Guidance for industry: Preparation of veterinary abbreviated new drug submissions (generic drugs) - Clinical and human safety requirements: Clinical requirements

Part 4: Clinical requirements

4.1 Bioequivalence

For generic drugs, the concept of bioequivalence is fundamental. The purpose of establishing bioequivalence is to demonstrate equivalence in biopharmaceutical parameters (for example, rate and extent of absorption) between the ANDS product and a reference product to allow the bridging of safety and efficacy data associated with the reference product. Refer to the VICH GL52 for information about bioequivalence study principles, designs and conduct.

Bioequivalence between two pharmaceutically equivalent formulations (test and reference) is demonstrated when both the rate and extent of absorption do not show a statistically and clinically significant difference. Bioequivalence should be demonstrated within pre-determined allowable limits, when administered at the same dose of the medicinal ingredient(s) and under similar experimental conditions.

When the test and reference products are shown to be pharmaceutically equivalent and bioequivalent, they can be considered therapeutically equivalent.

In vivo bioequivalence studies

Bioequivalence studies are conducted when a proposed generic product does not qualify for a biowaiver, or when in vivo data is required. Bioequivalence studies are considered pivotal studies to support an ANDS for a veterinary generic drug to confirm the therapeutic equivalence to the reference product.

It is recommended that bioequivalence studies be conducted according to Good Laboratory Practice (GLP) and Good Clinical Practice (GCP), as well as the Canadian Council for Animal Care (CCAC) guidelines. Refer to the US Center for Veterinary Medicine (CVM) Guidance for Industry #35 "Bioequivalence Guidance" and VICH GL52 "Blood level bioequivalence study" for additional information.

Blood level studies provide the most sensitive and accurate measure of the rate and extent of drug absorption. Note that for AUC and Cmax, the 90% confidence interval for the ratio of the reference and test products should be entirely within 80% to 125%. Widening of the limits of the 90% confidence interval to 70% to 143% to account for intraindividual variability could be acceptable given that:

Widening of the confidence interval has been predetermined in the study protocol (i.e. prior to the conduct of the study); and
A valid discussion with supportive data that safety and efficacy are not impacted by the widening of the confidence interval is provided.

If selecting this type of study, it is recommended to seek a protocol review before conducting the study (note that an Experimental Studies Certificate (ESC) may be required if the study is to be conducted in Canada).

There are other study options as well, such as:

pharmacological end-point studies - for use when a drug induces physiological changes over time related to its indications for use and when the measurement of the rate and extent of drug absorption in blood cannot be achieved, or when blood concentrations cannot be used as surrogate end-points for the demonstration of efficacy and safety of the particular pharmaceutical product in the target species (such as for drug with local effects, without systemic absorption)
clinical end-point studies - for use when blood concentrations cannot be measured or are not relevant, and pharmacological effects over time cannot be monitored (using a test product, reference product and a negative control)

If you have questions or would like further clarification on different bioequivalence studies that could be conducted, contact us: vdd.skmd.so-dgps.dmv.cp@hc-sc.gc.ca

For some drugs, in vivo bioequivalence studies may be waived - refer to the section below on biowaivers.

4.2 Biowaiver of in vivo bioequivalence studies

According to Section C.08.002.1 of the FDR, approval of a generic product for the Canadian market is contingent upon several requirements, including confirmation of pharmaceutical equivalence and bioequivalence with the CRP. For guidance on the requirements for demonstrating pharmaceutical equivalence as defined in Section C.08.001.1 of the regulations, see the Guidance for Industry: Preparation of Veterinary New Drug Submissions and Abbreviated New Drug Submissions (New and Generic Drugs) - Quality Requirements.

Bioequivalence is typically demonstrated by conducting in vivo studies. However, in certain circumstances, in vivo studies could be waived, and a biowaiver could be granted upon demonstrating bioequivalence using in vitro testing.

