kumarnaidu ★ Mumbai, India, 2014-11-10 09:16 (3453 d 02:58 ago) Posting: # 13848 Views: 14,270 |
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Dear All, Draft FDA guidance on Methylphenidate Hydrochloride Released: Draft Guidance on Methylphenidate Hydrochloride — Kumar Naidu |
Helmut ★★★ Vienna, Austria, 2014-11-10 14:57 (3452 d 21:17 ago) @ kumarnaidu Posting: # 13850 Views: 13,159 |
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Hi Kumar, THX for posting! These requirements will be tough to meet.
— 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 |
AngusMcLean ★★ USA, 2014-11-11 20:26 (3451 d 15:49 ago) @ Helmut Posting: # 13860 Views: 12,989 |
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Helmut, can the (subject by formulation) interaction be done in Phoenix WinNonlin? I wonder if it is in the Pharsight templates, which are being redeveloped for the new edition of Phoenix (6.4)? Angus |
Helmut ★★★ Vienna, Austria, 2014-11-11 22:05 (3451 d 14:09 ago) @ AngusMcLean Posting: # 13862 Views: 12,999 |
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Hi Angus, ❝ Can the (subject by formulation) interaction be done in Phoenix WinNonlin? You don’t need the templates. Run conventional ABE with the default setup:
Final Variance Parameters > lambda(2,2)_11 is the estimated subject×formulation interaction, Var(Period*Formulation*Subject)_21 is σ²wR, and Var(Period*Formulation*Subject)_22 is σ²wT. It should be possible to merge the degrees of freedom, get cinv(0.05, df) , and calculate the upper bound directly. Have to check. If not, all the necessary data to follow Step 4 of the guidance are available.— 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 |
AngusMcLean ★★ USA, 2014-11-12 20:25 (3450 d 15:49 ago) @ Helmut Posting: # 13863 Views: 12,896 |
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Thank you Helmut that appears to be fine: The subject-by-formulation interaction variance is the variation in the average T and R difference in PK parameter among individuals. The estimated lambda(2,2)_11 is the estimated variance for the subject×formulation interaction and is 8.3391924E-07 from the ABE Object in the Pharsight RSABE FDA template. It seems we should be able to calculate the upper 95% confidence interval from the information we have. Now fundamentally exactly how do we do that? I am told by Ana that this was never included in the templates. Angus |
AngusMcLean ★★ USA, 2014-11-21 01:28 (3442 d 10:46 ago) @ Helmut Posting: # 13896 Views: 12,076 |
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Helmut: Again I looked at he subject by formulation interaction from the Pharsight progesterone template it is a rather small number {8.3391924E-07 from the ABE Object in the RSABE FDA template, final variance paramaters tab} This number is taken from "Final Variance Parameters > lambda(2,2)_11 is the estimated subject×formulation" I am wondering am I misunderstanding the outpput. Surely it is way too low, I looked at a stick plot of the repsonse variable (AUC) Please can you comment, Angus |
jag009 ★★★ NJ, 2014-11-16 04:39 (3447 d 07:35 ago) @ Helmut Posting: # 13870 Views: 12,655 |
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Hi Helmut, ❝ THX for posting! These requirements will be tough to meet. Laszlo E is not amused John |
Helmut ★★★ Vienna, Austria, 2014-11-17 13:49 (3445 d 22:25 ago) @ jag009 Posting: # 13871 Views: 12,557 |
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Hi John, ❝ Laszlo E is not amused Yes. He also pointed to the last paragraph on page 6. On has to calculate the upper 95% confidence bound for σ²D – but the guidance doesn’t give an acceptance limit for it. Like in the 2001 stats guidance we only find “the recommended allowance for σ²D is 0.03”. Why struggle with its CL if only the estimate has to be assessed? — 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 |
jag009 ★★★ NJ, 2014-11-17 18:29 (3445 d 17:46 ago) @ Helmut Posting: # 13872 Views: 12,435 |
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Hi Helmut, Did he tell you that the calculation is not even correct or something? I don't remember his exact words but he said he proved something in his previous paper. I will find.. John |
Helmut ★★★ Vienna, Austria, 2014-11-18 04:56 (3445 d 07:18 ago) @ jag009 Posting: # 13873 Views: 12,486 |
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Hi John, ❝ Did he tell you that the calculation is not even correct or something? Yep: “[…] we demonstrated in our papers that the estimated interaction is related, and proportional, to the within-subject variance. Therefore, it does not make sense to set a critical value for its estimate or its confidence limit.” — 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 |
