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d_labes ★★★ Berlin, Germany, 2009-12-17 13:04 (6033 d 13:52 ago) Posting: # 4491 Views: 7,908 |
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Dear All, within the scope of bioequivalence studies one has usually not to deal with any 'center effects'. This is simply because BE studies are usually performed at one center only, monocentric. But usually ... is not always ever  .Thus in the near future I have to deal with my first multicenter cross-over bioequivalence study, moreover with patients instead of healthy volunteers. Since the guidelines do not deal with multi-center studies to a great extent (not to say the extent is not significant different from zero  ) I have some uncertainties. My questions:
BTW: The study is aimed to the European regulators. — Regards, Detlew |
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ElMaestro ★★★ Denmark, 2009-12-17 13:47 (6033 d 13:10 ago) @ d_labes Posting: # 4492 Views: 6,847 |
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Ahoy d_labes I am not sure I understand much of anything. I might not use a specification of centers in the final evaluation at all. It is a between-subject factor, so a phenomenon arising from center effects is not likely to affect your BE conclusion (perhaps a weird treatment by center interaction might potentially be confounding?!? perhaps test the raw center effect -low power- then exclude from model as nonsignificant). If in a deficiency letter it is asked for I would probably treat center as fixed. Subjects in Sequences in centers is treated the same as subjects in centers in sequences. Best regards, EM. |
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Helmut ★★★   Vienna, Austria, 2009-12-17 14:47 (6033 d 12:09 ago) @ d_labes Posting: # 4493 Views: 6,812 |
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Dear D. Labes, I agree with our Capt'n. Since the study is intended for European submission, I wouldn't bother too much. The NfG states (Section 3.6.1): The statistical analysis (e.g. ANOVA) should take into account sources of variation that can be reasonably assumed to have an effect on the response variable. (my emphasis)In many cases subjects are split into two (or more) groups due to logistic reasons, but only in a minority of cases 'group' is included in the model. I have seen just a few problems in the EU - but a lot of questions from the Gulf States... I would say, the same principle applies to more than one center. Since you use the same protocol, my simple mind doesn't see a big deal. I would have an eye not only on the clinical performance, but on identical handling of samples in the centers (e.g., time interval between sample draw and centrifugation, cooling, g-force and duration of centrifugation, storage). I wouldn't include center as a factor. From my personal experience (talking about the analogous 'group' factor), a significant effect is rarely seen (as the Capt'n said: between-subject factor has low power). But, what if? We can expect to see one in ~alpha of cases... To be prepared for the worst (the pooled analysis is not accepted), I would suggest to split subjects not in roughly equal group sizes amongst centers, but to try to allocate as many subjects as possible to the 'largest' center. An example: Clinical capacity 24 beds, T/R 93%, CV 20%, power 90% for n=32. If we allocate the 32 subjects to two centers of 16 subjects each, a significant effect is seen and pooling is not accepted by authorities, power drops to 64.6% (n=16). If we allocate 24/8, power in the larger center (n=24) would be still 81.7%. On the other hand it's interesting that FDA states: If the study is carried out in two or more groups and those groups are studied at different clinical sites, or at the same site but greatly separated in time (months apart, for example), questions may arise as to whether the results from the several groups should be combined in a single analysis. Such cases should be discussed with the appropriate CDER review division. (my emphases)Personal experience: nil. — 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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ElMaestro ★★★ Denmark, 2009-12-17 15:18 (6033 d 11:38 ago) @ d_labes Posting: # 4494 Views: 6,877 |
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Hi d_labes, I'd just like to add a little on basis of what's specified in ICH E9, page 12. Basically, the document gives two reasons for using multiple centers 1. Recruitment/speed issues 2. Generalisation Your situation is in my opinion covered by the first reason and not at all by the second (because you have no reason to generalise anything related to contre diversity, and that's also why center should imho be fixed, not random, in case it's to be included in the evaluation; but this is an issue that applies more frequently to originator drugs). To me most of chapter 3.2 must have been written with superiority trials in mind, not equivalence. Best regards, EM. Edit: ICH-E9 linked. [Helmut] |
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d_labes ★★★ Berlin, Germany, 2009-12-17 16:28 (6033 d 10:28 ago) @ ElMaestro Posting: # 4495 Views: 6,737 |
