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ratnakar1811 ★ India, 2011-08-03 09:21 (5442 d 09:30 ago) Posting: # 7253 Views: 6,054 |
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Dear All members, This is regarding the exclusion of subject from the calculation of AUCinf, in a study one of the subject did not arrive for any of the ambulatory sample (3 samples till 96 hr post dose) because of which AUC inf could not be calculated reliably (AUC% extrapolated was about 68%), in this situation can we exclude the subject with the justification? Because current EU guideline mentions in section Reason for exclusion page 14 of 27 that AUC(0-t) should cover at least 80% of AUC(0-∞). Subjects should not be excluded from the statistical analysis if AUC(0-t) covers less than 80% of AUC(0-∞), but if the percentage is less than 80% in more than 20% of the observations then the validity of the study may need to be discussed. This does not apply if the sampling period is 72 h or more and AUC(0-72h) is used instead of AUC(0-t). Further what does the last sentence signifies, "This does not apply if the sampling period is 72 h or more and AUC(0-72h) is used instead of AUC(0-t)." Best Regards, Ratnakar |
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Helmut ★★★   Vienna, Austria, 2011-08-03 15:55 (5442 d 02:56 ago) @ ratnakar1811 Posting: # 7254 Views: 5,252 |
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Dear Ratnakar! ❝ This is regarding the exclusion of subject from the calculation of AUCinf, in a study one of the subject did not arrive for any of the ambulatory sample (3 samples till 96 hr post dose) because of which AUC inf could not be calculated reliably (AUC% extrapolated was about 68%), in this situation can we exclude the subject with the justification? If it was stated in the protocol, yes (see the section of the GL you quoted already). If not, present a sensitivity analysis (i.e., with and without the subject). Remember that you don’t have to exclude all of the subject’s data, only AUC! You still may use his/her Cmax. Since generally the sample size of BE studies are based on the (higher variable) Cmax, I wouldn’t worry too much about loosing a little bit power of AUC. ❝ Further what does the last sentence signifies, "This does not apply if the sampling period is 72 h or more and AUC(0-72h) is used instead of AUC(0-t)." This is only a reminder that extrapolated AUC is of no importance if AUC truncated at 72h (AUC(0-72h)) was the main metric for extent of absorption according to protocol (see the GL Section 4.1.5). — 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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ratnakar1811 ★ India, 2011-08-04 10:51 (5441 d 08:00 ago) @ Helmut Posting: # 7256 Views: 5,182 |
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Dear HS, Thanks for your prompt reply. It is not mentioned in the protocol but it has been mentioned in my SOP and AUCinf is not a primary parameter as per protocol. As you rightly said, I am asking about exclusion of subject only from AUCinf analysis and not from complete analysis, but guideline also says that “Exclusion of data cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because….” in the same section. Further regarding the following sentence "This does not apply if the sampling period is 72 h or more and AUC(0-72h) is used instead of AUC(0-t)." I am confused about the word ‘..or more..', as in the situation of truncated study upto 72 hrs I can understand but what about the drugs where we have sampling period more than 72 hrs as mnetioned in the GL or drugs with small half life where AUCinf can be obtained before 72 or 96 hrs. Regards, Ratnakar |
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Helmut ★★★ Vienna, Austria, 2011-08-04 13:09 (5441 d 05:43 ago) @ ratnakar1811 Posting: # 7258 Views: 5,202 |
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Dear Ratnakar! ❝ It is not mentioned in the protocol but it has been mentioned in my SOP […] My suggestion: Always describe ‘critical’ steps in great detail in the protocol – not only in an SOP. The protocol goes through approval (regulatory + IEC), whereas SOPs do not. If an assessor has questions later on, you have much better arguments if the processes are already described. ❝ […] and AUCinf is not a primary parameter as per protocol. EMA doesn’t even ask for it as secondary. Report the GLSM (±CV) for test and reference only. AUC(0-∞) is only required to assess the extrapolated AUC. EMA thinks that AUC(0-t) is ‘the most reliable measure of extent of exposure’ if AUC(0-t) ≥80% of AUC(0-∞). Whilst it has been shown that this is not the case (sampling until 2 to 4×tmax is enough), it would be a tough job to convince EMA. ❝ I am asking about exclusion of subject only from AUCinf analysis and not from complete analysis, but guideline also says that “Exclusion of data cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because….” in the same section. IMHO excluding a subject based on a too high residual AUC is neither based on statistics nor on PK, but only to fulfill EMA’s requirement. Personally I have no problem keeping the subject in the study, but truncate his/her AUC in the respective other treatment period as well. ❝ Further regarding the following sentence "This does not apply if the sampling period is 72 h or more and AUC(0-72h) is used instead of AUC(0-t)." I am confused about the word ‘..or more..', as in the situation of truncated study upto 72 hrs I can understand but what about the drugs where we have sampling period more than 72 hrs as mnetioned in the GL or drugs with small half life where AUCinf can be obtained before 72 or 96 hrs. What? Sorry, but I don’t get the point. — 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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ratnakar1811 ★ India, 2011-08-04 16:58 (5441 d 01:53 ago) @ Helmut Posting: # 7259 Views: 5,095 |
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Dear HS, ❝ IMHO excluding a subject based on a too high residual AUC is neither based on statistics nor on PK, but only to fulfill EMA’s requirement. Personally I have no problem keeping the subject in the study, but truncate his/her AUC in the respective other treatment period as well. Will there be any regulatory issue? ❝ What? Sorry, but I don’t get the point. Further as you told about significance of the following statement in GL "This does not apply if the sampling period is 72 h or more and AUC(0-72h) is used instead of AUC(0-t)." is only to remind why it has been mentioned as ‘72 hrs or more’ as we generally truncate at 72 hrs only and even GL also specify the same? or used with different context? Best Regards, Ratnakar |
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Helmut ★★★ Vienna, Austria, 2011-08-05 12:38 (5440 d 06:14 ago) @ ratnakar1811 Posting: # 7264 Views: 5,090 |
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Dear Ratnakar! ❝ ❝ IMHO excluding a subject based on a too high residual AUC is neither based on statistics nor on PK, but only to fulfill EMA’s requirement. Personally I have no problem keeping the subject in the study, but truncate his/her AUC in the respective other treatment period as well. ❝ ❝ Will there be any regulatory issue? Sure there will be one. It’s against the guideline. If you want to follow GLs literally and think that you will never get a deficiency letter, good luck. On the other hand I have performed studies pretty straight against GLs, but only if I had strong reasons for doing so and laying down all planned procedures in the protocol. The more you deviate from any GL, the more intellectual horsepower should be invested in the design. Eventually a scientific advice strengthens your position (or at least, you get a more or less clear ‘no’ beforehand). ❝ ❝ What? Sorry, but I don’t get the point. ❝ ❝ Further as you told about significance of the following statement in GL "This does not apply if the sampling period is 72 h or more and AUC(0-72h) is used instead of AUC(0-t)." is only to remind why it has been mentioned as ‘72 hrs or more’ as we generally truncate at 72 hrs only and even GL also specify the same? or used with different context? I’m sorry, I still don’t understand what you mean. Maybe somebody else does. — 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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ratnakar1811 ★ India, 2011-08-06 11:34 (5439 d 07:17 ago) @ Helmut Posting: # 7273 Views: 5,018 |
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Dear HS, Thanks for your help and detail explanation. Regards, Ratnakar |
Ing. Helmut Schütz