Part 8 – Efficacy and target animal safety

1.   INTRODUCTION

This chapter sets out the requirements and guidelines for submitting efficacy and animal safety data for:

• applications to register veterinary chemical products containing new or existing active constituents
• applications to vary the particulars or conditions of registration of a registered veterinary chemical product, such as changes in the use pattern, or major formulation change.

The aim of the efficacy and safety submission is to enable the APVMA to evaluate an application for registration of a product, or variation to the product registration or label approval, without the need to refer to the applicant for clarification or further information.

Applicants must show that when the product is used according to label directions, it is effective for the purposes claimed and that administration to the indicated animal species will not cause any unintended adverse effect. The proposed use of the product must be consistent with existing legislation and codes of practice with respect to animal welfare in the relevant jurisdictions, and must not unreasonably or unnecessarily compromise animal welfare.

Volume 4 contains specific product guidelines for some types of products such as immunobiologicals and parasiticides.

1.1.     Pre-application advice

Applicants may seek a pre-application meeting with the relevant APVMA product evaluator from the Veterinary Medicines Program and/or may submit an application for evaluation of the trial protocol, under Category 25.

Evaluation of the trial protocol under a Category 25 application will provide the applicant with an expert reviewer’s assessment of the appropriateness of the design of an experimental trial for the generation of efficacy and animal safety data.

Applicants should consider seeking advice from a consultant if they are unsure about the validity of the data they intend to submit. APVMA evaluators are available to advise on legislative requirements and published APVMA guidelines. However, it would be inappropriate for them to act as consultants for an application on which they may later make a regulatory decision.

2.   TYPES OF APPLICATIONS

The level of assessment of efficacy and safety data required (ie module 8.1, 8.2 or 8.3) differs depending on the type of application.

2.1.     Modular categories

Volume 3: ‘ Module levels for modular categories ’ and the individual category chapters in Volume 2: Category requirements and guidelines provide information and guidance on the efficacy and safety data requirements for each type of application. Volume 3: ‘ Module levels for modular categories ’ provides the titles of the Part 8 data elements required for each of the Part 8 modules, ie module 8.1, 8.2 or 8.3.

Comprehensive assessment (module 8.1) requires submission of a full efficacy and safety data package, containing all of the data elements listed in the column titled ‘Data required’ in Volume 3, ‘ Module levels for modular categories ’ according to the type of product or application in the column title ‘Type of application’.

Reduced assessment (module 8.2) and limited assessment (module 8.3) comprise some of the data elements contained in comprehensive assessment (module 8.1) and may include data elements which do not usually apply to a comprehensive assessment such as bioequivalence studies or scientific argument.

The applicant must provide valid scientific argument as to why a data element has not been included if that data element is not included as part of the submission. For some products, studies included under the heading ‘Related studies’ may not be required because of the active constituent, or the target animal species for which the product is intended. For other products, Specific product guidelines are available, which provide guidance on which of the data elements listed in Table 1 are required for that type of product.

2.2.     Fixed categories

Applications which are evaluated under a fixed category (eg Category 5) may require efficacy and safety data. The level of data corresponds to module 8.1, 8.2 or 8.3. The module of Part 8 data required for a particular application is determined by the application category, and is provided in the relevant category chapter in Volume 2: Category requirements and guidelines.

3.   DATA REQUIREMENTS AND GUIDELINES

3.1.     General requirements

Efficacy and safety data packages must be submitted according to the procedures outlined in Volume 1, ‘Procedures for making an application’ .

All non-English data must be translated.

A template for submission of Part 8 data for comprehensive assessment (module 8.1) of efficacy and safety data is provided at paragraph 5. This template may also be used for reduced assessment (module 8.2) and limited assessment (module 8.3) by deleting the headings of those data elements which are not required by the module.

3.2.     Good clinical practice

The structure and content of study reports should follow the procedures and reporting mechanisms of good clinical practice (GCP). Although GCP is not a requirement for efficacy or safety trials, adherence to the GCP principles is strongly recommended by the APVMA as current best practice.

Applicants should refer to Veterinary Evaluation Guideline No. V58 (VICH GL 9 of the same name).

3.3.     Formulation

The formulation to be registered must be used in studies submitted as pivotal studies. If studies use a formulation that differs in any respect from the formulation to be registered, this must be clearly identified at the beginning of each study report or in the overall summary and the implication of the difference(s) discussed.

For studies using a formulation still in the developmental stage, company codes are often used to describe the formulation under test. Where company codes are used, they must 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 to the formulation which is to be registered is used in studies to support efficacy and safety use, data and/or argument to demonstrate bioequivalence must be provided. Applicants should refer to the APVMA guideline on bioequivalence.

3.4.     Individual animal data/study log

Individual animal data and a study log must be provided 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. The original or copies of the completed worksheets recording the raw data must be provided if the APVMA requests them.

Detailed reports of individual studies must be submitted and can be included as appendices.

3.5.     References

If specific references are cited, a legible copy of the whole article must be provided. References should be appropriately annotated to indicate which sections of the reference apply to the application.

For generally-accepted scientific information, full references will not usually be required. However, in some instances the APVMA may request a copy of a reference to substantiate data or argument.

Trial results and references must be accurately and consistently cross-referenced to each other where relevant.

3.6.     Testimonials

Testimonials and other forms of anecdotal evidence are normally not acceptable, and will usually be disregarded.

3.7.     Overseas data

Data from overseas countries may be used to support an application. However, in most cases Australian confirmatory studies will be required to show that the efficacy and safety of the product under Australian conditions is at least equal to that seen overseas (see paragraph 3.8).

Overseas field studies must have been 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 must have been carried out under typical farm management practices using relevant animal breeds and strains of disease-causing organisms and covering relevant geographic regions.

3.8.     Australian confirmatory studies

The APVMA will require Australian confirmatory studies where overseas studies do not adequately represent Australian conditions. Where applicable, contemporary pathogens/recent isolates must be used in these studies. For more detail on the number and type of Australian confirmatory studies required for specific types of products, applicants should refer to the relevant guidelines in MORAG Volume 4: Specific product guidelines.

If no specific product guidelines exist for a product, applicants must confirm overseas data by at least one controlled Australian study.

Australian confirmatory studies will be required for the following situations:

• 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
  • anticoccidials
  • antibiotics
• direct-fed microbial or enzyme products with specific claims, eg 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 different food-producing species than previously registered
• extension in use of a currently registered product to a new pest or disease.

Australian confirmatory studies may be required 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 different food/fibre-producing species than previously registered
• where management practices in overseas studies are different from those typical in Australia
• where the strains of the organism (bacteria, fungi, 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.

3.9.     Pilot studies and pivotal studies

Studies should be classified as pilot (developmental) studies or pivotal studies.

Pilot (developmental) studies may include pharmacokinetic and pharmacodynamic studies, describing the mode of action, pharmaceutical or physiological end-point studies, and in vitro studies.

Pivotal studies may include laboratory/pen trials and clinical/field trials for dose confirmation. In some instances, in vitro studies or pharmacological/physiological endpoints 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.

3.10.   Animal welfare

Where data to support efficacy and target animal safety are submitted from Australian trials, the current registration number of the experimenter and the Animal Ethics Committee approval number, as appropriate for each State in which the trial was undertaken, must be included in the study report for that study and in the appropriate summary for that study.

3.11.   Types of label claim

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. Some products have specified parameters for what constitutes the ability to claim 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, they should be referred to (see MORAG Volume 4: Specific product guidelines ).

There are different levels of therapeutic claim:

1. If the therapeutic claim is stand-alone for the product, eg:
   
   ‘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 must be submitted as described above in 3, Data requirements.
   
   For this type of claim, objective measurements of clinical end-points are required. Alleviation or (partial) prevention must include a percentage reduction in the incidence of the disease, or reduction in symptoms of [specific disease or condition] where prevention or cure is not claimed to be 100 per cent effective.
2. If the therapeutic claim requires other treatments or strategies in addition to the applicant product eg:
   
   ‘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 must be submitted as described in 3, Data requirements.
   
   For these types of claim, objective measurements of clinical end-points are required. Alleviation or (partial) prevention must include a percentage reduction in incidence or symptoms of [specific disease or condition].
3. If the products refer to general health claims that are well understood by product users (eg antiseptic, germicidal or gastrointestinal tract buffer), and provided no reference or mention is made of specific clinical effects, in vitro data may be sufficient to support the efficacy claims. Safety data will normally still be required for these products.

3.12.   Accuracy of dosing

The APVMA will not approve label claims, including use 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. 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.

3.13.   Specific product guidelines

For more technical detail on the number and type of studies required for Australian confirmatory studies for specific types of products, applicants should refer to the relevant guidelines in MORAG Volume 4: Specific product guidelines.

The guidelines provide a uniform approach for applicants for the development of data for product registration. They provide background information, an outline of registration requirements and recommended experimental procedures related to verification of efficacy and safety of the proposed new product. The guidelines are grouped under the headings:

General guidelines

VICH guidelines

Bioequivalence guideline

Stock feeds, vitamin and mineral supplements, feed enzymes, direct-fed microbials, therapeutic pet food diets

Ectoparasiticides

• food-producing animals
• companion animals
• World Association for the Advancement of Veterinary Parasitology (WAAVP) guidelines

Intramammary products

Immunobiological products

Veterinary complementary medicines.

If an applicant proposes to deviate from the guidelines as set out in Specific product guidelines , compelling justification and/or a Category 25 trial protocol assessment must be provided.

3.14.   Data elements

The data elements required for a comprehensive assessment (Module 8.1) of efficacy and target animal safety data are shown in Table 1.

If an applicant believes that the requirement for a data element is not relevant, a brief explanation to justify the absence of the required information must be provided under the heading of the data element.

Table 1: Data elements for a comprehensive Part 8 (Efficacy and target animal safety) submission

CONTENTS

A table of contents is essential.

A list of all studies submitted in support of the application must be included in the submission. It is important that the studies be clearly and consistently numbered throughout the submission. Consistent and clear identification is also vital to identify data for data protection requirements. Information on data protection is on the APVMA website at http://www.apvma.gov.au/registration/data_protection.shtml

Indicate which studies are pivotal and which studies are non-pivotal.

DATA SUMMARY

Each application must include a summary of the efficacy and safety data relating to the product, which concisely deals with each aspect of efficacy and safety studied. Normally, the summary will not extend beyond a few pages. Tables are favoured as a means of condensing data.

Where appropriate, a summary of each group of studies, eg a summary of the efficacy studies, should be provided in addition to the overall summary. Each study report must contain its own summary.

Information relevant to an overall summary which has been included in the Part 1 Overview need not be repeated here but may be referred to as being in Part 1.

Conclusions made must be drawn from all the data and any claims must be based on these conclusions. An explanation must be given of how the data support the proposed label claims. Conclusions must be stated for each experiment and comparisons must be made with data from other experiments.

Comparisons between Australian and overseas data may be useful. Relevant scientific literature may be used in support of conclusions.

All recommendations and claims not supported by data must be explained. Similarly, justification must be given for all instructions that are not supported by data but which are considered to constitute accepted good veterinary practice.

Applicants may use the template in section 6 for submission of the data elements required for Part 8 Efficacy and Target Animal Safety.

EFFICACY STUDIES

Summary

A comprehensive summary of the efficacy studies must be included, with a brief outline of the methods and a description and interpretation of the results. Individual summaries must also be provided with each study if not already included in the study report.

