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jag009 ★★★ NJ, 2012-05-07 17:13 (5148 d 03:04 ago) Posting: # 8524 Views: 6,595 |
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Hi everyone, I am working on a drug with a half life of 100-120 hrs  and so far I haven't been able to get any information about its intrasubject CV. Due to timing issues, I am considering running a pilot parallel study to compare a prototype generic against the innovator.Question. If I proceed with this, does that mean I will have to conduct my pivotal studies as parallel studies since the CV I get from the pilot is the total CV? Thanks John |
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Dr_Dan ★★ Germany, 2012-05-07 18:00 (5148 d 02:17 ago) @ jag009 Posting: # 8525 Views: 5,770 |
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Dear John running a pilot parallel study does not necessarily mean that you have to conduct your pivotal studies also as parallel studies. But considering the long half life of the drug it is IMHO not reasonable to conduct a cross-over study. The CV% you get from the pilot is the total CV%, right. You use this to calculate your sample size for the pivotal study but it does not predetermine the design of the pivotal study. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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d_labes ★★★ Berlin, Germany, 2012-05-07 18:24 (5148 d 01:53 ago) @ Dr_Dan Posting: # 8526 Views: 5,708 |
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Dear Dan! ❝ ... The CV% you get from the pilot is the total CV%, right. You use this to calculate your sample size for the pivotal study but it does not predetermine the design of the pivotal study. Totally  Can you please elaborate what this means?— Regards, Detlew |
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jag009 ★★★ NJ, 2012-05-07 20:15 (5148 d 00:02 ago) @ Dr_Dan Posting: # 8527 Views: 5,676 |
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Dear Dan, I don't see how I can proceed with a pivtoal crossover study later. The CV (total CV) obtained from the parallel pilot study is not appropriate for estimating the crossover study sample size since one cannot extract the intraCV from the total CV. The dilemma I have now is timing... If I go with a crossover pilot --> probably 16 day sampling and 30 day washout --> bloody long study... If I go with parallel study then cost will be a factor... Double edge sword... John |
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Helmut ★★★   Vienna, Austria, 2012-05-07 21:31 (5147 d 22:46 ago) @ jag009 Posting: # 8528 Views: 5,866 |
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![[image]](img/uploaded/image3.jpg) Dear John,agree what you have said about the CV. ❝ ❝ […] I am considering running a pilot parallel study to compare a prototype generic against the innovator. Consider to be more restrictive as usual (maybe just one sex, narrow BMI, etc…) because any demographic difference between groups masks the treatment effect and will make your decision (stop/go with the prototype) more difficult. On the other hand these restrictions likely result in a smaller CV than in the pivotal study where this restrictions can’t be applied. Allow for a safety margin – but don’t ask me about it’s size.  ❝ The dilemma I have now is timing... If I go with a crossover pilot --> probably 16 day sampling and 30 day washout --> bloody long study... Is this an IR formulation? If yes, why don’t you plan for a truncated AUC approach (sampling for three days only)? You mentioned a half life of 100–120 hours. Is this a range or mean values from the literature? The washout (six half lives) might be a close shave (remember my bad experience?)… ❝ If I go with parallel study then cost will be a factor... Double edge sword... The claymore is the brave man’s very best friend. — 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, 2012-05-07 22:15 (5147 d 22:02 ago) @ Helmut Posting: # 8529 Views: 5,708 |
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Hi Helmut, You do look like the guy in the picture --> Highlander  Well I did some literature research this morning and found an article which studied the pk of a combination product that contained my drug of interest. It was a simple one arm study (one product, single dose exposure). Based on the mean AUC and SD, I think the inter CV is around 30% (I know I know, this is rough and dirty..) Regarding truncate AUC (72 hours), yes that would help and it is an IR formulation. But I am still looking for a month for washout + 3 days... The half-life of 100-120 hr is the reported mean but there have been values of 150 hr reported as well. I still need to find out what the lab will have as the LLoQ.. Regarding LLoQ, is there any requirement as to how low you have to go? I mean if I am aiming for less than 5% of the theoretical Cmax, would that do? Claymore? I always wanted a samurai sword myself  John |
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Dr_Dan ★★ Germany, 2012-05-08 14:17 (5147 d 06:00 ago) @ jag009 Posting: # 8530 Views: 5,738 |
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Dear John According to CPMP/QWP/EWP/1401/98 Rev. 1 AUC truncated at 72 h may be used as an alternative to AUC(0-t) for comparison of extent of exposure as the absorption phase has been covered by 72 h for immediate release formulations. A sampling period longer than 72 h is therefore not considered necessary for any immediate release formulation irrespective of the half life of the drug. If you use a cross-over design you have to be sure that you do not include slow metabolizers leading to a drug half life of >150 days, otherwise you might have to discuss carry-over effects. Regarding intra-subject variability, as long as you decide to conduct a parallel design pilot study your sample size would be just a guess and not calculated estimate. I suggest to run the pilot study in a cross-over design and the pivotal study in a parallel design. This will take the same time for both studies as you planned vice versa but you would have more reliable data from the pilot study to plan the pivotal study. I hope this helps. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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jag009 ★★★ NJ, 2012-05-10 17:15 (5145 d 03:02 ago) @ Dr_Dan Posting: # 8554 Views: 5,584 |
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Thanks everyone, One question regarding the truncated AUC 0-72 hrs. Is it applicable only for generic filing or it also applies to supplemental NDA filing? ie, changing from a Tablet to a Capsule (same strength, same indication), from capsule to a tablet, dosage strength proportionality studies? John |
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Helmut ★★★ Vienna, Austria, 2012-05-10 17:56 (5145 d 02:21 ago) @ jag009 Posting: # 8555 Views: 5,674 |
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Dear John! ❝ […] truncated AUC 0-72 hrs. Is it applicable only for generic filing or it also applies to supplemental NDA filing? ie, changing from a Tablet to a Capsule (same strength, same indication), from capsule to a tablet,… I don’t see any reason why the justification (completed absorption of IR products) should not be applicable to NDAs. See the introduction of the ![[image]](img/uploaded/IAsmall.png) FDA’s Guidance:This guidance is intended to provide recommendations to sponsors and/or applicants planning to include bioavailability (BA) and bioequivalence (BE) information for orally administered drug products in investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and their supplements. […] We believe that the guidance will be useful for applicants planning to conduct BA and BE studies during the IND period for an NDA, BE studies intended for submission in an ANDA, and BE studies conducted in the postapproval period for certain changes in both NDAs and ANDAs. ❝ … dosage strength proportionality studies? IMHO that’s an exception. Think about nonlinear PK (saturation, autoinduction). In dose-proportionality studies we are not only interested in absorption but also in detecting potential changes in clearance and therefore would assess primarily AUC0-∞. ❝ Claymore? I always wanted a samurai sword myself Yep. — 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, 2012-05-14 17:22 (5141 d 02:55 ago) @ Helmut Posting: # 8565 Views: 5,622 |
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Hi Helmut, ❝ IMHO that’s an exception. Think about nonlinear PK (saturation, autoinduction). In dose-proportionality studies we are not only interested in absorption but also in detecting potential changes in clearance and therefore would assess primarily AUC0-∞. Sorry I wasn't clear in the last email. I meant dosage strength proportionality study (2x100 vs 1x200), not dose proportionality study (100 mg vs 2x100 mg). In any case, it makes sense to use AUC0-72 for BA studies since I am dealing with the same compound, same indication etc etc and just a change from a tablet to a capsule formulation (vice versa) Thanks John |
Ing. Helmut Schütz