Complementary animal health products: guidance for veterinary herbal and marine-derived remedies

1. Introduction

This provides guidance on the sorts of information an applicant may choose to submit to address the safety and efficacy criteria for veterinary herbal and marine-derived remedies. It also provides guidance about how the information might be presented and analysed. The Australian Pesticides and Veterinary Medicines Authority (APVMA) will consider each application on its merits.

1.1. Registration of a veterinary product

The Agvet Code does not distinguish between naturally derived remedies and synthetic pharmaceutical medicines. Many ingredients derived from natural sources are pharmacologically active and may be capable of having an effect that can modify the health, productivity, performance or behaviour of animals.

The data that may be submitted to support the registration of a veterinary product can vary according to the:

• nature of the product
• claims made for the product
• intended use.

1.2. The difference between pharmaceutical or immunobiological medicines and complementary animal health products

Pharmaceutical and immunobiological medicines are products that contain well-characterised active constituents that have been subject to validated quantitative chemical or biological assays for purity and/or potency. Their labels usually make specific therapeutic claims. The medicines may be administered or applied internally or externally, including parenterally or topically to tissue other than skin.

Products in one or more of the following categories are pharmaceutical products, not complementary animal health products:

• Products that are highly purified plant extracts (for example, where the extract is chemically or biologically well characterised and/or a quantitative test for purity or potency has been developed)
• Products administered parenterally (that is, by injection)
• Products applied topically to tissue other than the skin (for example, eye, nose or throat)
• Products that make specific therapeutic claims for the prevention, cure or alleviation of a specific disease or condition

Complementary animal health products (CAHPs) are products that:

• contain only natural ingredients as their active constituents
• make only general health claims, not specific therapeutic claims that refer to the prevention (or reduction), cure or alleviation of a specific disease or condition.
• are administered only orally or topically on the skin, not parenterally (for example, by injection) or applied topically to tissue other than skin (for example, eye, nose or throat).

‘General health claims’ refer to possible health, production or performance benefits for animals’ organs or physiological systems without mentioning specific diseases or conditions; for example, ‘May be of benefit for improving or promoting [organ or system] health.’

CAHPs include:

• herbal remedies
• probiotics (direct-fed microbials), prebiotics and enzyme products
• therapeutic diets
• homeopathic remedies
• oral vitamins, minerals, amino acids and fatty acids, and other nutrients or food-based derivatives, when used at concentrations higher than 100% of the daily nutritional requirement in order to derive a health benefit (also known as nutraceutical products).
• other naturally derived remedies (for example, marine-derived ingredients such as green-lipped mussel or shark cartilage), but not products such as antimicrobials, hormones and vaccines.

Other than nutraceutical products, CAHPs are not highly processed or well characterised, and therefore do not have validated quantitative assays for purity or potency.

Nutraceutical products, because they are either highly purified and well-characterised ingredients or synthetic duplicates of those ingredients, normally have validated quantitative assays for purity or potency. Therefore, you should submit a complete chemistry package (as expected for a pharmaceutical product) for these types of products. You should discuss and justify the impact of this on other criteria, such as the product’s toxicity, where appropriate.

2. Veterinary herbal and marine-derived remedies

2.1. Herbal and marine-derived products that do not require registration

Plant or animal material that is an ingredient of the normal diet of an animal, and that is only represented as being suitable and used to help maintain normal (optimal) health, production or performance, is a food and not a veterinary chemical product.

Plant material that is an ingredient in a product for application to the normal healthy skin or coat of an animal, and that is only represented as being suitable and used to modify the appearance (not the physiology) of the skin or coat by cleaning, moisturising or changing the colour, is a cosmetic and not a veterinary chemical product.

Therefore, products that meet all of the following criteria do not usually require registration:

• Products made from whole unprocessed plant or animal material and administered in feed or applied to the skin of animals
• Products intended only for use as a food or cosmetic
• Products that do not claim to contain biologically active constituents
• Products that do not claim to modify the health, productivity, performance or behaviour of an animal

Refer to the APVMA’s user guide What is or isn’t a veterinary product for further information.