Laboratory model efficacy studies

Laboratory model efficacy studies should be provided where appropriate. Data from such studies may indicate the extent and type of further studies required in target species. Laboratory model efficacy studies may also be used to support relevant scientific argument but not to replace target animal efficacy studies.

Target animal efficacy studies

Demonstration and confirmation of efficacy of a veterinary chemical product involves a three-step approach:

1. dose determination studies
2. dose confirmation studies
3. confirmatory clinical/field studies.

1. Dose determination studies

The purpose of dose determination studies is to 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 proposed new product and must use a formulation identical to, or closely similar to, the formulation which is proposed to be registered. Data obtained with closely similar formulations may be acceptable as supportive data provided that bioequivalence is also demonstrated with the final proposed formulation. The method of administration must be the same as for the proposed product and as instructed on the proposed label.

For some types of application, data from dose determination studies may be used to support efficacy claims provided that:

• the efficacy data 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.

2. Dose confirmation studies

The purpose of dose confirmation studies is to confirm the proposed dose. Such studies are usually conducted under controlled conditions eg pen trials or laboratory trials for companion animals.

The final product formulation must be used for at least one confirmation study. Data obtained with closely similar formulations may be acceptable as supportive data if bioequivalence is demonstrated. Dose confirmation study data may be used to support efficacy claims but the data must be statistically significant.

For some types of application, dose confirmation study data may be used to support efficacy claims provided that

• the efficacy data 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, pharmacokinetic data to justify the declared dosage regimen must be provided. The method of administration must be the same as proposed for the label.

3. Confirmatory clinical or field trials

The purpose of clinical or field trials is to demonstrate efficacy under real conditions. Efficacy claims must be supported by trials that generate clinically relevant, statistically significant data. Central to this is the need to use suitable clinical end-points which reflect the efficacy or safety issues.

The studies must use the product formulation that is to be marketed and must be carried out where the disease or condition occurs under optimum, rather than marginal, conditions. Where the disease or condition is rare or difficult to replicate in the field, the applicant is advised to discuss appropriate alternative clinical end-point studies with the relevant APVMA product evaluator from the Veterinary Medicines Program.

If the main clinical or field trials supporting efficacy are conducted overseas, Australian confirmatory trials are usually required.

Where efficacy relates to individual animal physiology and not local conditions, some product types may not require Australian confirmatory field trials eg anaesthetics.

 

Palatability

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 must be considered and demonstrated as part of confirmatory clinical or field trials.

Palatability studies may be required to justify a label claim for palatability of a product, or where dosage is critical and the dose ingested by the target animal may depend on the palatability of the product. Examples include:

• products where the use pattern specifically involves administration in food or water
• products where efficacy depends on voluntary ingestion of the product
• antibiotic or anthelmintic products in the form of oral pastes/gels
• heartworm preventative products in the form of chewable blocks.

Where relevant, the product label should recommend adding product to a small amount of food and monitoring of the animal’s consumption.

Palatability data may be required 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 (eg flavourants).

TARGET ANIMAL SAFETY STUDIES

The type of data that must be provided to support safety of the proposed new product in the treated species varies according to the nature of the basic toxicological data and the intended use of the proposed product.

Data must indicate the margin of safety to target animals and must 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 must also be considered. If there are no reproductive studies a standard precautionary statement will be required on the label.

Safety studies must use the formulation intended for marketing, administered by the means recommended on the product label and under the proposed conditions of use. Information on alternative routes of administration must be provided if 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 Target Animal Safety Guidelines for New Animal Drugs published on the United States Food and Drug Administration (USFDA) website. However, where requirements outlined in the USFDA guidelines differ from those outlined in this chapter, the APVMA requirements take precedence.

Irrespective of the results obtained during safety studies, any unanticipated reactions occurring during any other studies, or known or suspected by reports from users either in Australia or overseas, must be reported at the time of application.

Summary

A comprehensive summary of the safety studies must be included, with a brief outline of the methods and a description and interpretation of the results. Individual summaries must be provided with each study if they have not been included as part of the study report.

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. This must be determined as closely as possible when the margin of safety is less than 5×. Taking animal welfare principles into consideration for the study design, toxic effects must be identified and described.

1. Dose rate

Safety studies must use the proposed formulation. A safety study using multiples of the maximum proposed label dose (up to five×) for at least the proposed duration of use must be undertaken. In most cases, the combination of l×, 3× and 5× the maximum recommended dose plus controls (0×) is appropriate.

At least 10 typical target animals should be used in each treatment group, however the APVMA will accept data generated from a lower number of animals if the applicant provides argument which the APVMA accepts, that a lower number provides results which are statistically significant.

If there is existing evidence that 5× dosing would result in adverse effects, the combination of 1× , 2× , and 3× plus controls is adequate. In this case the number of animals in each treatment group should be increased to 20 or a less number if the applicant provides argument which the APVMA accepts, that a lower number provides results which are statistically significant. However, this should be discussed and confirmed with the APVMA before starting the trial.

The following parameters must be measured:

• clinical signs of adverse effect
• haematology, blood chemistry and, where appropriate, urinalysis and faecal analysis.

For some products, measurement of other parameters should also be included. Those parameters will be different for different types of product, active constituent, route of administration and organ system likely to be affected adversely. If clinical signs of adverse effect include observable changes in urine or urination, the product is potentially nephrotoxic or if the expected pharmacokinetics or pharmacodynamics of the product could be influenced by changes in urine, then it would be considered essential to include urinalysis as a parameter to be measured. Similarly, if clinically observable changes in faecal consistency or colour are observed, or the product has potential to cause gastrointestinal adverse effects, then faecal analysis 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. It is recommended that applicants check Specific product guidelines or seek advice from the relevant APVMA team.

When studies cannot follow a protocol of this nature (eg long-term administration, slow release or long-lasting products) the protocol can be modified, taking into account the pharmacokinetics of the product. These modified studies must be justified and will be assessed on their scientific merit.

2. Duration of treatment

A safety study must 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 product guidelines are available.

Products proposed for administration over a period less than two weeks must be studied over at least 3× the recommended maximum duration of use. If a product is recommended for long-term administration (>2weeks to <3 months), safety studies must be conducted with the drug administered for the recommended maximum duration of use, or longer (minimum of six weeks).

If the product is recommended for ongoing use, safety studies must be conducted for at least three months.

Topical studies, inhalation studies, tissue irritation studies

Standard toxicity tests may be used for dermal, ophthalmic, intranasal, vaginal, intrauterine and inhalation drugs. Secondary factors must be considered such as acceleration or delaying of healing when 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 must be submitted where appropriate for drugs administered by injection, scarification, implants, or pour-on, spray-on or spot-on application. Observations of inflammation, swelling, necrosis and histopathology (particularly of injection sites) must be included. The findings must be taken into account in establishing the maximum amount of the product recommended for administration, and the period of time required for the tissues at the injection site to return to an acceptable condition. These observations can also be used to prepare ‘carcase trim’ statements for the proposed label.

Bacterial endotoxin testing/pyrogen testing studies

Injectable products must be tested for endotoxins using a currently acceptable method as described in the European Pharmacopoeia, British Pharmacopoeia, British Pharmacopoeia (Veterinary), United States Pharmacopeia or USFDA guidelines.

Applicants may also refer to the APVMA's guidelines on Limulus Amebocyte Lysate (LAL) tests in MORAG Volume 4: Specific product guidelines.

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 intended 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 must be addressed. Data from teratology studies conducted in the intended species may also be required in some cases.

If data from reproduction or teratology studies are not available, a standard precautionary statement must be included on the label advising the user that such studies have not been done and therefore the effect of the chemical on the reproductive function of treated animals is unknown.

Reproductive function studies must be submitted for all products containing new active constituents.

