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Lucas ★ Brazil, 2014-02-10 21:01 (4516 d 21:08 ago) (edited on 2014-02-11 17:46) Posting: # 12389 Views: 11,381 |
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Hello. We conducted a crossover 2x2 study of Levothyroxine 25ug* and found a significant sequence effect (considering a significance level of 10%). According to ANVISA guidelines, a siginifcant sequence effect can only be desconsidered if the following criteria are met: “i. The study is a single dose study; ii. The study envolves only healthy subjects; iii. The drug is not an endogenous substance; iv. The washout period was adequate and the pre dose samples do not present any level of the drug for all subjects; v. The study satisfies all scientific and statistic criteria. Under others circustances, the study must be redone.” (my translation) I think it is worthy mentioning that ANVISA requires a basal correction where we have to collect three blood samples prior to the dose, and "correct" all values using the mean concentration of those three points (Quantified value - Mean basal concentration= Corrected Concentration). So, considering that, the study is useless, even though it was concluded the bioequivalence. What we can’t figure out is where the problem is. The washout period was 70 days (the FDA’s draft guidance on Levothyroxine suggests 35 days), the same as other 3 studies of Levothyroxine that we conducted with the same (or pretty close) dosage, between 600 – 630 ug. So it seems to me that this is not a true carry-over effect that the regulatory agencys fear so much. What are your thoughts on that? I mean, would you guys extend even more the washout period? Or even: can that sequence effect be somehow justified to be ignored? *At first I mistyped the strenght, where it was 65 ug it should say 25ug. |
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ElMaestro ★★★ Denmark, 2014-02-10 21:09 (4516 d 21:00 ago) @ Lucas Posting: # 12390 Views: 10,652 |
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Hi Lucas, ❝ We conducted a crossover 2x2 study of Levothyroxine 65ug and found a significant sequence effect (considering a significance level of 10%). According to ANVISA guidelines, a siginifcant sequence effect can only be desconsiderd if (...) This isn't sounding good. Before writing it off, I'd look at the data production. Did you observe a period effect (thyroid seasonal variation with 70day washout)? Did you check if your randomisation was useful? — Pass or fail! ElMaestro |
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Lucas ★ Brazil, 2014-02-11 13:24 (4516 d 04:45 ago) @ ElMaestro Posting: # 12394 Views: 10,597 |
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Hello ElMaestro! ❝ Did you observe a period effect (thyroid seasonal variation with 70day washout)? No, the p-value for period effect was >30%, so not even close to be significant. But, despite that, it seems like the second period baseline level was higher. This chart below is a representation of the ratio between the second period mean baseline and the first period mean baseline. ![[image]](img/uploaded/image221.png) Seems to me that there is a difference between the two period when it comes to baseline level. That behaviour was not noticed in the other studies. ❝ Did you check if your randomisation was useful? We did not ran any statistical test for that, but the study finalized with 12 subjects in one sequence and 13 in the other. |
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ElMaestro ★★★ Denmark, 2014-02-11 14:26 (4516 d 03:43 ago) @ Lucas Posting: # 12396 Views: 10,508 |
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Hi again, ❝ Seems to me that there is a difference between the two period when it comes to baseline level. That behaviour was not noticed in the other studies. A stability issue, then? Do you have comparative stability data and can you post the treatment means by period? — Pass or fail! ElMaestro |
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Lucas ★ Brazil, 2014-02-11 18:38 (4515 d 23:31 ago) @ ElMaestro Posting: # 12405 Views: 10,531 |
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ElMaestro ❝ A stability issue, then? Do you have comparative stability data and can you post the treatment means by period? You mean the stability of the samples? There was a variation of only 1% , levothyroxine is very stable. You want to see the plasma concentration means or the Cmax and AUC means? |
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jag009 ★★★ NJ, 2014-02-10 22:35 (4516 d 19:34 ago) @ Lucas Posting: # 12392 Views: 10,570 |
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Hi, Out of curiosity, how are the results if you don't correct for baseline (pass/fail, any sig effects?) John |
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Lucas ★ Brazil, 2014-02-11 13:28 (4516 d 04:41 ago) @ jag009 Posting: # 12395 Views: 10,547 |
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Hi John ❝ Out of curiosity, how are the results if you don't correct for baseline (pass/fail, any sig effects?) Pass with the same significant effects (only sequence effect for both analysis). P-value was 3.41% for Cmax and 6.92% for AUC0-72 in the non-corrected analysis and 8.84% for Cmax and 14.7% for AUC0-72. |
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jag009 ★★★ NJ, 2014-02-11 18:21 (4515 d 23:49 ago) @ Lucas Posting: # 12401 Views: 10,493 |
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Hi, ❝ Pass with the same significant effects (only sequence effect for both analysis). P-value was 3.41% for Cmax and 6.92% for AUC0-72 in the non-corrected analysis and 8.84% for Cmax and 14.7% for AUC0-72. Just to clarify (brain cramp this morning...) You meant: Non-corrected Analysis p values: Cmax = 0.0341, AUC 0.0692 Corrected Analysis p values: Cmax = 0.0884, AUC 0.1470 These are p values for sequence effect? If not, what are they? John |
