"As per latest Statistical Approaches to Establishing Bioequivalence Draft guidance
Topic: Studies in Multiple Groups:
Sometimes, groups reflect factors arising from study design and conduct. For example,
a PK BE study can be carried out in two or more clinical centers and the study may be
considered a multi-group BE study. The combination of multiple factors may complicate
the designation of group. Therefore, sponsors should minimize the group effect in a PK
BE study as recommended below:
1. Dose all groups at the same clinic unless multiple clinics are needed to enroll a sufficient
number of subjects.
2. Recruit subjects from the same enrollment pool to achieve similar demographics
among groups.
3. Recruit all subjects, and randomly assign them to group and treatment arm, at
study outset.
4. Follow the same protocol criteria and procedures for all groups.
5. When feasible (e.g., when healthy volunteers are enrolled), assign an equal sample
size to each group.
Bioequivalence should be determined based on the overall treatment effect in the whole
study population. In general, the assessment of BE in the whole study population should
be done without including the treatment and group interaction(s) term in the model, but
applicants may also use other pre-specified models, as appropriate. The assessment of interaction between the treatment and group(s) is important, especially if any of the first
four study design criteria recommended above are not met and the PK BE data are considered pivotal information for drug approval. If the interaction term of group and treatment is significant, heterogeneity of treatment effect across groups should be carefully examined and interpreted with care. If the observed treatment effect of the products varies greatly among the groups, vigorous attempts should be made to find an explanation for the heterogeneity in terms of other features of trial management or subject characteristics, which may suggest appropriate further analysis and interpretation."
Question 1: what should we do if treatment by group interaction is significant?
Question 2: Whether we need to check heterogeneity of treatment effect separately for each group?
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