Should you trust Canadian veterinary generic drugs to treat your patients?

Ever wondered how veterinary generic drugs are assumed to be interchangeable with the pioneer drugs in a clinical setting? What is the process by which they are approved in Canada? Are they safe? Are they really effective? Many Canadian veterinarians choose to prescribe generic drugs to their patients for the sole reason that they are cheaper than the pioneer drugs. Is this wise? Is there a difference between prescribing a veterinary versus a human generic drug to animals?

The objective of this article is to provide a general overview of how veterinary generic drugs are approved in Canada to help practitioners make informed decisions when individualizing drug treatments for their patients.

Introduction

The Veterinary Drugs Directorate (VDD) of the Health Products and Food Branch of Health Canada is responsible for the review of pioneer (new) and generic veterinary drug applications for approval in Canada. Up until 2010, the review process for veterinary generic drug submissions by the VDD was guided by the Therapeutic Products Directorate (Health Canada’s human counterpart of the VDD) guidance documents and by the US veterinary generic drugs guidelines. In April 2010, the VDD implemented its own Guidance for Industry entitled: Preparation of Veterinary Abbreviated New Drug Submissions: Generic Drugs (1). This guideline was created with an understanding of critical manufacturing and chemistry requirements, sound pharmacological and statistical principles, as well as key human safety requests, while keeping in mind the unique Canadian veterinary drug market and the growing movement of international harmonization of regulatory approval of veterinary generic drugs.

Approval process

The approval process of veterinary generic drugs relies on the Food and Drugs Act and Regulations of Health Canada. A generic drug must be pharmaceutically equivalent and bioequivalent to the Canadian Reference Product (CRP), i.e., the currently marketed pioneer drug. It must also have the same route of administration(s) and fall within the same condition(s) of use as the CRP. Pharmaceutical equivalence between the generic drug and the CRP is confirmed when both contain the same concentration of the same active ingredient(s) in the same dosage form but do not necessarily contain the same excipients (inactive ingredients), provided they are not known to influence the absorption characteristics of the active ingredient(s). The generic drug must meet the same potency, quality, purity and identity, and where applicable, content uniformity, disintegration, and solubility as the CRP. Accordingly, since the active ingredient source and manufacturing processes are expected to be different between the generic drug and the CRP, formulation differences are identified at the level of absorption. Bioequivalence (BE) is demonstrated when the rate and extent of absorption (relative bioavailability) of 2 formulations of drugs are sufficiently similar, within pre-determined allowable limits, when administered under similar experimental conditions. Bioequivalence studies are abbreviated pivotal studies performed to demonstrate comparable safety and efficacy of a generic drug to the pioneer drug. The underlying principle is that a bioequivalent generic drug is therapeutically equivalent to the CRP, thus considered interchangeable in a clinical setting.

There are 3 types of in vivo studies that may be used to demonstrate BE. These are, in descending order of sensitivity in measuring the rate and extent of absorption of drugs: blood-level, pharmacological endpoint, and clinical endpoint studies (Figure 1).

Figure 1.

Schematic representation of the 3 types of in vivo studies used for the demonstration of bioequivalence (BE) of veterinary generic drugs. PK — pharmacokinetics; PD — pharmacodynamics; A — absorption; D — distribution; M — metabolism; E — excretion.

The blood-level study is the preferred and most commonly used design as it directly measures the relative bioavailability [maximum concentration (Cmax) and area under the curve (AUC)] of the active ingredient(s) between 2 formulations. The clinical endpoint study, although the least sensitive study design to detect formulation differences due, in part, to the inherent variability of clinical trials, is often used when blood concentrations of the drug cannot be accurately measured. This generally applies to ectoparasiticides (topical administration), anthelmintics (oral administration with in-situ gastrointestinal activity), locally active topical drugs (dermal, ophthalmic, otic, and inhalant preparations), and intramammary products, where differences between formulations are detected through clinical endpoints relevant to each label claim. Pharmacological endpoint studies are less commonly used for veterinary drugs. This type of in vivo BE study measures pharmacodynamic surrogate endpoints as a function of time in a manner similar to the pharmacokinetic assessment of drug blood concentrations over time. All studies are conducted according to Good Laboratory Practices (GLP) or Good Clinical Practices (GCP).

Under exceptional circumstances, the requirements for in vivo BE studies may be waived for certain uncomplicated immediate-release dosage forms of generic drugs. When a waiver is granted, the rate and extent of absorption are not considered to be formulation-dependent factors (e.g., parenteral and oral aqueous solutions) and in vitro studies are requested as surrogate for in vivo BE studies.

Ensuring the quality of Canadian generic drugs

Active and inactive ingredients, manufacturing processes, and facilities must meet the VDD’s strict requirements for Good Manufacturing Practices (GMP) and manufacturers must conduct a series of tests, both during and after production, to show that every generic drug batch meets the same requirements as requested for pioneer drugs.

Clinical impact of the use of generic drugs

Through the regulatory approval process, generic drugs are confirmed to be therapeutically equivalent to the pioneer drugs, while allowing for a pre-determined formulation difference. Considering the fact that most veterinary drugs have a wide therapeutic range and wide safety margin, this allowable difference is generally not considered to be clinically relevant. Therefore, generic veterinary drugs offer Canadian veterinarians a safe and effective drug alternative for their patients. However, there are some instances when this difference may be clinically relevant for a particular patient. Examples of such potential instances include a change from a veterinary pioneer to veterinary generic drug (or vice versa) when the patient’s particular drug elimination pathway (kidney and/or liver) is dysfunctional or when the drug has a narrow therapeutic index and/or requires therapeutic drug monitoring. Another important example includes any change from a veterinary pioneer to a human generic drug, as safety and efficacy profiles have not been established in animals for these latter drugs (e.g., behavior-modifying, anticonvulsant, and endocrine drugs). Such circumstances may increase the risk of therapeutic failure or toxicity.

Conclusion

The Canadian regulatory approval process is currently in line with leading international veterinary guidelines for generic drugs. The demonstration of BE between pharmaceutically equivalent veterinary drugs is confirmed through in vivo and/or in vitro comparative studies which are abbreviated pivotal studies conducted to demonstrate comparable safety and efficacy of a generic drug to a CRP. These drugs may then be considered interchangeable in a clinical setting. It remains, however, the practitioner’s responsibility to take into consideration the individualized situation of the patient when making important pharmacological treatment decisions.