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Efficacy and target animal safety general guideline (Part 8)
This is a guideline about the types of information you can submit to address the efficacy and safety criteria for veterinary chemical products. It also provides guidance on how the information might be presented and analysed. This guideline should be considered in conjunction with any guidelines the APVMA has made or adopted that are specific to the type of product for which you intend to demonstrate efficacy and target animal safety.
Efficacy data, argument or use of a reference product to satisfy efficacy criteria may not be needed in an application for registration of some groups of products. For more information see the efficacy criteria legislative instrument.
When considering whether the chemical product meets the efficacy and safety criteria, your information must satisfy us that the use of the product in accordance with the APVMA approved instruction will be effective and safe.
1. Types of efficacy and safety information that can be submitted to support your application
1.1. Pharmacological data/studies
You should include a comprehensive summary of the pharmacological studies, with a brief outline of the methods and a description and interpretation of the results. Individual summaries should also be provided with each study if not already included in the study report.
Pilot (developmental) studies may include pharmacokinetic and pharmacodynamic studies describing the mode of action, pharmaceutical or physiological end-point studies, and in vitro studies.
Pharmacokinetic studies include single-dose bioavailability studies or bioequivalence studies. For multiple-dose or continuous-use medications, steady-state and peak and trough levels should be identified.
Pharmacodynamic studies, including any scientific studies to identify the mode of action of the product, should be presented here.
1.2. Efficacy studies
You should include a comprehensive summary of the efficacy studies, with a brief outline of the methods and a description and interpretation of the results. Individual summaries should also be provided with each study if not already included in the study report.
Pivotal studies may include laboratory/pen trials and clinical/field trials for dose confirmation. In some instances, in vitro studies or pharmacological/physiological end points may be used as pivotal data. This depends on the type of application, the active constituents and the type of product, and will be assessed on a case-by-case basis.
1.2.2. Laboratory model efficacy studies
You should provide laboratory model efficacy studies, where appropriate. Data from such studies may indicate the extent and type of further studies that may be submitted for the target species. Laboratory model efficacy studies may also be used to support valid scientific argument but not to replace target animal efficacy studies.
1.3. Target animal efficacy studies
Demonstration and confirmation of the efficacy of a veterinary chemical product generally uses a three-step approach involving dose determination studies, dose confirmation studies and confirmatory clinical/field studies.
1.3.1. Dose determination studies
Dose determination studies determine the optimal dose required to control or treat a disease or condition, which will be a label claim of the proposed formulation (or a very similar formulation).
Dose determination studies are usually conducted early in the development of a new product. You should use a formulation identical to, or closely similar to, the formulation that you propose to register, to provide validation of the study results. Data obtained with closely similar formulations may be acceptable as supportive data; however, we recommend that you submit bridging studies that demonstrate bioequivalence with the final proposed formulation. The method of administration should be the same as for the proposed product and as instructed on the proposed label to validate the intended use pattern.
For some types of applications, data from dose determination studies may be used to support efficacy claims. In such cases, the APVMA will consider whether:
- the efficacy data results are statistically significant
- the formulation is bioequivalent to the final formulation
- the product is administered according to label directions
- study records are complete
- the data are verifiable.
1.3.2. Dose confirmation studies
Dose confirmation studies confirm the proposed dose. Such studies are usually conducted under controlled conditions, such as in pen trials or laboratory trials for companion animals.
The final product formulation should be used for at least one dose confirmation study to satisfy us that the proposed label dose is appropriate for the product. Data obtained with closely similar formulations may be acceptable as supportive data; however, we recommend that you submit bridging studies that demonstrate bioequivalence with the final proposed formulation. Dose confirmation study data may be used to support efficacy claims, but the data results should be statistically significant.
For some types of applications, dose confirmation study data may be used to support efficacy claims. In such cases, the APVMA will consider whether:
- the efficacy data results are statistically significant
- the formulation is bioequivalent to the final formulation
- the product is administered according to label directions
- study records are complete
- the data are verifiable.
Where appropriate, you should provide pharmacokinetic data to justify the declared dosage regimen. The method of administration should be the same as proposed for the label to validate the intended use pattern.
1.3.3. Confirmatory clinical/field studies
Clinical or field trials demonstrate efficacy under real conditions. Efficacy claims should therefore be supported by trials that generate clinically relevant, statistically significant data results. Suitable clinical end points that reflect the efficacy or safety issues should be used.
The studies should use the product formulation that is to be marketed and should be carried out where the disease or condition occurs under optimal rather than marginal conditions. Where the disease or condition is rare or difficult to replicate in the field, you should apply to us for a technical?assessment on appropriate alternative clinical end-point studies.
If the pivotal clinical or field trials supporting efficacy are conducted overseas, Australian confirmatory clinical or field trials should also be submitted. See the 'Overseas studies' section and the specific guidelines?for further information.
For some product types (for example, anaesthetics), where efficacy relates to individual animal physiology and not local conditions, Australian confirmatory field trials may not be relevant.
1.3.4. Palatability studies
Depending on the nature, dose form and use pattern of an orally administered product, its palatability may directly influence the amount ingested by an animal and therefore may directly affect dosage and efficacy. Where relevant, the palatability of the product should be considered and demonstrated as part of confirmatory clinical or field trials.
You should consider submitting palatability studies to justify a label claim for the palatability of a product, or where dosage is critical and the dose ingested by the target animal might depend on the palatability of the product. Examples include:
- products for which the use pattern specifically involves administration in food or water
- products for which efficacy depends on the voluntary ingestion of the product
- antibiotic or anthelmintic products in the form of oral pastes/gels
- parasiticide products in the form of chewable blocks/tablets.
You should consider submitting palatability data for generic products where this is justified based on factors such as the dose form, use pattern, and formulation differences compared with the reference product (for example, flavourants).
1.4. Target animal safety studies
The type of data that may be provided to support the safety of the proposed new product in the treated species varies depending on the toxicological hazard and the intended use of the product.
Data should indicate the margin of safety to target animals and should take into consideration factors such as age, sex, breed, condition, dose regimen, animal husbandry practices, pregnancy, nutritional status and any other matters that could reasonably be expected to affect safety in use.
The effect of treatment on reproduction and the effect of repeat treatments should also be considered. If there are no reproductive studies, we may consider the inclusion of a standard precautionary statement on the label.
We recommend that safety studies use the formulation intended for marketing, administered by the means recommended on the product label and under the proposed conditions of use. These criteria help to satisfy us about the safety criteria relevant to target animals. If the formulation intended for marketing is not used, you should provide data and/or valid scientific argument to bridge differences between the formulations. You may provide information on alternative routes of administration if it is available.
Either local or overseas data on the safe use of the proposed product are acceptable.
Additional guidance on target animal safety data can be found in VICH GL43.
Irrespective of the results obtained during safety studies, any adverse effects occurring during any other studies, or known or suspected because of reports from users in Australia or overseas, should be reported at the time of application. Post-registration pharmacovigilance data from overseas countries are particularly useful.
A comprehensive summary of the safety studies should be included, with a brief outline of the methods and a description and interpretation of the results. Individual summaries should be provided with each study if they have not been included as part of the study report.
1.4.2. Margin of safety studies
The margin of safety is defined as the ratio between the maximum recommended dose and the minimum dose producing toxic effects. We recommend that the margin of safety be determined as closely as possible when the margin is less than 5×. Taking animal welfare principles into consideration for the study design, toxic effects should be identified and described.
18.104.22.168. Dose rate
We recommend that safety studies use the proposed formulation to provide validation of the study results. A safety study using multiples of the maximum proposed label dose (up to 5×) for at least the proposed duration of use is recommended. In most cases, the combination of 1×, 3× and 5× the maximum recommended dose plus controls (0×) is appropriate.
Generally, eight typical target animals (both males and females) should be used in each treatment group; however, we may accept data generated from a lower number of animals if you provide valid scientific argument that is acceptable to us. The lower number should provide results that are statistically significant, which you should demonstrate by providing the relevant power analysis. You should also consider the age of the animals carefully: if the product is intended for use in immature animals, the safety studies should usually be conducted using the youngest age proposed in the label claim.
If there is existing evidence that 5× dosing would result in adverse effects, the combination of 1×, 2×, and 3× plus controls may be adequate. In such a case, we recommend that the number of animals in each treatment group be increased to 20, or to a smaller number if you provide valid scientific argument acceptable to us. The lower number should provide results that are statistically significant, which you should demonstrate by providing the relevant power analysis. We encourage you to apply to us for a technical assessment before starting the trial.
The following parameters should be measured:
- clinical signs
- haematology, blood chemistry and, where appropriate, urinalysis and faecal analysis results.
For some products, measurement of other parameters should also be included. Those parameters will be different for different types of product, active constituents, routes of administration and organ systems likely to be adversely affected. If clinical signs of adverse effects include observable changes in urine or urination and the product is potentially nephrotoxic, or if the expected pharmacokinetics or pharmacodynamics of the product could be influenced by changes in urine, it would be appropriate to include urinalysis results as a parameter. Similarly, if clinically observable changes in faecal consistency or colour are observed, or the product has potential to cause adverse gastrointestinal effects, faecal analysis results should be a measured parameter. If the active constituent is likely to have an adverse effect on the gastric mucosa, endoscopic examination should be included as a parameter for measurement. We recommended that you review the specific guidelines under?Efficacy and safety (Part 8) of the Data guidelines?and/or apply to us for a?technical assessment.
When studies cannot follow a protocol of this nature (for example, long-term administration, slow release or long-lasting products), the protocol can be modified, taking into account the pharmacokinetics of the product. Modified studies should be justified and will be assessed on their scientific merit.
22.214.171.124. Duration of treatment
A safety study should also be conducted using the recommended dose rate over a period that is a multiple of the proposed duration of treatment. Different study periods may be required, depending on the nature of the product, the target animal species and the use pattern. For some products, specific guidelines are available under Efficacy and safety (Part 8) of the Data guidelines.
Products proposed for administration over a period of less than two weeks should be studied over at least three times the recommended maximum duration of use. If a product is recommended for long-term administration (more than two weeks and less than three months), you should conduct safety studies in which the drug is administered for the recommended maximum duration of use or longer (with a minimum of six weeks).
If the product is recommended for ongoing use, safety studies should be conducted for at least three months.
1.5. Related studies
1.5.1. Compatibility studies
If particular treatments, conditions or procedures are likely to be used in combination with the proposed new product, data and/or valid scientific argument should be provided to show that there is no interaction to compromise the efficacy or safety of the product. If compatibility with particular treatments or conditions is claimed, this should be proven.
1.5.2. Effects on hides and fleeces
You should demonstrate by data or valid scientific argument that chemicals applied externally to cattle, sheep and other hide- or fibre-producing animals will not cause damage to the hides, skins, fleeces or fibres produced by those animals.
If you are seeking registration of products to be externally applied to sheep, you should refer to the?specific guidelines?for further details on reporting effects on hides and skin.
Wool scourability data should be provided for pour-ons, dips, shower sprays and other products containing dyes or other pigments that are applied to wool. This issue may be addressed by valid scientific argument, if appropriate.
1.5.3. Accidental administration or exposure to non-target animals
You should provide any evidence of possible adverse effects from accidental administration to or exposure of animals other than those for which the product is recommended. Appropriate warnings should be proposed for inclusion in the product label. This is particularly important for feed additive products, ectoparasiticide products where the product remains on the target species for a long period, and products used in situations where different species occupy the same area.
1.5.4. Effects on taste or produce (organoleptic effects)
If data suggest that the use of a veterinary chemical product or its metabolites is likely to affect the taste of animal produce (for example, products that may affect milk), those data should be included in this part of the application and clearly identified as a separate section.
If there is any reason to believe that the use of a veterinary chemical product (or its metabolite) could cause an off-flavour or tainting of a food product, you should undertake an adequate investigation, supported by taste-panel tests or other organoleptic tests, to verify that no unacceptable tainting occurs. The data obtained should be included in this part of the application and clearly identified as a separate section.
1.6. Other studies or data
1.6.1. In vivo or in vitro bioequivalence studies
Bioequivalence studies can be used as supporting evidence that the efficacy and possibly safety of one formulation are equivalent to those of another. These studies may be used to support applications for the registration of generic products and for some formulation changes, including those generated during product development.
