Shatha
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2022-03-20 15:51
(765 d 13:06 ago)

Posting: # 22844
Views: 1,763
 

 Corrections for Potency [Regulatives / Guidelines]

Hello

My question is related to Health Canada guidance for industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part B: Oral Modified Release Formulations:

For the data mentioned in Table 11-T, I performed the potency correction calculations for Cmax and AUCT.
The results were identical except for Cmax 90% CI Upper limit (my calculations: 91%, guidance: 99%). I think that the value " 99%" isn't correct in the guidance itself.

Any feedback on this issue, please.

The calculations related to uncorrected data were identical to table 11-L and 11-I.


Thank you.
Helmut
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2022-03-20 16:08
(765 d 12:49 ago)

@ Shatha
Posting: # 22845
Views: 1,506
 

 Typos…

Hi Shatha,

this guidance (of 1996!) is hopelessly outdated and notorious for typos… The current one is of 2018.

Why are you interested in reproducing such stuff? If for validation purposes, consider this series of articles instead:
  1. Schütz H, Labes D, Fuglsang A. Reference Datasets for 2-Treatment, 2-Sequence, 2-Period Bioequivalence Studies. AAPS J. 2014; 16(6): 1292–7. doi:10.1208/s12248-014-9661-0. [image] Free Full text.
  2. Fuglsang A, Schütz H, Labes D. Reference Datasets for Bioequivalence Trials in a Two-Group Parallel Design. AAPS J. 2015; 17(2): 400–4. doi:10.1208/s12248-014-9704-6. [image] Free Full text.
  3. Schütz H, Tomashevskiy M, Labes D, Shitova A, González-de la Parra M, Fuglsang A. Reference Data­sets for Studies in a Replicate Design intended for Average Bioequivalence with Expanding Limits. AAPS J. 2020; 22(2): Article 44. doi:10.1208/s12248-020-0427-6.


Edit: Just checked Cmax of TABLE 11-T. You are correct.$$\small{\{L,U\}=100\exp(-0.2708+0.0360\,\mp 1.812\times0.0799)\approx \{68.41\%,91.39\%\}}$$Not rocket science.

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Shatha
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2022-03-20 16:57
(765 d 11:59 ago)

@ Helmut
Posting: # 22846
Views: 1,472
 

 Typos…

❝ this guidance (of 1996!) is hopelessly outdated and notorious for typos… The current one is of 2018.


Ok, thank you. So, correction for potency is no longer described in Canadian guidelines?

❝ Why are you interested in reproducing such stuff?


For Validation purposes.

❝ If for validation purposes, consider this series of articles instead:

  1. Schütz H, Labes D, Fuglsang A. Reference Datasets for 2-Treatment, 2-Sequence, 2-Period Bioequivalence Studies. AAPS J. 2014; 16(6): 1292–7. doi:10.1208/s12248-014-9661-0. [image] Free Full text.

  2. Fuglsang A, Schütz H, Labes D. Reference Datasets for Bioequivalence Trials in a Two-Group Parallel Design. AAPS J. 2015; 17(2): 400–4. doi:10.1208/s12248-014-9704-6. [image] Free Full text.

  3. Schütz H, Tomashevskiy M, Labes D, Shitova A, González-de la Parra M, Fuglsang A. Reference Data­sets for Studies in a Replicate Design intended for Average Bioequivalence with Expanding Limits. AAPS J. 2020; 22(2): Article 44. doi:10.1208/s12248-020-0427-6.

Thank you for the provided references, but I need data to validate potency correction equations.


Edit: Standard quotes restored; see also this post #8[Helmut]
Helmut
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2022-03-20 17:32
(765 d 11:25 ago)

@ Shatha
Posting: # 22848
Views: 1,472
 

 Typos…

Hi Shata,

❝ So, correction for potency is no longer described in Canadian guidelines?


Yep, gone with the wind. Somewhat surprising because even the EMA accepts a potency-correction if you provide evidence that it was not possible to obtain a reference which differs ≤ 5% from the test.

❝ Thank you for the provided references, but I need data to validate potency correction equations.


Well, the formula given in Health Canada’s old guidance(s) is correct. In the example instead of \(\small{0.0360}\) plug in \(\small{\log_{e}\tfrac{Potency_\textrm{ R}}{Potency_{\,\textrm{ T}}}}\).
Alternatively, multiply all dose-related PK metrics (Cmax, AUC) of \(\small{\textrm{T}}\) with \(\small{Potency_\textrm{ R}}\) and the ones of \(\small{\textrm{R}}\) with \(\small{Potency_\textrm{ T}}\). Perform the comparison with the corrected values and you should obtain the same result than with the correction formula.

