The inclusion of newly licensed or repurposed drugs in regimens to treat children for multidrug-resistant tuberculosis (TB) may lead to treatment that is shorter than traditional regimens and composed only of oral medications. As an all-oral regimen may be more acceptable and have a better safety profile than current regimens, demonstrating non-inferiority may be satisfactory. Demonstrating non-inferior efficacy requires setting a non-inferiority margin and safeguarding study assay sensitivity. Multi-arm, multistage designs may currently not be appropriate in pediatric trials because of the lack of sensitive and specific intermediate outcomes. However, including an arm with an agent to ameliorate toxicity would be efficient. Covariates can be used to stratify randomization, define subgroups, and improve efficiency of analysis. Enriching the sample for the confirmed-TB subgroup to ensure that they are well represented may be important. Primary outcomes using a fixed timepoint from randomization for all study arms will result in variations in post-treatment duration, but may be the best choice. While blinding of site personnel and patients may not be possible when regimens differ substantially in drugs and modes of administration, blinding should be maintained for independent endpoint review groups and other personnel. Type I error and family-wise error rates should be tightly controlled.