jag009 Hero NJ, 20170320 03:42 (edited by jag009 on 20170320 04:22) Posting: # 17166 Views: 915 

Hi all, Just want to know what your experience is on this matter. The FDA stated that "Special Considerations: Applicants may consider using a referencescaled average bioequivalence approach for x drug. If using this approach, the applicant should provide evidence of high variability (i.e., withinsubject variability ≥30%) in bioequivalence parameters. Applicants who would like to use this approach are encouraged to submit a protocol for review by the Division of Bioequivalence in the Office of Generic Drugs." The above implies that one can conduct replicate studies (RSABE) if he/she has supportive data (ISCV>=30%). What if one conducted pilot studies and found that the ISCV is like 28/29%? My concensus still would be to proceed with RSABE approach since the it is a mixed approach which allows both RSABE (if Ref SD<0.294) and ABE analysis (if Ref SD>0.294) John 
ElMaestro Hero Denmark, 20170320 05:55 @ jag009 Posting: # 17167 Views: 825 

Hi jag009, » What if one conducted pilot studies and found that the ISCV is like 28/29%? My concensus still would be to proceed with RSABE approach since the it is a mixed approach which allows both RSABE(if Ref SD<0.294) and ABE analysis(if Ref SD>0.294) That's valid, but if you are not really sure if you are just "borderline" then the additional overhead associated with the replicated design may not be worth it. You find an intraCV_{R} of 31%, and you scale the limits a wee bit etc. But the price you paid for this moderate scaling option could be much higher than you'd be paying for a conventional 222BE trial with a few extra volunteers. Would be interesting to discuss an objective function here This isn' the answer, but just a view. — I could be wrong, but… Best regards, ElMaestro Here's the good news, folks: If you leave operational excellence, (c)LEAN, six sigma and management consultancy firms out of your development programmes, then you may have a chance to be first to market and to beat your competitors. 
Helmut Hero Vienna, Austria, 20170320 12:12 @ ElMaestro Posting: # 17169 Views: 799 

Hi ElMaestro & John, » » My concensus still would be to proceed with RSABE approach since the it is a mixed approach which allows both RSABE(if Ref SD<0.294) and ABE analysis(if Ref SD>0.294) » That's valid, but if you are not really sure if you are just "borderline" then the additional overhead associated with the replicated design may not be worth it. You find an intraCV_{R} of 31%, and you scale the limits a wee bit etc. But the price you paid for this moderate scaling option could be much higher than you'd be paying for a conventional 222BE trial with a few extra volunteers. I lean towards John’s idea. Say you estimated the 31% from a previous 2×2×2 study in 40 subjects and assume that CV_{wR}=CV_{wT}=CV_{w}. The 95% CI of the CV is 25.1–40.6%. Hence, in the best case (high CV_{wR}) the FDA’s implied BElimits would be 70.58–141.69%. That’s rather substantial. » Would be interesting to discuss an objective function here Some ideas: The number of treatments in a 2×2×4 study is roughly the same as in a 2×2×2 study – if we don’t plan for referencescaling (which I likely would do in a borderline case).
Calculation of costs is complicated (fixed & variable costs, blahblah). In my CRO we had a spreadsheet with 100 rows… Had a quick look (19 samples / period, last sampling 16 hours; 2×2×2 in 42 subjects vs. 2×2×4 in 22). The replicate design would be ~4% cheaper. If you hope for RSABE (for CV_{wR} 31% 18 subjects instead of 22 for ABE) the reduction in costs would be ~12%. — All the best, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
VStus Regular Poland, 20170321 11:49 @ Helmut Posting: # 17172 Views: 697 

Hi Helmut, We were able to get more than 4% discount for replicate versus equivalent '2x2'. Our internal belief is that replicate is cheaper, but will take more time... And time is money... We would rather do replicate study instead of large '2x2' with 2 or more groups due to the capacity of the clinic (if washout is not long). Regards, VStus 
Dr_Dan Senior 20170321 12:06 @ VStus Posting: # 17173 Views: 691 

Dear VStus For your calculation please keep in mind: the more study periods you have the higher the risk of drop outs. — Kind regards and have a nice day Dr_Dan 
Helmut Hero Vienna, Austria, 20170321 13:50 @ Dr_Dan Posting: # 17176 Views: 679 

Hi Dan, I agree with VStus. » For your calculation please keep in mind: the more study periods you have the higher the risk of drop outs. As I wrote above: » » I would not be worried about the higher chance of dropouts in the replicate study. The impact on power is low (unless the drug is nasty and dropouts are caused by AEs). Try:
— All the best, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
d_labes Hero Berlin, Germany, 20170321 14:16 @ Helmut Posting: # 17177 Views: 669 

Dear All! Don't confuse the usage of "expected power" here by Helmut with the functions in package PowerTOST which estimate the expected power and / or sample size based on expected power, some sort of Bayesian power, taking into account the uncertainty of an observed point estimate of T vs. R and / or the uncertainty of an observed CV.See f.i. ?exppower.TOST and references given in that man page.— Regards, Detlew 
VStus Regular Poland, 20170323 13:24 @ Helmut Posting: # 17180 Views: 549 

Daer Helmut, Dear Colleagues, It even hurts less (or doesn't hurt at all) in case of scaled bioequivalence. Last chunk of code modified:
CV < 0.42 Best regards, VStus 
mahmoudteaima Junior Cairo, Egypt, 20170323 07:17 @ Helmut Posting: # 17178 Views: 574 

Hi Helmut, » Calculation of costs is complicated (fixed & variable costs, blahblah). In my CRO we had a spreadsheet with 100 rows… Had a quick look (19 samples / period, last sampling 16 hours; 2×2×2 in 42 subjects vs. 2×2×4 in 22). The replicate design would be ~4% cheaper. If you hope for RSABE (for CV_{wR} 31% 18 subjects instead of 22 for ABE) the reduction in costs would be ~12%. Can you please help me for in the approximate estimation of cost of bioequivalence study?, would you please send me the template sheet that you use for such calculations. Greetings. — Mahmoud Teaima, PhD. Assistant Professor at Department of Pharmaceutics and Industrial Pharmacy. Vicedirector at Center of Applied Research and Advanced Studies (CARAS). Faculty of Pharmacy, Cairo University, Cairo, Egypt. 