CFR 21 Part 320 bioavailability/bioequivalence MCQs With Answer

CFR 21 Part 320 Bioavailability/Bioequivalence MCQs With Answer

This quiz collection is tailored for M.Pharm students studying Clinical Research & Regulatory Requirements, focusing on CFR 21 Part 320 and FDA bioavailability/bioequivalence principles. It covers regulatory definitions, study designs, key pharmacokinetic parameters (AUC, Cmax, Tmax), statistical approaches (log-transformation, two one-sided tests, 90% confidence intervals), special designs for highly variable drugs, BCS-based biowaivers, fed vs fasting studies, washout periods, and handling of active metabolites. Each question aims to deepen conceptual and practical understanding needed for designing, analyzing and interpreting BE studies under the FDA framework. Answers are provided to facilitate efficient revision and exam preparation.

Q1. What is the primary statistical acceptance criterion for conventional bioequivalence studies under CFR 21 Part 320 as interpreted by FDA guidance?

• Mean difference between formulations less than 10%
• 90% confidence interval for the ratio of log-transformed means within 80.00–125.00%
• 95% confidence interval for the difference of raw means within ±20%
• P-value below 0.05 for a paired t-test comparing Cmax

Correct Answer: 90% confidence interval for the ratio of log-transformed means within 80.00–125.00%

Q2. Which pharmacokinetic parameters are typically required by CFR 21 Part 320 for single-dose bioequivalence assessment?

• Half-life (t1/2) and volume of distribution (Vd)
• AUC0–t, AUC0–∞ and Cmax
• Clearance (CL) and bioavailability (F) estimated directly
• Tmax and elimination rate constant only

Correct Answer: AUC0–t, AUC0–∞ and Cmax

Q3. For drugs with linear pharmacokinetics, why is log-transformation of PK metrics recommended before bioequivalence testing?

• To convert parameters into percentages
• To stabilize variance and make the distribution more symmetric for ratio-based inference
• To avoid calculating AUC altogether
• To allow use of nonparametric tests for Tmax

Correct Answer: To stabilize variance and make the distribution more symmetric for ratio-based inference

Q4. The Two One-Sided Tests (TOST) procedure used in BE analysis is designed to test which hypothesis?

• Equality of variances between test and reference
• That the test formulation is neither unacceptably less nor unacceptably greater than reference within predefined limits
• Superiority of test over reference
• That the mean difference equals zero

Correct Answer: That the test formulation is neither unacceptably less nor unacceptably greater than reference within predefined limits

Q5. What is the usual recommended washout period between treatment periods in a crossover BE study?

• At least 1 half-life of the drug
• At least 3 half-lives of the drug
• At least 5 half-lives of the drug
• At least 10 half-lives of the drug

Correct Answer: At least 5 half-lives of the drug

Q6. When is a multiple-dose (steady-state) bioequivalence study required instead of a single-dose study?

• For drugs with short half-life under 2 hours
• For drugs intended for chronic dosing where accumulation and steady-state kinetics are relevant
• Whenever the drug is administered orally
• Only for controlled-release topical formulations

Correct Answer: For drugs intended for chronic dosing where accumulation and steady-state kinetics are relevant

Q7. What is the primary rationale for using replicate crossover designs in bioequivalence studies?

• To reduce the total number of subjects required for any study
• To estimate within-subject variability separately for test and reference and allow reference-scaling for highly variable drugs
• To enable pooling of data across studies without heterogeneity
• To eliminate the need for washout periods

Correct Answer: To estimate within-subject variability separately for test and reference and allow reference-scaling for highly variable drugs

Q8. Under FDA guidance, what is meant by a “highly variable drug” in the context of BE studies?

• A drug with between-subject CV > 30%
• A drug with within-subject variability (CV) for a PK metric typically ≥ 30% for the reference product
• A drug with half-life longer than 24 hours
• A drug that is unstable in plasma samples

Correct Answer: A drug with within-subject variability (CV) for a PK metric typically ≥ 30% for the reference product

Q9. What is “reference-scaling” for highly variable drugs?

• Adjusting the bioanalytical assay to the reference product concentration
• Widening the BE acceptance limits based on the within-subject variability of the reference product using a statistical scaling approach
• Using a higher dose of reference product for comparison
• Applying an average BE approach without replicate design

Correct Answer: Widening the BE acceptance limits based on the within-subject variability of the reference product using a statistical scaling approach

Q10. Which sampling consideration is most important to ensure accurate Cmax estimation in BE studies?

