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

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Appendix 1: Technical information to support biowaiver eligibility of additional strengths of solid oral immediate release dosage forms that have demonstrated bioequivalence with the highest strength of the CRP (tablets, capsules, and boluses)

Biowaiver eligibility for additional strengths of solid oral immediate release dosage forms that have demonstrated bioequivalence with the highest strength of the CRP (tablets, capsules, and boluses) is conditional, including provided that all of the following criteria are met:

  1. In vivo bioequivalence between the reference and generic products has been demonstrated with the highest strength available (or the next highest strength if there are safety/tolerability issues with the highest strength).

  2. The CRP has linear pharmacokinetics at the intended strength range. Linear pharmacokinetics could be demonstrated by generating data using the reference product or by providing data available in the public domain.

    Example: Drug X, an immediate release innovator capsule, is available in five strengths: 5, 10, 20, 40 and 80 mg. The sponsor for Drug Y, an immediate release generic capsule, provided data that demonstrates linear pharmacokinetics for strengths 10-100 mg. Therefore, an in vivo bioequivalence study could be conducted at the highest strength (i.e., 80 mg) between Drug X and Drug Y. Strengths 10, 20, and 40 mg are eligible for a biowaiver given that the formulation of Drug Y is proportional (see below for further details). The 5 mg strength is not eligible for a biowaiver as it is outside the range of demonstrated linearity. To register the 5 mg strength, an in vivo bioequivalence study is required.

    Note that if there are safety/tolerability issues at the highest strength (i.e. 80 mg), the next highest strength (i.e. 40 mg) could be used instead to conduct the in vivo bioequivalence study.

  3. The formulation of different strengths of the generic product is proportional.

    Proportional strengths can be defined as the ratio between the amount of each excipient to the amount of the medicinal ingredient(s). Proportional strength(s) is the same in the additional strength(s) as for the initial strength (see example provided in Table A below). Coating components, capsule shell, colour agents and flavours are not required to follow this rule.

    For more information, refer to the following policy document:

Table A: Formulation of Proportional Strengths
  25 mg 50 mg 100 mg
mg % mg % mg %
Medicinal ingredient 25 25 50 25 100 25
Excipient 1 40 40 80 40 160 40
Excipient 2 25 25 50 25 100 25
Excipient 3 3.5 3.5 7 3.5 14 3.5
Excipient 4 3.0 3.0 6 3.0 12 3.0
Excipient 5 3.5 3.5 7 3.5 14 3.5
TOTAL 100 100 200 100 400 100

Appendix 2: Definitions

Acute reference dose (ARfD)
The estimate of the amount of a substance in food or drinking water, expressed on a body weight basis, that can be ingested in a period of 24 h or less without appreciable health risk to the consumer. It is derived on the basis of all the known facts at the time of evaluation. The ARfD is expressed in milligrams of the chemical per kilogram of body weight.
Aqueous solution
A solution with water as the predominant solvent. Dosage forms characterized as solutions are normally classified by their route of administration (e.g. oral, dermatological, ophthalmic, otic, nasal, inhalation, injection).
Bioavailability
the rate and extent of absorption of a drug into the systemic (blood) circulation.
Bioequivalence
situation when the rate and extent of absorption of two drug formulations (test and reference) are sufficiently similar, within pre-determined allowable limits, when administered under similar clinical conditions.
Canadian reference product
  1. a drug in respect of which a notice of compliance is issued under section C.08.004 or C.08.004.01 and which is marketed in Canada by the innovator of the drug,
  2. a drug, acceptable to the Minister, that can be used for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics, where a drug in respect of which a notice of compliance has been issued under section C.08.004 or C.08.004.01 cannot be used for that purpose because it is no longer marketed in Canada, or
  3. a drug, acceptable to the Minister, that can be used for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics, in comparison to a drug referred to in paragraph (a). (FDR, C.08.001.1)
Critical dose drugs
drugs where comparatively small differences in dose or concentration lead to dose- and concentration-dependent serious therapeutic failures and/or serious adverse drug reactions which may be persistent, irreversible, slowly reversible, or life threatening.
Dissolution testing (in vitro quality control)
A dissolution test procedure identified in the pharmacopoeia for routine quality control of product batches, generally a one time-point dissolution test for immediate release products and a three or more time-points dissolution test for modified release products.
Drug

any substance or mixture of substances manufactured, sold, or represented for use in

