This document specifies the functional requirements for the BioEq software package, designed for analyzing bioequivalence studies. These requirements are aligned with FDA guidance for statistical approaches to establishing bioequivalence.
FR-2.1.1: The system shall calculate AUC using the trapezoidal rule.
FR-2.1.2: The system shall handle non-uniform time points.
FR-2.1.3: The system shall calculate AUC from time zero to the last measured time point (AUC₀-ₜ).
FR-2.1.4: The system shall calculate AUC extrapolated to infinity (AUC₀-∞) using the terminal elimination rate constant.
FR-2.1.5: The system shall report the percentage of AUC extrapolated beyond the last time point.
FR-2.2.1: The system shall determine the maximum observed concentration.
FR-2.2.2: The system shall identify the time point at which Cmax occurs (Tmax).
FR-2.3.1: The system shall calculate the terminal elimination rate constant (λz) using log-linear regression.
FR-2.3.2: The system shall calculate the elimination half-life (t½) as ln(2)/λz.
FR-2.3.3: The system shall provide criteria for selecting points for the terminal elimination phase.
FR-3.1.1: The system shall perform ANOVA for 2×2 crossover designs.
FR-3.1.2: The system shall include sequence, period, and treatment effects in the ANOVA model.
FR-3.1.3: The system shall calculate least-squares means for test and reference treatments.
FR-3.1.4: The system shall implement mixed-effects models with subject as a random effect.
FR-3.2.1: The system shall perform t-tests comparing test and reference groups.
FR-3.2.2: The system shall perform ANOVA with treatment as the only factor.
FR-3.3.1: The system shall support partial replicate (3-way) crossover designs.
FR-3.3.2: The system shall support full replicate (4-way) crossover designs.
FR-3.3.3: The system shall calculate within-subject variability for the reference product.
FR-3.3.4: The system shall implement reference-scaled average bioequivalence (RSABE) methods for highly variable drugs.
FR-3.3.5: The system shall calculate expanded bioequivalence limits based on reference variability.
FR-3.3.6: The system shall use mixed-effects models appropriate for replicate designs.
FR-3.4.1: The system shall calculate point estimates for the Test/Reference ratio.
FR-3.4.2: The system shall calculate 90% confidence intervals for bioequivalence assessment.
FR-3.4.3: The system shall assess whether the calculated intervals fall within the 80-125% bioequivalence limits.
FR-3.4.4: The system shall perform analyses on log-transformed PK parameters.
FR-4.1: The system shall accept data in standardized formats (CSV, Excel).
FR-4.2: The system shall validate input data for completeness and consistency.
FR-4.3: The system shall handle missing data appropriately.
FR-4.4: The system shall provide data summary statistics by treatment group.
FR-5.1: The system shall generate summary tables of PK parameters.
FR-5.2: The system shall produce statistical output in a format similar to established software.
FR-5.3: The system shall enable export of results to standard formats.
FR-5.4: The system shall provide measures of variability (SD, CV%) for all parameters.
FR-6.1: The system shall provide detailed documentation of all calculation methods.
FR-6.2: The system shall include references to established literature for all implemented methods.
FR-6.3: The system shall maintain traceability between requirements and implementation.
FR-6.4: The system shall include comprehensive test coverage for all calculations.
FR-7.1: The system shall produce consistent results for identical inputs.
FR-7.2: The system shall maintain precision in calculations to minimize rounding errors.
FR-7.3: The system shall validate inputs and provide appropriate error messages.
FR-7.4: The system shall maintain an audit trail of analysis steps.
This requirements specification will serve as the foundation for development, testing, and validation of the BioEq package.