The International Council for Harmonisation (ICH) is expected to adopt its M13A guideline on bioequivalence (BE) testing of immediate-release (IR) solid oral dosage form drugs this summer, announced Lei Zhang, of the US Food and Drug Administration (FDA) and the rapporteur of the M13A Expert Working Group, at the PQRI/EUFEPS Global Bioequivalence Harmonisation Initiative meeting held on 16 April.
The ICH guideline, which also covers evaluating BE after postapproval changes, was released as a Step 2 document for consultation in December 2022 and represents a major advancement in how BE testing is conducted for immediate-release solid oral dosage forms.
“This is the first harmonized guideline that focuses on BE” for these dosage forms and impacts a “large portion of the generic drug market,” Zhang said, adding that once the guideline is adopted, FDA will need to revise a majority of its product-specific guidances (PSGs) for immediate-release solid oral dosage products.
Once adopted, the guideline will reduce the need for additional BE studies due to divergent regulatory requirements, said Zhang. Such divergence leads to companies having to generate multiple sets of data to support marketing authorizations in different jurisdictions. This can lead to limited availability of drugs in certain markets.
Zhang said the guideline takes a risk-based approach to determine BE studies with regards to meals and fasting or fed conditions, which she called a major area of divergence. One of the biggest changes is that under the guideline, BE testing need only be conducted under fasting or fed conditions, while high-risk products may be subject to both types of testing.
Under the guideline 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. It further specifies that sponsors should provide a rationale on why they are using fasting or fed studies; the rationale can be supported by modelling and semi-mechanistic absorption models.
Zhang said this guideline culminates years of work, starting with a 2017 ICH reflection paper and the work of the ICH Generic Drug Discussion Group, which recommended BE topics ripe for harmonization. There was a decision to start with non-complex dosage forms, such as solid oral dosage forms, then move on to other more complex dosage forms and products.
As a result of these discussions, plans are in the works to release two complementary guides: an upcoming M13B Step 1 draft technical document will cover BE for additional strengths, including additional strengths for biowaivers, and an M13C guideline will address BE data for highly variable drugs (HVDs) and drugs of a narrow therapeutic range (NTI) as well as complex study designs; work on this guideline will being after the ICH M13B reaches Step 2.
There are plans to issue an ICH M13A Step 4 guideline either in June or July 2024, following face-to-face meeting in June.
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