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mittyri ★★ Russia, 2014-12-21 19:04 (3780 d 18:50 ago) Posting: # 14127 Views: 10,411 |
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Dear All, Are there any "rules of thumb" about the ISV prediction for a study with a new strength? For exapmle, the formulation 50mg is registered and we're going to conduct the study with the formulation 100 mg. The drug has linear PK to 120 mg according to the literature. Could we plan our study with ISV derived from the previous data? Is it safe enough? Thanks in advance! — Kind regards, Mittyri |
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ElMaestro ★★★ Denmark, 2014-12-21 21:42 (3780 d 16:13 ago) @ mittyri Posting: # 14129 Views: 8,523 |
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Hi again mittyri, ❝ For exapmle, the formulation 50mg is registered and we're going to conduct the study with the formulation 100 mg. ❝ The drug has linear PK to 120 mg according to the literature. ❝ Could we plan our study with ISV derived from the previous data? Is it safe enough? A difficult topic. I am aware of people have a theoretical concern about ISV varying with strength but I don't remember ever having seen solid data quantifying the phenomenon. I think I would just use the ISV from the previous study if that's available. — Pass or fail! ElMaestro |
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Helmut ★★★   Vienna, Austria, 2014-12-22 04:07 (3780 d 09:48 ago) @ ElMaestro Posting: # 14134 Views: 8,594 |
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Hi ElMaestro & Mittyri, ❝ I am aware of people have a theoretical concern about ISV varying with strength… Are these the ones wearing waist-belts plus suspenders to exercise caution? ❝ … but I don't remember ever having seen solid data quantifying the phenomenon. So do I. ❝ I think I would just use the ISV from the previous study if that's available. Yep – with one possible exception. If you enter nonlinear PK (high doses: saturation of enzymes and/or transporters) genetics and day-to-day variability may become increasingly important. Add some % to the %. Don’t ask me how much. If in doubt, run a pilot. @Mittyri: I would not worry in your case. — 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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mittyri ★★ Russia, 2014-12-22 21:33 (3779 d 16:21 ago) @ Helmut Posting: # 14140 Views: 8,468 |
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Dear Helmut and ElMaestro, Many thanks for useful advice! — Kind regards, Mittyri |
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mittyri ★★ Russia, 2015-02-11 20:23 (3728 d 17:31 ago) @ Helmut Posting: # 14407 Views: 7,900 |
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Hi ElMaestro & Helmut, I would like to continue the discussion on the practical level. So we conducted the BEQ study on the Test product (50 mg). Our results for Cmax were: 90%CI=[0.847; 1.134] CV=38%, PE=0.98, N=36 Does it mean that with a probability 90% the real GMR of Cmax lies between 0.847 and 1.134? Does it mean that the mentioned probability normally distributed in this interval? We're planning to perform the second study with the same API, but another strength (100mg). Which GMR would you propose? 0.98% (optimistic from previous study)? 0.95% (standard)? — Kind regards, Mittyri |
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ElMaestro ★★★ Denmark, 2015-02-11 21:29 (3728 d 16:25 ago) @ mittyri Posting: # 14408 Views: 8,094 |
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Hi Mittyri, ❝ Our results for Cmax were: ❝ 90%CI=[0.847; 1.134] ❝ CV=38%, PE=0.98, N=36 ❝ Does it mean that with a probability 90% the real GMR of Cmax lies between 0.847 and 1.134? Does it mean that the mentioned probability normally distributed in this interval? It means that if the assumptions are correct (the residual is normal) and if the true GMR is 0.98 and if the CV is 38% then there is a 90% chance that the estimated GMR will be between your observed limits when you conduct a study on 36 subjects. ❝ We're planning to perform the second study with the same API, but another strength (100mg). ❝ Which GMR would you propose? 0.98% (optimistic from previous study)? 0.95% (standard)? If you can afford it, it might be a good idea to go even a little lower. After all, this is a new formulation, right? There are no rules, and you'll be going by gut feeling. If you intend the next study to be pivotal then the choice of GMR guess should reflect a ton of factors including biology, dissolution, gut feeling, Saturn's moons, your biorhythms, personal horoscope (you've gotta ask yourself one question: "Do I feel lucky?" Well, do ya, punk?) etc but not your management's desire to save money. — Pass or fail! ElMaestro |
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Helmut ★★★ Vienna, Austria, 2015-02-12 14:31 (3727 d 23:23 ago) @ mittyri Posting: # 14411 Views: 7,982 |
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Hi Mittyri, ❝ Does it mean that with a probability 90% the real GMR of Cmax lies between 0.847 and 1.134? Yes. ❝ Does it mean that the mentioned probability normally distributed in this interval? No. These are backtransformed values. They are normal distributed with a mean of ln(0.98) = -0.0202 and 90% limits of ln(0.847, 1.134) = -0.1661, +0.1258. These limits are symmetrical around ln(PE): (-0.1661+0.1258)/2 = -0.0202. ❝ Which GMR would you propose? 0.98% (optimistic from previous study)? 0.95% (standard)? First of all I agree with what ElMaestro wrote. As you know I’m not a friend of post hoc power, but in the previous study with 61% you were lucky to show BE. You are dealing with a HVD / HVDP (CV 38%). For these drugs the PE “jumps around” between studies. Therefore, the two Lászlós recommended in their paper about sample size estimation a conservative T/R of 0.90 – even if you have observed a “better” one in a previous study. — 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