion to Virulence—Annexes Spread of the vaccine strain.
Spread of the vaccine strain
The Expert should provide a brief description of the investigations into the spread and shedding of the vaccine strain from vaccinated to unvaccinated target animals using the recommended route of administration most likely to result in spread.
Additionally it may be appropriate in this section to describe the investigations into spread to non-target species, which could be highly susceptible.
Investigations to examine the spread of an antibiotic resistance gene into the environment, if relevant, can also be included in this section.
Comment on whether the investigations and the data provided were adequate to characterise the risk of spread and whether an acceptable risk has been adequately demonstrated.
Dissemination in the vaccinated animal
The Expert should provide a brief description of the tests in faeces, urine, milk, oral, nasal and other secretions for the presence of the organism as well as the bio-distribution of the organism and its dissemination in the body’s predilection sites for replication.
In the case of live vaccines against zoonotic diseases for food-producing animals, these studies would be expected and should include an assessment of persistence at the injection site.
Comment on whether the investigations and the data provided were adequate to characterise the risk of dissemination and whether an acceptable risk has been adequately demonstrated.
Additionally, in the case of live vaccines for zoonotic diseases the determination of residues at the injection site may be required.
Reversion to virulence of attenuated vaccines
The Expert should provide a brief description of the tests with material from the passage level that is least attenuated between the master seed and the final product.
Comment on whether the master seed was used and if not whether adequate justification was provided (ie if sufficient quantity of the master seed was not available for testing). Generally, for each target species, the most sensitive class, age, sex and serological status of animals should be used.
Comment on the route of administration, which should be using a recommended route of administration or natural route of infection that is the most likely to lead to reversion to or increase in virulence and result in recovery of the organism following replication in the animal. The route used must be justified. In cases where alternative approaches are used, alternatives should be justified.
Comment on the groups and number of animals used and whether appropriate for this type of study.
Comment on whether the inoculum and the passages used were appropriate (ie initial one should contain the maximum release titre expected in the recommended dose or, in the cases where the maximum release titre to be registered is not specified, then a justifiable multiple of the minimum release titre can be used).
Comment on whether the clinical observations were typical for the disease, which could indicate reversion to or increase in virulence. If signs consistent with the target disease were observed, confirm whether there was any evidence of an increase in virulence, indicative of reversion, with passage and whether the test organism is suitable for use as a live vaccine.
Provide a conclusion as to whether the applicant adequately demonstrated an acceptable risk with respect to reversion to virulence.
Biological properties of the vaccine strain
The Expert should provide a brief description of any other tests that may be necessary to determine as precisely as possible the intrinsic biological properties of the vaccine strain (eg neurotropism). Information on the characterisation of the live virus strains and the stability of the attenuation can also be included in this section. Were other tests necessary in relation to the properties of the vaccine strain? If so, were they adequately performed?
Provide a conclusion as to whether the biological properties of the vaccine strain have been adequately presented and whether on the basis of this data the safety profile of the strain is acceptable.
Field trials
The purpose of the field safety studies is to demonstrate the safety of the vaccine when used in field conditions where disease, husbandry and housing conditions are similar to those as of farms within Australia for which the product is intended for use.
If combined efficacy and safety field trials have been conducted these should be summarised in Part 8—Efficacy field trials and a note added to the Part 8—Safety field trials section.
Describe briefly the design of the studies with information on the animals used, dose tested, formulation used, duration of tests and observations. Field trials should conform to the standards of GCP (VICH GL 9 Good Clinical Practice) with any deviation highlighted by the Expert and an assessment made to the acceptability of the study design, data and QA systems in place ensure accurate and detailed records.
Comment on whether the site(s) chosen and the conditions of those sites were appropriate for the evaluation of the safety parameters (ie exposure to the disease).
Comment whether animals were in the age range/class intended for treatment as indicated in the proposed label. Their serological status should also be mentioned, whether a negative or positive control group was included and whether treated and control animals were managed similarly.
Comment on whether (a) representative batch(es) of the product (was) were used and the titre used.
