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Bioequivalence Guidelines for Veterinary Chemical Products

Guideline 13

Contents

1. Introduction

Under the Agricultural and Veterinary Chemicals Code Act 1994, the National Registration Authority has the responsibility for the evaluation, assessment and registration of veterinary chemicals. Data requirements for different categories for registering veterinary chemical products are outlined in The Requirements Manual for Veterinary Chemicals. The NRA is required under section 14 of the Agricultural and Veterinary Chemicals Code Act 1994 to be satisfied with respect to target animal efficacy and safety, among other criteria, when considering registration of a veterinary chemical product.

The NRA may be satisfied, with respect to target animal and safety, because of close similarity of a proposed product to a currently registered product. An applicant may choose to apply for the registration of a new product based on similarity to that registered product. Commercial confidentiality prevents the NRA from disclosing the formulation of the reference product to the applicant of the new product.

If products are not closely similar, the NRA could not be satisfied unless bioequivalence data is submitted or efficacy and safety data on the proposed veterinary chemical product is submitted.

Bioequivalence studies can be used to demonstrate claims that the new product will have the same target species efficacy and safety  (Part 8 Efficacy and Safety to Treated Animals) as the reference product. Such studies may obviate the conduct of clinical trials that would otherwise be needed to establish the safety and efficacy of the reference product. Bioequivalence studies are not compulsory, and applicants may prefer to perform clinical trials to provide data on efficacy and safety.

This guideline replaces previous draft Bioequivalence Guidelines and the Draft Policy - The Requirement to Demonstrate Bioequivalence and Bioavailability (dated 6/6/95)

Scope of this guideline : This guideline pertains to the requirement for data demonstrating bioequivalence under Part 8 Efficacy and Safety to Treated Animals, in particular for Category 24 and 25 applications in Schedule 7 of the Agricultural and Veterinary Chemicals Code Regulations 1995

Data requirements for vaccines and immunobiologicals are not addressed in this guideline. Applicants are encouraged to read carefully the data requirements for Category 7 products (see NRA Guideline for Format and Data Requirements for Application to Register New Veterinary Immunobiologicals available from the NRA or from the NRA website).

Data requirements for residues (Part 5a Residues) are not addressed in this guideline. Applicants are encouraged to carefully read the Residues guidelines pertaining to their type of product, available from the NRA or from the NRA website.

The guideline is divided into seven major parts :

  1. introduction;
  2. definitions used in these guidelines;
  3. veterinary categories for which bioequivalence data are required;
  4. veterinary categories for which bioequivalence data are not required;
  5. veterinary categories for which bioequivalence may be required;
  6. conduct of bioequivalence studies;
  7. presentation of data.

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2. Definitions used in this guideline

Bioequivalence

Bioequivalence studies are scientific methods designed to compare two products containing the same active constituent, based on their formulation and pharmacokinetic and pharmacodynamic characteristics. In pharmacokinetic studies, two products are considered bioequivalent if the bioavailability of the active ingredient only differs between the two products within acceptable limits.

Bioavailability

The rate and extent of absorption into the systemic circulation of an active constituent

Closely similar (relevant to Category 26 applications)

A proposed product is considered to be closely similar to a reference product if :

  1. ingredients are of equivalent pharmaceutical compendial standard, and
  2. the active constituents are the same substances and are within ± 5% of that in the reference product or the dose range to the animal is within ± 5% of the reference product, and
  3. the non-active constituents are the same substances and are within ± 5% of that in the reference product, except for those constituents defined in the Guidelines on Minor Formulation Changes, where they can vary by more than ± 5%, and
  4. the product is in the same dosage form, and
  5. the product has the same physico-chemical properties as the reference product (including pH, particle size, crystal form, and dissolution profile where applicable).

Direct scale

A proposed product is considered to be a direct scale of a reference product if the same formulation is used to manufacture various strengths, but the products are compressed or filled to varying weights corresponding to the various strengths, where

  1. the pharmacokinetics of the drug are linear within the therapeutic dose range, and
  2. the ingredients are of equivalent pharmaceutical compendial standard, and
  3. the product is in the same dosage form, and
  4. the product has the same physico-chemical properties as the reference product (including pH, particle size, crystal form, and dissolution profile where applicable)
  5. both products are produced by licensed manufacturers and to the same standard.

Dissolution profile

Data that describes the in vitro dissolution of dosage units using pharmacopoeial methods

Data should be generated in a comparative manner as follows:

The methodology used must be that described in the British Pharmacopoeia, European Pharmacopoeia or U.S. Pharmacopoeia.  At least six dosage units (e.g. tablets, capsules) of each batch should be tested individually and mean, standard deviation and individual results reported. The percentage of nominal content released should be measured at a number of suitably spaced time points providing a profile for each batch, eg. at l0, 20 and 30 minutes, or as appropriate to achieve virtually complete dissolution. The batches  should be tested using the same apparatus and if possible on the same day.  Under some circumstances, insufficient recently manufactured batches may be available to meet this requirement. It would then be acceptable to test retention samples, and to explain in the test report why this was done, stating the age and storage history of the samples.

Identical (relevant to Category 27 applications)

A product is considered to be identical to a reference product if the formulation ingredients are the same, are from the same sources, formulated at the same plant by the same procedures and equipment and packaged in the same size container made from identical material.

Pharmaceutical equivalence

For certain dosage forms (intravenous solutions, oral solubilized forms, topical dose forms, non-absorbed antacids and radioopaque media and oral tablets), an applicant may wish to address bioequivalence by providing in vitro data demonstrating pharmaceutical equivalence of a product to a reference product. Such data should include :

  1. nature of dosage form
  2. solubility of active constituent/s in water
  3. relevant pharmaceutical characteristics including particle size, crystal form, and dissolution profile where applicable
  4. rate limiting steps in absorption of the active constituent/s eg. disintegration, dissolution, gut absorption where applicable or in access to the site of effect
  5. relevant scientific argument regarding clinical consequences of inequivalence

Reference product

A veterinary chemical product currently registered in Australia (including its label) as nominated by the applicant.

Similar (relevant to Category 24 and 25 applications)

A product is considered to be similar to a reference product if :

  1. ingredients are of the same pharmaceutical compendial standard, and
  2. the active constituents are the same substances within ± 5% of that in the reference product or the dose range to the animal is within 5% of the reference product, and
  3. the product is in the same dosage form, and
  4. the product has the same physico-chemical properties as the reference product (including pH, particle size, crystal form, and dissolution profile where applicable).

Simple aqueous solution

A solution that contains the active constituent/s, water and buffers, preservatives, colouring or flavouring agents and no other types of constituents. A simple aqueous solution can be further defined as an homogenous mix in which the solute is in molecular dimensions. Simple aqueous solutions do not include emulsions or suspensions.

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3. Vet Item Categories where Bioequivalence Data are Required

Applicants can contact the NRA before studies are commenced to determine the data required.

SUMMARY EXPLANATION CATEGORY
New product based on a reference product;companion animals When a product has a formulation and use pattern that are similar to a reference product, but which, in the opinion of the NRA, are different enough to require bioequivalence data. 24
New product based on a reference product;food-producing animals When a product has a formulation and use pattern that are similar to a reference product, but which, in the opinion of the NrA, are different enough to require bioequivalence data. 25

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4. Vet Item Categories where Bioequivalence Data are NOT Required

SUMMARY EXPLANATION CATEGORY
Repack Repacks for which the formulation and use pattern are identical to the reference product apart from name and label 27
New products based on a reference product where constituents are closely similar 'Closely similar' as defined in Section 2.3 26
Direct scales Further bioequivalence data is not necessary where these products can be shown to have pharmaceutical equivalence Modular(Modules 1 and 2 minimum)
Minor formulation changes As defined in the Guidelines for Minor Formulation Changes 37
Change of site and/or standard of manufacture of active constituents or change of site of manufacture of the formulated product When manufactured to same standard. Refer to 'OTHER VARIATIONS TO EXISTING PRODUCTS' in the Vet Manual Modular as required
New products based on existing active constituents approved by the NRA intended for use on cats, dogs and horses Products include vitamins / minerals / electrolytes; liniments etc. as described under Category 16 in the Vet Manual; also antacids and radio-opaque media 16
Simple aqueous solutions Similar to a reference product for administration by intravenous, intramuscular, subcutaneous, dermal, ophthalmic, aural and oral routes 26
Volatile inhalant anaesthetic solutions   26
Intravenous solutions   26 or modular (Modules 1, 2 minimum)
Oral solubilised forms, tablets and powders Further bioequivalence data is not necessary where these products can be shown to have pharmaceutical equivalence Modular Modules 1, 2 and 13 minimum)
Topical dermal, oral, aural or ophthalmic) dosage forms intended for local therapeutic effect (non-food producing animals only) Further bioequivalence data is not necessary where these products can be shown to have pharmaceutical equivalence Modular (Modules 1, 2 and 13 minimum)

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5. Vet Item Categories where Bioequivalence Data may be Relevant

Applicants can contact the NRA before studies are commenced to determine whether bioequivalence studies are appropriate and to determine the data required.

