Testimonials

It is very nice to visit Lambda facility and thanks to warm welcome provided by all the teams. I can easily say one of the best CRO I ever visited. People here are wonderful and doing great job

Reputed Client of Israel

Awesome hospitality & fantastic office. All the best!

Reputed Client of Japan

Excellent hospitality and cooperation received throughout the audit. People are knowledgeable and extremely transparent. Looking for long time relation

Reputed Client of Asia

Facility is too good to conduct the BABE studies and adherence to protocol and quality assurance in conducting studies are meeting sponsor expectations and requirements.

Reputed Client of India

Facility is good, people r trained well and know the subject on which they r working. All the best.

Reputed Client of USA

Highly innovative and advanced research centre that possess bright future for the development of the country.

Reputed International Government Body

It is one of the best facility in India for BA/BE

Reputed Regulatory Authority

Lambda is a very professional CRO. All the staff here are experienced and very knowledgeable. I'm grateful for their accommodations and hospitality. The future, if we want to carry out BE study, we will ask Lambda help again.

Reputed Client of Europe

It was a really pleasant meeting with the PV department, and I am looking forward to the next visit.

Reputed Client of Europe

Amazing and best CRO I ever seen

Reputed Client of China

Blog

Blog

Home / Blog

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)

4_1b

Full Replicate Design with Two Consecutive Administrations (Sequence: TR/RT)
4_2b
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.





Looking for a Globally Proven Research Partner?

Contact Us