Comment on whether observations recorded where appropriate and if the frequency and duration of observations were adequate. Observations should cover local (ie size, duration and nature of any lesions at the site of injection) and systemic (ie pyrexia, allergic reaction, mortality, anorexia, weight gain, milk/egg production, fertility, etc) reactions.
Summarise adverse events documented and any attempts to determine causality for the adverse events. The results should be evaluated in relation to the safety of the final product under field condition when used as recommended in the proposed label.
Copy the final, relevant conclusion(s) to the overall conclusion on safety.
The Expert should present each study in a table using the example summary of field trials table below.
|
Reference and study title Include the dossier reference (study title as it appears on the front of the study summary) |
|
|---|---|
|
Objectives |
Specific objectives/aims of the study |
|
Study design |
Randomised/blinded/placebo or active-controlled/superiority/non-inferiority |
|
Study sites |
Setting/location, single/multi-centre |
|
Compliance with regulatory guidelines |
GCP |
|
Animals |
Species, sex, physiological status (with or without MDA, conventional/SPF, laying/broilers, fattening/piglets/sows, pregnant/non pregnant etc), age, allocation (randomly or not, how many groups, number of animals in each group, etc) |
|
Animal status on inclusion |
Eligibility (disease status) |
| Vaccine |
Name, active substance, pilot batch, commercial batch
Standard or maximum potency batch for safety |
| Control product/placebo |
Nominal dose rate/regimen
Method of administration |
|
Vaccination scheme |
Primary/booster vaccination schedule according to label? |
|
Statistical method |
Which test(s) and why they were chosen |
|
Results |
|
|
Safety parameters |
For each safety parameter, please provide a summary of the results |
|
Discussion |
|
| Deviations | Add information on major deviations from the study protocol |
| Interactions | Evidence (or lack) of significant interactions with concomitantly administered products should be reported |
|
Discussion |
Summarise the results. This should take account of the aims of the study and address the safety of the test product |
| Conclusions | Conclude briefly on the study by indicating whether it fulfilled its objectives, at least the primary objective of establish the safety of the immunobiological product administered according to label instructions |
Conclusion on field trials
Provide an overall conclusion on the field trials summarising the strength of support all the studies together provided for the safety of the product, but also any major outstanding issues on these.
Other concerns can be mentioned but do not need to be specified. Flag up any major issues arising from the field trials that should also be reflected in the product information, for example warnings (target animals, user, animals in contact, etc) or other advice.
Overall conclusion on safety
The Expert should briefly summarise the conclusions for each safety section normally without repeating individual study findings, and review concerns raised in the assessment of the safety sections. Include information as to whether the product might adversely affect the immune response of the target animal or of its progeny, and therefore justify the need and/or adequacy of suitable tests on the immunological functions that were carried out.
If the product is a live vaccine or contains a GMO, describe the additional investigations and on basis of results provided, include a conclusion on the level of risk posed by the product from the key safety studies and their acceptability.
In addition to a short section on overall conclusion on safety, complete a summary table for safety laboratory trials/pen studies and field trials that support the safety of the immunobiological product.
|
Reference/study title: |
Animals |
Vaccine |
Trial design |
Results |
Discussion |
Conclusion |
|---|---|---|---|---|---|---|
|
APVMA#:00013 DYR5634 Safety of the administration of one dose |
|
|
|
|
|
|
|
APVMA#: 00012 TXN08631 Safety of one administration of an overdose |
|
|
|
|
|
|
|
Safety of the repeated administration of one dose |
|
|
|
|
|
|
|
Examination of reproductive performance |
|
|
|
|
|
|
|
Examination of immunobiological functions |
|
|
|
|
|
|
|
Special requirements for live vaccines |
|
|
|
|
|
|
|
Spread of the vaccine strain |
|
|
|
|
|
|
|
Dissemination in the vaccinated animal |
|
|
|
|
|
|
|
Reversion to virulence of attenuated vaccines |
|
|
|
|
|
|
|
Biological properties of the vaccine strain |
|
|
|
|
|
|
Overall conclusions on the application
Enter an overall conclusion taking account of the quality, safety and efficacy profile of the product and critical issues that need to be addressed for a registration to be granted.