Eligibility of a generic product for a biowaiver is dependent on multiple criteria, such as dosage form, formulation, health risk, pharmacokinetic profile, solubility of the medicinal ingredient and others. The importance and weight of each criterion can vary for different products in the decision to grant a biowaiver. It is important to note that pharmaceutical equivalence between a generic product and the CRP does not guarantee a biowaiver for in vivo bioequivalence studies.

Eligibility for a biowaiver based on dosage form

Table 1: ANDS eligibility for a biowaiver based on dosage form
May be eligible for a biowaiver	Generally not eligible for a biowaiver
Oral and parental solutions (aqueous and non-aqueous) Water-soluble powder intended for use in drinking water Feed premixes (powder or granules) with water-soluble medicinal ingredients Topical solutions (aqueous and non-aqueous) administered via the dermal, otic, ophthalmic, or nasal route and intended for systemic or local therapeutic effects, in all animal species Suspensions, gels, lotions, creams, ointments, sprays, and aerosols that are administered topically and intended ONLY for local therapeutic effects (systemic absorption is either absent or limited), in all animal species Inhalant volatile anesthetic solutions Syrups (aqueous and non-aqueous) Additional strengths of solid oral immediate release dosage forms that have demonstrated bioequivalence with the highest dose of the CRP (tablets, chewable tablets, capsules, and boluses) Refer to Appendix 1 for more technical information on the eligibility criteria for these dosage forms	Oral and parenteral emulsions Oral and parenteral suspensions Oral pastes Feed premixes (powder or granules) with a water insoluble medicinal ingredient Solid oral immediate release dosage forms where bioequivalence has not been demonstrated at the highest dose for at least one strength Modified release dosage forms (such as enteric-coated tablets, and extended-release tablets, capsules, boluses, implants, or inserts or some intra-ruminal boluses) Topical dosage forms, other than solutions, that are systemically absorbed

Eligibility for a biowaiver based on identicality

Identicality occurs when a generic product has an identical formulation and essentially the same physicochemical characteristics to that of the CRP. An identical formulation requires that the generic product contains identical amounts of the identical medicinal ingredient, as well as qualitatively and quantitatively identical non-medicinal ingredients.

The dosage forms indicated in Table 2 are eligible to be granted a biowaiver, if identicality can be demonstrated.

Table 2: Dosage forms requiring identicality for a biowaiver
Dosage forms ONLY eligible for a biowaiver based on identicality
Oral and parenteral non-aqueous solutions Topical solutions (aqueous and non-aqueous) administered via the dermal, otic, ophthalmic, or nasal route, and intended for systemic or local therapeutic effects, in all animal species Gels, lotions, creams, ointments, sprays, and aerosols that are administered topically and are intended for local therapeutic effects, in all animal species Inhalant volatile anesthetic solutions (if not pure medicinal ingredient solution) Non-aqueous syrups

Generic products, regardless of the dosage form, manufactured by the same manufacturer of the CRP, using the same manufacturing process and medicinal ingredient source, are eligible for a biowaiver based on identicality of formulation with the CRP.

Not eligible for a biowaiver

Regardless of the dosage form and formulation identicality, the following are not eligible for a biowaiver due to a high risk to health:
- Products with a medicinal ingredient with a narrow therapeutic range in animals (i.e. a safety margin 2X or less than the recommended label dosage), such as warfarin, cyclosporine, theophylline, etc.
- Products with a high incidence or risk of adverse events in animals
- Products containing a critical-dose medicinal ingredient that needs titration to effect (such as digoxin and phenobarbital, etc.)
- Products containing nanoparticles or a delivery system on the nanometer scale
Regardless of the dosage form and formulation identicality, the following are not eligible for a biowaiver due to complex pharmacokinetics (PK) or pharmacodynamics:
- Products with medicinal ingredients with non-linear kinetics (such as acepromazine, omeprazole and phenylbutazone)
- Products with integrated dose-delivery devices (such as a metered-dose inhalers)
- Products with a conjugated medicinal ingredient (such as conjugation with polyethylene glycol, liposomes, or an immunologic carrier protein)
- Products containing a medicinal ingredient with possible in vivo interactions (such as some endogenous hormones like insulin and levothyroxine)
The following are not eligible for a biowaiver due to a complicated/high risk route of administration:
- Intramammary products
- Intrauterine products