AngusMcLean ★★ USA, 2014-11-19 14:28 (3443 d 21:46 ago) @ Helmut Posting: # 13878 Views: 12,278 |
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Helmut, presumably they have decided not to set a limit, since right now they do not have the data to do it. Once they have submissions coming in from sponsors then they could look at the values then set a limit or alternatively drop the requirement. |
kumarnaidu ★ Mumbai, India, 2014-12-09 09:36 (3424 d 02:38 ago) @ Helmut Posting: # 14032 Views: 11,199 |
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Hello all, One thing I want to confirm here that if for any of the parameter Swr >0.294 observed then can we use scaled approach there? — Kumar Naidu |
Helmut ★★★ Vienna, Austria, 2014-12-09 14:18 (3423 d 21:56 ago) @ kumarnaidu Posting: # 14033 Views: 11,167 |
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Hi Kumar, ❝ One thing I want to confirm here that if for any of the parameter Swr >0.294 observed then can we use scaled approach there? I don’t think so. Quoting the guidance: The 90% confidence intervals of the geometric mean test/reference (T/R) ratios for the above five Cmax and AUC metrics (Cmax, AUC0-T1, AUCT1-T2, AUCT2-T3, AUC0-∞) should fall within the limits of 80–125%. Not a single word about reference-scaling. Given the intrasubject variabilities of these metrics I don’t see a justification.— 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 |
kumarnaidu ★ Mumbai, India, 2014-12-09 15:19 (3423 d 20:56 ago) @ Helmut Posting: # 14034 Views: 11,220 |
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Hi Helmut, Actually one of my friend recently did this study and according to him he is getting ISCV around 32% for one of the partial AUCs and the upper limit of T/R ratio for that parameter is 127%. And he planning to use scaled approach. One more thing for one of the parameter he is getting σ²D >0.03 and the T/R ratio within 80 to 125 (borderline pass). How to justify here ? (I dont know how he completed this study in one month) — Kumar Naidu |
Helmut ★★★ Vienna, Austria, 2014-12-09 15:50 (3423 d 20:25 ago) @ kumarnaidu Posting: # 14035 Views: 11,410 |
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Hi Kumar, ❝ Actually one of my friend recently did this study and according to him he is getting ISCV around 32% for one of the partial AUCs and the upper limit of T/R ratio for that parameter is 127%. Tell your friend that he should evaluate the study according to the protocol. Since the study is already completed it was performed according to the ”old” guidance, right? Not a word about RSABE. Upper CL 127% = study failed to show BE. Interesting that he performed a replicate design. ❝ And he planning to use scaled approach. In an attempt to “safe” a study which failed according to the protocol? Maybe. See the RTR guidance, Section “Failed In Vivo BE Studies”: FDA will refuse-to-receive an ANDA if only a failed in vivo BE study is submitted. FDA regulations require applicants to submit information on failed BE studies. Typically, a failed study is one that does not satisfy the 90% confidence interval (CI) criterion (i.e., falls outside of the 0.8–1.25 acceptance criterion limits) for either area under curve (AUC) or the peak plasma concentration (Cmax) parameter. If this occurs for highly variable drug products, the applicant should submit a study using a replicate study design and analyze data using a reference-scaled average (RSA) approach for the failed parameter. Alternatively, applicants should consult the BE recommendations webpage for product-specific study information or contact OGD’s Division of Bioequivalence via a BE Guidance Request for further guidance if needed. Some thoughts:
❝ One more thing for one of the parameter he is getting σ²D >0.03 and the T/R ratio within 80 to 125 (borderline pass). How to justify here ? What do you mean by “justify”? That’s really bad luck. — 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 |
drgunasakaran1 ★★ 2014-11-10 19:29 (3452 d 16:46 ago) @ kumarnaidu Posting: # 13852 Views: 12,994 |
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Dear Kumar, Thanks for sharing the revised guidance. As Mr Helmut rightly said, they are asking for additional partial AUCs which will be difficult to match and suggested to estimate subject-by-formulation interaction..! Will this subject-by-formulation estimation applies for other Bimodal release formulations too.? — Dr S Gunasakaran MBBS MD Disclaimer: The replies/posts are my personal opinions and it does not represent my company views on the same. |