If you wish to use bioequivalence to demonstrate efficacy comparable to that of a reference product, the reference product should be a product registered by the APVMA, and preferably the pioneer product. This is because we have assessed the registered reference product against the statutory criteria and can therefore be satisfied that it is a suitable product to use in comparative trials. If the nominated reference product has protected data associated with it, you should provide consent to access the protected data from the owner of that data.
Bioequivalence may be determined by one of several direct or indirect methods. The selection of the method depends on the purpose of the study, the analytical method available and the type of product. Bioequivalence testing should be conducted using the most appropriate method available for the specific use of the product.
In descending order of sensitivity, in vivo bioequivalence studies include:
- blood level studies
- pharmacologic end-point studies
- clinical end-point studies.
If absorption of the drug is sufficient to measure drug concentration directly in the blood (or other appropriate biological fluids or tissues) and systemic absorption is relevant to the drug action, a blood-level (or other biological fluid or tissue) bioequivalence study should be conducted. The blood level study is usually preferred above all others as the most sensitive measure of bioequivalence.
If the rate and extent of absorption of the drug in biological fluids cannot be measured or is unrelated to the drug action, a pharmacologic end-point study (that is, a study of drug-induced physiologic change that is related to the approved indications for use) may be conducted.
If drug concentrations in blood (or fluids or tissues) are not measurable or are inappropriate, and there are no appropriate pharmacologic effects that can be monitored, a clinical end-point study may be conducted, comparing the proposed product to the reference product and a negative control.
A bioequivalence study should be conducted for each species claimed in the label particulars and for each route of administration of the product to be registered. If you are not providing multiple studies, you should provide a valid scientific justification.
For some types of product, suitable in vitro tests may be used in lieu of bioequivalence testing to support equivalence of efficacy and safety in the target species. For example, disintegration times and solubility profiles of the proposed product and the nominated APVMA reference product may be compared. This approach may be acceptable for tablets that contain active ingredients known to have high solubility and high permeability. You should consider the in vivo – in vitro correlation of such active ingredients.
For more information on bioequivalence studies, refer to the bioequivalence page. We encourage you to apply to us for technical assessment before commencing any bioequivalence studies.
1.6.2. Clinical case studies
Depending on the type of product, type of application and type of claim, clinical case reports may be submitted as data to support the efficacy, and more commonly safety, of a product. They will usually only be considered in support of products that will be used by or under the direct supervision of a registered veterinary surgeon. Clinical case study reports should come from the records of registered veterinary surgeons and should use the formulation proposed for registration in the target species.
1.6.3. Scientific references or extrapolated scientific argument
For some types of products, registration or the issue of a permit may be considered on a case-by-case basis, based on extrapolation from available data, such as:
- evidence of efficacy for the proposed formulation in a non-target species and/or a related formulation in the target or a non-target species
- evidence of registration by a European Union or United States regulatory authority of the proposed or related formulation in the target or non-target species (evidence of registration by other regulatory authorities should include an officially stamped copy of the registration notice and registered label)
- trial data for the proposed formulation and target species that is not completely validated or statistically significant, but is supportive of safe use
- relevant scientific information from peer-reviewed journals, recognised textbooks or other reputable sources for the active constituent(s) in the target species, subject to:
- a suitably worded claim, such as ‘treats …’
- claims of a physiological end point rather than clinical end points
- qualifiers such as ‘… responsive to treatment with [name constituent(s)]’, and/or
- the product only being advertised and supplied to veterinarians for use by them or under their direction in the course of treating animals under their professional care
- evidence of safety for the proposed formulation in an appropriate non-target species and/or a related formulation in the target or a non-target species, subject to:
- placing a suitably worded precautionary statement on the main panel of the label, and/or
- advertising and supplying the product only to veterinarians for use by them or under their direction in the course of treating animals under their professional care.
When submitting published scientific papers, you should explain their role in the summary so that the relevance of such additional data is explained to the reviewer.
