Crossover study designs MCQs With Answer

Crossover study designs MCQs With Answer

This set of MCQs is designed for M.Pharm students studying Modern Bio-Analytical Techniques (MPA 202T). The questions focus on crossover trial principles used in pharmacokinetics and bioequivalence — including design types (2×2, Williams, replicate), washout and carryover considerations, statistical analysis (ANOVA, mixed models), PK endpoints (AUC, Cmax), and regulatory expectations. Each question probes concepts important for designing, analyzing and interpreting crossover studies in drug development and BE studies. Use these items for revision, self-assessment, or classroom quizzes to deepen understanding of within-subject comparisons, sources of variability, and practical issues such as missing data and sample size.

Q1. What best describes a crossover study design?

• Different groups of subjects each receive only one treatment and are compared between groups
• Each subject receives multiple treatments in a randomized sequence with washout periods between treatments
• Treatments are assigned by cluster and compared at a single time point
• Treatment allocation depends on subject preference and not randomization

Correct Answer: Each subject receives multiple treatments in a randomized sequence with washout periods between treatments

Q2. What is the main statistical advantage of a crossover design compared with a parallel design?

• Eliminates period effects completely
• Removes the need for randomization
• Reduces required sample size by controlling between-subject variability through within-subject comparisons
• Avoids the need for washout periods

Correct Answer: Reduces required sample size by controlling between-subject variability through within-subject comparisons

Q3. In the context of crossover trials, what does “carryover effect” mean?

• Variation in measurements due to different laboratories
• Residual influence of a previous treatment on outcomes measured in a subsequent period
• Effect of period length on treatment tolerability
• Random subject dropout between periods

Correct Answer: Residual influence of a previous treatment on outcomes measured in a subsequent period

Q4. What is the primary purpose of a washout period in a crossover trial?

• To allow subjects to forget which treatment they received
• To ensure the analytic instrument is recalibrated
• To eliminate or minimize carryover of the prior treatment before the next period
• To allow recruitment of replacement subjects

Correct Answer: To eliminate or minimize carryover of the prior treatment before the next period

Q5. Which sequences are used in a standard 2×2 crossover design?

• AA and BB
• AB and BA
• ABC and CBA
• AB and AC

Correct Answer: AB and BA

Q6. Which analysis method is generally preferred for modern crossover studies, especially with missing data or complex variance structure?

• Unpaired t-test on period means
• Mixed-effects model (linear mixed model) with subject as a random effect
• Nonparametric rank-sum test across sequences
• Simple ratio of group means without transformation

Correct Answer: Mixed-effects model (linear mixed model) with subject as a random effect

Q7. How is a classical carryover (residual) effect commonly assessed in ANOVA for a 2×2 crossover?

• By testing the treatment by subject interaction term
• By including and testing a sequence term in the ANOVA model
• By comparing baseline demographics only
• By testing the random error term variance

Correct Answer: By including and testing a sequence term in the ANOVA model

Q8. For bioequivalence of AUC and Cmax, what is the commonly accepted 90% confidence interval equivalence range after log-transformation?

• 70% to 130%
• 80% to 125%
• 90% to 110%
• 75% to 140%

Correct Answer: 80% to 125%

Q9. When is a Williams design preferred in crossover studies?

• When only two treatments are compared
• When more than two treatments need balanced first-order carryover control across sequences
• When no washout period is possible
• Only for parallel-group studies

Correct Answer: When more than two treatments need balanced first-order carryover control across sequences

Q10. Which condition would generally make a crossover design inappropriate?

• A stable chronic condition with reversible treatment effects
• A short-acting treatment with rapid elimination
• A permanent cure or progressive disease where treatment effects cannot be fully washed out
• A highly variable within-subject response where each subject acts as their own control

Correct Answer: A permanent cure or progressive disease where treatment effects cannot be fully washed out

Q11. Which is a key assumption underlying valid inference from a crossover trial?

• Subjects must be aware of treatment allocation
• The condition of participants remains stable across periods and there is no residual carryover after washout
• There must be equal numbers of males and females in each sequence
• Analytical assays need not be validated for precision

Correct Answer: The condition of participants remains stable across periods and there is no residual carryover after washout

Q12. What is the recommended approach for handling missing PK measurements in crossover trials?

• Exclude all subjects with any missing value (complete-case analysis) by default
• Use mixed-effects models assuming data are missing at random to produce valid inference when appropriate
• Impute missing values with zero
• Always use last observation carried forward (LOCF)

Correct Answer: Use mixed-effects models assuming data are missing at random to produce valid inference when appropriate

Q13. Compared with a parallel design, how does sample size requirement typically change when switching to a crossover design for the same treatment contrast?

• Sample size usually increases because of carryover
• Sample size is typically much larger due to period effects
• Sample size is usually smaller because within-subject comparisons reduce variance
• Sample size remains identical for all designs

Correct Answer: Sample size is usually smaller because within-subject comparisons reduce variance

Q14. What randomization method is commonly used to allocate subjects to sequences in crossover trials to ensure balance over time?

• Simple random sampling without stratification
• Block randomization or permuted blocks to maintain balance across recruitment
• Allocation by date of birth
• Alternating assignment by enrollment order without randomization

Correct Answer: Block randomization or permuted blocks to maintain balance across recruitment

Q15. What does a significant period effect indicate in a crossover study?

• Treatment has no effect
• Time-related changes or conditions between periods that affect outcomes independent of treatment
• Complete absence of carryover
• Perfect washout efficacy

Correct Answer: Time-related changes or conditions between periods that affect outcomes independent of treatment

Q16. What is the purpose of a replicate crossover design?

• To reduce the number of periods to only one
• To estimate within-subject variability and allow reference-scaled average bioequivalence for highly variable drugs
• To eliminate the need for pharmacokinetic sampling
• To compare more than ten treatments simultaneously

Correct Answer: To estimate within-subject variability and allow reference-scaled average bioequivalence for highly variable drugs

Q17. Are formal statistical tests for carryover recommended as a routine precondition to primary analysis in regulatory bioequivalence trials?

• Yes, they are mandatory and conclusive in all cases
• No, they are often low-powered and regulatory guidance typically discourages routine reliance on such tests
• Yes, but only when sample size exceeds 200
• No, because carryover cannot occur in pharmacokinetic studies

Correct Answer: No, they are often low-powered and regulatory guidance typically discourages routine reliance on such tests

Q18. Which terms are typically included in the fixed-effects ANOVA model for a two-period, two-sequence crossover bioequivalence study?

• Treatment, period, sequence and subject nested within sequence as random effect
• Only treatment and baseline covariate
• Period by subject interaction as a fixed effect only
• Site effect only

Correct Answer: Treatment, period, sequence and subject nested within sequence as random effect

Q19. For PK bioequivalence studies, which primary pharmacokinetic parameters are most commonly evaluated?

• Time to steady state and trough concentration only
• AUC (area under the curve) and Cmax (maximum concentration)
• Heart rate and blood pressure
• Renal clearance only

Correct Answer: AUC (area under the curve) and Cmax (maximum concentration)

Q20. On what pharmacokinetic basis should washout duration between periods generally be determined?

• Fixed 24 hours for all drugs regardless of half-life
• Based on multiple (commonly ~5) terminal elimination half-lives of the drug to allow negligible residual concentrations
• Equal to the dosing interval of the drug irrespective of elimination half-life
• Chosen arbitrarily by the investigator

Correct Answer: Based on multiple (commonly ~5) terminal elimination half-lives of the drug to allow negligible residual concentrations

Download