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Dear ElMaestro, dear Helmut, THX for sharing your opinion. If I understand you right you suggest me to do the usual evaluation (ignoring the centers) and to wait for a deficiency letter?  And if it happens (low chance) then answer "Due to the identical protocol, due to the identical handling of blood samples, central assay of the blood samples, blah, blah ... no influence of the different centers was expected at all."? Eventually this could/should be included in the study report beforehand. Helmut: Your suggestion of splitting the number of subjects not even between the centers sounds very reasonable. But we can not follow it. As I said, the multicenter design is used for speed reasons and therefore each center is asked to do its very best. At the whole I agree with your (both of you) views. I think its the same story as with carry-over. We make our best to avoid any differences between centers and should therefore base our evaluation on that assumption that there are no such differences. If we do it not that way, we ran into the same difficulties as with a test of carry-over. Test it with a test of low power and then decide on that test what to do next. Meanwhile its widely recognized (also between regulators) that this approach is flawed in the context of carry-over. But especially the FDA citation and the discussions about 'group effect' here in the forum had let me to my questions, also the study is not intended for an FDA submission (at lest not yet). To be prepared ... — Regards, Detlew |
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Helmut ★★★ Vienna, Austria, 2009-12-17 16:52 (6033 d 10:05 ago) @ d_labes Posting: # 4496 Views: 6,726 |
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Dear D. Labes, ❝ If I understand you right you suggest me to do the usual evaluation ❝ (ignoring the centers) and to wait for a deficiency letter? First part: yes, second part: no. OK, all of us are waiting for deficiency letters all the time. So it doesn't make a difference here.  ❝ And if it happens (low chance) then answer "Due to the identical protocol, ❝ due to the identical handling of blood samples, central assay of the blood ❝ samples, blah, blah ... no influence of the different centers was expected ❝ at all."? Eventually this could/should be included in the study report ❝ beforehand. I would suggest to write the "blahblah" in the study protocol (not the report). — 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, 2009-12-18 09:12 (6032 d 17:44 ago) @ Helmut Posting: # 4499 Views: 6,566 |
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Dear Helmut, ❝ I would suggest to write the "blahblah" in the study protocol ❝ (not the report). Sadly: Too late! As it happens, the statistician was asked after finalizing the protocol (as it happens as nearly always under time pressure). — Regards, Detlew |
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ElMaestro ★★★ Denmark, 2009-12-17 19:41 (6033 d 07:15 ago) @ d_labes Posting: # 4498 Views: 6,704 |
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Dear d_labes, ❝ And if it happens (low chance) then answer "Due to the identical protocol, ❝ due to the identical handling of blood samples, central assay of the blood ❝ samples, blah, blah ... no influence of the different centers was expected ❝ at all."? How about: "In order to address the concern of the assessor, it is necessary to consider how center as a factor may affect the conclusion of bioequivalence. The conclusion about BE is based on the T/R point estimate and the intra-subject variability (ln(T)-ln(R) and variability of it); if the decision of BE hinges on center performance in a manner that is unfavourable to the patient then it implies - one or more centres affecting the intrasubject variability negatively and/or - one or more centres resulting in flawed estimation of the T/R point estimate. This effectively translates into presence of a treatment by center interaction, for example that the performance of T is truly constant across centers while the performance of R truly varies across centers (or vice versa and et cetera). It is dfficult to see how the two factors could interact, especially because the production of a formulation in a time and space that is separate from the centre. Differential handling ability among the centres cannot be ruled out (*), but this would increase the intra-subject variability (sponsor's risk) but would not affect the patient's risk. Center is therefore not considered a concern for the evaluation of bioequivalence." Or something like that ...  EM. (*): The study nurse at centre X had rheumatism and could not open the bottles of T because the caps were screwed too tight while she handled the bottles of R just as well as the nurse at the other center (who was not rheumatic) handled both the T bottles and the and R bottles. Obviously lacking T tablets at centre X, the nurse decided to give the subjects aspirin in stead????? Yeah right, this treatment by centre interaction thing sounds really realistic. |
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d_labes ★★★ Berlin, Germany, 2009-12-18 09:34 (6032 d 17:23 ago) @ ElMaestro Posting: # 4500 Views: 6,618 |
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Dear ElMaestro, ❝ How about: ❝ "In order to address the concern of the assessor ... ❝ ...  THX so very much! I will keep this gem of a text and, if the low chance comes true, use it! But I think the footnote I will leave better out. There is a chance greater than zero that an assessor may argue: You wanna shit'n me? Or in Berlin slang: "Verarschen kann ick ma alleene!". — Regards, Detlew |
Ing. Helmut Schütz