Mikkabel Junior Belgium, 20180123 17:29 Posting: # 18277 Views: 975 

Dear All, I have a question regarding the choice of the comparator to be chosen in a classical CO study. To summarize, my company get the marketing autorisation for a generic product (Tablet, called T1) based on a PK study demonstrating the bioequivalence versus the original product (called R). Furthermore, according to the originator's SPC, the recommended dose is 1 or 2 Tablets. Therefore, the R&D branch of my company would like to develop a new dosage of the product T1 corresponding to 2 tablets of the original product (R) in order to increase patients' comfort and compliance with the treatment (only quantitative change to the active substance). The new proposed dosage will be called T2. Could you please advise which design should be better for a PK study:
Thank you in advance for your answer, 
Helmut Hero Vienna, Austria, 20180123 17:40 @ Mikkabel Posting: # 18278 Views: 859 

Hi Mikkabel, Luckily you are not exceeding the recommended dose of the originator. Hence, I would opt for a simple line extension (T2 vs. 2×T1) since you can expect a better match than in BE – which is possible as well (T2 vs. 2×R). I don’t see how you could perform a doseproportionality study with just two levels (zero degrees of freedom). — Regards, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
mittyri Senior Russia, 20180123 18:30 @ Helmut Posting: # 18282 Views: 849 

Hi Helmut, » I don’t see how you could perform a doseproportionality study with just two levels (zero degrees of freedom). But we have more than one observation for each level, so regression is possible, isn't it? — Kind regards, Mittyri 
Helmut Hero Vienna, Austria, 20180123 18:41 @ mittyri Posting: # 18283 Views: 846 

Hi Mittyri, » » I don’t see how you could perform a doseproportionality study with just two levels (zero degrees of freedom). » » But we have more than one observation for each level, so regression is possible, isn't it? Yeah, well, cough… — Regards, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Mikkabel Junior Belgium, 20180124 10:17 @ Helmut Posting: # 18285 Views: 767 

» Luckily you are not exceeding the recommended dose of the originator. Hence, I would opt for a simple line extension (T2 vs. 2×T1) since you can expect a better match than in BE – which is possible as well (T2 vs. 2×R). » I don’t see how you could perform a doseproportionality study with just two levels (zero degrees of freedom). Hi Helmut, Thank you for your quick reply! I would also opt for a simple Pk study (T2 versus 2*T1) but do you have any idea to which guidelines I can refer to justify the rationale of the study and in particular the choice of the comparator (T1 instead of the originator). Regarding the dose proportional study, I meant a PK study (T1 vs T2) and the results corrected by the dose should be compared. Kind regards, 
Helmut Hero Vienna, Austria, 20180124 11:56 @ Mikkabel Posting: # 18287 Views: 769 

Hi Mikkabel, » I would also opt for a simple Pk study (T2 versus 2*T1) but do you have any idea to which guidelines I can refer to justify the rationale of the study and in particular the choice of the comparator (T1 instead of the originator). See Annex I to EC 1234/2008 about Type II variations … 2. Changes to strength, pharmaceutical form and route of administration: In the line extensions I was involved in (example) we always used the approved strength of our product as the comparator (and not the innovator’s product).^{1} » Regarding the dose proportional study, I meant a PK study (T1 vs T2) and the results corrected by the dose should be compared. I did it once in 2003.^{2} The German BfArM told me “OK, we accept it this time but please don’t do it in the future…”. Makes perfect sense indeed (I learned): Demonstration of BE requires administration of the same molar dose(s).^{3} Let T_{2} = ƒ×T_{1}, F the absolute BA, and R the response in any given PK metric of interest (AUC, C_{max}, …).
D_{T1} 1 (F 100%) ▬▬, D_{T2} 2 (F 90%) ▬▬, and at the high dose elimination is prolonged by ~12% due to saturation. If we dosecorrect T_{1} ▬▬, we get for T_{2} – false – GMR estimates of 100% for AUC_{0–t}, 103% for AUC_{0–∞}, and 94% for C_{max}. We wouldn’t adjust individual profiles. I expect that the rather small prolongation of the elimination would not be evident in the data (hidden by biological noise). And no, we would never notice the seven minutes delay in t_{max}. However, if we administer the same doses, elimination should be prolonged to a similar extent (CL_{T2} ≈ CL_{T1}). Hence, GMR estimates for all PK metrics would be unbiased (≈90%)^{4} reflecting the true relative BA.
— Regards, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 