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Shatha
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2022-03-21 11:02
(764 d 17:55 ago)

@ Helmut
Posting: # 22852
Views: 1,362
 

 Typos…

❝ Well, the formula given in Health Canada’s old guidance(s) is correct. In the example instead of \(\small{0.0360}\) plug in \(\small{\log_{e}\tfrac{Potency_\textrm{ R}}{Potency_{\,\textrm{ T}}}}\).

❝ Alternatively, multiply all dose-related PK metrics (Cmax, AUC) of \(\small{\textrm{T}}\) with \(\small{Potency_\textrm{ R}}\) and the ones of \(\small{\textrm{R}}\) with \(\small{Potency_\textrm{ T}}\). Perform the comparison with the corrected values and you should obtain the same result than with the correction formula.


Thank you. I performed this step for a balanced design and the results were similar.

It is also applicable for unbalanced design, right?


Edit: Standard quotes restored; see also this post #8[Helmut]
Shatha
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2022-03-20 17:03
(765 d 11:54 ago)

@ Helmut
Posting: # 22847
Views: 1,465
 

 Typos…


Edit: Just checked Cmax of TABLE 11-T. You are correct.$$\small{\{L,U\}=100\exp(-0.2708+0.0360\,\mp 1.812\times0.0799)\approx \{68.41\%,91.39\%\}}$$Not rocket science.


Thank you :-)
Helmut
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2022-03-20 17:57
(765 d 11:00 ago)

@ Shatha
Posting: # 22849
Views: 1,461
 

 Wrong formula for CV

Hi Shatha,
$$\small{CV_\textrm{intra}=100\sqrt{MSE}}\tag{1}$$$$\small{CV_\textrm{intra}=100\sqrt{\exp(MSE)-1}}\tag{2}$$
\(\small{(1)}\) was given in Health Canadas’ guidances of 1992 and 1996. \(\small{(1)}\) is only approximate for relatively small variances. The bias is always negative and hence, when used in sample size estimations misleading (studies will be underpowered).

library(PowerTOST)
CV        <- seq(0.05, 0.5, 0.05)
mse       <- CV2mse(CV)
CV.appr   <- sqrt(CV2mse(CV))
bias      <- sprintf("%+.2f%%", 100 * (CV.appr - CV) / CV)
# sample size for T/R-ratio 0.95, at least 80% power
res       <- data.frame(CV = CV, CV.appr = CV.appr, bias = bias,
                        n = NA_integer_, power = NA_real_,
                        n.appr = NA_integer_, power.appr = NA_real_)
for (j in seq_along(CV)) {
  res$n[j]      <- sampleN.TOST(CV = CV[j], print = FALSE)[["Sample size"]]
  res$n.appr[j] <- sampleN.TOST(CV = CV.appr[j], print = FALSE)[["Sample size"]]
  # minimum acc. to GLs
  if (res$n[j] < 12)      res$n[j]      <- 12
  if (res$n.appr[j] < 12) res$n.appr[j] <- 12
  res$power[j]      <- round(power.TOST(CV = CV[j], n = res$n[j]), 5)
  res$power.appr[j] <- round(power.TOST(CV = CV[j], n = res$n.appr[j]), 5)
}
CV.appr   <- round(CV.appr, 5)
print(res, row.names = FALSE)

   CV    CV.appr   bias  n   power n.appr power.appr
 0.05 0.04996879 -0.06% 12 1.00000     12    1.00000
 0.10 0.09975135 -0.25% 12 0.98835     12    0.98835
 0.15 0.14916638 -0.56% 12 0.83052     12    0.83052
 0.20 0.19804220 -0.98% 20 0.83468     20    0.83468
 0.25 0.24622068 -1.51% 28 0.80744     28    0.80744
 0.30 0.29356038 -2.15% 40 0.81585     38    0.79533
 0.35 0.33993873 -2.87% 52 0.80747     50    0.79168
 0.40 0.38525317 -3.69% 66 0.80525     62    0.77978
 0.45 0.42942138 -4.57% 82 0.80691     76    0.77602
 0.50 0.47238073 -5.52% 98 0.80322     88    0.75845


It took Health Canada until 2018 to give the correct \(\small{(2)}\). Never trust in guidances. ;-)

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