• Collecting only pre-dose samples
• Frequent sampling around the expected Tmax and early absorption period
• Sampling only at fixed long intervals (e.g., every 6 hours)
• Measuring trough concentrations only

Correct Answer: Frequent sampling around the expected Tmax and early absorption period

Q11. Under FDA guidance, which immediate-release oral products may be eligible for a biowaiver based on the Biopharmaceutics Classification System (BCS)?

• BCS Class II products (low solubility, high permeability)
• BCS Class I and some Class III products when additional permeability/dissolution criteria are met
• All BCS classes automatically qualify
• Only parenteral formulations qualify for BCS biowaiver

Correct Answer: BCS Class I and some Class III products when additional permeability/dissolution criteria are met

Q12. How should active metabolites be handled in BE studies according to regulatory expectations?

• Active metabolites are never measured; only parent drug is relevant
• If an active metabolite significantly contributes to effect, BE should assess parent and/or metabolite as appropriate with justification
• Metabolites are measured but ignored in statistical analysis
• Only urinary excretion of metabolites is required

Correct Answer: If an active metabolite significantly contributes to effect, BE should assess parent and/or metabolite as appropriate with justification

Q13. What is the preferred statistical metric to report central tendency in BE studies after log-transformation?

• Arithmetic mean ratio (test/reference)
• Geometric mean ratio (test/reference)
• Median difference
• Mode ratio

Correct Answer: Geometric mean ratio (test/reference)

Q14. For Tmax, which statistical approach is commonly used in BE studies?

• Parametric log-transformed ANOVA similar to AUC and Cmax
• Nonparametric analysis (e.g., Wilcoxon signed-rank test) because Tmax is often not normally distributed
• Ignoring Tmax as it is not relevant
• Using two one-sided tests on raw Tmax values

Correct Answer: Nonparametric analysis (e.g., Wilcoxon signed-rank test) because Tmax is often not normally distributed

Q15. Which design is most appropriate when testing a generic immediate-release product against a reference where high within-subject variability is expected?

• Parallel design with a single period
• Two-period, two-sequence crossover without replication
• Replicate crossover design (e.g., four-period) to allow reference-scaling
• Single-administration, single-period observational study

Correct Answer: Replicate crossover design (e.g., four-period) to allow reference-scaling

Q16. Why are fed-state BE studies sometimes required in addition to fasting studies?

• Food never affects oral drug absorption, so fed studies are redundant
• To assess the impact of a high-fat meal on the rate and extent of absorption when food may alter bioavailability
• Fed studies are required only for parenteral drugs
• To reduce within-subject variability artificially

Correct Answer: To assess the impact of a high-fat meal on the rate and extent of absorption when food may alter bioavailability

Q17. What is the typical regulatory requirement for sample size determination in BE studies?

• Use the smallest sample size possible without justification
• Base sample size on expected within-subject variability, desired power (commonly 80–90%), and expected ratio close to 1.00
• Fixed at 12 subjects for all studies by regulation
• Choose sample size based on availability of subjects rather than statistical considerations

Correct Answer: Base sample size on expected within-subject variability, desired power (commonly 80–90%), and expected ratio close to 1.00

Q18. Which regulatory concept allows widening of BE limits for Cmax or AUC based on variability but requires prespecified statistical scaling and constraints?

• Average Bioequivalence without constraints
• Reference-Scaled Average Bioequivalence with upper regulatory cap
• Parallel-group equivalence with unlimited limits
• Non-inferiority testing with no confidence intervals

Correct Answer: Reference-Scaled Average Bioequivalence with upper regulatory cap

Q19. In a BE report, which assay validation characteristics are essential to ensure reliable PK data?

• Only linearity matters; precision and accuracy are optional
• Accuracy, precision, selectivity/specificity, sensitivity (LLOQ), and stability under sample handling conditions
• Validation is not necessary if using a commercial kit
• Only the calibration curve needs to be reported

Correct Answer: Accuracy, precision, selectivity/specificity, sensitivity (LLOQ), and stability under sample handling conditions

Q20. Which situation would most likely invalidate a conventional crossover BE analysis and require additional handling or an alternative design?

• Low intra-subject variability and rapid absorption
• Significant carryover effect due to inadequate washout or long half-life
• Perfect symmetry of period and sequence effects
• Complete absence of measurable drug in all samples

Correct Answer: Significant carryover effect due to inadequate washout or long half-life

Download