Should your product fit in any of the above categories, it is recommended to contact VDD for more specific guidance: vdd.skmd.so-dgps.dmv.cp@hc-sc.gc.ca

Data requirements in support of a biowaiver

For all biowaiver requests, the following information is to be submitted:

A written biowaiver request to waive in vivo studies
A justification, including a scientific rationale, as to why the product is eligible for a biowaiver
A side-by-side quantitative and qualitative comparison of the proposed generic and CRP formulations
Comparative analytical testing of a minimum of two (2) lots of the generic product and a minimum of one (1) lot of the CRP, using the drug product specifications established for the generic product for the following parameters:
- The medicinal ingredient(s) and excipients (if available)
- Impurity profile
- Relevant comparative physicochemical properties (see Table 3 for more information)
A copy of a Certificate of Analysis (CoA) needs to be included for all tested generic product lots; and
Information identifying the CRP used in any comparative studies conducted in connection with the submission (as per paragraph C.08.002.1(2) of the FDR), including photos of the CRP and FRP labels (if relevant) of the product(s) purchased that clearly show the following information: company name, brand name, product identifier (e.g. DIN, National Drug Code (NDC) number, etc.), lot number, and expiry date.

Notes:

Additional information may be required in specific circumstances, as outlined below regarding dosage forms, product formulation, palatability and pharmacovigilance.
It is the responsibility of the generic product manufacturer to ensure that the CRP lot is not expired at the time of analytical testing. It is recommended that the testing date and expiry date be included in the CoA.
If there are discrepancies between the CRP and generic product, additional lots of the CRP may need to be tested.

Physicochemical properties

Physicochemical properties or characteristics between the generic product and the CRP should be essentially the same, so there would not be differences in bioavailability. For this reason, a comparison of these properties is to be provided for granting a biowaiver.

Depending on the dosage form, route of administration or due to clinical considerations, relevant physicochemical characteristics to be tested for comparison purposes may vary. Table 3 summarizes comparative physicochemical parameters commonly tested.

The information in this table has been adapted from the Health Canada's guidance document "Guidance for Industry: Pharmaceutical Quality of Aqueous Solutions". It includes examples of physicochemical characteristics or properties to be tested for different dosage forms, yet it is not intended to cover every possible case. Additional physicochemical properties may be clinically relevant, based on the nature of the drug substance or type of drug product, and require comparison. If you have questions about a particular scenario that may not be covered, contact us: vdd.skmd.so-dgps.dmv.cp@hc-sc.gc.ca

Table 3: Relevant comparative physicochemical properties of different dosage forms
Injectable route of administration
Physicochemical properties	Aqueous solution		Non-aqueous solution		Powder
pH	✓		--		✓*
Specific gravity/density	✓		✓		✓*
Osmolality	✓		✓		✓*
Viscosity	--		✓		--
Syringeability	--		✓		--
Oral route of administration
Physicochemical properties	Aqueous solution	Non-aqueous solution	Powder	Granules	Gel
pH	✓	--	--	--	✓
Specific gravity/density	✓	✓	--	--	✓
Viscosity	--	✓	--	--	✓
Particle size	--	--	✓	✓	--
Topical route of administration (products with local and/or systemic effects)
Physicochemical properties	Aqueous solution	Non-aqueous solution	Ointment and cream	Gel	Spray and aerosol
pH	✓	--	✓	--	✓
Specific gravity/density	✓	✓	✓	✓	✓
Viscosity	--	✓	✓	✓	--
Particle size	--	✓	✓	✓	✓
Delivery and/or dosing device (container closure system) tests
Droplet size or volume**	✓	✓	✓	✓	✓
Droplet size distribution**	✓	✓	✓	✓	✓
Otic, ophthalmic, intranasal routes of administration
Physicochemical properties	Aqueous solution	Non-aqueous solution	Ointment and cream	Gel	Spray and aerosol
pH	✓	--	✓	✓	--
Specific gravity/density	✓	✓	✓	✓	✓
Osmolality	✓	✓	✓	✓	--
Viscosity	N/A	✓	✓	✓	--
Delivery and/or dosing device (container closure system) tests
Droplet size or volume**	✓	✓	✓	✓	✓
Droplet size distribution**	✓	✓	✓	✓	✓
Legend: ✓ = needs to be provided -- = not applicable to the route of administration * For lyophilized powder for reconstitution as an aqueous solution ** If applicable to the product or clinically relevant

Situations when additional data are required

Based on the dosage form or product formulation, additional data may need to be submitted.

