Comment: How do we really determine sample size? What if the number which is determined by statistical approaches is not feasible from a practical point of view, or because the disease is too rare. What does one do in such cases if (a) extrapolation is not possible and (b) the sample size required for a pivotal is not feasible? Comment: Do you follow the same recommendations as FDA when it comes to sample size of a PK study (Wang et al, J Clin Pharmacol 2012)? If so it would be able to mention it here, and reference the article. Comment: On the feasibility of the required sample size, would it be possible to clarify where and how this should be addressed (at the moment it states that it should be addressed separately but not where)? 397-401 Comment: Some guidance will be helpful on the upper limit of the higher nominal significance level, the widened margin or amount of information may be borrowed from the source population. Proposed change (if any): Either provide general guidance in the document or provide reference to related guidelines. 400 Comment: Widening of non-inferiority margins dilute interpretation of evidence with respect to clinical relevance and should be restricted only to cases where clinically justified. Moreover, Bayesian methods are only mentioned in the context of explicitly borrowing information. However, similar like using higher significance levels than 5%, the
Comment: How do we really determine sample size? What if the number which is determined by statistical approaches is not feasible from a practical point of view, or because the disease is too rare. What does one do in such cases if (a) extrapolation is not possible and (b) the sample size required for a pivotal is not feasible? Comment: Do you follow the same recommendations as FDA when it comes to sample size of a PK study (Wang et al, J Clin Pharmacol 2012)? If so it would be able to mention it here, and reference the article. Comment: On the feasibility of the required sample size, would it be possible to clarify where and how this should be addressed (at the moment it states that it should be addressed separately but not where)? 397-401 Comment: Some guidance will be helpful on the upper limit of the higher nominal significance level, the widened margin or amount of information may be borrowed from the source population. Proposed change (if any): Either provide general guidance in the document or provide reference to related guidelines. 400 Comment: Widening of non-inferiority margins dilute interpretation of evidence with respect to clinical relevance and should be restricted only to cases where clinically justified. Moreover, Bayesian methods are only mentioned in the context of explicitly borrowing information. However, similar like using higher significance levels than 5%, the