Bioequivalence and Bioavailability Forum

Dear NK!

❝ How to handle this subject’s data? Outlier? Can the regulatory accept the based on C_max and AUC_0-t results?

❝ Can we select the time point manually for K_el calculation instead of best fit method by the tool?

The CRO have SOP for handling such observation. Kindly follow the SOP and treat accordingly.

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The SOP I am talking of CRO are mainly w.r.t. repeat analysis.

Kindly ask for Investigation for failed analytical runs or abnormal/unexpected results or Anomalous Value repeats.

1. An investigation must be conducted to determine the cause whenever analytical run failure or abnormal / unexpected results are observed.

b. A detailed investigation is required in case, low or below LLOQ concentration obtained in an entire period, re-analysis of a particular set of samples, poor chromatography obtained in a particular period and others, but not limited to above list.


Regards,
Divyen

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Edit: Second part merged with a later (now deleted post). You can edit your original post for 24 h. [Helmut]

Hi NK,

❝ […] T½ is >1000 hrs […] After reaching T_max at 2.00 hr the Concentration declined and reached BQL in 12 hours and after that few measurable concentrations was observed in 14 hr, 16 hr & 18 hr in elimination phase.

It doesn’t need rocket science to tell that such a t_½ obtained by an automatic algorithm (e.g., \(\small{\textsf{max}\,\textsf{R}_\textsf{adj}^2\,}\)) is plain nonsense. Recall that the A&P of the bioanalytical method at the LLOQ is 20%. Furthermore, concentrations follow a lognormal distribution. Hence, it is not uncommon to face some values >LLOQ.

❝ How to handle this subject’s data? Outlier? Can the regulatory accept the based on C_max and AUC_0-t results?

When you explore ANDAs you will find many cases were the number of AUC_0–∞ is less than the one of AUC_0–t. Hence, it is acceptable in principle. In the recent ICH M13A draft guideline AUC_0–∞ is not a primary parameter. It serves only to assess the validity of the study. Once the guideline will be final, the FDA will update theirs.

❝ Can we select the time point manually for K_el calculation instead of best fit method by the tool?

Of course, if specified in an SOP (see Divyen’ post above). Manual selection / exclusion of data is provided in any software I know. Certara states¹

Using this methodology, Phoenix will almost always compute an estimate for Lambda Z. It is the user’s responsibility to evaluate the appropriateness of the estimated value.
(my emphasis)

Similarly in Lixoft’s PKanalix² any many others.
For transparency I state the procedure also in the protocol (see this article). In 40+ years I never received a single (‼) deficiency letter in this respect.

Since you obviously didn’t have a suitable SOP in place, you can only present a sensitivity analysis with the AUC_0–∞ of the one subject excluded. Supportive would also be an outlier test (Lund’s, Thompson’s τ, Cook’s distance, …) and/or graphical EDA (box plots, QQ-plots, histograms, scatter plots of studentized model residuals). See also this post about the method recommended by Health Canada. Though reanalysis based on PK grounds is not acceptable according to current bioanalytical guidances, I would do it anyway – not only the suspect values but the entire profile. Discuss it, and cross fingers.

I strongly recommend to update your SOP – mandating visual inspection of fits (see references 3, 5, 8, 20 in the article linked above) and allow to exclude data in the estimation of λ_z. Then you don’t have to exclude the nonsensical AUC_0–∞ obtained by an automatic algorithm and keep the subject with a realistic AUC_0–∞ in the analysis.
Maybe over the top, but I recommend also to perform the entire NCA in a blinded manner (see this thread). Avoids the impression of cherry-picking.

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1. Certara USA, Inc. Princeton, NJ. 7/9/20. Lambda Z or Slope Estimation settings. Online.
   
2. LIXOFT, Antony, France. 2022. PKanalix Documentation. Check lambda_z. Online.