BE assessment regarding first time point Cmax [Study As­sess­ment]

posted by Mann – India, 2018-12-09 10:14  – Posting: # 19670
Views: 1,479

Hello Friends,

Can anyone help me with your experience or suggestions considering the below details?

One of BE study (for MHRA, two way, crossover, IR tablet with parent, no active metabolites) with intra-subject CV with 20-25% was conducted in 40 subjects and sampling schedule (0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75,2, 2.25, 2.5, 2.75, 3, 3.5, 4, 6, 8, 10,12, 16 & 24 hr) was designed considering 2hr tmax and 3 hr half life.

2 subjects did not complete the study and hence dropped, eventually 38 subjects completed the study. The concentration vs time profiles revealed the following:
  1. Both test and reference products showed more than one peak (an inherent characteristics of the drug, clear literature evidence)

  2. In reference product, 3 subjects reflected first time point (0.25 hr) as Cmax and 25 subjects in test treatment reflecting first time point Cmax (as per the guidelines, these subjects are not considered for the analysis as there was no reliable Cmax appearance and no single sampling time between 0 to Cmax point).

  3. An outliers analysis (Lund's) confirmed two subjects with an outlier concentration levels.There are no change in concentration levels for the repeat analysis samples as per the SOPs. Hence, we have considered that the overall eligible subjects are 13 of 38 (2 outliers, 23 with first time point Cmax).

  4. With all 36 subjects (excluding 2 outliers), AUCt and AUCinf 90% CI are within 80-125. However, Cmax is out of the boundary (96.56 -133.45) and inta-CV is 24.56.

  5. The final analysis with 13 eligible subjects reflecting all the primary PK parameters within 80-125. Cmax also appearing 99.42 - 122.34. Power for AUCt, AUCinf and Cmax = 100, 100 & 79.7.
My questions for your suggestions are:
  1. Whether final selection of the subjects for BE assessment is correct or not?
  2. The final positive BE result (Total transparent reflection of overall assessment of the analysis in CSR) with 13 subjects with slightly less power for Cmax is acceptable for MHRA?
  3. What other points we need to consider and report?
  4. Anybody had an experience with the similar case?

Thanking you.

Best regards,

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