Outstanding points on chemistry, manufacturing, efficacy and safety
Any major or minor points to be addressed by the Applicant should be listed under the relevant section of chemistry and manufacture or efficacy and safety.
The points should state clearly what additional information is required either as additional data, a clarification or scientific rationale/justification for a particular approach.
The questions should provide enough information for the applicant to understand the issues and the relevant section of the data package, report, study etc and provide a response by the due date.
The questions should be phrased politely using the following examples, with the word 'should' rather than 'must':
- the applicant should provide an updated GMP Certificate for the manufacturing site of the active ingredient
- the applicant should further justify the maximum release titre for the vaccine in light of the results of the pivotal safety study using a batch of vaccine with a potency of X
- the applicant should provide the duration of immunity study to support the DOI of 12 months following the primary vaccination schedule. The study should support the label claims of the product for a reduction in mortality, clinical signs and reduction in weight loss.
References
Covering letter template
It is essential that the Expert's recommendations comply with the APVMA’s legislative framework. The recommendations the Expert provides to the APVMA will form the basis on which decisions on efficacy and target safety will be made. The wording provided in the covering letter template ensures compliance with the APVMA’s legislative framework.
For both the DTR and FTR:
- clearly state your position (there are five options in the templates)
- state what is supported, what is not supported and any caveats
- elaborate on recommendations, if relevant
- give advice on future applications, if relevant
- comment on policy or other issues, if appropriate.
How to return your completed report
Please return the completed form to your designated Case Manager in the APVMA Case Management and Administration Unit (CMAU).
Glossary
|
Abbreviations/acronyms |
Full term |
|---|---|
|
(95%) CI |
Confidence Interval |
|
3Rs |
Replace, Reduce Refine the use of animals in research |
|
9CFR |
Code of Federal Regulations (US codified Regulations for veterinary biologicals) |
|
BICON |
Australian Department of Agriculture Biosecurity Import Conditions |
|
BP |
British Pharmacopeia |
|
CPE |
Cytopathic Effect |
|
CPV |
Canine Parvovirus |
|
CVMP |
Committee for Veterinary Medicinal Products (EU) |
|
D+ |
Diarrhoea |
|
DIVA |
Differentiate between Infected and Vaccinated Animals |
|
DOI |
Duration of immunity |
|
DTR |
Draft Technical Report |
|
EMA |
European Medicines Agency |
|
EMEA |
European Medicines Evaluation Agency (now EMA) |
|
ERA |
environmental risk assessment |
|
EU |
European Union |
|
EUDRA GMP |
The name for the European Union database of GMP Certificates, Manufacturing Authorisations and statements of non-compliance |
|
FTR |
Final Technical Report |
|
GCP |
Good Clinical Practice |
|
GL |
Guideline |
|
GMO |
Genetically Modified Organism |
|
GMP |
Good Manufacturing Practice |
|
LN |
Lymph Node |
|
MBS |
Master Bacterial Seed |
|
MCS |
Master Cell Seed |
|
MDA |
Materially derived antibodies |
|
MSV |
Master Seed Virus |
|
OGTR |
Office of the Gene Technology Regulator (Australian) |
|
OOI |
Onset of Immunity |
|
PCR |
Polymerase Chain Reaction |
|
PH. Eur |
European Pharmacopoeia |
|
P-value |
Or probability value, is the probability of obtaining a test result at least as extreme as the result actually observed during the test, assuming that the null hypothesis is correct |
|
QA |
Quality Assurance |
|
QC |
Quality Control |
|
SPF |
Specific Pathogen Free |
|
TAS |
Target Animal Safety |
|
TCID |
Tissue Culture Infective Dose |
|
TSE |
Transmissible Spongiform Encephalopathy |
|
USP |
United States Pharmacopeia |
|
VICH |
International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products |
|
WBS |
Working Bacterial Seed |
|
WCS |
Working Cell Seed |
|
WSV |
Working Seed Virus |