inclusion in the Summary of Product Characteristics, in order to be consistent with guidance in Section 6.1. Lines 406-409 Comment: While the hierarchical test may be suitable when the order of hypotheses is easy to establish, it may be too strict for other situations, where more flexible procedures have clear advantages (e.g., Bonferroni-Holm, gatekeeping and graphical procedures). Thus it would be helpful to mention some well-established procedures which are also appropriate for multiplicity adjustments for primary and secondary endpoints. Proposed change: Delete the sentences in Lines 406-409: more complex methods to control type I error over both primary “However, and secondary endpoints, and these could be more useful in some circumstances. Depending on the degree of complexity, regulatory dialogue is recommended to assure that the outcome of the procedure can be interpreted in clinical terms.” Insert a new paragraph as follows after reflects their relative importance in “…, the study.”: are situations in practice where the hierarchical order is less clear among “There the secondary endpoints. In these cases, a hierarchical test may be too strict. Thus more flexible methods that do not impose a strict hierarchy may be preferred. These procedures are well established and usually have power advantages to reject at least one secondary hypothesis.” Lines 413-418 Comment: Please consider providing guidance and examples on assigning the clinically very important endpoint also as primary endpoint and adjust for multiplicity with the
inclusion in the Summary of Product Characteristics, in order to be consistent with guidance in Section 6.1. Lines 406-409 Comment: While the hierarchical test may be suitable when the order of hypotheses is easy to establish, it may be too strict for other situations, where more flexible procedures have clear advantages (e.g., Bonferroni-Holm, gatekeeping and graphical procedures). Thus it would be helpful to mention some well-established procedures which are also appropriate for multiplicity adjustments for primary and secondary endpoints. Proposed change: Delete the sentences in Lines 406-409: “However, more complex methods to control type I error over both primary and secondary endpoints, and these could be more useful in some circumstances. Depending on the degree of complexity, regulatory dialogue is recommended to assure that the outcome of the procedure can be interpreted in clinical terms.” Insert a new paragraph as follows after “…, reflects their relative importance in the study.”: “There are situations in practice where the hierarchical order is less clear among the secondary endpoints. In these cases, a hierarchical test may be too strict. Thus more flexible methods that do not impose a strict hierarchy may be preferred. These procedures are well established and usually have power advantages to reject at least one secondary hypothesis.” Lines 413-418 Comment: Please consider providing guidance and examples on assigning the clinically very important endpoint also as primary endpoint and adjust for multiplicity with the
efpia-comments_draft-guideline-on-multiplicity-issues-300617final-1.docx