Table 4: Dosage forms requiring additional data for biowaiver
Dosage forms	Additional data required
Water-soluble powders intended for use in drinking water (i.e. pure medicinal ingredient)	Comparative drug substance solubility under the range of physical conditions (e.g. pH, water temperature and hardness) that a user of the product would typically encounter when adding the soluble powder to animal drinking water in the field
Drug premixes with water soluble medicinal ingredient	Comparative drug substance solubility under the range of physical conditions (e.g. pH, water temperature and hardness) that a user of the product would typically encounter when adding the soluble powder to animal drinking water in the field Comparative drug product dissolution testing in three (3) dissolution media*: 0.1 N HCl, pH 4.5 buffer, and pH 6.8 buffer
Water-soluble powders with excipients in the final drug product intended for use in drinking water
Oral solutions with a water-soluble medicinal ingredient	Comparative drug substance solubility in three (3) different buffers*: 0.1 N HCl, pH 4.5 buffer, and pH 6.8 buffer
Tablets and other solid immediate release dosage forms	Comparative drug substance solubility in three (3) different buffers: 0.1 N HCl, pH 4.5 buffer, and pH 6.8 buffer Comparative drug product dissolution testing in three (3) dissolution media: 0.1 N HCl, pH 4.5 buffer, and pH 6.8 buffer
* or appropriate pH, suitable for the species under consideration

Product formulation

For dosage forms eligible for a biowaiver other than those listed in Table 2 (i.e. where there is a difference in the quantity and/or nature of non-medicinal ingredients), a difference in formulation between the generic product and CRP is allowed under the following conditions:

The rate and extent of absorption of the medicinal ingredient(s) is not altered;
Physicochemical characteristics are essentially the same; and
The animal safety profile and expected efficacy are not altered.

When there are any differences in excipient(s) between the generic product and the CRP, the biowaiver request needs to include a rationale supported with scientific evidence that addresses the above points.

If the formulation is (or needs to be) identical to that of the CRP (see Eligibility for a biowaiver based on identicality above), the submission should include a comparative side-by-side table demonstrating:

Identical formulations between the generic product and CRP in the final generic product; and
Relevant physicochemical characteristics for both products to demonstrate their identicality.

Supportive analytical data (for example, results of de-formulation tests on the CRP, analytical testing of all medicinal and non-medicinal ingredients in the generic product) or a rationale (when the CRP formulation is not publicly available) should be submitted to justify how the CRP formulation was obtained or determined.

4.3 Palatability data

For innovator products in which palatability is integral to the administration of the dosage form, the generic product requires some evidence of palatability. The generic product need only demonstrate that it is considered palatable in the target species; demonstration of statistical non-inferiority with the CRP is not required. A variety of different palatability study designs may be feasible for generating relevant evidence of palatability. For more details on palatability studies, contact VDD: vdd.skmd.so-dgps.dmv.cp@hc-sc.gc.ca

For innovator products with an implied claim of palatability (for examples, "flavoured" oral solutions, suspensions, or pastes; "odour of meat" or "fish smell"), but in which palatability is not integral to the dosage form, the manufacturer of the generic product may choose to remove all claims of palatability instead of providing evidence. If the manufacturer chooses to include a comparable palatability claim, evidence of palatability would be required.

4.4 Pharmacovigilance data

For generic products already licensed/marketed in other jurisdictions with available Periodic Safety Update (PSU) reports or other similar documentation, the information should be provided at the time of filing the ANDS in Canada.

Page details

2025-08-07

Language selection

Search