Design of bioequivalence studies MCQs With Answer

Introduction: Designing bioequivalence (BE) studies is a critical skill for M.Pharm students preparing for careers in clinical research, regulatory affairs, or pharmacokinetics. This collection of multiple-choice questions with answers focuses on core concepts such as study designs (crossover, replicate, parallel), choice of pharmacokinetic endpoints (Cmax, AUC), statistical methods (log-transformation, ANOVA, 90% confidence intervals), regulatory acceptance criteria, handling high intra-subject variability, and issues with narrow therapeutic index drugs. The questions emphasize practical considerations—washout periods, sample size estimation, carryover, and PK sampling—so students gain deeper understanding beyond definitions and can apply principles when planning or evaluating BE studies.

Q1. Which study design is most commonly used for single-dose bioequivalence studies comparing two oral formulations in healthy volunteers?

• Parallel design
• Crossover design
• Factorial design
• Sequential adaptive design

Correct Answer: Crossover design

Q2. For standard average bioequivalence, which pharmacokinetic parameters are most frequently used as primary endpoints?

• Half-life (t1/2) and volume of distribution (Vd)
• Cmax and AUC
• Total clearance and bioavailability
• Time to steady state and trough concentration (Cmin)

Correct Answer: Cmax and AUC

Q3. Regulatory agencies typically require which statistical condition for concluding bioequivalence between test and reference products?

• P-value < 0.05 for difference in means
• 90% confidence interval of the geometric mean ratio within 80–125%
• 95% confidence interval of the arithmetic mean ratio within 70–130%
• Equivalence of median values without confidence intervals

Correct Answer: 90% confidence interval of the geometric mean ratio within 80–125%

Q4. Why are pharmacokinetic data typically log-transformed before statistical analysis in BE studies?

• To linearize a non-linear PK model
• To stabilize variance and make differences multiplicative rather than additive
• To convert concentration units to a common scale
• To satisfy sample size assumptions

Correct Answer: To stabilize variance and make differences multiplicative rather than additive

Q5. Which design is preferred when within-subject variability is very high for one or both formulations?

• Two-treatment, two-period crossover
• Parallel group design
• Replicate crossover design
• Single-arm pharmacodynamic study

Correct Answer: Replicate crossover design

Q6. In a two-period, two-sequence crossover BE study, which effect must be tested to ensure internal validity of results?

• Sequence effect only
• Period and sequence effects (including carryover assessment)
• Only treatment effect is required
• Only subject-by-treatment interaction

Correct Answer: Period and sequence effects (including carryover assessment)

Q7. For drugs with a narrow therapeutic index (NTI), regulatory authorities often recommend what modification to the bioequivalence acceptance criteria?

• Widen the acceptance interval to 70–143%
• Keep the standard 80–125% interval
• Tighten the acceptance interval, e.g., 90–111% or use scaled limits
• Replace AUC with Cmin as the primary endpoint

Correct Answer: Tighten the acceptance interval, e.g., 90–111% or use scaled limits

Q8. How is washout period between periods in a crossover BE study typically determined?

• At least one half-life of the drug
• Based on the investigator’s preference
• Usually 3–5 half-lives to minimize carryover effects
• No washout needed for fasted studies

Correct Answer: Usually 3–5 half-lives to minimize carryover effects

Q9. Which statistical model is commonly used to analyze PK parameters in a two-period crossover BE study?

• Mixed-effects ANOVA on log-transformed PK metrics with fixed effects for sequence, period, treatment and random effect for subject
• Linear regression on raw PK data
• Non-linear mixed-effects population PK model for each subject
• Chi-square test comparing categorical concentration ranges

Correct Answer: Mixed-effects ANOVA on log-transformed PK metrics with fixed effects for sequence, period, treatment and random effect for subject

Q10. When calculating AUC0–t for a single-dose BE study, what is the most appropriate method for concentrations measured at discrete time points?

