Between-Batch Bioequivalence (BBE): An Alternative Statistical Method to Assess In Vitro Bioequivalence of Nasal Product
In the pharmaceutical industry, we can see the development of generics is significantly growing. This trend is mainly driven by countries to give patients easier access to drugs and to define regulations accordingly.
From an industrial perspective, the success of a generic product development is based on two elements: compliance with all the regulatory requirements and safety for patients (ie, has the same final therapeutic effect than the brand-name product).
One way to prove the equivalence, without long and expensive clinical trials, is to conduct in vitro bioequivalence evaluation between the Innovator (Reference product) and the proposed generic (Test product).
This evaluation is generally done through average bioequivalence (ABE) , or population bioequivalence (PBE) for in vivo and in vitro testing, through statistical methods.1-8 In vitro bioequivalence testing is not considered and evaluated in the same way by all instances taking part in the process.
Indeed, in the US FDA recommends the use of population bioequivalence (PBE), whereas Europe recommends using average bioequivalence (ABE).
While both ABE and PBE tests consider the device total variability, the between-batch variability, which is part of the total variability, is not considered individually in the mathematical definitions proposed by the FDA and EMA guidelines.
On one side, ABE only considers within-product variability. On the other side, the FDA guidance on Budesonide recommends to decompose the variance as a composite of a super-batch variability (ie, after pooling all batches per product) and the within-individual variability to study the life-stages (begin, middle, and end-of-use) equivalence.
Considering this, an alternative statistical test, named between-batch equivalence (BBE), is proposed to assess in vitro bioequivalence. This statistical approach is based on the comparison between the mean difference (Reference − Test) and the Reference between-batch variability. The main hypothesis is that considering the between-batch variability of the Reference, the BBE test will be more appropriate to demonstrate equivalence in the case of variable drug products, without needing to increase the total required sample size. This statistical method can deal with normal scale data as well as after log transformation of the raw data.
To read the full article : NASAL SPRAY BIOEQUIVALENCE – Drug Development & Delivery
To download the full magazine: Drug Development & Delivery – September 2021
About the authors:
Céline Petitcolas is Customer Technical Support for nasal range at Nemera. Holding a Materials Engineering degree from the École Nationale Supérieure de Chimie et de Physique in Bordeaux, France, she joined Nemera in 2012 to develop pharmaceutical devices, focusing especially on the nasal spray area. Her role consists in helping and assisting customers from a technical point of view in their development of nasal sprays and more specifically in the area of bioequivalence. She is the preferred technical contact for customers as she interfaces with multiple Nemera teams (marketing, sales, technical) to bring customers and partners the support they need.
Manuela Basso is an experienced communications professional, with a journalism and marketing background. She holds a European Master in Management and specializes in International Marketing. After various experiences in different fields, she has been working at Nemera for 6 years, developing effective communications to support Nemera’s overall vision and mission: to put patients first.
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