2.2. Criteria for reduced data submissions for herbal and marine-derived remedies

Herbal and marine-derived remedies may be eligible for evaluation for registration with reduced data submissions, compared with the data requirements for pharmaceutical or immunobiological products, if the products:

• make only general health claims
• are administered only by topical application to the skin, oral administration or consumption by an animal
• are for use only in non-food-producing species of animals (that is, companion animals).

The summary claim on the main panel of the label must clearly state:

• as the first statement:
  ‘This product is registered as a Complementary Animal Health Product’
• followed by a general health claim, such as:
  ‘May be of benefit for improving or promoting [organ/system] health or production or performance’.

3. Guidance on data requirements

You should provide data and/or valid scientific argument to address each data type included in the veterinary data guidelines when applying to register a CAHP.

Data should generally be submitted for Chemistry and manufacture, Health, and Efficacy and target animal safety, as described below.

Data packages to support Metabolism and kinetics, Residues and trade, Environment, Other trade aspects and Special data – antibiotic resistance, are not normally expected for herbal and marine-derived remedies used in companion animals. However, you should ensure that the omission of any data part is adequately justified in your submission.

3.1. Chemistry and manufacture (Part 2)

Validated quantitative assays for purity and potency are not generally expected, as quality will be determined by good manufacturing practice (GMP) controls on the raw materials, manufacturing processes, release and expiry specifications for testing physical and chemical properties other than assays and, when available, testing for marker substances. Where validated quantitative assays exist (such as for nutraceuticals), they should be provided.

You should provide:

• a description of the dose form or formulation type of the product
• the Australian approved name(s), botanical name(s) and descriptions of the plants or plant parts used as active constituents in the product
• a description of the extraction and/or purification process and quality controls for the active constituent(s)
• the results of identification and characterisation tests, including the analytical procedure(s) used to control the method of extraction (for example, fingerprint chromatogram, ultraviolet spectrum, biological test or other procedure for active constituents; refer to a pharmacopoeial monograph where relevant, or to details in a recognised herbal pharmacopoeial monograph such as the European or British herbal pharmacopoeias or Max Wichtl, Herbal drugs and phytopharmaceuticals)
• the specifications and analytical procedures for the analysis of purity and impurities, including tests for potential contamination by organic and inorganic impurities and residual solvents where they are likely to occur, such as microorganisms, products of microorganisms, pesticides, toxic metals and fumigants
• the complete formulation, composition and specification of each non-active constituent if the product contains such constituents
• a description of the physical and chemical properties of the product
• a description of the manufacturing process and quality controls for the product
• the specifications and details of any analytical procedures to ensure the batch-to-batch consistency and quality of the final product, such as assays of active constituents or relevant marker substances or acceptable bioassays
• where relevant, data used to support the proposed shelf life and stability of the product during storage and at the end of the proposed shelf life (if validated analytical methods are not available for stability testing, a product that has been stored for a period of time may be used in a repeat of the efficacy and safety trials to support the proposed shelf life).

We may also consider applications for default shelf lives of 12 months for liquid and semi-solid products and 18 months for dry solid products if you provide valid scientific argument.

3.2. Health (previously Toxicology Part 3)

If the product is for use in only companion animals, you may choose to address the safety criteria related to the toxicology of the product by nominating an APVMA-registered reference product that contains the same active constituents in the same concentrations.

Alternatively, you may provide evidence that:

• the product’s active constituents are included in the Australian Register of Therapeutic Goods as a registered (AUST R) product, or are included in Part 2, 3 or 5 of Schedule 4 of the Therapeutic Goods Regulations (A) and are not included in Part 4 of the schedule, or have been gazetted to be thus included, which renders them eligible for listed registration (AUST L)
• both the active and non-active ingredients have been approved by the APVMA or Therapeutic Goods Administration (TGA) for inclusion in the type of formulation and packaging proposed.

If the above scenarios do not apply, you should consider the following when preparing a submission to address toxicology:

• The purity and concentration of constituents
• Whether they are manufactured in accordance with a pharmacopoeial monograph
• Whether they are registered overseas

You should submit copies of relevant material safety data sheets together with all available toxicity data.

For products containing more than one active constituent, we will consider any additional concerns about toxicology on a case-by-case basis.

We encourage you to review Veterinary chemical products – Toxicology (Part 3) when preparing a submission. You should address the submission recommendations by providing data and/or valid scientific argument.

