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Steady-State Bioequivalence Study (EMA) Full Replicate 2-Period Study Design with Two Consecutive Day Profile

02 Feb 2018

In line with the guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms (EMA/CPMP/EWP/280/96 Corr1) effective from 1 June 2015, multiple-dose BE studies are recommended for the Prolonged Release Formulations when a drug has a tendency to accumulate after multiple-dosing at the recommended dosing interval.

Whenever multiple-dose studies are performed, it should be demonstrated that steady-state has been reached. Hence, multiple dosing is required till steady-state achievement, which is generally 4?5 times the half-life.

In such multiple-dose studies, bioequivalence needs to be proved on Cmax,ss, Cτ,ss and AUC(0-τ)ss as per EMA requirements. The bioequivalence approach considering usual acceptance limits (80–125%) is applicable for generic modified release products (see CPMP/EWP/QWP/1401/98). Any widening of the acceptance criteria for Cmax,ss and Cτ,ss should follow the recommendations on highly variable drug products in the guideline – Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98). Hence, widening of the Cmax,ss and Cτ,ss can be applied if high intra-subject variability is observed for the reference-product with replicated study design.

Generally, it is difficult to meet bioequivalence requirements for pharmacokinetic parameter Cτ,ss due to high variability in most of the cases.

As per conventional replicate design, entire period needs to be repeated 3 times (Partial Replicate: 2 periods for Reference and 1 period for Test Product) or 4 times (Full Replicate: 2 periods for Reference and 2 periods for Test Product).

Hence, to avoid the repeated periods in replicate design of multiple-dose studies, EMA guideline recommended two consecutive administrations of the same product after reaching steady-state. In multiple-dose studies, all pharmacokinetic parameters are required to be estimated after steady-state achievement. In two consecutive administrations of the same product after reaching steady-state, we can skip the steady-state build up phase for the replica, both for reference as well as test.


Conventional Full Replicate Design (Sequence: TRTR / RTRT)


Full Replicate Design with Two Consecutive Administrations (Sequence: TR/RT)
T=Test Formulation; R=Reference Formulation

For widening of the acceptance criteria, only repeated pharmacokinetic profile of the reference formulation is required. Calculation of the intra-subject variability in multiple-dose studies can be based on two consecutive administrations of the same product after reaching steady-state. Hence, basic requirement of the replicate study design is fulfilled with the full replicate design, with two consecutive administrations.


Advantages of the Full Replicate Design with Two Consecutive Administrations:

  • Less number of subjects required in the study as compared to nonreplicated study.
  • Only by one additional study drug administration after steady-state, the entire steady-state achievement phase can be skipped for another period with the replicate design.
  • The total study duration reduces as compared to conventional replicate design.
  • Two consecutive administrations after steady-state achievement will give more accurate intra-subjects variability of the formulation as compared with conventional replicate design. In conventional replicate design, variation of external factors during the entire steady-state achievement phase may play a critical role in the obtained intra-subject variability.

Hence, full replicate design with two consecutive administrations is beneficial considering ethical as well as scientific aspects.

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