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Dr_Dan ★★ Germany, 2010-12-15 10:49 (5662 d 19:32 ago) Posting: # 6304 Views: 6,776 |
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Dear all "In general, a bioequivalence study should be conducted under fasting conditions as this is considered to be the most sensitive condition to detect a potential difference between formulations." (CPMP/QWP/EWP/1401/98 Rev. 1). The drug under discussion can not be administered in the fasted state due to gastro-intestinal complications. The SmPC does not contain any information about the composition of a meal to be taken. When given with a high-fat meal, the rate of absorption of the drug under discussion was reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a reduction in AUC (7.4%) compared to fasting conditions. The Q&A document points out that: "The composition of the meal should be described and taken into account, since a light meal might sometimes be preferable to mimic clinical conditions, especially when the fed state is expected to be less sensitive to differences in pharmacokinetics." We performed a BE study: two-way cross-over single dose after administration of a light meal in 28 subjects. The results show perfect bioequivalence, low inter-subject (ca. 25%) and low intra-subject (>10%) variability. At time of clinical conduct the old Guideline CPMP/QWP/EWP/1401/98 with the respective Q&A document EMEA/CHMP/EWP/40326/2006 was effective. The study was performed in accordance with these guidelines. At time of clinical conduct the revision of above mentioned guideline was plannned and a draft version already existed. The study was also performed in accordance with this draft guideline. Only after clinical conduct the revised version of Guideline CPMP/QWP/EWP/1401/98 Rev. 1 was published. In fact now a high-fat and high-calorie meal is demanded. Therefore we performed a second BE study: two-way cross-over single dose after administration of a high-fat and high-calorie meal in 18 subjects. The results show again perfect bioequivalence with nearly exact the same results, approximately the same low inter-subject and low intra-subject variability. The studies were performed by the same CRO with the same test and reference batches. Now my question: Would it be possible to evaluate both studies together to show retrospectively that (at least in case of the drug under discussion) the demand for a high-fat and high-calorie meal is unnecessary (as I predicted a priori)? Could I use an inbalanced parallel design approach? I am looking forward to your replies. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★   Vienna, Austria, 2010-12-15 14:50 (5662 d 15:31 ago) @ Dr_Dan Posting: # 6305 Views: 5,731 |
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Dear Dan! ❝ [...] The study was also performed in accordance with this draft guideline. ❝ Only after clinical conduct the revised version of Guideline ❝ CPMP/QWP/EWP/1401/98 Rev. 1 was published. In fact now a high-fat and ❝ high-calorie meal is demanded. ❝ Therefore we performed a second BE study: two-way cross-over single dose ❝ after administration of a high-fat and high-calorie meal in 18 subjects. Wow, using belt and braces! (German: Gürtel mit Hosenträger)  ❝ Would it be possible to evaluate both studies together to show retrospectively ❝ that [...] the demand for a high-fat and high-calorie meal is unnecessary ❝ [...] ? Could I use an inbalanced parallel design approach? Definitely. You will get estimates of the 'influence of the type of food on BE', both for test and reference. — 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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d_labes ★★★ Berlin, Germany, 2010-12-15 16:37 (5662 d 13:44 ago) @ Helmut Posting: # 6306 Views: 5,699 |
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Dear Dan, dear Helmut! ❝ ❝ Would it be possible to evaluate both studies together ... ❝ ❝ [...] ? Could I use an inbalanced parallel design approach? ❝ ❝ Definitely. You will get estimates of the 'influence of the type of ❝ food on BE', both for test and reference.  ? Both studies are cross-over. Pooling them should give a parallel group comparison? Moreover I wonder what new information a pooled evaluation should show? In both cases, normocaloric or high fat meal, BE has shown. What else? — Regards, Detlew |
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Helmut ★★★ Vienna, Austria, 2010-12-15 17:10 (5662 d 13:11 ago) @ d_labes Posting: # 6307 Views: 5,643 |
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Dear D. Labes! ❝ ❝ ❝ Would it be possible to evaluate both studies together ... I missed the term 'together'! ❝ I'm not quite sure what type of evaluation you mean with imbalanced ❝ parallel design approach? ❝ Both studies are cross-over. Pooling them should give a parallel group ❝ comparison? Well, pooling doesn't make sense, of course. A comparison of subjects under test (meal type 1 in study 1 vs. meal type 2 in study 2) is a parallel design and imbalanced (Dan knows). The same holds for reference. Therefore one would get two assessments. — 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, 2010-12-15 17:53 (5662 d 12:28 ago) @ Helmut Posting: # 6309 Views: 5,647 |
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Dear Helmut! ❝ Well, pooling doesn't make sense, of course. A comparison of subjects ❝ under test (meal type 1 in study 1 vs. meal type 2 in study 2) is a ❝ parallel design and imbalanced (Dan knows). The same holds for reference. ❝ Therefore one would get two assessments. Ok. I understand  . But this relies on the assumption of no period effect I think?What do you think about an evaluation via incomplete blocks cross-over (I hope the terminus is the correct one )? I.e. 4-treatment-4-sequence-2-period cross-over. T1, R1 are under normocaloric conditions, T2, R2 under high-fat.— Regards, Detlew |
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Helmut ★★★ Vienna, Austria, 2010-12-15 18:03 (5662 d 12:18 ago) @ d_labes Posting: # 6310 Views: 5,631 |
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Dear D. Labes! ❝ Ok. I understand ❝ effect I think? Yes. But there are similar designs commonly applied. Think about a PK study where we compare MD profiles with the first SD profiles. That's a paired design, but (has to) assume no period effect as well. ❝ What do you think about an evaluation via incomplete blocks cross-over (I ❝ hope the terminus is the correct one ❝ 4-treatment-4-sequence-2-period cross-over. T1, R1 are under normocaloric ❝ conditions, T2, R2 under high-fat. Nice question, next question. But I guess that should be possible. — 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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Dr_Dan ★★ Germany, 2010-12-15 17:33 (5662 d 12:48 ago) @ Helmut Posting: # 6308 Views: 5,667 |
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Dear Helmut! ❝ Wow, using belt and braces! (German: Gürtel mit Hosenträger) Marketing people don't like risks, they always want to be on the absolut safe side as long as they do not understand the problem... In his own company the prophet will not be accepted. I did not want to conduct a second study. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
Ing. Helmut Schütz