Description
The Food and Drug Administration (FDA) is announcing the availability of a guidance for industry entitled “Statistical Approaches to Establishing Bioequivalence.” This guidance provides recommendations to sponsors and/or applicants who intend to use equivalence criteria in analyzing in vivo or in vitro bioequivalence (BE) studies for investigational new drug applications (IND’s), new drug applications (NDA’s), abbreviated new drug applications (ANDA’s) and supplements to these applications. The guidance discusses the use of average, population, and individual BE approaches to compare in vivo and in vitro bioavailability (BA) measures. (This guidance replaces the draft guidance that was issued in 1999 entitled “Average, Population, and Individual Approaches to Establishing Bioequivalence.”)
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
2Product failure could occur with a sustained-release dosage form exhibiting dose dumping.
Product failure could occur with a delayed-release dosage form.
Stakeholders
6Entity responsible for submitting applications under section 524B
The number of subjects provided in the table (N)
Entities submitting supplements to BLAs
Assist sponsors in the nonclinical evaluation
Entity submitting development data and knowledge; Entity performing the work process for change
A minimum number of 12 evaluable subjects should be included in any BE study
Regulatory Context
Regulatory Activities
4Investigational New Drug submissions
New Drug Application
Abbreviated New Drug Application
Conducted with the 10 mg strength comparing it to the accepted comparator product
Document Types
5Critical for individual BE approach to allow estimation of variances.
describes method for statistical test of individual bioequivalence
Should include biological rationale for subgroups
Standard two-formulation, two-period, two-sequence crossover design.
Defines the standard of veterinary practice and limits for anesthetic regimens
Attributes
10AUC or Cmin may correlate with efficacy
Within-subject variance of the test product.
Within-subject variance of the reference product.
Variance component representing subject-by-formulation interaction.
Parameter used to select between reference-scaled or constant-scaled criteria.
present the mean value with variance components (standard deviation and percent CV); Establishing standard deviation (SD) for the Allowable Total Difference (ATD) zone
To test for population bioequivalence, compute the 95% upper confidence bound of the linearized criterion.
Determined during the planning of a research study
statistical effects that can confound BE analysis; assumption of no (or equal) carryover effects
variance term difference added to the average BE criterion
Technical Details
Testing Methods
10used for fully replicate (4-way) BE studies; Statistical procedure used for intermediate analysis and unscaled BE calculation
Statistical threshold used to conclude bioequivalence.
DDFM=SATTERTH in PROC MIXED
Sample sizes for population and individual BE should be based on simulated data.
statistical model often assuming a common effect across trials
Clinical trial designs used for assessing bioequivalence.
A data treatment method for bioequivalence data.
Criteria for discounting unequal carryover effects.
Analysis of variance for % TBWL
Sponsors considering alternative methods to Method of Moments (MM).
Processes
10Transformation of pharmacokinetic data
Study design used for construction of confidence bounds.
A combination of reference and constant scaling for testing individual BE.
Method for Statistical Test of Population Bioequivalence Criterion Four-Period Crossover Designs
Simulation studies for 3-period and 4-period designs.
Results for four-period designs use relative efficiency data of Liu.; statistical model assuming a four-period design with equal replication
Results for two-period designs use method of Diletti et al.
Uses sequences TR, RT, TT, and RR
Design allowing for a within-subject test for unequal carryover effects.
A study carried out in two or more groups of subjects.; Replicated crossover designs used for sample size determination.; model definition can be extended to other crossover designs
Identified Hazards
Hazards
2Residual effects where the response to a formulation is affected by previous formulations.
potential cause of product failure in sustained-release dosage forms
Standards & References
External Standards
1statistical software used for BE analysis
Specifications
10Standard bioequivalence acceptance intervals for confidence intervals.
Regulatory constant for within-subject standard deviation used as a switching point.
regulatory constant for switching between constant and reference scaling
suggests a minimum of 12 subjects in all BE studies.
Tables 1-4 below give sample sizes for 80% and 90% power.
Tables 1-4 below give sample sizes for 80% and 90% power.
range for average T to R ratios
maximum allowable IDR and upper BE limit for average BE criterion
The square root of the ratio of the expected squared difference between T and R administered to the same individual.
The square root of the ratio of the expected squared T-R difference compared to the expected squared R-R' difference.
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use: Guidance for Industry (Status: Final)
- Final In Vivo Bioavailability-Bioequivalence Studies- Analytical (Status: Final)
- Topical Dermatologic Corticosteroids: in Vivo Bioequivalence (Status: Final)
- Bioresearch Monitoring Technical Conformance Guide (Status: Final)
- Data Integrity for In Vivo Bioavailability and Bioequivalence Studies (Status: Draft)
- Fixed-Combinations and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment or Prevention of Human Immunodeficiency Virus-One Under the President’s Emergency Plan for Acquired Immunodeficiency Syndrome Relief (Status: Draft)
- CVM GFI #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 (Status: Final)
- Statistical Approaches to Establishing Bioequivalence (Status: Draft)