Two products are considered to be bioequivalent when they are equal in the rate and extent to which the active pharmaceutical ingredient (API) becomes available at the site(s) of drug action. Bioequivalence (BE) studies are used in a variety of situations, most often when a sponsor proposes manufacturing a generic version of an approved new animal drug. BE studies (i.e., blood level, pharmacologic end-point, and clinical end-point studies) and tissue residue depletion studies should be conducted in accordance with good laboratory practice (GLP) regulations (21 CFR Part 58). Sponsors should consult with CVM early in the product development process to discuss the design of studies adequate for drug approval.
The proposed generic product should be tested against the original new animal drug which bears the labeling that the generic sponsor intends to copy, referred to as the Reference Listed New Animal Drug (RLNAD). For information on BE study design and statistical methods, please consult Guidance for Industry #35, Bioequivalence Guidance. We highly encourage sponsors to submit in vivo BE study protocols as an E submission in question based review (QbR) format for each major species approved for use with the RLNAD. For a sponsor planning to conduct a blood level BE study, we encourage submission of the bioanalytical method validation report in an H submission for review prior to beginning the study. For information on bioanalytical method validation, please consult Guidance to Industry #145, Bioanalytical Method Validation.
The requirement for the in vivo BE study may be waived (biowaiver) for certain generic products (21 USC 360 b (n) (1) (E)). Categories of products which may be eligible for biowaivers include, but are not limited to, the following:
- Parenteral solutions intended for injection by the intravenous, subcutaneous, or intramuscular routes of administration.
- Oral solutions or other solubilized forms such as soluble powders and some Type A medicated articles. Guidance to Industry #171, Demonstrating Bioequivalence for Soluble Powder Oral Dosage Form Products and Type A Medicated Articles Containing Active Pharmaceutical Ingredients Considered to Be Soluble in Aqueous Media provides additional information pertaining to soluble powders and some Type A medicated articles that may be eligible for a biowaiver.
- Topically applied solutions intended for local therapeutic effects. Other topically applied dosage forms intended for local therapeutic effects for non-food animals only.
- Inhalant volatile anesthetic solutions.
In general, the generic product being considered for a biowaiver must contain the same active and inactive ingredients (Q1) in the same dosage form and concentration (Q2) and have the same pH and physico-chemical characteristics (Q3) as an approved RLNAD. If your generic product meets the above criteria you may request a biowaiver be granted by submitting the following information in an R submission:
- Identification of the proposed generic drug, established name, dosage form, and strength;
- Identification of the proposed RLNAD, including proprietary and established names, dosage form, strength, sponsor name, and the new animal drug application (NADA) number;
- Provide information, to the extent such information is available, comparing the proposed formulation of the generic drug to that of the RLNAD. This side by side comparison should be transparent about any differences between the RLNAD and the proposed generic drug formulation.
- Include a Certificate of Analysis of all ingredients if available;
- Physico-chemical properties, such as pH, should also be included in the comparison. For some products, additional information to address solubility, particle size of active ingredient(s), and the presence and significance of polymorphs or enantiomers of the active ingredient(s) may be needed for comparison. If you have questions about what physico-chemical properties to include, please contact us at CVMDGADMGT@fda.hhs.gov.
- Include a justification for granting the waiver.
BE Technical Section
Whether BE is demonstrated through a biowaiver or through studies, a request for a BE technical section is still needed under phased review. In addition to this request, we will ask that you address all other information (AOI) pertaining to BE of the generic animal drug. This information may include:
- Abstracts of published manuscripts or proceedings
- Results of literature searches
- Study reports not previously submitted to the JINAD or ANADA
- Foreign marketing experiences
- Adverse drug experience information
- Evaluations from the sponsor’s veterinary or medical department, expert committees, or consultants
Please note that this list is not intended to be comprehensive, and alternate applicable information should also be submitted. If there is no additional AOI pertaining to BE to report, or none beyond the information already provided in previous submissions to the JINAD please indicate that in your request for a BE technical section complete (or your ANADA).
Question Based Review
- In August 2017, FDA officially deployed the eSubmitter Blood Level BE Study Protocol QbR Template. This template was designed to increase transparency and efficiency of the blood level BE study protocol review process as part of the generic animal drug approval process.
- In December 2018, FDA officially deployed the eSubmitter BE Study Data Submission QbR Template. This template was designed to increase efficiency of the data submission review process. While it is highly encouraged that a generic sponsor follow this QbR template in order to submit BE data for review, it is not mandatory.
- If you have questions regarding the eSubmitter Blood Level Bioequivalence Study Protocol QbR Template or would like to obtain a written copy of the template, please contact CVMDGADMGT@fda.hhs.gov.