Bioequivalence and Bioavailability Forum

Dear all!

Another one from a consultant’s diary. For a similar story see this thread.
Another (but also large) CRO, another continent. PK report from 2013. 4-period replicate; the double peak is specific for the formulation.

In four cases the last concentration was increasing. The CRO followed EMA’s GLs and could not reanalyse the samples (PK reason alone not sufficient). Obviously they tried to ‘save’ the profiles by including more data points…

Below the most extreme case. Two samples (at 10 and 12 h) were BLQ; the last 5.47 ng/mL (~2.7× LLOQ).
Left what the CRO did (first data point in the estimation of λ_z was at t_max); right what I suggest:



My half life of 2.074 h is consistent with what I see in the other periods of the same subject (2.116, 1.999, 2.185 h). Clearly the CRO’s procedure is crap (but backed by SOPs the size of a telephone directory).

Since nothing about excluding data points was stated in the protocol I think the sponsor has two options:

• Follow my approach and keep the profile for the AUC comparison.
  Justification: Half life similar to the ones in the other three periods, two values between 8 and 16 hours were BQL – which agrees with what I predict from my λ_z.
  
• Drop the profile from the AUC comparison, but keep C_max (higher variable anyway and scaling intended in the protocol).

How is your experience? Regulatory acceptance?