Bioequivalence and Bioavailability Forum

Slowly going OT: BE study simulations [Regulatives / Guidelines]

posted by Helmut  – Vienna, Austria, 2016-02-12 16:47 (3259 d 20:16 ago) – Posting: # 15983
Views: 19,936

Hi nobody!

❝ ❝ "The impact of bioanalytics on the outcome BE-studies is overrated anyhow."

❝

❝ That was my gut feeling when starting, but better to have some solid numbers, or?

Agree. See this stupid example (slides 46–49) from the early days of LC/MS-MS (no stable isotope IS and hit by the matrix effect). Slide 49 compares results of the first 12 (of 24) subjects obtained by the lousy LC/MS-MS method with stable isotope IS GC/MS. Does it matter? No.
In his paper Mr. Gaffney replicated everything (administrations, analytics) in order to estimate the contribution of variances. Bioanalytics = least important. IMHO, you could screw more easily up in the clinical phase. But that’s difficult to assess by assessors/inspectors. Hence, they concentrate on the weakest link of the chain, bioanalytics (numbers, numbers…).

❝ Optimizing calibration concs is more based on the weighting factors/variance distribution and principles of linear regression, not that difficult, disagreeeeee?

Yes and no. If the model is not established yet (linear, quadratic,…) the optimal locations would be equally spaced. Note that equally spaced calibrators are mandatory in most accredited methods in environmental analysis. Once a model is confirmed to be linear, the optimal* placement of calibrators would be ½ at the LLOQ and the other half at the ULOQ. Yes, nothing in between. Try it.
Of course the BMV-GL does not allow that.

The optimal weighting factor (Fisher information…) is 1/s². Impossible if one runs just duplicates (you may always loose one). I know two labs routinely validating methods both with 1/s² and 1/y². The first weighting scheme is the standard and the SOP allows to switch to the second one if they end up with a single determination within a batch. One of them faced a deficiency letter stating that “samples were not treated equally”. Under protest they recalculated the entire study with 1/y². Difference in the BE-outcome? Third decimal. Rounded away…
The exponentially increasing spacing of calibrators likely goes back to the dark ages where weighted regression was not available (pocket calculator, Excel?) in an attempt to shift the inaccuracy/imprecision (which due to the hyperbolic CI is minimal at x|y) towards lower values. Duno. No spare time to check.

❝ I wanted to use this simulation framework as a starting point to study other influences on BE and other pk parameters.

Can imagine. Was my point as well.

❝ Especially the nonsense terminal half-life...

Ahem. What to you mean by nonsense – apart from the word “terminal”?

---

• Optimal = lowest SEs of estimated slope and intercept.

—
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

Complete thread:

• Baseline correction vs non-baseline cor­rection jag009 2015-09-15 20:29 [Regulatives / Guidelines] 
  • Baseline correction vs non-baseline correction Lucas 2015-09-16 14:16
    • Baseline correction vs non-baseline correction Relaxation 2015-09-18 10:25
  • Baseline correction or supra-thera­peu­tic dose Helmut 2015-09-16 15:16
    • Baseline correction or supra-thera­peu­tic dose Ohlbe 2015-09-16 17:55
      • Baseline profile prior to each period? Helmut 2015-09-16 18:15
      • Baseline correction examples Helmut 2015-09-17 15:44
        • Baseline correction examples Lucas 2015-09-18 14:19
          • Baseline correction examples Helmut 2015-09-18 17:28
            • Baseline correction examples Mauricio Sampaio 2016-02-07 03:05
              • Baseline correction examples Lucas 2016-02-10 11:48
                • Postmenopausal women Helmut 2016-02-10 12:26
                • Baseline correction examples Mauricio Sampaio 2016-02-11 01:38
                • Baseline correction examples Dr_Dan 2016-02-11 09:22
                  • Postmenopausal women Mauricio Sampaio 2016-02-12 03:24
                    • Postmenopausal women Dr_Dan 2016-02-15 17:45
            • Baseline correction examples BEQool 2024-11-11 07:34
              • Baseline correction GeoMean and Median mittyri 2024-11-11 11:20
                • Geometric mean? Helmut 2024-11-11 14:53
                  • Geometric mean? BEQool 2024-11-14 08:19
                    • Geometric mean ≈ MLE of median Helmut 2024-11-14 09:54
                      • Geometric mean ≈ MLE of median Mahmoud 2024-11-15 11:26
                        • Bias? Helmut 2024-11-16 08:43
                          • Bias? Mahmoud 2024-11-16 11:12
      • Baseline; another example Helmut 2015-09-18 17:16
        • Baseline; another example nobody 2016-02-12 09:10
          • Baseline; another example Helmut 2016-02-12 13:37
            • Baseline; another example nobody 2016-02-12 14:08
              • Slowly going OT: BE study simulationsHelmut 2016-02-12 15:47
                • Slowly going OT: BE study simulations nobody 2016-02-12 16:15
                  • Religious debate Helmut 2016-02-12 17:04
                    • Religious debate nobody 2016-02-12 17:26
                      • Religious debate ElMaestro 2016-02-13 12:53
                        • Religious debate nobody 2016-02-14 15:23
                • Slowly going OT: BE study simulations Ohlbe 2016-02-13 13:10
                  • Slowly going OT: BE study simulations Helmut 2016-02-13 15:02
                    • Slowly going OT: BE study simulations lizhao 2016-02-25 17:31
                      • Business as usual Helmut 2016-02-25 17:44
                        • Business as usual lizhao 2016-02-25 17:59