Other factors to consider when submitting valid scientific arguments are:
- the effects that the excipients in a formulation may have on the bioavailability of the active constituent
- the effects that the excipients may have on the solubility or permeability of the active constituent
- the effects that the excipients may have on gastric motility and gastric emptying
- the physicochemical properties of the excipients (for example, excipients that adjust pH may affect the biological activity of active constituents that are pH-dependent, and excipients that adjust viscosity may affect the distribution of a pour-on product)
- the effect of the manufacturing process (such as dry granulation versus wet granulation)
- the comparison of specifications of the active constituent from different sources
- the toxicity profile of an excipient when addressing the safety aspects of the product
- discussions based on pharmacokinetic and pharmacodynamic principles, comparisons of pharmacokinetic parameters, comparisons of pharmacodynamic indices, and literature supporting comparable bioavailability of an active constituent when administered by the oral or parenteral route
- the change in the drug:excipient ratio when excipients are substituted, deleted or added to a formulation.
1.6.4. Topical studies, inhalation studies, tissue irritation studies
Standard toxicity tests may be used for dermal, ophthalmic, intranasal, vaginal, intra-uterine and inhalation drugs. Secondary factors should be considered, such as acceleration or delaying of healing if the product is intended for application to wounds, and systemic toxicity if the product is likely to be appreciably absorbed after topical application or is likely to be ingested as a result of licking.
Tissue irritation studies should be submitted where appropriate for drugs administered by injection, scarification or implants, or by pour-on, spray-on or spot-on application. Observations of inflammation, swelling, necrosis and histopathology (particularly of injection sites) should be included. The findings should be taken into account in establishing the maximum amount of the product recommended for administration and the time required for the tissues at the application site to return to an acceptable condition. These observations can also be used to prepare ‘carcase trim’ statements for the proposed label.
1.6.5. Reproductive function studies
The nature of the chemical or its effects on reproduction in laboratory animals may indicate the type and extent of the studies required in the target species.
If the product is recommended for use in replacement stock and/or animals intended for breeding, the product’s effect on male and female reproductive functions should be addressed. Data from teratology studies conducted in the target species should also be submitted in some cases.
If data from reproduction or teratology studies are not available, you should propose a standard precautionary statement for inclusion on the label, advising the user that such studies have not been done and that the effect of the chemical on the reproductive function of treated breeding, pregnant or lactating animals or their offspring is therefore unknown.
Reproductive function studies should be submitted for all products containing new active constituents. For more information on reproductive function studies, refer to VICH GL43.
1.6.6. Minimum inhibitory concentration studies
We recommend that you conduct minimum inhibitory concentration (MIC) studies for antibiotics using Australian isolates of the target bacterial pathogens. If such studies are not conducted, you should provide scientific arguments outlining why previously derived overseas or Australian MIC50s and/or MIC90s are still applicable.
2. Additional information the APVMA will consider when assessing your application
2.1. Good clinical practice
The structure and content of study reports should follow the procedures and reporting mechanisms of good clinical practice (GCP). We strongly recommend adherence to GCP principles as current best practice.
The formulation to be registered should be used in studies submitted as pivotal studies to provide validation of the results of those studies. If studies use a formulation that differs in any respect from the formulation to be registered, that should be clearly identified at the beginning of each study report or in the overall summary, and the implication of the difference(s) should be discussed.
For studies using a formulation still in the developmental stage, company codes are often used to describe the formulation under test. Where such codes are used, they should be clearly identified and referenced to the product name and formulation to avoid confusing the reviewer. The relationship between company code, formulation and product name could be presented as a table in the overall summary. As far as possible, product names should be used rather than company codes.
Where a formulation different from the formulation that is to be registered is used in studies to support efficacy and safety, you should provide data and/or valid scientific argument to demonstrate bioequivalence. For further information, refer to the bioequivalence page.
2.3. Individual animal data/study log
You should provide individual animal data and a study log if reports of dose confirmation studies, confirmatory clinical or field studies and case studies have not been published in a peer-reviewed scientific journal. This is best presented as an appendix. You should provide the completed worksheets recording the raw data.
Detailed reports of individual studies should be submitted and can be included as appendixes.
2.4. Published references
If specific references are cited, you should provide a legible copy of the whole article, in English. References should be annotated to indicate which sections of the reference apply to the application.
Trial results and references should be accurately and consistently cross-referenced to each other where relevant.
