Bioequivalence and Bioavailability Forum

Hi Mahesh,

❝ What is the sparse sample design?

⇐ click here
In such a design only a few samples are collected from subjects. Hence, the name. Since C_max, AUC, etc. are not directly accessible, it is always used together with a population pharmacokinetics (PopPK) model. This designs is mainly employed in the target population (patients). It is possible to collect as few as 2–3 samples / subject:

• Routine sampling in Phase II/III.
  
• Special populations (children, cancer/AIDS, critical care patients, elderly…).

Unlike in “rich” data sets missing data and imbalance are not problematic:

• Different doses / subject.
  
• Different number of samples / subject.
  
• Different sampling times / subject.

❝ How it use in bioequivalence studies?

No way. BE requires “rich” data sets, where NCA / SHAM is used to calculate PK-metrics – as opposed to PK modeling, where PK-parameters are estimated.

• EMA BE-GL Section 4.1.4
  A sufficient number of samples to adequately describe the plasma concentration-time profile should be collected. The sampling schedule should include frequent sampling around predicted t_max to provide a reliable estimate of peak exposure. […] The sampling schedule should also cover the plasma con­cen­tra­tion time curve long enough to provide a reliable estimate of the extent of exposure which is achieved if AUC_(0-t) covers at least 80% of AUC_(0-∞).
  
• FDA ANDA-guidance (draft) Attachment
  We recommend drawing blood samples at appropriate times to describe the absorption, distribution, and elimination phases of the drug. For most drugs, we recommend collecting 12 to 18 samples, in­cluding a predose sample, per subject, per dose. This sampling should continue for at least three or more terminal elimination half-lives of the drug. […] The sample collection can be spaced in such a way that the maximum concentration of drug in the blood (C_max) and terminal elimination rate constant (K_el) can be estimated accurately.

❝ Is it acceptable by regulatory body like FDA and EMA?

No.

• EMA BE-GL Section 4.1.5
  The use of compartmental methods for the estimation of parameters is not acceptable.
  
• FDA
  Modeling not mentioned; only NCA throughout the text.