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ABE1580 ☆ India, 2012-10-09 17:42 (4596 d 05:41 ago) Posting: # 9358 Views: 11,275 |
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Dear All In our BE studies we are finding that most of the times fed studies are passing BE in comparison with fasting studies. What could be the probable reason of such observations? Is it formulation that is playing a role or variable behavior of drug moleule in fasting state or study design? What are the factors to be considered in such cases for fasting study design? Regards Edit: Category changed. [Helmut] |
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drgunasakaran1 ★★  2012-10-09 22:07 (4596 d 01:16 ago) @ ABE1580 Posting: # 9364 Views: 10,156 |
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Dear Mr ABE, It may be due to the variable absorption of the drug under fasting conditions. Sometimes, food enhances the absorption of the molecule and its pharmacokinetic parameters will show less variations under fed conditions. In these cases, the formulation will pass under fed conditions, but will fail in fasting study. In these cases, it is better to do a pilot study in Fasting condition first, if the literature shows high variability and lesser absorption under fasting condition. If the formulation passes in Fasting condition, then it has higher chances of passing under Fed condition. Say for example, if the formulation shows highly variable nature under fasting conditions, doing a routine two period, two way, cross over design is not going to help. You need to change your design to a Replicate design so that the formulation passes under fasting condition too. In the above scenario, I will suggest you to go for Replicate design for Fasting study and Two period, Two way, Cross over under Fed conditions. — Dr Gunasakaran Sambandan MD Disclaimer: The replies/posts are my personal opinions, and they do not represent my company's views on the same. LinkedIn |
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cakhatri ★ India, 2012-10-10 09:34 (4595 d 13:50 ago) @ drgunasakaran1 Posting: # 9369 Views: 10,118 |
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Dear Dr.Gunasakaran, Can you confirm if the regulatory will accept two different designs for fast and fed study, to the best of my understanding both the studies have to be of the same design. In case of replicate design, the criteria for establishing BE will differ based on the ISCV obtained from reference. Regards Chirag |
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Dr_Dan ★★ Germany, 2012-10-10 15:09 (4595 d 08:15 ago) @ cakhatri Posting: # 9374 Views: 10,182 |
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Dear Chirag why shouldn't regulatory authorities accept two different designs? Bioequivalent is bioequivalent regardless if this is demonstrated by replicate or two way cross-over design. The reason why two different designs (+ blood sampling time points) were choosen is easily explained. To be on the safe side you should use the same batches of test and reference in both studies conducted at the same CRO (one site and one analytical method). Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★   Vienna, Austria, 2012-10-10 15:48 (4595 d 07:36 ago) @ cakhatri Posting: # 9376 Views: 10,122 |
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Dear Chirag, agree with what Dan said above. We once performed a fasting study in a parallel design (long half life according to the literature). The long half life turned out to be nonsense. I guess the analytical method in the publication had some selectivity issues and measured parent + one minor metabolite. Consequently we performed the fed study in a cross-over. No problem. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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cakhatri ★ India, 2012-10-12 12:42 (4593 d 10:41 ago) @ Helmut Posting: # 9403 Views: 9,951 |
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Dear Dr_Dan and Helmut, Thanks for the confirmation, it helps.... Regard Chirag |
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drgunasakaran1 ★★ 2012-10-10 21:14 (4595 d 02:09 ago) @ cakhatri Posting: # 9380 Views: 10,041 |
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Dear Dr Chirag, I fully agree with answers of Dr_Dan and Mr Helmut. Regulatory will accept two different study designs for fasted and fed conditions. — Dr Gunasakaran Sambandan MD Disclaimer: The replies/posts are my personal opinions, and they do not represent my company's views on the same. LinkedIn |
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ABE1580 ☆ India, 2012-10-11 08:10 (4594 d 15:14 ago) @ drgunasakaran1 Posting: # 9381 Views: 9,970 |
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Dear All, Thank you for all your suggestions. What are the factors to be considered in designing the protocol for fasting study in above cases? Regards, |
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drsinghs ☆ India, 2012-10-11 11:28 (4594 d 11:55 ago) @ drgunasakaran1 Posting: # 9382 Views: 10,001 |
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❝ Say for example, if the formulation shows highly variable nature under fasting conditions, doing a routine two period, two way, cross over design is not going to help. You need to change your design to a Replicate design so that the formulation passes under fasting condition too. Dear Dr. Gunasakaran, Can you elaborate more on the above statement with some illustrations (If possible)? Is it possible that a formulation will pass in replicate design and same will fail in 2 way crossover? What impact will be on ratio and 90% CI, If I test same formulation in 2 way crossover and replicate design? Regards, drsinghs |
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Dr_Dan ★★ Germany, 2012-10-11 13:43 (4594 d 09:41 ago) @ drsinghs Posting: # 9385 Views: 10,093 |
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Dear drsinghs ❝ Is it possible that a formulation will pass in replicate design and same will fail in 2 way crossover? ❝ ❝ What impact will be on ratio and 90% CI, If I test same formulation in 2 way crossover and replicate design? If the replicate design and the 2 way crossover have the same power and the same intra-subject variability then these two studies will have the same chance to pass (or fail). In your case (same formulations) it solely depends on sample size:
Upper acceptance limit = 125 %For a given intra-subject CV of for example 20.0 % you need in a full replicate design 10 subjects, in a half replicate dasign 16 subjects and in a 2 way crossover design 20 subjects to show bioequivalence in the general acceptance range of 80 - 125% with a power of more than 80% each. I hope this helps Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★ Vienna, Austria, 2012-10-11 15:05 (4594 d 08:19 ago) @ Dr_Dan Posting: # 9389 Views: 10,015 |
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Dear Dan! ❝ 2. Power (%): the least statistical power to detect (1-Power) differences between the Test and the Reference formulation. Not necessarily. The regulatory BE limits in the general case are based on a 20% difference Δ [where BElower = 1–Δ and BEupper=(1–Δ)-1], which is not related to the producer’s risk (β). The fact that with 80% power both the producer’s risk and the difference to detect are 20% is just coincidental. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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d_labes ★★★ Berlin, Germany, 2012-10-11 15:10 (4594 d 08:13 ago) @ Dr_Dan Posting: # 9390 Views: 10,050 |
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Dear Dr_Dan ❝ ❝ Expected ratio T/R = 95.00 % ❝ Target power = 80.00 % ❝ Intra-subject CV = 20.0 % ❝ ❝ design crossover replicated replicated ❝ ------- ----------- ------------ ------------ ❝ N 20 16 10 ❝ That looks like Bear if I'm right? Bear has implemented only the power and sample size for the 2x2x2 crossover based on the non-central t-distribution approximation. For the 3-period and 4-period replicate designs the rules n(2x2x3)=0.75*n(2x2x2) and n(2x2x4)=0.5*n(2x2x2) are used. But rules are rules only.PowerTOST (exact via Owen's Q-function) gives you for your above settings: Design N powerOf course qualitatively and practically nearly the same. — Regards, Detlew |
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Helmut ★★★ Vienna, Austria, 2012-10-11 19:53 (4594 d 03:31 ago) @ d_labes Posting: # 9394 Views: 10,053 |
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Dear Detlew & Dan ❝ PowerTOST (exact via Owen's Q-function) gives you for your above settings: ❝ ❝ ❝ ❝ Nitpicking: “2×2×3” is the full replicate 3-period design (TRT|RTR). The fashionable partial replicate (TRR|RTR|RRT) would give: 2x3x3 15 0.844011 – since the sample size has to be a multiple of 3.— Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Ing. Helmut Schütz