Adverse experiences

All adverse effects encountered during the clinical use of the product must be described in detail. Clinical use of the product provides evidence for the safety of the product under actual field use conditions and situations not encountered in toxicity studies.

If the product is registered in other countries, results of those countries’ post-registration vigilance reports must be included in the submission.

The severity and incidence of adverse reactions must also be classified by organ system.

This section must 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 must also be tabulated according to sex, age, breed, dosage form, formulation or other relevant factors as appropriate.

Any abnormal finding or adverse reaction must 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
• effect on pregnancy and various other physiological states.

PHARMACOLOGICAL DATA OR STUDIES

Summary

A comprehensive summary of the pharmacological studies must be included with a brief outline of the methods and a description and interpretation of the results. Individual summaries must also be provided with each study if not already included in the study report.

If data from target animal pharmacological studies, which support the efficacy of the product, have already been presented in Part 4 (Metabolism and Kinetics) they need not be repeated, but should be referred to in the Part 8 submission.

Pharmacokinetics

Pharmacokinetic studies include single-dose bioavailability studies or bioequivalence studies. For multiple-dose or continuous-use medications, steady-state and peak and trough levels must be identified.

Pharmacodynamics

Pharmacodynamic studies, including any scientific studies to identify the mode of action of the product, should be presented here but are not mandatory.

RELATED STUDIES

Compatibility studies

If particular treatments, conditions or procedures are likely to be used in combination with the proposed new product, data and/or relevant scientific argument must be provided to show that there is no interaction to compromise efficacy or safety of the products. If compatibility with particular treatments or conditions is claimed, this must be proven.

Effects on hides and fleeces

Applicants must demonstrate by data or 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.

Applicants seeking registration of products to be externally applied to sheep should refer to the Specific product guidelines for ovine lousicides for further details on reporting effects on hides and skin.

Wool scourability data must be provided for pour-ons, dips, shower sprays, and other products containing dyes or other pigments that are applied to wool. This issue can be addressed by argument, if appropriate.

Accidental administration or exposure to non-target animals

Applicants must 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 must be included on the product label. This is particularly important for feed additive products.

Effects on taste of 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 (eg products that may affect milk), those data must be included in this part of the application and clearly identified as a separate section.

Where 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, applicants must undertake an adequate investigation, supported by taste-panel tests or other organoleptic tests, to verify that no unacceptable tainting occurs. The data obtained must be included in this part of the application and clearly identified as a separate section.

OTHER STUDIES OR DATA

Bioequivalence studies

Bioequivalence studies can be used as supporting evidence that the efficacy and possibly safety of one formulation are equivalent to another. These studies may be used to support applications for registration of generic products and for some formulation changes, including those done during product development.

If the applicant wishes to use bioequivalence to demonstrate efficacy comparable to that of a reference product, the reference product must be a product registered by the APVMA. If an overseas-registered product is used in the bioequivalence study, the applicant must demonstrate that the overseas product is identical to the APVMA-registered reference product.

For more information on prerequisites and requirements for bioequivalence studies, applicants should refer to the bioequivalence guidelines (accessed through MORAG Volume 4: Specific product guidelines).

Information on bioequivalence can also be found on the USFDA website at http://www.fda.gov/cvm/Guidance/bioequivalence_Oct02.htm.

Before commencing any bioequivalence studies, applicants are strongly encouraged to contact the APVMA to discuss the proposed studies.

Bioequivalence may be determined by one of several direct or indirect methods. Selection of the method depends upon the purpose of the study, the analytical method available, and the type of product. Bioequivalence testing must 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 study
• pharmacologic end-point study
• clinical end-point study.

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 must be conducted. The blood level study is generally preferred above all others, as the most sensitive measure of bioequivalence.

If the measurement of the rate and extent of absorption of the drug in biological fluids cannot be achieved or is unrelated to drug action, a pharmacologic end-point (ie drug-induced physiologic change which is related to the approved indications for use) study might 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.

For some types of product, suitable in vitro tests may be used to support equivalence of efficacy and safety in the target species in lieu of bioequivalence testing.

Clinical case studies

Clinical case reports may be submitted as data to support the efficacy, and more commonly safety, of a product depending on the type of product, type of application and type of claim. In general, they will only be considered for support of products that will be used by or under the direct supervision of a registered veterinary surgeon. Clinical case study reports must come from the records of registered veterinary surgeons and must use the formulation proposed for registration in the target species.

Any other studies

For some types of applications and for some types of product, other studies may be appropriate to support efficacy and/or safety.

Scientific references or extrapolated scientific argument

For some types of products, registration or issue of a permit may be considered on a case-by-case basis, based on extrapolation from available data such as:

• proof of efficacy for the proposed formulation in a non-target species and/or a related formulation in the target or non-target species
• proof of registration by an EU or US regulatory authority of the proposed or related formulation in the target or non-target species. Proof of registration by other regulatory authorities requires an officially stamped copy of the registration notice and registered label
• trial data for the proposed formulation and target species which may not be completely validated or statistically significant, but is supportive of safe use
• relevant scientific information from recognised textbooks or other reputable sources for the active constituent/s in the target species. This is subject to:
  1. 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
  2. the product is only to be advertised and supplied to veterinarians for use by them or under their direction in the course of treating animals under their professional care.
• proof of safety for the proposed formulation in an appropriate non-target species and/or a related formulation in the target or non-target species. This is subject to:
  1. placing a suitably worded precautionary statement on the main panel of the label; and/or
  2. 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, their role must be explained in the summary so that the relevance of such additional data is explained to the reviewer.

4.   STUDY OR TRIAL REPORT FORMAT

Each study or trial report must provide a comprehensive description of the study or trial including:

• a description of the materials and methods
• a presentation and evaluation of the results
• statistical analyses
• a critical clinical and statistical appraisal.

Each study or trial report should follow the following basic structure and content:

1. Title of the study and identifying number, dates of commencement and completion of the trial, investigator and personnel involved and trial location details. Where Australian trials are included, the registration number of the investigator and the Animal Ethics Committee approval number for each State in which the trial was undertaken must be included.
2. Summary of the investigation, including a statement of the objective, general methods and conclusions drawn from the results (any constraints such as economic or animal welfare issues must also be detailed).
3. Objectives must include defining null and alternative hypotheses and the appropriate level of statistical significance for rejecting or accepting the hypothesis to be set.
4. Statistical methodology regarding statistical or biometrical analysis proposed, statistical justification for numbers of animals/groups used including need to replicate, statistical power and confidence of the study.
5. Positive and/or negative control(s) used with details of reference products used. Animal ethics must be considered when choosing controls.
6. Appropriate strategy for the minimisation of bias such as randomisation, blinding, cross-over.
7. Criteria for selection of animals including the number, age, species, breed, sex, physiological condition (ie pregnancy, lactation) and inclusion/exclusion criteria.
8. Details of geographic location and climatic conditions.
9. Details of animal husbandry, especially the use of any medicinal products prior to, during, or after the trial, even if those products are used in routine husbandry of the species.
10. Details of the challenge, including justification of challenge dose, strain, origin, and history of the disease-causing organism.
11. Treatment regime with details of the formulation used (including batch numbers and certificate of analysis), method, route, dose, frequency, time and duration of administration of treatment and acclimatisation period.
12. Measurement parameters, ie what measurements are taken and when. Generally, the criteria for evaluation are determined by the objectives of the trial and where appropriate, must include diagnostic criteria such as severity/stage of disease/condition.
13. Detail of deviation from trial protocol such as missed observations or animals removed from experiments.
14. Appropriate recording of treatments, measurements and results including records of unfavourable results and adverse reactions.
15. Test reports from diagnostic laboratory procedures, clinical, post-mortem or other procedures conducted prior to, during, or at termination of the studies. These reports, individual raw animal data, standard operating procedures that are study-specific and other records may be appended to the submission.
16. The evaluation and conclusions will relate back to the objectives and hypothesis from a clinical and statistical perspective.

