The International Council for Harmonisation (ICH) last month released a draft M13A guideline which proposes harmonized bioequivalence (BE) testing of new orally administered immediate-release (IR) solid oral drugs and assessing BE after post-approval changes.
The draft guideline does not address pharmacokinetic (PK) study designs or data analytics to support BE assessments but covers the scientific and technical aspects of study designs used to support BE assessments.
While most regulators have BE guidelines in place and follow similar assessment approaches, there remain some significant differences that hamper global harmonisation of drug development.
The draft guideline covers BE study designs, including study population, sample sizes, comparator and test products, fasting and fed condition and moieties to be measured. It recommends a randomized, single-dose, two-period, two-sequence crossover study design when comparing the test and reference formulations. Multiple-dose studies may be conducted if a single-dose study cannot be conducted for safety or tolerability reasons.
Batches used in pivotal BE studies should provide a high level of assurance that the product and process will be feasible on a commercial scale. The test product should originate from a batch of at least 1/10 of production scale or 100,000 units, whichever is greater.
The decision to use fasting or fed conditions depends on the dosing instructions of the comparator product and the properties of the drug substance and product formulation. The draft guideline states that sponsors should provide a rationale on why they are using fasting or fed studies, and if fed, the fat and calorie content. The rationale can be supported by modelling and semi-mechanistic absorption models.
To be considered statistically acceptable, studies should enrol at least 12 subjects. A test product can be deemed bioequivalent to a reference product if the 90% confidence interval for the geometric mean ratio of these PK parameters used to establish BE should lie within a range of 80.00 – 125.00%.
This is the first in a series of three guidelines to address BE; a forthcoming M13B guideline will describe biowaiver considerations for additional strengths not investigated in BE studies and M13C will address BE assessments for highly variable drugs.
The draft guideline was released for public consultation on 20 December and is available at: