Nav Coelho 20070720 16:14 Posting: # 916 Views: 13,014 

Dear all, I have data from a parallel pilot study and am using that to estimate the sample size for a pivotal study. The formula that I am using requires an estimate of the inter subject variability which I don't have. I have the total variability (sqrt(MSE)). Is there a way to estimate intersubject variability from a parallel design or would it be correct to use the total variability instead? Would it be correct to estimate intersubject var as sd/mean for test and reference separately and then take the average? And one last question, how correct is it to take 60% of inter subject (calculated as sd/mean) to be the intrasubject variability? Thanks in Advance! Nav Coelho 
Helmut Hero Vienna, Austria, 20070720 16:29 @ Nav Coelho Posting: # 917 Views: 11,866 

Dear Nav! » I have data from a parallel pilot study and am using that to estimate the sample size for a pivotal study. The formula that I am using requires an estimate of the inter subject variability which I don't have. I have the total variability (sqrt(MSE)). Is there a way to estimate intersubject variability from a parallel design or would it be correct to use the total variability instead? Hhm, yes you have the total variability (inter + intrasubjects); the same will be true for your pivotal study. I don’t get your point of trying to estimate intersubject variability from total. Which formula are you referring to? » Would it be correct to estimate intersubject var as sd/mean for test and reference separately and then take the average? » » And one last question, how correct is it to take 60% of inter subject (calculated as sd/mean) to be the intrasubject variability? I don’t think so (both questions). For an example please have a look at Chow SC, Wang H. On Sample Size Calculation in Bioequivalence Trials. J Pharmacokin Pharmacodyn. 2001;28(2):15569. and Errata given at J Pharmacokin Pharmacodyn. 2002;29(1):1012. You will also need two letters to the editor: Hauschke D. A Note on Sample Size Calculation in Bioequivalence Trials. J Pharmacokin Pharmacodyn. 2002;29(1):8994. Blood P. Sample Size Calculation in Bioeqivalence Trials. J Pharmacokin Pharmacodyn. 2002;29(1):957. H Wang H, SC Chow SC. Authors’ Response. J Pharmacokin Pharmacodyn. 2002;29(1):99. — All the best, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Nav Coelho 20070720 18:38 (edited by Jaime_R on 20070720 22:51) @ Helmut Posting: # 918 Views: 11,835 

Thanks for your response Helmut. Well, I am not sure how to estimate the sample size for a parallel design? The formula that I am using uses intersubject variability and the reference is attached (Tutorial in Biostatisitcs: Sample sizes for clinical trials with Normal data by Steven A. Julious). Formula is on page 1970 #69. But how would you get the intersubject variability from the ANOVA for parallel design in order to calculate the sample size. Thanks for the reference, I'll take a look. Re: 60% of inter to estimate the intra: I am a statistician and I routinely see the PK individuals taking 60% of inter to be the intra for estimating sample size for a crossover design and always wondered about the validity of the approach. Appreciate your feedback! Nav  Edit: Full quote removed. Please see this post! [Jaime] 
Helmut Hero Vienna, Austria, 20070722 01:17 @ Nav Coelho Posting: # 921 Views: 12,011 

Dear Nav, I’m not in my office, so be a little patient to get a thorough response – first I have to read your 66 pages of statistics. Just for completeness (because you sent me the paper by private mail): SA Julious SA. Tutorial in Biostatistics. Sample sizes for clinical trials with Normal data. Stat Med. 2004;23(12):192186. » Well, I am not sure how to estimate the sample size for a parallel design? We’ll handle that… » Re: 60% of inter to estimate the intra: I am a statistician and I routinely see the PK individuals taking 60% of inter to be the intra for estimating sample size for a crossover design and always wondered about the validity of the approach. Hey, that’s black magick! Examples
again as black magick. — All the best, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Helmut Hero Vienna, Austria, 20070723 17:44 @ Nav Coelho Posting: # 925 Views: 13,280 

Dear Nav! » […] But how would you get the intersubject variability from the ANOVA for parallel design in order to calculate the sample size. Some more references and explanations. In a parallel design we have no direct access to intersubject variability, what we see is the total (sometimes called pooled) variability. From a crossover design we may estimate
» Re: 60% of inter to estimate the intra: I am a statistician and I routinely see the PK individuals taking 60% of inter to be the intra for estimating sample size for a crossover design and always wondered about the validity of the approach. I give you two examples from my 2×2 crossover studies (for low/medium/high intrasubject CV) to get an impression about the lacking relationship of CVintra/inter/total:^{2} Methyphenidate 20 mg MR single dose sprinkled, AUC_{t}, n=12 CVintra 7.00% [=36% of inter, 34% of total] CVinter 19.1%CVtotal 20.4%Paroxetine 30 mg IR steady state, AUC_{tau}, n=32 CVintra 25.2% [=46% of inter, 41% of total] ≈CVinter 55.1%CVtotal 62.1%Lansoprazole 30 mg single dose fasting, C_{max}, n=47 CVintra 47.0% [=187% (!) of inter, 86% of total] CVinter 25.1%CVtotal 54.6%I can’t see this rule of thumb of ‘CVintra = 60% CVinter’ to be applicable …
— All the best, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Nav Coelho 20070723 19:58 @ Helmut Posting: # 927 Views: 11,742 

Dear Helmut, I really appreciate you taking the time to answer my questions in such detail. In regards to the sample size calculation for a parallel design, I agree that the worst case scenario for taking total CV as the estimate for inter CV would only result in slight overestimation in power. Thanks for the confirmation!! As for the 60% rule, you are absolutely right. It's not a one size fits all. Nav Edit: Full quote removed. Please see this post! [HS] 
Dipesh Jayswal 20070724 08:52 @ Nav Coelho Posting: # 928 Views: 11,681 

Dear Nav Coelho, The following article may help u out for determination of sample size assuming different variances of test and reference formulation which is recommanded by FDA. "Hansheng Wang and SheinChung Chow, A practical approach for comparing means of two groups without equal variance assumption, Statistics in Medicine 2002; 21:3137–3151" Dipesh Jayswal Edit: Online resource. [HS] 