Changing the regulations: Hope dies last. [NCA / SHAM]

posted by Helmut Homepage – Vienna, Austria, 2021-10-01 11:18 (65 d 14:30 ago) – Posting: # 22610
Views: 963

Hi PharmCat,

» I don't think that our regulators will be able to understand this, …

Well, the majority of regulators is not stupid. ;-)
That’s basic PK and \(\small{CL=\textrm{const}}\) is a pretty strong assumption, which might be outright false. Then the entire concept is built on sand: Studies are substantially larger than necessary, exposing innocent subjects to nasty drugs.

» … or there will be a desire and dare to change the foundations.

Correct. However, the FDA1 gives in its regulatory definitions of BE ‘rate and extent of absorption’ without mentioning any PK metrics, the EMA2 ‘BE with the reference medicinal product […] demonstrated by appropriate bioavail­ability studies’. Only the WHO3 gives specifically AUC for the extent of absorption. Too lazy to check other jurisdictions.
Somehow it reminds me on the comparison of \(\small{AUC_{t_\textrm{last}}}\), which is known to be biased if \(\small{t_\textrm{last,T}\neq t_\textrm{last,R}}\). Nobody gives a shit. Remember the endless story of the inflated Type I Error in SABE? For HVDs (not HVDPs) probably we could counteract the high variability, use ABE with fixed limits, and all is good.
Of course, it would mean changing the guidelines.

Abdallah (FDA/CDER):

It is recommended that area correction be attempted in bioequivalence studies of drugs where high intrasubject variability in clearance is known or suspected. […] The value of this approach in regulatory decision making remains to be determined.

Lucas et al.:

Performance of the AUC·k ratio test […] indicate that the regulators should consider the method for its potential utility in assessing HVDs and lessening unnecessary drug exposure in BE trials.


» Also, I think NLME modeling can be applied.

Hhm, can you elaborate?


  1. CFR 21–320.23(b)(1). 2021.
  2. Directive 2001/83/EC, Article 10(2)(b). 2001.
  3. TRS 992, Annex 6. 2017.

P.S.: \(\small{C_\textrm{max}}\) is a lousy metric for comparing rates of absorption, since it is composite of \(\small{k_\textrm{a}}\) and \(\small{AUC_{0-\infty}}\). Lots of publications… What about: $$\small{\frac{F_\textrm{T}}{F_\textrm{R}}\sim \frac{C_\textrm{max,T}\big{/}\left(AUC_{0-\infty,\textrm{T}}\cdot k_\textrm{T} \right)}{C_\textrm{max,R}\big{/}\left(AUC_{0-\infty,\textrm{R}}\cdot k_\textrm{R} \right)}}$$ Deserves a paper.

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