balakotu ★ India, 20190618 15:03 (1852 d 14:01 ago) Posting: # 20333 Views: 5,227 

Dear All, As per the FDA guidance of Sapropterin Dihydrochloride Tablets, The total dose should be included in the ANOVA model. Please any one suggest the terms should be consider in the ANOVA model, since it is a cross over study. Regards Kotu Edit: Guidance linked; see also this post #3. [Helmut] 
ElMaestro ★★★ Denmark, 20190618 15:14 (1852 d 13:49 ago) @ balakotu Posting: # 20334 Views: 4,596 

Hi balakotu, ❝ As per the FDA guidance of Sapropterin Dihydrochloride Tablets, The total dose should be included in the ANOVA model. Please any one suggest the terms should be consider in the ANOVA model, since it is a cross over study. Thanks for highlighting this. It is a funny, odd wording. I believe they meant to do an ANCOVA with total dose as covariate. Your (fixed) factors would be subject, sequence, period, treatment. Note that even with the bogus random statement in SAS when using PROC GLM the model is fit with a single random term (the 'error').— Pass or fail! ElMaestro 
Helmut ★★★ Vienna, Austria, 20190618 15:39 (1852 d 13:24 ago) @ ElMaestro Posting: # 20335 Views: 4,584 

Hi ElMaestro, ❝ I believe they meant to do an ANCOVA with total dose as covariate. So do I. At the 2^{nd} GBHI conference (Rockville 2016) body weight as a covariate was a hot topic. Body weight changes quite often in studies of anticancer drugs. The FDA was happy with that. No way for the EMA – as usual. — 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 
ElMaestro ★★★ Denmark, 20190618 17:51 (1852 d 11:12 ago) @ Helmut Posting: # 20336 Views: 4,535 

Hi Hötzi, ❝ At the 2^{nd} GBHI conference (Rockville 2016) body weight as a covariate was a hot topic. Body weight changes quite often in studies of anticancer drugs. The FDA was happy with that. No way for the EMA – as usual. So odd. "The statistical analysis should take into account sources of variation that can be reasonably assumed to have an effect on the response variable." A larger person has larger plasma volume and will, all other factors equal, be expected to have lower AUC and Cmax. Thus, body weight is definitely a source of variation that can be assumed to have some effect. And this is how it is in practice; those metrics correlate significantly with body weight in many trials albeit not always in a p<0.0000001 fashion when doing e.g. Spearman's rank or Pearson (but hey, period for example is usually not significant but has to be included in the model). The fact that one can do potency correction in the right circumstances is in fact an introduction of a kind of ANCOVA principle. So why they decide to shut the door on body weight is not clear to me, is it clear to anyone? Does this really have to do with concern for sources of variation, or are we in an altogether different territory here? — Pass or fail! ElMaestro 
Kumarnaidu2 ☆ India, 20210305 15:56 (1226 d 12:07 ago) @ Helmut Posting: # 22247 Views: 2,660 

Dear All, I have one query, In PK biosimilarity study in healthy volunteer if the recommended dose is as per bodyweight (say 5mg/kg) then in this case subject with higher bodyweight will receive more total dose as compared to the subject with lower bodyweight. Will this going to impact the serum drug level? If yes then what corrections we need to apply? Thanks in advance 
balakotu ★ India, 20190621 09:31 (1849 d 19:32 ago) @ ElMaestro Posting: # 20354 Views: 4,480 

❝ ❝ As per the FDA guidance of Sapropterin Dihydrochloride Tablets, The total dose should be included in the ANOVA model. ❝ ❝ I believe they meant to do an ANCOVA with total dose as covariate. ❝ Your (fixed) factors would be subject, sequence, period, treatment. Note that even with the bogus Dear ElMaestro, Thaks for your response. When i keep totaldose is a factor along with normal fixed effects (seq sub(seq) per trt) the model is not execute, Please let us know what are the fixed effects is required in ANOVA model. SAS code: model Cmax AUCt AUCi= seq sub(seq) per trt totaldose / ss3; Regards Kotu. 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] 
ElMaestro ★★★ Denmark, 20190621 22:54 (1849 d 06:10 ago) @ balakotu Posting: # 20357 Views: 4,367 

Hello balakotu, ❝ When i keep totaldose is a factor along with normal fixed effects (seq sub(seq) per trt) the model is not execute, Please let us know what are the fixed effects is required in ANOVA model. ❝ ❝ SAS code: ❝
I am not a SAS user, so I googled this one. It is important to tell the program which ones are fixed factors and which ones are covariates. Am absolutely not sure, but I believe you might need to use class for seq , sub(seq) , per and trt to indicate that those are the fixed effects. For trt and seq this may not be an issue if the stats program does not coerce them to integers or other other numerics. I have no idea if SAS does this in the absence of a class statement.Otherwise it could have no way to know if you did not mean per and sub(seq) as covariates. Bear in mind the levels of those are typically coded with integers like 1, 2, 3... — Pass or fail! ElMaestro 
d_labes ★★★ Berlin, Germany, 20210306 16:22 (1225 d 11:41 ago) @ ElMaestro Posting: # 22250 Views: 2,585 

Dear ElMaestro, ❝ ❝ SAS code: ❝ ❝
❝ ❝ I am not a SAS user, so I googled this one. It is important to tell the program which ones are fixed factors and which ones are covariates. ❝ Am absolutely not sure, but I am , absolutely. Trust me. ❝ but I believe you might need to use Totally correct. — Regards, Detlew 