jag009 ★★★ NJ, 2014-11-11 19:04 (3451 d 17:10 ago) @ drgunasakaran1 Posting: # 13858 Views: 12,888 |
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I don't like the subject x formulation interaction evaluation. What if a sponsors conducted the studies based on last guidance (2way studies), there is no way to perform the sub x form interaction analysis (?) even if they managed to pass every PK parameters... Why do we need to evaulate the sub x form interaction??? Looks to me like an overkill. John |
AngusMcLean ★★ USA, 2014-11-11 20:22 (3451 d 15:53 ago) @ drgunasakaran1 Posting: # 13859 Views: 12,960 |
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I think it may be applied to other MP bimodal formulations. I would study the fundamental release aspects of Concerta in vitro and invivo. Then I would think of analogous metrics as is appropriate for your drug of interest. In other words make a plan in case you are asked to include partial exposure metrics. If it applies to Concerta I myself can see no reason why this would not be applied to other bimodal drugs. Any comments, Angus |
jag009 ★★★ NJ, 2014-11-11 21:08 (3451 d 15:06 ago) @ AngusMcLean Posting: # 13861 Views: 12,923 |
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I kind of understand the logic for this with Concerta due to its zero order release ER component. Whereas for other bimodals like Adderall XR, Metadate CD, it's different. John |
jag009 ★★★ NJ, 2014-11-13 21:17 (3449 d 14:58 ago) @ jag009 Posting: # 13864 Views: 12,892 |
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The biggie starts! http://finance.yahoo.com/news/mallinckrodt-plc-responds-fda-expected-110000949.html Wonder if we will see Adderall XR generic on the same topic soon. |
AngusMcLean ★★ USA, 2014-11-14 00:06 (3449 d 12:08 ago) @ jag009 Posting: # 13866 Views: 12,701 |
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I am thinking "yes". But the metrics should be appropriate for XR (double- pulsed delivery), since XR comprises an IR bead plus an EC bead releasing at pH 5.5. |
nobody nothing 2014-11-19 10:30 (3444 d 01:45 ago) @ AngusMcLean Posting: # 13875 Views: 12,540 |
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Clix me What I think is interesting is that the FDA started BE AND clin. study, apparently not fully trusting the concept of BE anymore regarding some special drugs. Comes down to the discussion we had lately on how to set up "appropriate" BE limits in general (and how products tested according to these limits perform under real-life conditions)... — Kindest regards, nobody |
AngusMcLean ★★ USA, 2014-11-19 14:42 (3443 d 21:32 ago) @ nobody Posting: # 13879 Views: 12,327 |
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What they are doing with methylphenidate (Concerta in this case) is linking the established onset and duration of the drug effect (12 hours) with corresponding BE AUC intervals across the 12 hour period. As far as I know they generally stick with the usual 80-125 intervals. Perhaps in Europe, in general, there is more flexibility on occasions for the intervals? Angus |
nobody nothing 2014-11-19 14:55 (3443 d 21:19 ago) @ AngusMcLean Posting: # 13880 Views: 12,665 |
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Other range of 90%-111% only for narrow therapeutic index drugs in Europe The truncated AUC concept is clear, but they don't trust a BE trial in healthy adults at the FDA and started a PK-PD study in children, that's the point where I say: The concept of BE is not accepted any more in general. — Kindest regards, nobody |
Helmut ★★★ Vienna, Austria, 2014-11-19 16:44 (3443 d 19:31 ago) @ nobody Posting: # 13884 Views: 12,425 |
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Hi nobody & Angus, ❝ Other range of 90%-111% only for narrow therapeutic index drugs in Europe AFAIK a generic of Concerta passed a centralised procedure a while ago. EMA accepted ABEL (i.e., widening of the acceptance range) not only for Cmax, but also for the (first only?) pAUC. The same is mentioned in the MR-Draft (line 810). Let’s wait for the final version. I’m pretty sure that most (all?) other MR formulations in the EU were hybrid applications: BA-studies against IR MPH given twice (τ 4 hours) plus one (or more) therapeutic equivalence studies in children. BTW, approved MR formulations are not interchangeable.1,2
— 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 |
nobody nothing 2014-11-19 17:05 (3443 d 19:09 ago) @ Helmut Posting: # 13886 Views: 12,253 |
