Loky do ★ Egypt, 2020-07-15 14:57 (1611 d 16:27 ago) Posting: # 21698 Views: 4,041 |
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Dears if a subject didn't have any evaluable concentrations for only test product all intervals are BLQ and according to our SOPs and SAP, the BLQ is considered "zeros", could be excluded from PK and statistical analysis? thanks Edit: Category changed; see also this post #1. [Helmut] |
Helmut ★★★ Vienna, Austria, 2020-07-16 16:30 (1610 d 14:54 ago) @ Loky do Posting: # 21714 Views: 3,492 |
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Hi Loky do, ❝ if a subject didn't have any evaluable concentrations for only test product all intervals are BLQ and according to our SOPs and SAP, the BLQ is considered "zeros", could be excluded from PK … What does you protocol say? See also this recent thread. Even if the outcome of investigations is negative, likely it would ring the alarm bells of regulators, esp. since you found no concentrations after the test product. What if it was a product failure (example: bad coating of a gastro-resistant PPI)? Regulators are more relaxed about the reference product since it “works” in clinical practice despite occasional failures. The EMA accepts exclusion in exceptional cases:
In your case (test only) cards are stacked against you. ❝ … and statistical analysis? $$\lim_{x \to 0} \log x=-\infty.$$For simplicity we can say that \(\small{\log 0}\) is undefined. Hence, the common analysis based on log transformed PK metrics without excluding the subject is not possible at all. — 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 |
Loky do ★ Egypt, 2020-07-17 00:29 (1610 d 06:55 ago) @ Helmut Posting: # 21724 Views: 3,385 |
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Many Thanks, Helmut for your reply ❝ ... it is considered acceptable that low-lier profiles can be excluded from statistical analysis […] if they occur with the same or lower frequency in the test product compared to the reference product. ❝ (my emphases) Is this case-specific for this product, and its formula? or it could be followed for other products with the same cases? thanks in advance |
Helmut ★★★ Vienna, Austria, 2020-07-17 03:01 (1610 d 04:23 ago) @ Loky do Posting: # 21727 Views: 3,441 |
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Hi Loky do, ❝ ❝ ... it is considered acceptable that low-lier profiles can be excluded from statistical analysis […] if they occur with the same or lower frequency in the test product compared to the reference product. ❝ ❝ Is this case-specific for this product, and its formula? Yes. It’s based on numerous replicate design studies reviewed by the PKWP. AFAIK, in all more outliers were seen after the reference. It’s a terrible product showing also funky batch-to-batch variability. ❝ or it could be followed for other products with the same cases? If it’s a delayed release product, see my previous post. However, note the subtle different wording “number” vs. “frequency”. In the draft MR-GL “comparable frequency” was used as well. From a statistical point of view that calls for a two-sided test. When I showed an example at the GL-meeting in Bonn (2013) I stirred up a hornets’ nest. Imagine: 64 subjects, 4 outliers after T and 3 after R. Is the frequency comparable? Yes, the p-value is 0.7139!1 The members of the PKWP did not like that at all. Oops, one (!) more. Changed in the final GL. Not acceptable. You can have it even more extreme. A 4-period full replicate study, one outlier (0.78%) after T and none after R → p-value 0.5.2 Not acceptable because the bloody number is higher! Lesson learned: Bad science (statistics is taboo). If you have one more outlier after T than after R – independent of the sample size – you’re dead.
— 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 |
Loky do ★ Egypt, 2020-07-22 13:29 (1604 d 17:55 ago) @ Helmut Posting: # 21774 Views: 3,276 |
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Thanks for your reply Now another case for a non highly variable drug, a bioequivalence study performed on 27 subjects, where only 2 subjects had an odd behavior for test product (almost double the concentration of the reference product also double concentration of the rest of test product's subjects) and accordingly the study failed and by excluding the probability of double dosing the 2 subjects by mistake (accountabilities are correct), and the results of incurred sample reanalysis for both are satisfactory Is it applicable to consider these subjects as outliers, is there any way to conclude this? or could we re-dose them again to be confirmed? or simply the product fails ? thanks |
Helmut ★★★ Vienna, Austria, 2020-07-22 14:03 (1604 d 17:22 ago) @ Loky do Posting: # 21775 Views: 3,367 |
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Hi Loky do, ❝ Now another case for a non highly variable drug, […] What you confirmed already:
❝ Is it applicable to consider these subjects as outliers, is there any way to conclude this? That’s similar to the cases we discussed before. Even if you would perform a statistical test (which is not acceptable acc. to current regulatory practice), you would get a p-value of 0.2453 which would speak against excluding them. Even for Health Canada (where an outlier assessment of studentized model residuals can be done if pre-specified in the protocol) you could exclude only one subject (≤5% if the sample size is ≥20). ❝ or could we re-dose them again to be confirmed? Re-dosing is discouraged and likely not accepted. ❝ or simply the product fails ? I’m afraid, yes. — 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 |
Loky do ★ Egypt, 2020-07-26 13:30 (1600 d 17:54 ago) @ Helmut Posting: # 21791 Views: 3,051 |
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Thanks a lot |