SUMMARY EXPLANATION CATEGORY
Change in site and/or standard of manufacture of active constituents or change of site of manufacture of the formulated product When not manufactured to same standard or when manufacturing site of formulated product does not meet GMP standards. Refer to 'OTHER VARIATIONS TO EXISTING PRODUCTS' of Module B, Vet Manual Modular; if bioequivalence data required by NRA.
Identical product; new route of administration When a product has an identical formulation and use pattern to a reference product except for a new route of administration e.g. intramuscular to subcutaneous Modular(Modules 1 and 11 minimum)
New dosage form; same route of administration When the applicant wants to extend the use of a registered product to a new dosage form (e.g. tablet to paste) 28 or 29, depending on whether food -producing animal species
New dosage form; different route of administration When the applicant wants to extend the use of a product to a new dosage form (e.g. injectable to tablet) with a different route of administration 28 or 29, depending on whether food - producing animal species
New combination product based on existing active constituents Where equivalent efficacy and safety can be argued based on the bioequivalence of actives in the new combination product and reference product 12
Major change in formulation in food-producing animals Where equivalent efficacy and safety can be argued based on the bioequivalence of actives in the new and reference formulations 28
Product with approved active constituents for use on an animal other than a food producing species Where equivalent efficacy and safety can be argued based on the bioequivalence of actives in the new and reference formulations 29

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6. Conduct of Bioequivalence Studies

6.1  The NrA encourages applicants to consider the study methods and trial design sections of the bioequivalence guidelines published by the Centre for Veterinary Medicine of the USA Food and Drug Administration as optimal experimental conditions for the conduct of bioequivalence studies. Refer to the Centre for Veterinary Medicine Food and Drug Administration (U.S.A.) Bioequivalence Guidance 1996 (Docket 94D-0401) Sections II. C through to, and including V.C. These sections are for guidance on bioequivalence study methods and trial design.

The internet address is http://www.fda.gov/cvm/Guidance/bioequivalence_Oct02.htm

6.2  In general, bioequivalence studies must be performed in the target species, using the reference product.  Bioequivalence studies may not be required for each species for which the reference product is approved. When the pharmacological properties of an active constituent have been demonstrated to be similar between two species, bioequivalence for additional species may be presented as relevant scientific argument for consideration by the NrA Please note that the reference product must be registered for a particular use in a particular species for that use and species to be included in the claim for the new product. Claims made need not be identical to the reference product but should not exceed those of the reference product without provision of additional data.

6.3  Whenever possible the pioneer (first registered) product should be used as the reference product. If the pioneer product is no longer marketed, bioequivalence studies should be performed using another appropriate reference product.An appropriate reference product can be determined by contacting the NRA or by reference to PUBCRIS (available on the NRA Website)

6.4  Bioequivalence data will normally be provided on each active constituent of the product. However under some circumstances, bioequivalence studies may not be required for each active constituent and the NrA should be approached for possible exemptions, based on relevant scientific argument.

6.5  It is essential that the product, under consideration for registration on the basis of bioequivalence, be administered according to proposed label directions. Such directions may include species, category or class of animal, dose, route of administration, maximum dose per injection site, and frequency of use. In addition, the reference product should be administered in bioequivalence studies according to that product's label directions.

6.6  A multiple dose study may be necessary when the action of the product is dependent on steady-state blood concentrations.

6.7  Blood concentration (pharmacokinetic) studies may not be the most appropriate studies eg. for active constituents which are active in the organ or tissue on, or in which the product is administered (e.g. skin, gut) and which may also be absorbed and act systemically. Examples include ectoparasiticides (topical administration) and anthelmintics (oral administration). Clinical end-point studies such as comparative field trials are indicated in these situations and advice should be sought from the NrA

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7. Presentation of Data

Data should be presented as the Part 8 (Efficacy and safety to treated animals) data requirement package.

The report of a bioavailability or bioequivalence study should give the complete documentation of its protocol, conduct and evaluation.  This implies that the authenticity of the whole of the report is attested by the signature of the study monitor.  The responsible investigators should sign for their respective sections of the report.

Names and affiliations of the responsible investigators, site of the study and period of its execution should be stated.  The names and batch numbers of the products used in the study as well as the composition(s) of the new product(s) should be given.  In addition, the applicant may submit a signed statement, confirming the identity of the test product with the product which is submitted for registration.  All results should be presented in a clear way.

The way of calculating the characteristics used (e.g. AUC, Cmax) from the raw data should be specified. If results are calculated using pharmacokinetic models, the model and the computing procedure used should be justified.  Individual plasma concentration / time curves should be drawn on a log/linear scale.  All individual data and results should be given, including any  eventually dropped-out subjects.  Drop-out or withdrawal of subjects and deletion of data should be reported and accounted for.  Where appropriate, a representative number of chromatograms should be included.  The analytical validation report should be provided.