  1. the diagnosis, treatment, mitigation, or prevention of a disease, disorder or, abnormal physical state, or its symptoms, in human beings or animals
  2. restoring, correcting, or modifying organic functions in human beings or animals; or
  3. disinfection in premises where food is manufactured, prepared, or kept. (FDA, Section 2).

Note: Any reference to a drug within this guidance document is referring to a Division 8 new drug.

Inhalant
a gas, a volatile liquid, a finely aerosolized liquid, or a powder for administration by nasal or oral respiratory routes for local or systemic effects.
Major target species
Animal species that include cattle, swine, chickens and turkeys as food producing animals, and cats, dogs and horses as non-food producing animals.
Medically important antimicrobials
the antimicrobials or antimicrobial classes used in human medicine or first in-class antimicrobial active pharmaceutical ingredients included in Health Canada's List A.
Narrow therapeutic range
situation where the ratio of the lowest concentration at which clinical toxicity occurs, to the median concentration providing a therapeutic effect, is less than or equal to 2.
New Drug

a new drug means a drug, other than a veterinary health product,

  1. that contains or consists of a substance, whether as an active or inactive ingredient, carrier, coating, excipient, menstruum or other component, that has not been sold as a drug in Canada for sufficient time and in sufficient quantity to establish in Canada the safety and effectiveness of that substance for use as a drug;
  2. that is a combination of two or more drugs, with or without other ingredients, and that has not been sold in that combination or in the proportion in which those drugs are combined in that drug, for sufficient time and in sufficient quantity to establish in Canada the safety and effectiveness of that combination and proportion for use as a drug; or
  3. with respect to which the manufacturer prescribes, recommends, proposes or claims a use as a drug, or a condition of use as a drug, including dosage, route of administration or duration of action, and that has not been sold for that use or condition of use in Canada for sufficient time and in sufficient quantity to establish in Canada the safety and effectiveness of that use or condition of use of that drug. (FDR, C.08.001)
Pharmaceutical equivalent
a new drug that, in comparison with another drug, contains identical amounts of the identical medicinal ingredients, in comparable dosage forms, but that does not necessarily contain the same non-medicinal ingredients (FDR, C.08.001.1)
Pharmacovigilance
for the purpose of this guideline, pharmacovigilance refers to the reporting of adverse drug reactions and to post-market surveillance to monitor the safety and efficacy of veterinary drugs.
Solubility
for the purpose of this guideline, solubility refer to "aqueous" solubility; the ability of a substance to dissolve in water.
Therapeutic equivalence
Two products are considered to be therapeutically equivalent when they are pharmaceutically equivalent and bioequivalent (i.e. have the same absorption and bioavailability of the active ingredient and safety profile).
Withdrawal period
the length of time (in days) between the last administration of a drug to an animal and the time when tissues or products collected from the treated animal for use as food contain a level of residue of the drug that would not likely cause injury to human health (Regulations, section C.01.001).
Withholding time
the length of time, specified in 12-hour milking intervals, up to a maximum of 8 intervals (96 hours) that must elapse after the last administration of a veterinary drug to a lactating animal before milk can be collected for human use.

Appendix 3: Master index for preparing an abbreviated new drug submission

The following index outlines the folder structure for preparing an ANDS that aligns with this guidance document, including Part 3: Regulatory Requirements, Part 4: Clinical Requirements, Part: 5 Human Safety Requirements and Labelling. For the Part 2 folder structure of the quality information, refer to Appendix 2 of the Guidance for Industry: Preparation of Veterinary New Drug Submissions and Abbreviated New Drug Submissions (New and Generic Drugs) - Quality Requirements. For the fulsome ANDS index, refer to the electronic zip folder structure for filing submissions.

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