5.   TEMPLATE FOR SUBMISSION OF PART 8 EFFICACY AND TARGET ANIMAL SAFETY DATA

CONTENTS

DATA SUMMARY

EFFICACY STUDIES

Summary

Laboratory model efficacy studies

Target animal efficacy studies

1. Dose determination studies

 

2. Dose confirmation studies

 

3. Confirmatory clinical or field studies

 

TARGET ANIMAL SAFETY STUDIES

Summary

Margin of safety studies

1. Dose rate

 

2. Duration of treatment

 

Topical studies, inhalation studies, tissue irritation studies

Bacterial endotoxin testing/pyrogen testing studies

Reproductive function studies

Adverse experiences

PHARMACOLOGICAL DATA OR STUDIES

Summary

Pharmacokinetics

Pharmacodynamics

RELATED STUDIES

Compatibility studies

Effects on hides and fleeces

Accidental administration or exposure to non-target animals

Effects on taste of produce (organoleptic effects)

OTHER STUDIES OR DATA

Bioequivalence studies

Clinical case studies

Any other studies

Scientific references or extrapolated scientific argument

Appendices

6.   GLOSSARY

Adverse product experiences

Any unexpected effects on animals, human beings, plants or the environment that are thought to be associated with a formulated product when used in accordance with label instructions.

Direct-fed microbial

A product that contains viable micro-organisms for oral administration. These may be administered as mass medication in feed or water, or individually administered to single animals. If a product is a fermentation by-product (eg a fermentation extract from yeast) and fits the definition of a veterinary chemical product, evaluation will be similar to that for direct-fed microbials.

Enzyme

A high molecular weight protein with catalytic effect, composed of amino acids, produced by living cells. Enzymes may also contain non-protein parts such as carbohydrates, lipids, phosphate groups and metals. The enzymes that are used in animal feeds may be of plant, animal or microbial origin.

Fibre-producing animal

Any animal used to produce fibre for human use, including wool and mohair.

Food-producing animal

Any buffalo, cattle, deer, fish (other than ornamental fish), goat, kangaroo, pig, poultry, rabbit, sheep, bee, crustacean or mollusc; or any animal declared by the regulations to be a food-producing species.

Palatability

Palatability of an orally administered veterinary medicinal product is a measure of the acceptability of the product in the mouth of the target animal, based on its organoleptic properties such as flavour and texture. Veterinary products that are not palatable are generally only partially swallowed or are totally rejected by the animal.

Pharmacodynamic studies

The study of the interaction of pharmacologically active substances with target sites, and the biochemical and physiological consequences leading to therapeutic or adverse effects.

Pharmacokinetic studies

The study of the movement of drugs within the body (ie the absorption, distribution via the blood, metabolism and excretion).

Product

A formulation containing one or more active constituent(s), and possibly non-active constituent(s), which is intended for administration or application, with or without dilution prior to use and which is labelled with directions for use.

Also referred to as formulated product or end-use product.

Reference product

A product which is currently registered by the APVMA and its approved label.

Study/trial

The term ‘study’ is generally used for preclinical and in vitro investigations while the term ‘trial’ tends to be used for in vivo ie field or clinical investigations. Additionally, a ‘study’ can comprise several ‘trials’. In this document, they are used interchangeably.

Trial protocol

A document describing a trial design used to generate data to support applications for approval and registration or for a permit (also called a trial protocol).

Use pattern

The combination of all factors involved in the use of a formulated product, including the concentration of active constituent in the preparation being applied, rate of application, method of application, frequency and duration of treatments, additives recommended and other directions which determine total quantity applied, timing of treatment and withholding period.

Revision history