d_labes ★★★ Berlin, Germany, 20080123 17:00 (5801 d 00:04 ago) Posting: # 1547 Views: 9,517 

Dear all, can anybody give me a hint about nonparametric evaluation of BE (average) within replicate crossover design (2sequence4period and/or 4sequence4period)? This will be needed for Tmax evaluation, for which most guidances recommend a nonparametric evaluation. Thanks & regards DLabes — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20080123 17:50 (5800 d 23:15 ago) @ d_labes Posting: # 1548 Views: 8,411 

Dear DLabes! ❝ can anybody give me a hint about nonparametric evaluation of BE (average) within replicate crossover design (2sequence4period and/or 4sequence4period)? First of all congratulations for being the first colleague posting in my personal favorite category “Nonparametrics”… … but such a difficult question! To my knowledge there’s simply no specific method published at all. Since replicate designs were at least to some degree submitted to the FDA, t_{max} did not play an important role, because evaluation of early exposure (partial AUC up to median t_{max} of the reference – rather than a direct comparison of t_{max} itself) performed by a parametric method is considered the standard over there. ❝ This will be needed for Tmax evaluation, for which most guidances recommend a nonparametric evaluation. You are right. But if you go beyond the conventiona 2×2 design, nonparametrics will leave you out in the rain. I know of just two publications (for a 2treatment, 2period, 4sequence design^{1} and a 6×3 Williams’ design^{2}), although
But I must confess, I have neither done such an analysis myself nor seen it anywhere…
— Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
d_labes ★★★ Berlin, Germany, 20080124 09:36 (5800 d 07:28 ago) @ Helmut Posting: # 1550 Views: 8,217 

Dear HS, ❝ First of all congratulations for being the first colleague posting in my personal favorite category “Nonparametrics”... thanks. But nonparametrics is not in the scope of standard statistical education or standard statistical text books. Moreover there is not a lot of software out there to deal with. In SAS for instance, which I have to deal with, no standard method is implemented for obtaining CIs. You have to program methods from the scratch. Not an easy task. ❝ One possibility comes into my mind: Performing a parametric evaluation of the replicate design, but not on the untransformed raw data of t_{max}, but on the ranks within each period. Ok, that may help for p values but not for confidence intervals, at least not in SAS. Thanks a lot for the references. I have some more for you or whom it concerns, dealing with confidence intervals for designs with p>2 periods, but not specifically with all forms of replicate designs. [1] Putt, ME and VM Chinchilli Nonparametric approaches to the analysis of crossover studies Statistical science 19(4), 712719 (2004)[2] Duchateau L and P Jansen Pairwise nonparametric noninferiority tests in 3x3 crossover trials: should we adjust for period Statist. Med. 24, 15251536 (2005)[3] Willavize SA and EA Morgenthien Nonparametric confidence intervals for tmax in sequencestratified crossover studies Pharmaceut. Statist. (in press) published online Wiley Interscience— Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20080124 13:13 (5800 d 03:51 ago) @ d_labes Posting: # 1552 Views: 8,129 

Dear DLabes! ❝ But nonparametrics is not in the scope of standard statistical education or standard statistical text books.
❝ Moreover there is not a lot of software out there to deal with. True. At least for a 2×2 design EquivTestPK would help, but even the freeware R is an option (references). ❝ In SAS for instance, which I have to deal with, no standard method is implemented for obtaining CIs. You have to program methods from the scratch. Not an easy task. OK, but you may opt for Cytel’s StatXact PROCs for SAS. Caution: The correct HodgesLehmann CI is not available from the pulldown menu but must be obtained from the command line according to Senn (2002 p.121). I’ve had a lot of conversations with Cytel’s support in the past (and finally gave up with v6.1 of 2003 – maybe the issue is resolved in the current version 8). ❝ ❝ One possibility comes into my mind: Performing a parametric evaluation of the replicate design, but not on the untransformed raw data of t_{max}, but on the ranks within each period. ❝ Ok, that may help for p values but not for confidence intervals, at least not in SAS. OK, since I’ve got no SAS license, this is beyond my horizon. Thanks a lot for your references! — Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
kimhuang ☆ China, 20230614 12:43 (180 d 05:21 ago) @ Helmut Posting: # 23592 Views: 478 

Dear Helmut, Is there any nonparametric evaluation of BE (average) within replicate crossover design (2sequence4period and/or 4sequence4period) now? Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut] 