Bioequivalence and Bioavailability Forum

Dear ElMaestro!

Great ideas!
But I guess it’s even worse. The half-life of this drug is reported in the literature with 1–4 hours. The CRO has a pretty good analytical method – with a worse LLOQ you wouldn’t see the slower phase(s). He/she/it didn’t run a script, since in some subjects with lower concentrations he/she/it was happy with just the last 3–4 points. I think that he/she/it tried to tweak the results in such a way that results are not too far away from the literature.
According to the report (54 profiles): x̃ 4.61 h (2.49 – 8.34 h), while my eyeballing PK gives 5.05 h (2.78 – 8.34 h). Since the CRO had no problems with extrapolations (C_last >LLOQ in all pro­files; max. residual AUC 6.2%) probably he/she/it wanted to avoid trouble in reporting a ‘long’ t_½…
Perhaps a case of anticipatory obedience (vorauseilender Gehorsam). No, the CRO was not in Germany).

❝ Probably the wise guy has already been promoted as we speak?

Oh goodness!

Dear D. Labes!

❝ The more interesting question is: What do regulators think?

According to our Master the average time for assessing a BE report is one hour – therefore, nothing.

❝ I never have seen deficiency questions […]

Me not either.

❝ Although I find the fit a little bit strange, […]

Right. Actually the sponsor wants to perform another study and felt that they had too many data points in the previous one (little bit tricky, three drug combo). First I asked for spaghetti plots. Nil. Next for raw data. Received an M$-DOC (actually part of the Appendix to the study report) con­tain­ing SAS-output like the following (one page per profile):
                                                               Plasma
         Age/                               Actual  Blood   concentration
 Site/   Sex/                        Sample  time    vol.      (ng/mL)
Subject  Race   Per. Treat. Sched.   taken  (hh:mm)  (mL)   XXXX    YYYY  Comment
-------------------------------------------------------------------------------------
AA/BBBB 22/M/Ca  1   Tablet pre      Yes    07:37   10.0      BLQ    BLQ
[…]
                            16 h pd  Yes    23:54   10.0   121.33  12.10  late sampl.
[…]
Really handy to be imported into PK software. Next: An Excel-file converted from the SAS-binary. Finally something to work with.

❝ BTW: What is Your eyeball solution for this curve?

Last three data-points. t_½ 8.00 h, R² 0.751 (R with 0.867 below the CRO’s cut-off 0.95). Before I start to fit individuals I use to have a look at spaghetti plots. Subjects with higher concentrations consistently showed such a slow phase (t_½ >6 h). The quality of fits was sometimes pretty good (R²_adj 0.998) and mainly >0.9… Taking the overall-PK into account, I would say that the bad fit of this subject is still justified (haha – I don’t have a R-cutoff…).

I this study residual AUCs were not an issue, but I’m concerned about careless fitting – which might tweak residual AUCs to <20%.

  The only people who see the whole picture
are the ones who step out of the frame. Salman Rushdie

Hi ElMaestro!

❝ In the description above do you mean to say that the CROs internal requirement is an r squared of at least 0.95…

Not R² – R!

❝ … but that data like this are reported even though -in this case at least- the r sq is less than 0.95?

Well, their fit’s R was 0.9610 (R² 0.9235, R²_adj 0.9172). They didn’t report any of those at all.
For my fit see above.