CVM GFI #35 Bioequivalence Guidance | Guideline Explorer

Description

This document is intended to provide guidance for the design and analysis of in vivo bioequivalence studies.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

8

New Animal Drugs

Products subject to clinical investigation guidance.

Pioneer drug product

Reference product used to compare against generic versions.

Solid Oral Dosage Forms

Subject of the minor changes guidance

Generic Animal Drug

Subject of ANADA submissions

Pioneer Product

The original approved animal drug used as a reference for bioequivalence testing.; The potency of the pioneer and generic products should be assayed; The reference/pioneer product used as a control in bioequivalence studies.

Generic drug

basis for approval of the generic drug; Sponsors of generic drugs may propose alternatives for confidence limits.

Enteric coated product

demonstration of bioequivalence in both the fasted and the fed states may be necessary

Oral sustained release product

demonstration of bioequivalence in both the fasted and the fed states may be necessary

Stakeholders

2

Food-Producing Animals

Animals intended for human consumption; Animals within a building, house, or feedlot intended for human consumption.; Category for veterinary drug approval including cattle, swine, and chickens.

Sponsor

Entity responsible for submitting applications under section 524B

Regulatory Context

Regulatory Activities

6

Abbreviated New Animal Drug Application

Application type identifier A; three-day ANADA field alert reports

ANADA

Abbreviated new animal drug applications

Multiple dose study

Study conducted to steady state if single dose results are insufficient.

Single dose bioequivalence study

Study type where AUC is calculated from time 0 to last sampling time.

Bioequivalence study

In vivo assessment required for highest and lowest strengths in bracketing; Required when biowaiver criteria are not met

New Animal Drug Application

Application type identifier N; three-day NADA field alert reports

Document Types

6

SOP

Standard Operating Procedures for evaluating suppliers; Based on the manufacturer's established SOP for evaluating suppliers.; Standard Operating Procedures for regulatory compliance

Final study report

Differences in results due to adaptations should be addressed in the final study report.

FOI summaries

information contained with FOI summaries pertaining to the particular drug

Protocol

Defines the standard of veterinary practice and limits for anesthetic regimens

Bioequivalence Protocols

Reviewed to identify new topics for guidance

Biobatch

A pilot batch used in pivotal studies, stability studies, and validation studies.

Attributes

10

AUC

AUC or Cmin may correlate with efficacy

AUC(0-INF)

Area under the curve from zero to time infinity

Geometric mean

Initial estimate of central tendency for parasite counts

Terminal elimination half-life

Used to determine the duration of blood sampling.

CMIN

Minimum drug concentrations observed during a dosing interval at steady-state.

Area Under the Curve

Pharmacokinetic parameter (AUC) derived from mass balance studies

Potency

Measurement of potency for biological products

TMAX

sampling times should extend to at least 3 terminal elimination half-lives beyond TMAX; Time to reach maximum concentration.

CMAX

Pivotal parameter for bioequivalence determination; maximum blood concentrations (CMAX) are achieved; Maximum observed drug concentration used to estimate rate of absorption.

Withdrawal Period

time required for drugs to clear from animal tissues

Technical Details

Substances

1

Marker residue

residue whose concentration is in a known relationship to total residue

Testing Methods

10

Log Transformed Data

Used to calculate confidence bounds

Multiplicative Model

used for sample size determination for bioequivalence assessment

Two One-Sided Tests Procedure

Statistical analysis for pharmacokinetic measures; recommended method for testing if a parameter is within a defined interval

Natural log of the pharmacokinetic parameter

dependent variable used in the data analysis for calculating confidence intervals

Log-transformed data

Statistical method used to calculate AUC statistics for bioequivalence.

Logarithmically transformed data

Statistical approach where AUC and CMAX values are transformed for analysis.

Analysis of variance

Analysis of percentage weight change from baseline

Two-period crossover design

Total number of subjects required in a two-period crossover design

Linear trapezoidal rule

Method frequently used for AUC estimation.

Pilot study

recommended as a means of estimating the appropriate sample size

Processes

10

In Vivo Bioequivalence Studies

Design and analysis of studies for animal drugs

Tissue residue depletion study

Required for generic animal drugs in food-producing species to ensure safety.

Clinical end-point studies

Acceptable for bioequivalence when blood or pharmacologic end-points are impractical.

Pharmacologic end-point studies

Used when direct measurement of drug absorption in biological fluids is inappropriate.

Tissue Residue Depletion Studies

Required for generic products for food-producing animals

Bioequivalence Study

BE studies conducted to support ANDAs

Tissue Residue Study

Required for drug products for food-producing animals to address depletion.

In Vitro Dissolution Testing

Used to compare generic product strengths to reference products.

Sample preparation

assure that the complete analytical method, sample preparation, extraction, clean-up, and instrumental analysis perform

Extraction

Process involving a filtration step or solvent other than water or alcohol.

Standards & References

Specifications

8

Limit of Quantitation

LOQ for nitrosamine detection

Bioequivalence Range (0.80, 1.25)

referenced in the bibliography regarding power and sample size

90% confidence interval

Statistical criterion for similarity factor using bootstrapping

Acceptability limits

Set of bounds within which confidence intervals must fall to indicate bioequivalence.

90% confidence intervals

The assessment of BE is based on 90% confidence intervals for the geometric mean ratios.

AUC(0-LOQ)/AUC(0-INF) >= 0.80

Threshold to determine if the sampling duration adequately reflects the extent of absorption.

Compendial specifications

ensure that FDA or compendial specifications are met

Limit of Detection

Define and document a minimum set of metrics (e.g., limit of detection (LoD))

Related CFR Sections (3)

21CFR514.1§ 514.1 Applications.
(a) Applications to be filed under section 512(b) of the act shall be submitted in the form and contain the information described in paragraph (b) of this section, as appropriate to support the particular submission. If any part of the application is in a foreign language, an accurate and complete ERead full regulation →
21CFR514.106§ 514.106 Approval of supplemental applications.
(a) Within 180 days after a supplement to an approved application is filed pursuant to § 514.8 , the Commissioner shall approve the supplemental application in accordance with procedures set forth in § 514.105(a)(1) and (2) if he/she determines that the application satisfies the requirements of applRead full regulation →
21CFR10.115§ 10.115 Good guidance practices.
(a) What are good guidance practices? Good guidance practices (GGP's) are FDA's policies and procedures for developing, issuing, and using guidance documents.Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure of the study director to assure protocol compliance and accurate data recording

1

Failure of the study director to assure experimental data are accurately recorded and verified

1

Failure to properly identify specimens

1

Failure to assure experimental data were accurately recorded and verified

1

Failure to authorize and document deviations from standard operating procedures

1

QAU failed to assure reported results accurately reflect raw data

1

Failure to maintain a Quality Assurance Unit

1

Study director failed to assure protocol compliance and data accuracy

1

Fabrication of animal weight data

1

Failure to establish procedures for handling test and control articles

1

Recent Cases

Related Warning Letters (9)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics