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jag009 ★★★ NJ, 2013-06-13 18:49 (4338 d 02:10 ago) Posting: # 10778 Views: 11,991 |
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Question guys... Does FDA (or EMA) really care about the power of a study? Example, hypothetically speaking, lets say I set up a study with a sample size of xx (yes n>12) based on a power of 70% and the study passes. Does it matter that my power is less than 80%? Why do I ask? My recent pilot study (3-way partial rep, n=60, withinsubject CV of ref = 55-60%) ended up with a (Highest) ratio of 1.2 and 95% upper confidence limit of -0.12456 ⇒ Tada, it passed BE. We will proceed with a pivotal study, the formulation will be identical with no potential variabilities (So if there is then it's not my fault!). If I follow Endrenyi et al's paper on sample size for HVD then I will be looking at n~200 subjects for a 3-way partial replicate study at 80% power. For a 4-way full replicate study at 80% power, n~120. Management said no go. For a compromise I think we should be able to go with n=80. Based on R, with a ratio=1.2 & CV=0.6, the power will be ~70%. I think we are good to go but I am curious if the agency would care about this power business... Any comment? Thanks John Edit: Category changed. [Helmut] |
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Helmut ★★★   Vienna, Austria, 2013-06-13 19:40 (4338 d 01:19 ago) @ jag009 Posting: # 10779 Views: 11,016 |
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Hi John! ❝ Does FDA (or EMA) really care about the power of a study? I don’t think so. FDA says “The study should have 80 or 90% power to conclude BE between these two formulations.” – not “must have”. EMA requires only an “appropriate sample size estimation” – whatever this might be. Since lower power translates into higher producer’s risk agencies shouldn’t care (their job is to deal with the patient’s risk). It might be that the IEC/IRB will be reluctant to approve a study given an expected 30% chance of failure. The IEC/IRB is concerned about the safety of subjects in the study – you can only try to convince them. Might be difficult for a drug with a nasty safety profile – which on the other hand is unlikely for an HVD/HVDP. ❝ Example, hypothetically speaking, lets say I set up a study with a sample size of xx (yes n>12) based on a power of 70% and the study passes. Does it matter that my power is less than 80%? No; a posteriori power is irrelevant. BTW, AFAIK not stated anywhere explicitly IMHO FDA wants at least 24 subjects. ❝ My recent pilot study (3-way partial rep, n=60, withinsubject CV of ref = 55-60%) ended up with a (Highest) ratio of 1.2 and 95% upper confidence limit of -0.12456 ⇒ Tada, it passed BE. Hhm, why don’t you save the money (or wire somefink to my bank account instead) and submit the pilot study as pivotal evidence of BE? See ![[image]](img/uploaded/IAsmall.png) III.A.2. Pilot study“A pilot study that documents BE can be appropriate, provided its design and execution are suitable and a sufficient number of subjects (e.g., 12) have completed the study.” ❝ We will move to a pivotal study, the formulation will be identical with no potential variabilities (So if there is then it's not my fault!). Or the GMR and/or CV go loony and jump around between studies. Wouldn’t surprise me with a CV of 60%… ❝ If I follow Endrenyi et al's paper on sample size for HVD then I will be looking at n~200 subjects for a 3-way partial replicate study at 80% power. For a 4-way full replicate study at 80% power, n~120. Yep. PowerTOST comes up with 201 and 134. I would really forget the partial replicate – both for pilots and pivotal studies. In many cases CVWT < CVWR. If this is the case (but from a partial replicate you don’t get the information) you will be rewarded. Example: 2×2×4 replicate, CVWT=CVWR=60%, n=134. For CVWT 40%, CVWR 60% you need only 100 (~25% less subjects). Try: sampleN.RSABE(targetpower=0.8, theta0=1.2, CV=c(0.4, 0.6), design="2x2x4", details=F)❝ Management said no go. Power. That which statisticians are always calculating but never have. Stephen Senn ❝ For a compromise I think we should be able to go with n=80. Based on R, with a ratio=1.2 & CV=0.6, the power will be ~70%. Yessir. power.RSABE(theta0=1.2, CV=0.6, n=81, design="2x3x3", details=F)❝ I am curious if the agency would care about this power business... Me too. I’m not a regulator. Some thoughts above.  — 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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jag009 ★★★ NJ, 2013-06-13 21:57 (4337 d 23:02 ago) @ Helmut Posting: # 10780 Views: 10,593 |
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Thanks Helmut! ❝ No; a posteriori power is irrelevant. BTW, AFAIK not stated anywhere explicitly IMHO FDA wants at least 24 subjects. n≥12 is what FDA wants. ❝ ❝ My recent pilot study (3-way partial rep, n=60, withinsubject CV of ref = 55-60%) ended up with a (Highest) ratio of 1.2 and 95% upper confidence limit of -0.12456 ⇒ Tada, it passed BE. ❝ ❝ Hhm, why don’t you save the money (or wire somefink to my bank account instead) and submit the pilot study as pivotal evidence of BE? Good question. I asked the Senior mgt too and they said it's a pilot batch but manufactured with pivotal specification. I don't understand their answer. I will go digging and see if they know what they are talking about. ❝ ❝ We will move to a pivotal study, the formulation will be identical with no potential variabilities (So if there is then it's not my fault!). ❝ ❝ Or the GMR and/or CV go loony and jump around between studies. Wouldn’t surprise me with a CV of 60%… That's my concern now since we are only 5% away from failing the T/R ratio. ❝ ❝ Management said no go. ❝ ❝ Power. That which statisticians are always calculating ❝ but never have. Stephen Senn Corporate decision comes first  John |
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Helmut ★★★ Vienna, Austria, 2013-06-13 22:04 (4337 d 22:55 ago) @ jag009 Posting: # 10781 Views: 10,634 |
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Hi John! ❝ ❝ […] IMHO FDA wants at least 24 subjects. ❝ ❝ n≥12 is what FDA wants. Yes, for 2×2. Do you have a reference that 12 are enough for scaling? ❝ ❝ Hhm, why don’t you save the money (or wire somefink to my bank account instead) and submit the pilot study as pivotal evidence of BE? ❝ ❝ I asked the Senior mgt too and they said it's a pilot batch but manufactured with pivotal specification. I don't understand their answer. I will go digging and see if they know what they are talking about.  ❝ ❝ Or the GMR and/or CV go loony and jump around between studies. Wouldn’t surprise me with a CV of 60%… ❝ ❝ That's my concern now since we are only 5% away from failing the T/R ratio. Yes, it will be a close shave. ❝ ❝ Power. That which statisticians are always calculating ❝ ❝ but never have. Stephen Senn ❝ ❝ Corporate decision comes first Sigh. — 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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jag009 ★★★ NJ, 2013-06-13 23:24 (4337 d 21:35 ago) @ Helmut Posting: # 10782 Views: 10,515 |
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Hi Helmut! ❝ ❝ n≥12 is what FDA wants. ❝ ❝ Yes, for 2×2. Do you have a reference that 12 are enough for scaling? A minimum number of 12 evaluable subjects should be included in any BE study. When an average BE approach is selected using either nonreplicated or replicated designs, methods appropriate to the study design should be used to estimate sample sizes.* If I interpret this correctly then any design should have a min n=12, to finish. Okay, it's from the 2001 guidance and RSABE was introduced much later... John
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Helmut ★★★ Vienna, Austria, 2013-06-13 23:33 (4337 d 21:25 ago) @ jag009 Posting: # 10783 Views: 10,498 |
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Hi John! ❝ […] Okay, it's from the 2001 guidance and RSABE was introduced much later... I think that’s the crucial point. At a Pharmaceutical Science Advisory Committee Meeting FDA suggested a minimum of 36 subjects and was voted down (have to dig out the reference). From what I’ve heard at conferences they want 24 – but I was never able to find a reference. — 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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jag009 ★★★ NJ, 2013-06-13 23:42 (4337 d 21:17 ago) @ Helmut Posting: # 10784 Views: 10,466 |
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❝ ❝ […] Okay, it's from the 2001 guidance and RSABE was introduced much later... ❝ ❝ I think that’s the crucial point. At a Pharmaceutical Science Advisory Committee Meeting FDA suggested a minimum of 36 subjects and was voted down (have to dig out the reference). From what I’ve heard at conferences they want 24 – but I was never able to find a reference. You mean this? Link Given the fact that the CV>30%, do you think that it's possible for anyone(I mean would anyone dare to)try and pass a RSABE study with n=12? It's risky enough to run a regular submission BE study with n=12 already at CV<30%... I will go check with my professor and see (Dr.Endrenyi) when I go have dinner with him later...  John |
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Helmut ★★★ Vienna, Austria, 2013-06-14 00:12 (4337 d 20:47 ago) @ jag009 Posting: # 10785 Views: 10,480 |
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Hi John! ❝ ❝ I think that’s the crucial point. At a Pharmaceutical Science Advisory Committee Meeting FDA suggested a minimum of 36 subjects and was voted down (have to dig out the reference). From what I’ve heard at conferences they want 24 – but I was never able to find a reference. ❝ ❝ You mean this? Link Well, this gives a hint where to search. At the April 14, 2004 meeting of the Advisory Committee of Pharmaceutical Science (ACPS), different approaches were discussed, […] Most members favored a minimum sample size of 24. This was the one where FDA was voted down. I think nothing was mentioned at the October 6, 2006 meeting (though not sure). I’m not aware of any official statement about a minimum sample size.❝ Given the fact that the CV>30%, do you think that it's possible for anyone (I mean would anyone dare to) try and pass a RSABE study with n=12? Well, if the study was planned for 80% power, CV <50%, and a GMR of 1 you would need 21. With a lot of drop-outs… In a full replicate (CV 30, GMR 1) you need only 16. ❝ It's risky enough to run a regular submission BE study with n=12 already... Is it? With EMA I never had any problems. ❝ I will go check with my professor and see (Dr.Endrenyi) when I go have dinner with him later... Best regards! Tell him that we haven’t forgotten the α-inflation story (hint). Detlew just returned from his vacation. — 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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jag009 ★★★ NJ, 2013-06-14 01:06 (4337 d 19:53 ago) @ Helmut Posting: # 10786 Views: 10,500 |
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Hi Helmut! ❝ Well, if the study was planned for 80% power, CV <50%, and a GMR of 1 you would need 21. With a lot of drop-outs… In a full replicate (CV 30, GMR 1) you need only 16. 16 to finish I assume? ❝ ❝ It's risky enough to run a regular submission BE study with n=12 already... Is it? With EMA I never had any problems. I've been dealing with too many nasty drugs... ❝ ❝ I will go check with my professor and see (Dr.Endrenyi) when I go have dinner with him later... ❝ ❝ Best regards! Tell him that we haven’t forgotten the α-inflation story (hint). Detlew just returned form his vacation. Will do  John |
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Helmut ★★★ Vienna, Austria, 2013-06-14 17:43 (4337 d 03:16 ago) @ jag009 Posting: # 10796 Views: 10,401 |
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Hi John! ❝ ❝ Well, if the study was planned for 80% power, CV <50%, and a GMR of 1 you would need 21. With a lot of drop-outs… In a full replicate (CV 30, GMR 1) you need only 16. ❝ ❝ 16 to finish I assume? No, 16 planned. In the actual study you might pass with fewer by luck. I tried to track the sample size issue down. ACPS Meeting, October 6, 2006, Topic 3: ACPS Questions – Highly Variable Drugs presented by Barbara Davit:
Question 1 (PE constraint): yes (8), no (0), abstain (1) 80 – 125% constraint: yes (2), no (3), abstain (4) The Committee asked the FDA to rephrase Question 2 to: We propose a minimum sample size of subjects when evaluating the BE of highly variable drugs. Does the Committee concur? If yes, what would be the minimum sample size? yes (6), no (1), abstain (2)Four members voted for a minimum sample size of 24, three members voted for a minimum sample size of 36, and two members abstained. For the discussion see this part of the transcript. At the August 5, 2009 meeting FDA’s Dale Conner presented an update. See slides 18–19: Protocol for Reference-Scaled ABE Approach
Fascinating: Scaled BE limits given on slide 20. Also interesting that in none of the API-specific guidances (first one progesterone, April 2010) a minimum sample size is mentioned. — 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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jag009 ★★★ NJ, 2013-06-15 00:06 (4336 d 20:53 ago) @ Helmut Posting: # 10800 Views: 10,266 |
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Hi Helmut, ❝ • At least 24 subjects should be enrolled ❝ • Reference replicate data analyzed for determination of σwr ❝ • If σwr < σw0 then data analyzed using unscaled average BE method ❝ • If σwr ≥ σw0 then data analyzed using scaled average BE and point-estimate criteria ❝ (my emphasis) ❝ Fascinating: Scaled BE limits given on slide 20. ❝ ❝ Also interesting that in none of the API-specific guidances (first one progesterone, April 2010) a minimum sample size is mentioned. "24 should be enrolled", so they want us to start with 24 but not necessary finish with 24. This # concur with Endrenyi et al's sample size article of n=24 at CV=30% with Ratio = 0.95 or 1.05 → 80% power. Thanks John |
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ElMaestro ★★★ Denmark, 2013-06-14 03:57 (4337 d 17:02 ago) @ jag009 Posting: # 10787 Views: 10,387 |
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Hi John, ❝ ❝ Hhm, why don’t you save the money (or wire somefink to my bank account instead) and submit the pilot study as pivotal evidence of BE? ❝ ❝ Good question. I asked the Senior mgt too and they said it's a pilot batch but manufactured with pivotal specification. I don't understand their answer. I will go digging and see if they know what they are talking about. Sounds to me like the batch size was insufficient for a pivotal trial. Then the production will be upscaled and a pivotal trial run 'soon' with the usual risk of funny outcomes. T/R can be a joker in these cases. — Pass or fail! ElMaestro |
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jag009 ★★★ NJ, 2013-06-14 22:49 (4336 d 22:10 ago) @ ElMaestro Posting: # 10799 Views: 10,348 |
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Hi ElMaestro, ❝ Sounds to me like the batch size was insufficient for a pivotal trial. Then the production will be upscaled and a pivotal trial run 'soon' with the usual risk of funny outcomes. T/R can be a joker in these cases. No no. Batch size is sufficient. Something to do with methods being not validated with the "pilot" Batch. I just don't feel well with such a large CV that's all. John |
Ing. Helmut Schütz