What should the analysis plan consider regarding early withdrawals and protocol violations?

• A. Early withdrawals can be ignored in the analysis.
• B. The analysis plan should not address early withdrawals.
• C. Early withdrawals do not affect the validity of results if intention-to-treat is used.
• D. The analysis plan should consider early study withdrawal and protocol violations.

Answer: (D)

Handling early withdrawals and protocol violations is essential in planning the analysis. These deviations affect who contributes data and how complete that data are, which can bias results if not pre-specified. The analysis plan should lay out how withdrawals will be treated (for example, using intention-to-treat as a baseline, and defining any per-protocol or other sensitivity populations), how missing data will be handled, and how protocol violations will be incorporated or excluded in primary and secondary analyses. It should also describe planned sensitivity analyses to assess robustness to different handling of withdrawals and deviations. Ignoring these issues or leaving them unmanaged risks biased conclusions and regulatory concerns, so the plan must explicitly address early withdrawals and protocol violations.