2.5. Australian confirmatory studies
If overseas studies do not adequately represent Australian conditions, you should provide Australian confirmatory studies. Where applicable, contemporary pathogens/recent isolates should be used in these studies. For more detail on the number and type of Australian confirmatory studies that are recommended for submission for specific types of products, you may apply to us for a?technical assessment.
If no specific product guidelines exist for a product, we recommend that you confirm overseas data by at least one controlled Australian study.
Australian confirmatory studies should be presented for the following products:
- products containing new active constituents to be used in food/fibre-producing species as mass medications or as flock or herd treatments, including:
- ectoparasiticide and endoparasiticide products
- growth promotants and performance enhancers
- direct-fed microbial or enzyme products with specific claims, such as claims for improved feed conversion, productivity gains or administration to animals with impaired physiology
- products of the classes listed above based on APVMA-approved active constituents to be used in food-producing species different from those previously registered.
Australian confirmatory studies may also be required for the following products or in the following situations:
- products containing new active constituents for individual animal treatment for either food/fibre-producing or non-food/fibre-producing animals
- products based on APVMA-approved active constituents to be used in food/fibre-producing species different from those previously registered
- where management practices in overseas studies are different from those typical in Australia
- where the strains of the organism (bacterium, fungus, virus or parasite) causing the disease used in overseas studies are different from those known to occur in Australia
- where the product formulation used in the overseas studies is significantly different from that intended to be marketed in Australia.
Where Australian studies are not submitted, we will consider valid scientific argument on a case-by-case basis.
2.6. Overseas studies
In assessing overseas data, the APVMA may take into account the results of any trials or experiments already carried out in a foreign country or any decisions or evaluations made by regulators of veterinary chemicals in a foreign country. However, we will consider such other matters as we think appropriate when assessing overseas data, such as:
- any significant differences in the use of the constituent or product in Australia and in the foreign country
- any different environmental factors (for example ,disease-causing organisms, animal breeds, husbandry practices and geographical regions) affecting the use of the constituent or product in Australia and in the foreign country
- any significant additional information relating to the properties of the constituent or product that has become available since the conduct of those experiments or trials
- any significant differences in the way decisions or evaluations are made in Australia and by the national regulatory authority in the foreign country.
If you choose to submit overseas data to support an application, you should consider the following:
- Overseas field studies should be carried out under conditions that are typical of Australian climatic conditions and, if applicable, production conditions.
- For products intended to be used in food-producing animals, field studies should be carried out under typical farm management practices using relevant animal breeds and strains of disease-causing organisms and covering relevant geographic regions.
- In many cases, Australian confirmatory studies should be provided to show that the efficacy and safety of the product under Australian conditions are at least equal to those seen overseas.
2.7. Animal welfare
If you submit data to support efficacy and target animal safety from Australian trials, you should include the registration number of the experimenter and the animal ethics committee approval number, as appropriate, for each state in which the trial was undertaken. You should include this information in the study report for that study and in the summary for that study.
2.8. Types of label claims
The type of claim that can be made on an approved label, and the amount and type of data needed to support that claim, depend on the type of product, the active constituent and the type of application. For some products, there are specified parameters for claims that the product can be said to treat, prevent or aid in the control of a disease, infection or condition. Where specific guidelines are available, particularly for products such as vaccines and parasiticides, they should be referred to (see the specific guidelines section within Efficacy and Safety (Part 8) of the data guidelines).
There are different levels of therapeutic claim:
If the therapeutic claim is for the stand-alone use of the product (for example, ‘For the prevention, cure or alleviation of [specific disease(s), condition(s) or symptom(s)] in [animal(s)]’), efficacy data in the target species for the product should be submitted.
For this type of claim, you should provide objective measurements of clinical end points. Claims for alleviation or (partial) prevention should include a percentage reduction in the incidence of the disease, or the reduction in symptoms of the specific disease or condition where prevention or cure is not claimed to be 100 per cent effective.
If the therapeutic claim requires other treatments or strategies in addition to the product (for example, ‘To assist or aid in the prevention, cure or alleviation of [specific disease(s), condition(s) or symptom(s)] in [animal(s)]’, efficacy data in the target species for the product should be submitted.
For this type of claim, you should submit objective measurements of clinical end points. Claims for alleviation or (partial) prevention should include a percentage reduction in incidence or symptoms of the disease or condition.
- If the product makes general health claims that are well understood by product users (for example, antiseptic, germicidal or gastrointestinal tract buffer), and provided no mention is made of specific clinical effects, in vitro data may be sufficient to support the efficacy claims. Safety data should usually still be submitted for these products.
2.9. Accuracy of dosing
The APVMA may not approve label claims, including the use of the name of the target species in the name of the product, for use in a target species where the dosage form does not allow accurate dosing in accordance with the label-recommended dose rate. The appropriate dosage form and dose rate depend on the therapeutic index of the active constituent, the species to which it is intended to be administered and the route of administration.
2.10. Adverse experiences
APVMA’s legislation requires registrants to provide us with any new information that they become aware of in relation to an active constituent or chemical product. This includes adverse experience information relating to human health, harm to animals, damage to plants, property or the environment, and lack of efficacy when the product is used according to the label directions.
All adverse effects encountered during the clinical use of the product should be described in detail. Clinical use of the product provides evidence for the safety of the product under field conditions and in situations not encountered in safety studies. If the product is registered in other countries, results of those countries’ post-registration vigilance reports should be included in the submission. The severity and incidence of adverse reactions should also be classified by organ system.
This section should include tables detailing all side-effects and adverse experiences, including drug interactions and abnormal laboratory findings, regardless of whether the reported effect is considered to be drug-related. The information should also be tabulated according to sex, age, breed, dosage form, formulation or other relevant factors, as appropriate.
Any abnormal finding or adverse reaction should be further investigated. Evaluation for signs of toxicity should include:
- feed and water consumption, clinical observation and physical examination
- a complete gross and histopathological examination on all animals that die during or as a result of the study
- changes to blood haematology, and chemistry, urine and faecal analysis results
- effects on pregnancy and various other physiological states.
Through selection pressure, antibiotic-resistant bacteria become the dominant population over time. The MIC50s and MIC90s on which the registration of a pioneer antibiotic was based may no longer be indicative of efficacy. If you are seeking the registration of generic antibiotics, you should consider the relevance of those older MIC values to your products in today’s context and address this aspect in your submission. You should consider excluding resistant strains of bacteria from the statement of claims in label particulars, and you should provide evidence to support claims for efficacy against resistant bacteria.
3. Information that the APVMA considers unsuitable for submission
3.1. Studies or published articles submitted in languages other than English
It is your responsibility to ensure that all information that you submit to the APVMA is legible and in English. We do not review studies or published articles submitted to us in languages other than English when determining applications.
You should provide certified translations if you have translated information, particularly data, to English from another language.
Poorly printed or illegible copies of studies will be disregarded.
3.2. Abstracts of studies or published articles
If you want us to take a study or published article into consideration, it is your responsibility to provide the complete study or article.
We will usually disregard testimonials and other forms of anecdotal evidence.
3.4. Incorrectly formatted overseas data packages
It is not appropriate to submit overseas data packages that have been prepared to suit the format of other regulatory agencies, such as the European Medicines Agency. It is your responsibility to submit overseas data packages in the appropriate APVMA format (see the template for submission below).
To enable us to review the submission, we suggest that you incorporate a comprehensive table of contents aligning the APVMA format to the location in the overseas package where the data can be found.
4. Template for submission
Use the following template when submitting an efficacy and safety data package. Please address all parts of the template.
4.2. Data summary
4.2.1. Pharmacological data/studies
4.2.2. Efficacy studies
- Laboratory model efficacy studies
- Target animal efficacy studies
- Dose determination studies
- Dose confirmation studies
- Confirmatory clinical/field studies
- Palatability studies
4.2.3. Target animal safety studies
- Margin of safety studies
- Dose rate
- Duration of treatment Related studies
- Compatibility studies
- Effects on hides and fleeces
- Accidental administration or exposure to non-target animals
- Effects on taste or produce (organoleptic effects)
4.2.4. Other studies or data
- In vivo or in vitro bioequivalence studies
- Clinical case studies
- Scientific references or extrapolated scientific argument
- Topical studies, inhalation studies, tissue irritation studies
- Reproductive function studies
- Minimum inhibitory concentration studies