• Linear trapezoidal rule for increasing concentrations and log trapezoidal for decreasing concentrations
• Simple summation of concentrations
• Use only the highest concentration timepoint
• Non-compartmental method with Monte Carlo integration

Correct Answer: Linear trapezoidal rule for increasing concentrations and log trapezoidal for decreasing concentrations

Q11. What is the purpose of performing non-compartmental analysis (NCA) in BE studies?

• To estimate population PK parameters using covariates
• To derive empirical exposure metrics like AUC and Cmax without assuming a specific compartmental model
• To simulate long-term dosing regimens
• To perform model-based dose optimization

Correct Answer: To derive empirical exposure metrics like AUC and Cmax without assuming a specific compartmental model

Q12. In BE studies, what does “scaled average bioequivalence” address?

• Differences in median PK values between populations
• Adjustment of BE limits based on within-subject variability of the reference product
• Scaling PK data to body weight
• Comparing absolute bioavailability between formulations

Correct Answer: Adjustment of BE limits based on within-subject variability of the reference product

Q13. When a test product shows much higher variability than the reference, which regulatory strategy can help avoid excessively large sample sizes?

• Switch to a parallel design to reduce variance
• Use replicate design and apply scaled average bioequivalence if permitted
• Exclude high-variability subjects post hoc
• Use non-inferiority testing instead of equivalence testing

Correct Answer: Use replicate design and apply scaled average bioequivalence if permitted

Q14. Which sampling consideration is critical to accurately capture Cmax in an oral BE study?

• Sparse sampling only at trough and peak times
• Dense sampling around the expected Tmax to avoid missing the peak concentration
• Collect samples only at 0, 8, and 24 hours
• No specific timing is necessary if AUC is primary

Correct Answer: Dense sampling around the expected Tmax to avoid missing the peak concentration

Q15. What role does a partial AUC (e.g., AUC0–t’) play in bioequivalence assessments?

• Used only for IV studies
• Can be used to assess early exposure relevant to onset of action or safety
• Replaces total AUC in all BE submissions
• Is irrelevant for immediate-release oral formulations

Correct Answer: Can be used to assess early exposure relevant to onset of action or safety

Q16. Which population is most commonly recruited for standard single-dose BE studies and why?

• Patients with the target disease to mimic therapeutic conditions
• Healthy volunteers to reduce variability and avoid disease-related confounding
• Pediatric subjects to evaluate dosing safety
• Elderly subjects because they represent worst-case PK

Correct Answer: Healthy volunteers to reduce variability and avoid disease-related confounding

Q17. If a BE study shows a significant period effect but no sequence or treatment effect, what is the likely interpretation?

• Strong evidence that the test product is superior
• Potential time-related change in subjects (e.g., adaptation) that must be examined but may not invalidate the BE conclusion if no carryover
• Immediate rejection of the study and all results
• Indication that washout period was too long

Correct Answer: Potential time-related change in subjects (e.g., adaptation) that must be examined but may not invalidate the BE conclusion if no carryover

Q18. For steady-state bioequivalence studies, which primary PK metrics are commonly compared?

• Cmax, AUCtau (AUC over dosing interval at steady state), and Cmin
• Only AUC0–∞ from single dose
• Volume of distribution and clearance at steady state
• Time to peak and half-life only

Correct Answer: Cmax, AUCtau (AUC over dosing interval at steady state), and Cmin

Q19. What is the main advantage of using replicate designs over conventional 2×2 crossover designs?

• They require fewer blood samples per subject
• They allow direct estimation of within-subject variability for each formulation and support scaled BE approaches
• They eliminate the need for washout periods
• They simplify the ANOVA model by removing sequence effects

Correct Answer: They allow direct estimation of within-subject variability for each formulation and support scaled BE approaches

Q20. Which regulatory document or guidance is most relevant when planning a bioequivalence study for an oral immediate-release product?

• ICH E14 on cardiac safety
• FDA and EMA guidances on bioequivalence for generic drug development (e.g., FDA Guidance for Industry: Bioavailability and Bioequivalence Studies)
• ICH Q9 on quality risk management
• USP monograph on dissolution only

Correct Answer: FDA and EMA guidances on bioequivalence for generic drug development (e.g., FDA Guidance for Industry: Bioavailability and Bioequivalence Studies)

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