Safety and effectiveness of veterinary generic drugs (Proceedings)

Ever wondered how a veterinary generic drug is assumed to be interchangeable with the pioneer drug in a clinical setting? What is the process by which it is approved by the Food and Drug Administration/Center for Veterinary Medicine (FDA/CVM)? What does pharmaceutical equivalence and bioequivalence really mean? Many veterinarians confidently choose to prescribe generic drugs to our patients for the sole reason that it is cheaper than the pioneer drug. There is nothing wrong with that, however if you are curious to find out about the safety and effectiveness of generic drugs approved in the US, this presentation will enlighten you.

Objectives

1. Provide the practitioner with an overview of how veterinary generic drugs are approved in the US by the FDA/CVM.

2. Provide the practitioner with a general understanding of bioequivalence and its implications in the approval of veterinary generic drugs.

3. Provide the practitioner with a general understanding of blood-level studies, pharmacological endpoint studies and clinical endpoint studies used for confirmation of bioequivalence.

4. Provide the practitioner with some insight on which drugs may qualify for biowaivers.

Important definitions

What is considered a generic drug?

A generic drug is the term used for a product that contains the same medicinal ingredient(s) as the off-patent original brand name (pioneer) product, but is generally cheaper in price. The generic and original pioneer products are referred to as pharmaceutically equivalent.

What is an original pioneer drug?

A pioneer drug is the first approved and marketed drug product in the US. The original pioneer drug is also referred to as the reference formulation used for in vitro comparative studies and in vivo bioequivalence studies with the generic formulation.

What does pharmaceutical equivalence mean?

Pharmaceutical equivalence between two formulations is confirmed when they both contain the identical amount of the identical medicinal (active) ingredients 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 ingredients.

What is bioequivalence?

Bioequivalence is demonstrated when the rate and extent of absorption of two formulations of drugs (test and reference) are sufficiently similar, within pre-determined allowable limits, when administered under similar experimental conditions. The underlying principle is that the products should be therapeutically equivalent if the products show bioequivalence with respect to each other and hence, be interchangeable in a clinical setting. Thus, the rate and extent measures of absorption become surrogate indicators of therapeutic outcome.

What constitutes a bioequivalence study?

A bioequivalence study is a useful surrogate in vivo study used to demonstrate comparable safety and efficacy in several situations such as between generic (test) and reference products, for registration of multiple products with the same active ingredient but in different concentrations, to support approval of an alternate route of administration or dosage form, of a minor formulation change or of a manufacturing change which may affect bioavailability. Although it would be difficult to account for all situations, a common template to assess bioequivalence results is desirable.

Key information

The FDA/CVM may approve a veterinary generic drug based on the demonstration of comparable safety and efficacy data to the veterinary pioneer drug, when filed as an Abbreviated New Animal Drug Application (ANADA). In order to do that, several studies may be conducted such as in vivo bioequivalence studies and/or in vitro comparative studies. The CVM has a Guidance for Industry document that help pharmaceutical companies conduct the appropriate studies needed for the approval of their proposed generic drug formulation. This Guidance document #35 can be found at the following website: (http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm052363.pdf).

General considerations for conducting in vivo bioequivalence studies

Since species is considered a factor that may potentially interact with the drug formulation, studies should be conducted for each major target species for which the reference product is approved for on the label. Furthermore, bioequivalence studies should be conducted at the same highest labeled dose for the test and reference products, approved for the reference drug for which the Sponsor has demonstrated linear kinetics through published literature or a pilot study. There are three types of in vivo bioequivalence studies that can be used to demonstrate bioequivalence. These are, in descending order of sensitivity in measuring the rate and extent of absorption of drugs (i.e. bioequivalence), the blood-level study, the pharmacological endpoint study and the clinical endpoint study (Figure 1). All studies are recommended to be conducted in accordance with Good Laboratory Practices (GLP) regulations (21 CFR Part 58).

In vivoBE studies

Figure 1 – Diagram of the three types of in vivo studies used for the demonstration of bioequivalence (BE) between a generic drug (test) and an original pioneer drug (reference).

1. Blood-level study

This type of in vivo bioequivalence study is considered the most sensitive and accurate measure of the rate and extent of drug absorption. The blood-level study should be chosen over the pharmacological and clinical end-point studies, whenever possible, especially when drug concentrations can be readily measured in the blood. In the blood-level study, each healthy subject, under the same experimental conditions, receives the generic (or test) and the reference products on two separate occasions in a crossover study design to decrease inter-individual (between subject) variability. The drug concentration in the blood is measured in all subjects and key mean pharmacokinetic (PK) parameters such as the Area Under the Curve (AUC) and the maximum concentration (Cmax) are statistically compared to show that the generic drug delivers the same amount of medicinal ingredient at the same rate as the reference drug, within a ± 20% difference. Bioequivalence data is required for each active ingredient present in the product formulations.

2. Pharmacological endpoint study

A pharmacological end-point studies is used when a drug induces physiological changes related to its indications for use and when the measurement of the rate and extent of drug absorption in blood cannot be achieved, or 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 (e.g. for drugs with local effects with no systemic absorption). Demonstration of bioequivalence between the test and reference products for any given pharmacodynamic (PD) effect does not guarantee the bioequivalence of other effects, as concentration-response curves may be different for different drug effects. Each label claim must be accompanied by an appropriate pharmacological end-point study. Statistical considerations for the assessment of mean PD pivotal parameters (AUEC, Emax and tEmax) are, in principle, the same as for corresponding mean PK parameters estimated from a blood-level study.

