Bioequivalence and Bioavailability Forum • Baseline correction examples

Baseline correction examples [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2015-09-18 19:28 (3406 d 18:23 ago) – Posting: # 15432
Views: 22,508

Hi Lucas,

❝ Two questions though:

❝ 1. Do you know a example of a endogenous substance that has a constant (or nearly constant enough) baseline level in the first example of yours?

I’m too lazy to browse the FDA’s product specific guidances, but you will find examples.
If you have evidence that the BL is stable over the day you may subtract average predose levels – measured in each period. This is what my example is based upon. The EMA’s GL states:

The exact method for baseline correction should be pre-specified and justified in the study protocol. In general, the standard subtractive baseline correction method, […] subtraction of the mean of individual endogenous pre-dose concentrations […]

Which mean? Though often applied I hope not the arithmetic one. The geometric would be better but what if at least of the values is BQL? I always use the median and never got any requests.
BTW, be aware of softwares’ interpretation of non-numerics like "BQL". Example: 5.0, 7.0, "BQL"

Excel PHX/WNL R arithmetic mean 6.0 6.0 NA geometric mean 5.9 5.9 Error median 6.0 6.0 "7.0"

Excel ignores the "BQL" and works with the numbers only. Same in PHX/WNL but we get the information that 2 values are used and 1 is missing. R essentially gives up.

❝ 2. I see that you only considered one baseline profile. We wouldn't have to measure the baseline level before each period of the study because we ate assuming that the cycle is the same through time. Right? But what about feminine hormones produced in a 28-day cycle?

Hey funny – coincidentally this afternoon I was working on this post and missed yours. ;-)

In a 2-period study likely I would sample a complete baseline prior to each period myself. However, if there are more periods you would end up with an extreme blood volume. Agencies’ standard phrase “improve the analytical method” sometimes is not realistic.

If I switch the amplitudes of my other example (flucations within the day lower than within the 28-days cycle) I got:

method 1 2 1 2 period AUC_t C_max 1 +3.24 -0.10 +1.59 -0.08 2 -0.74 -2.28 -0.22 -0.55 3 -3.20 -3.22 -1.59 -0.25 4 -0.74 -2.28 +0.22 +0.21

No method is “perfect”. What about performing such a study in postmenopausal women?

❝ I've also seen a lot of what you've described in the last graph, our triangulation points (or embedded concentrations) that we've discussed. :-D

Don’t remind me, please. :cool:

PS. Too bad that GL’s don’t allow modeling… Should be an easy task to estimate parameters even for composite sinusoidal baselines. We need three for the circadian rhythm and four for the one with a lower frequency. Try this:

a <- c( 3.5, 1.5, 1) # parameters for circadian rhythm b <- c(15 , 10 , 0, 28) # parameters for 28-days cycle t <- -24:(27*24) BL <- a[1]+a[2]*sin(pi/180*(t+a[3])/24*360) + b[1]+b[2]*sin(pi/180*(t+b[3])/24*360/b[4]) plot(t/24, BL, type="l", ylim=c(0, sum(c(a[1:2], b[1:2]))), xlab="days") abline(v=0, lty=3)

If you have data of a study with one full baseline profile and predose concentrations in the other periods, give it a try in Phoenix!

—
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Helmut Schütz

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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 examplesHelmut 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 simulations Helmut 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