Bioequivalence and Bioavailability Forum

Hello Essar!

❝ Just as we receive recommendations from Office of Generic Drugs (OGD) of US-FDA regarding which BE study design to be followed and what in-vitro dissolution criteria to be adopted, does any regulatory authority in EU provides similar recommendations?

Let's start with the easy one: BCS is part of the European Note for Guidance (NfG) on BA/BE (Appendix II), which is - with minor differences - the same as the US-regulation. Some conditions of US-FDA's regulations (e.g., the pH range) are expected to be relaxed in the near future.
pH-range
US: 1.0-7.5
EU: 1.0-6.8
Sampling points
US: <4
EU: <3
Coefficient of variation
US: <20% at earlier time points
EU: no restrictions
US: <10% at other time points
EU: <10% at other time points

Concerning BE designs, recommendations are less specific in the European guideline than US-FDA's are; at '3.1 Design' the EU-NfG states:

The study should be designed in such a way that the formulation effect can be distinguished from other effects. If the number of formulations to be compared is two, a two-period, twosequence crossover design is often considered to be the design of choice.
However, under certain circumstances and provided the study design and the statistical analyses are scientifically sound alternative well-established designs could be considered such as parallel design for very long half-life substances and replicate designs for substances with highly variable disposition.

As a consequence in my experience designs with more than 2 periods (e.g., 3- or 4-period Williams' designs) are more common in the EU than in the US.

• Pro: additional flexibility
  
• Con: may lead to discussions with authorities

Since it's possible to perform a study in the EU (e.g., test product vs two reference products) which is not possible in the US (one and only one RLD), you should have an eye on statistical multiplicity issues (the overall patient's risk must be kept <5%).
EMEA published a document concerning multiplicity in 2002 (in the example given above you should calculate a 95% confidence interval instead of the common 90% CI).

Another point are acceptance ranges other than 80%-125% (standard for all drugs in the US): an extended acceptance range of e.g., 75%-133% was possible (if based on sound clinical justification) in the EU for many years, but according to a recently published document European authorities are expected to be more restrictive in their practice (see also this post).

A concept paper for Highly Variable Drugs / Drug Products is currently in preparation: replicate designs and reference scaled average BE are on their way (= current practice in the US).

Population and Individual Bioequivalence is not covered in any European Guideline; if you want to perform such a study, a scientific advisory meeting is almost inevitable.

In advanced engineering, you expected failure; you learned as much from
failures as from successes - indeed if you never suffered a failure you
probably weren't pushing the envelope ambitiously enough.
                      Stephen Baxter; Transcendent, Chapter 36 (2006)