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Lucas ★ Brazil, 2014-02-11 18:33 (4515 d 23:36 ago) @ jag009 Posting: # 12404 Views: 10,518 |
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Hi John ❝ These are p values for sequence effect? If not, what are they? Yes they are. You understand correctly. |
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Helmut ★★★   Vienna, Austria, 2014-02-11 16:07 (4516 d 02:02 ago) @ Lucas Posting: # 12399 Views: 11,248 |
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Hi Lucas, ❝ According to ANVISA guidelines, a siginifcant sequence effect can only be desconsidered if the following criteria are met: ❝ iii. The drug is not an endogenous substance; ❝ iv. The washout period was adequate and the pre dose samples do not present any level of the drug for all subjects; ❝ The washout period was 70 days (the FDA’s draft guidance on Levothyroxine suggests 35 days),… (iv.) 35 days are consistent with FDA’s general suggestion of five half-lives (average t½ ~one week in euthyroid subjects). IMHO, your ten weeks were not a bad idea (exceeding ANVISA’s seven half-lives). Nasty is (iii). You administered >10× the average therapeutic dose. Of course, the idea is to have a clear separation from the baseline. Since this is an endogenous compound and the dose is that high, who knows the impact on the hormone system? ❝ … the same as other 3 studies of Levothyroxine that we conducted with the same (or pretty close) dosage, between 600 – 630 ug. So it seems to me that this is not a true carry-over effect that the regulatory agencys fear so much. What are your thoughts on that? Duno. It might be a statistical artifact as well. See the meta-analyses by D’Angelo et al.1 They found significant effects in about the level of the test. See also the follow-up,2 comment3 and especially the rejoinder.4 ❝ I mean, would you guys extend even more the washout period? Or even: can that sequence effect be somehow justified to be ignored? Good questions. Next question.  I have some mixed feelings when it comes to endogenous compounds. You never know which effects you might induce in the body. In all (‼) cross-over studies on biosimilars I have seen there were significant sequence effects… Have a look at the total CVs of your studies. Maybe you can consider running a parallel study?
— 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, 2014-02-11 18:16 (4515 d 23:54 ago) @ Helmut Posting: # 12400 Views: 10,481 |
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Hi Helmut, Okay if you can send me these? 1. D’Angelo G, Potvin D and J Turgeon Carry-Over Effects in Bioequivalence Studies J Biopharm Stat 11(1–2), 35–43 (2001) DOI:10.1081/BIP-100104196 2. Senn S, D’Angelo G, and D Potvin Carry-over in cross-over trials in bioequivalence: theoretical concerns and empirical evidence Pharmaceut Statist 3(2), 133–42 (2004) DOI: 10.1002/pst.111 Thanks John |
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Lucas ★ Brazil, 2014-02-11 18:45 (4515 d 23:24 ago) @ Helmut Posting: # 12406 Views: 10,518 |
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Hello Helmut! ❝ Good questions. Next question. ❝ I have some mixed feelings when it comes to endogenous compounds. You never know which effects you might induce in the body. In all (‼) cross-over studies on biosimilars I have seen there were significant sequence effects… Have a look at the total CVs of your studies. Maybe you can consider running a parallel study? The inter-subject CV was 24~25%, so a parallel study may be a practical solution. I'll suggest that. Thanks. |
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Lucas ★ Brazil, 2014-02-11 18:32 (4515 d 23:37 ago) @ Lucas Posting: # 12403 Views: 10,507 |
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Hi everybody We have just finished the 4th study of Levothyroxine from the same manufacturer, on the strenghts of 25 ug, 63 ug, 100 ug and 200 ug. Only the 25ug presented a sequence effect. Someone here raised a question about the amount of tablets administered in that study, and if it may have any impact that could have caused the sequence effect. In order to use a dosage of 600 ug, 24 tablets had to be administered to the subjects. Is it possible that the high amount of tablets have caused a different response? Maybe some of the tablets did not release the drug immediatelly, causing a retard effect that affected the second period data, or something like that. Besides that, someone mentioned to me a "Memory effect", in which the human body learns how to deal with the drug, causing a different reaction at the second administration. I personally think that this is very hard to happen at only 1 single dose administration. |
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jag009 ★★★ NJ, 2014-02-11 21:01 (4515 d 21:08 ago) @ Lucas Posting: # 12407 Views: 10,469 |
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24 tables? wt* ❝ Maybe some of the tablets did not release the drug immediatelly, causing a retard effect that affected the second period data, or something like that. Possible, in one study we dosed 4x100 mg tablets and one subject data was weird (low concentration). ❝ Besides that, someone mentioned to me a "Memory effect", in which the human body learns how to deal with the drug, causing a different reaction at the second administration. I personally think that this is very hard to happen at only 1 single dose administration. I doubt that. Too sci-fi for me. John |
Ing. Helmut Schütz