Helmut ★★★ ![]() ![]() Vienna, Austria, 2013-04-23 21:30 (4417 d 00:58 ago) Posting: # 10477 Views: 9,199 |
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Dear all, stupid question. Sometimes I feel I’m lacking the most basic skills. EMA’s GL states: The concentration obtained for the initial analysis and the concentration obtained by reanalysis should be within 20% of their mean for at least 67% of the repeats. In the past we have calculated the percent deviation of the difference between measurements from their mean. Example: 1st 2nd x ∆2-1 |∆ (% x)| Have we been too stringent? Does EMA expect instead: 1st 2nd x ∆1-x ∆2-x ∆1 (% x) ∆2 (% x) |∆1,2 (% x)| Confusing. — 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 |
ElMaestro ★★★ Denmark, 2013-04-23 22:30 (4416 d 23:58 ago) @ Helmut Posting: # 10478 Views: 8,125 |
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Hi Helmut, ❝ stupid question. Sometimes I feel I’m lacking the most basic skills. EMA’s GL states: The concentration obtained for the initial analysis and the concentration obtained by reanalysis should be within 20% of their mean for at least 67% of the repeats. In the past we have calculated the percent deviation of the difference between measurements from their mean. Example:❝ ❝ ❝ Have we been too stringent? Yes. ❝ Does EMA expect instead: ❝ ❝ Yes. Reported ISR Avg. LimitLo LimitHi Pass_Rpt Pass_ISR — Pass or fail! ElMaestro |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2013-04-24 00:08 (4416 d 22:20 ago) @ ElMaestro Posting: # 10479 Views: 7,871 |
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Hi ElMaestro, wow! THX for enlightening me. Halving all values given in this post would add a new level of absurdity to the story. ![]() — 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 |
Roberto ☆ Italy, 2013-12-09 13:52 (4187 d 07:36 ago) @ ElMaestro Posting: # 12026 Views: 7,179 |
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Hi ElMaestro, What do you think about my interpretation here below described? I do not think that EMA provides broader limits for ISR than those widely knew and shared. I believe that what is written in the BIOANALYTICAL GUIDELINE ON METHOD VALIDATION of 21 July 2011, it's just bad written. If we start from the DRAFT 19 November 2009, at paragraph 6. Incurred Samples Reanalysis, at line 485 is reported: "The difference between the two values obtained should be within 20% of the mean (30% for ligand-binding assays) for at least 67% of the repeats." Continuing in the document "Overview of comments received on 'Guideline on validation of bioanalytical methods' (EMEA/CHMP/EWP/192217/2009)", the concept widely reported in the WPs is mentioned and i would highlight a couple of points: Line no. 467-477 Stakeholder no. 24 Comment and rationale;proposed changes: Chapter should be adapted according to EBF recommendations. as described in “Incurred Sample Reproducibility: Views and Recommendations by the European Bioanalysis Forum, P. Timmerman et al” (PDF attached) Outcome: It is considered that the revised paragraph covers sufficiently the recommendations of the EBF. Regarding the criteria, 20% difference from the mean would be in line with the White paper (Fast et all., AAPS Journal, DOI 10.128/s12248-009-9100-9) Line no. 467-486 Stakeholder no. 39 Comment and rationale;proposed changes: … And finally, the requirement for the difference of two measurements to be within 20% is more strict than that for QC samples. Outcome:There was an international consensus on this criteria (see White Paper). Finally, in the document "Appendix IV of the Guideline on the Investigation on Bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1): Presentation of Biopharmaceutical and Bioanalytical Data in Module 2.7.1" at the point "Table 4.3 Sample analysis of <Study ID> ", under the heading Incurrent sample reanalysis, it is repeated the same acceptance criterion "Percentage of samples where the difference between the two values was less than 20% of the mean for chromatographic assays or less than 30% for ligand binding assays. " In conclusion, I believe that the ISR acceptance criteria for EMA is that well known and internationally recognized: Variability (%)= (Repeat – Original) × 100/Mean and that what is reported in the current GL is written in a not clear way and misleading. What is your opinion on this? Thanks at all and best regards Roberto |
Ohlbe ★★★ France, 2013-04-24 11:40 (4416 d 10:48 ago) @ Helmut Posting: # 10484 Views: 7,863 |
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Dear Helmut, ❝ Confusing. Yes, I agree ! The wording in the guideline is awkward. My understanding is what is described in the Crystal City white papers: (C1-C2)/((C1+C2)/2). — Regards Ohlbe |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2013-04-24 16:07 (4416 d 06:21 ago) @ Ohlbe Posting: # 10489 Views: 7,889 |
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Dear Ohlbe! ❝ My understanding is what is described in the Crystal City white papers: ❝ ❝ (C1-C2)/((C1+C2)/2). OK, that’s what we have done in the past. Which CCIII WP are you referring to? I can’t find anything in the Conference Report. Do you mean Rocci ML, Devanarayan V, Haughey DB, and P Jardieu Difference = (Repeat–original)/average expressed as a percentage BTW, nice examples for the number of ISRs (astonishingly small).What makes me wonder is that I had to use the ratio of the first to the second measurements in order to reproduce their results. # Rocci et al. Example 1 Edit: A more comprehensive code over there. — 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 |
Ohlbe ★★★ France, 2013-04-25 00:37 (4415 d 21:50 ago) @ Helmut Posting: # 10492 Views: 7,716 |
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Dear Helmut, ❝ Which CCIII WP are you referring to? Sorry I was a bit short in time this morning and I didn't link the paper. I was actually thinking of the white paper of the "Crystal City 3.5" meeting of 2008, by Douglas Fast et al.. The paper by Rocci et al. was published before that meeting and did not involve the FDA. Regarding the number of samples, do you know this paper by Hoffman ? Too much stats in it for my brain, but you should be able to understand it better ![]() — Regards Ohlbe |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2013-04-25 04:00 (4415 d 18:27 ago) @ Ohlbe Posting: # 10493 Views: 7,772 |
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Dear Ohlbe, ❝ I was actually thinking of the white paper of the "Crystal City 3.5" meeting of 2008, by Douglas Fast et al. OK, here we are: % Difference = 100 × (Repeat – Original) / Mean ❝ Regarding the number of samples, do you know this paper by Hoffman ? Too much stats in it for my brain, but you should be able to understand it better I like it. Of course it makes sense to come up with a number of samples depending on the variability. 5 (or 10%) of the study’s samples are arbitrary. Fig. 4 is telling: With a CV of 10% it is simply irrelevant whether 40 or 160 samples are tested. Edit: R-code in this post. — 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 |