3.3. Efficacy and target animal safety (Part 8)

Australian or overseas efficacy and safety data for the use of the proposed product may be submitted for companion animal uses.

3.3.1. Products containing existing active constituents

For products containing existing active constituents, you may be able to provide scientific data or argument for the equivalence of your proposed product with a registered reference product, because these products are not considered to be highly formulation-dependent. Otherwise, you should refer to the guidance below for products containing new active constituents.

3.3.2. Products containing new active constituents

This section provides guidance on data packages for products containing new active constituents.

3.3.2.1. Efficacy

Although it is generally not appropriate to extrapolate between animal species or between different formulations, or to rely on non-clinical endpoints, we will consider a reduced efficacy data package for herbal and marine-derived remedies if any of the following cases apply:

• There are scientifically valid clinical data for a related formulation and/or in non-target species.
• There is relevant scientific information from recognised textbooks or other reputable sources that recognises the efficacy of the active constituent in the target species. This information may be derived from clinical veterinary practices and well-constructed client surveys.
• A physiological or pharmacological endpoint, rather than a clinical endpoint, is proven in the target species efficacy trials using the proposed formulation.

Otherwise, one or both of the following types of clinical studies, using the proposed formulation together with preclinical pharmacokinetic data and dose-determination studies, is desirable:

• A randomised controlled experimental trial using objective measurements of clinical endpoints in the target species.
• Clinical case studies in the target species for which either the raw data are available or results are published in a peer-reviewed scientific journal.

Refer to the APVMA’s data guidelines – veterinary for further information about efficacy trials.

3.3.2.2. Safety

You should refer to internationally acceptable guidelines, such as Target animal safety guidelines for new animal drugs, which is published on the website of the United States Food and Drug Administration (FDA). More information is available on the APVMA’s specific guidelines page.

The following are minimum requirements:

• Studies should be adequately designed, well-controlled and conducted by a qualified investigator.
• Product formulation and use patterns used in studies should be identical to those being proposed for registration.
• The selection of study animals should consider the classes of the target species (age, sex, weight range) most at risk.
• Animals should be studied for at least three times the recommended maximum duration of use, up to a maximum of 3 months.
• A tolerance test should be conducted on five animals at 5 times the recommended maximum label dose, administered for the duration specified above. If the tolerance test indicates any sign of toxic effects, a margin of safety study as per the FDA guideline should be conducted.
• The evaluation for signs of toxicity should include:
  • feed and water consumption, clinical observation and physical examinations
  • changes to haematology and blood chemistry
  • urine and faecal analysis.
• Any abnormal finding or adverse reaction should be further investigated. A complete gross and histopathological examination should be carried out on all animals that die during, or as a result of, the study.

Two weeks or longer may be appropriate to acclimatise test animals. Baseline parameters should be established before the study begins. All prophylactic and therapeutic medications should be administered before the baseline study period so that they will not interfere with the study.

In the absence of reproductive studies, a standard label precautionary statement should be proposed; for example: ‘Use with caution in pregnant or lactating animals'.

Compatibility studies may be appropriate for some products if they are mixed with other products.

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

4. Examples

4.1. Example 1

An application is made to register a new herbal-extract tablet product for use in dogs and cats with a claim of ‘May help relieve symptoms associated with travel sickness’.

The product contains a new herbal active constituent that the TGA has approved for use in humans.

The following modules and data parts are expected to apply:

 The evaluation timeframe in this example is 11 months.

4.2. Example 2

An application is made to register a new feed-additive powder product for use in dogs with a claim of ‘May aid in improving joint health’.

The product contains a new active constituent derived from a marine animal. The TGA has not approved the constituent for use in humans, but it is likely to be of low toxicity.

The following modules and data parts are expected to apply:

The evaluation timeframe in this example is 12 months.

Scheduling may be required in some instances. If so, an additional module 4.1 will apply (13 month timeframe).

4.3. Example 3

An application is made to register a new product for companion animals that contains an existing active constituent. The product is not closely similar to any product already registered by the APVMA.

The product contains a herbal active constituent that the TGA has approved for use in humans.

The following modules and data parts are expected to apply:

The evaluation timeframe in this example is 8 months.