3. Clinical endpoint study

This type of in vivo bioequivalence study is considered the least sensitive and accurate measure of the rate and extent of absorption of a drug. The clinical end-point study is used when blood concentrations cannot be measured or are not relevant, and pharmacological effects over time cannot be monitored. A clinical end-point study is conducted by comparing the test product to the reference product and a negative control. This generally applies to, but is not limited to, the following: ectoparasiticides (topical administration), anthelmintics (oral administration with in situ gastrointestinal activity) and locally active topical drugs (dermal, ophthalmic, otic and inhalant preparations). Clinical end-point studies are randomized, controlled, double blinded studies using target animals in relevant feeding and husbandry conditions, with either naturally or experimentally induced disease. This type of study is generally conducted using a parallel group design with, at a minimum, three treatment groups (negative control(s), test and reference products), requiring a larger number of subjects compared to blood-level studies. The purpose of the negative control is to confirm the sensitivity and validity of the study. The target parameter(s) or response(s) to be measured must be based on the labeled claim(s) of the reference product. Demonstration of bioequivalence between the test and reference products for any given clinical response does not guarantee the bioequivalence of other clinical response or therapeutic effects. Each label claim should be accompanied by the appropriate clinical end-point study. The clinical evaluation of the selected target parameters(s) should be appropriately validated and justified. When applicable, it may be relevant to include safety end-points in the final comparative assessments.

Criteria for biowaivers

In general, there must be an in vivo demonstration of a limited acceptable difference in the rate and extent of drug absorption associated with the test and reference formulations when administered at the same dose and under the same experimental conditions. However, in certain circumstances, the requirements for the in vivo bioequivalence study may be waived for certain generic products (21 USC 360b (n) (1) (E)). According to the latest version of the FDA/CVM Guidance for Industry #35 (2006), these include parenteral solutions intended for intravenous, subcutaneous and intramuscular administrations, oral solutions (or other solubilized forms), topically applied solutions intended for local therapeutic effects only, and inhalant volatile anesthetic solutions. In general, the generic formulation being considered for a waiver must contain the same active and inactive (excipients) ingredients, in the same dosage form and concentration, and has the same pH and physicochemical characteristics as the reference product.

Ensuring the quality of generic drugs

The ingredients, manufacturing processes and facilities must meet the FDA/CVM guidelines for Good Manufacturing Practices (GMP). All manufacturers must conduct a series of tests, both during and after production, in order to show that every drug batch meets the requirements for that product. When active ingredients are being manufactured, small amounts of impure materials may be produced. Manufacturers have to set limits for any impurities that may remain after the drug is produced. They may also show that the low levels of impurities remaining will not affect the safety and effectiveness of the active ingredients, while meeting regulatory requirements.

Additional information

Since bioequivalence studies can demonstrate comparable animal safety with a reference product only in terms of the active ingredient, differences in excipients in product formulations and different product specifications may result in tissue irritancy and other adverse effects. Hence, animal safety aspects of a new product formulation may need to be addressed by additional animal safety studies and/or provision of relevant scientific rationale.

Several issues associated with the current criteria for bioequivalence have given rise to international re-consideration of established guidelines by most regulatory agencies, in particular for highly variable drugs, drugs with a narrow therapeutic ratio or with a long half-life, and criteria for granting waivers. An international harmonization of bioequivalence Guidance for veterinary drugs would benefit both the pharmaceutical industry and government bodies, and be a testament to the continued collective effort toward progress in the design and interpretation of bioequivalence studies for companion animal drugs.

Conclusion

Two products are considered to be bioequivalent when they are equally bioavailable; that is equal in the rate and extent to which the active ingredient(s) or therapeutic ingredient(s) is (are) absorbed and become(s) available at the site(s) of drug action (Guidance for Industry #35 – Bioequivalence Guidance). The demonstration of bioequivalence then replaces the need for repeating safety and efficacy studies already conducted by the original pioneer drug. The generic and pioneer products would then be considered therapeutically equivalent in a clinical setting. Exceptionally, biowaivers may be granted in certain cases where absorption would not be considered an issue.

General information as to how a particular veterinary generic drug was approved by the FDA/CVM can be found at the following FDA website Freedom of Information (FOI) Drug Summaries, starting with ANADA application 200-007: http://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm056939.htm.

References

Rani, S. 2007. Bioequivalence: Issues and perspectives. Indian Journal of Pharmacology, 39(5):218-225.

Guidance for Industry - Bioequivalence guidance #35. FDA/CVM. November 8, 2006. http://www.fda.gov/cvm/Guidance/bioequivalence_Oct02.pdf

Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System. FDA/CDER August 2000. www.fda.gov/CDER/GUIDANCE/3618fnl.pdf

Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations. FDA/CDER October 2000.http://www.fda.gov/cder/guidance/5356fnl.pdf Articles. FDA/CVM February 16, 2006. http://www.fda.gov/cvm/Guidance/guide171.doc

Guidance for Industry - Food-Effect Bioavailability and Fed Bioequivalence Studies. FDA/CDER. December 2002. http://69.20.19.211/cder/guidance/5194fnl.pdf