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Why not interchangeable when MA was granted based on BE-studies for at least one formulation? Could you provide some details on the reasons? Thanx nobody PS: Found somefink interesting, a strange company called BEBAC has apparently been digging deep into methylphenidate in the past... http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Methylphenidate_Hexal/WC500156885.pdf — Kindest regards, nobody |
Helmut ★★★ Vienna, Austria, 2014-11-19 17:59 (3443 d 18:16 ago) @ nobody Posting: # 13887 Views: 12,405 |
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Hi nobody, ❝ Why not interchangeable when MA was granted based on BE-studies for at least one formulation? Could you provide some details on the reasons? This particular one was BE to Concerta and no clinical studies were performed. The other products stand on their own (clinical data) and these two papers show lack of BE between them. ❝ PS: Found somefink interesting, a strange company called BEBAC has apparently been digging deep into methylphenidate in the past... Well yes, though I didn’t support Hexal in this project. My presentations are licensed and they quoted the source correctly. But they used it for commercial purposes (violating the license). Shall I sue them? — 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 |
nobody nothing 2014-11-19 18:10 (3443 d 18:04 ago) @ Helmut Posting: # 13888 Views: 12,184 |
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They didn' ask or pay for that? WOW, that's a bold move... at the best. But pharma-world is small in Europe, so... YOUR choice Maybe call Ms T-F? — Kindest regards, nobody |
Helmut ★★★ Vienna, Austria, 2014-11-19 18:16 (3443 d 17:59 ago) @ nobody Posting: # 13889 Views: 12,252 |
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Hi nobody, ❝ They didn' ask or pay for that? Neither nor. ❝ WOW, that's a bold move... at the best. Yep. ❝ But pharma-world is small in Europe, so... YOUR choice Maybe call Ms T-F? Good idea! PS: A cut-off time of two hours in fed state is crap. — 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 |
AngusMcLean ★★ USA, 2014-11-19 18:45 (3443 d 17:29 ago) @ Helmut Posting: # 13890 Views: 12,231 |
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I think the fed within subject variability chart is interesting: it shows the variability at the earlier time intervals in the fed state is huge and that makes the point very well. I am thinking that the food delays gastric emptying so the formulations are retained in the stomach ~ 3 hours prior to transiting to the small intestine. {would have thought that Concerta would be OK, since it has an IR overcoat component}. I wonder how the within subject variability in the fasted state compares with the fed state for such formulations at the corresponding time intervals. Angus |
Helmut ★★★ Vienna, Austria, 2014-11-19 21:15 (3443 d 15:00 ago) @ AngusMcLean Posting: # 13891 Views: 12,279 |
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Hi Angus, ❝ […] it shows the variability at the earlier time intervals in the fed state is huge and that makes the point very well. I am thinking that the food delays gastric emptying so the formulations are retained in the stomach ~ 3 hours prior to transiting to the small intestine. Exactly. That’s actually the idea behind formulations with differently coated pellets. ❝ {would have thought that Concerta would be OK, since it has an IR overcoat component}. Concerta shows a smaller food effect, but we see some shift in osmotic pumps as well. ❝ I wonder how the within subject variability in the fasted state compares with the fed state for such formulations at the corresponding time intervals. That’s a difficult question. There are formulations with different release mechanisms on the market. All show a food effect (practically only on rate metrics), some don’t work in fasted state very well (dose dumping), most fail in vitro alcohol-induced dose dumping, variability of the early phase in fed state might be higher (most formulations) or lower (some drugs)… — 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 |
nobody nothing 2014-11-19 22:04 (3443 d 14:11 ago) @ Helmut Posting: # 13892 Views: 12,275 |
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…if you want to reduce food effect, multiple-unit formulations is usually a good try, but no guarantee.. — Kindest regards, nobody |
Helmut ★★★ Vienna, Austria, 2014-11-19 22:49 (3443 d 13:25 ago) @ nobody Posting: # 13893 Views: 12,314 |
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Hi nobody, ❝ …if you want to reduce food effect, multiple-unit formulations is usually a good try, … which AFAIK all non-osmotic pump formulations of MPH are. ❝ … but no guarantee.. Xactly. — 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 |