Generic industry group wants clarity on ICH bioequivalence guideline
The Association for Accessible Medicines (AAM) said the US Food and Drug Administration (FDA) should ensure alignment between the International Council on Harmonisation’s (ICH) M13A guidance on bioequivalence testing (BE) of new orally administered immediate-release (IR) solid oral drugs and the agency’s numerous product-specific guidances (PSGs).Not doing so could delay ongoing ANDA development programs and affect pending approvals. If FDA decides to incorporate ICH M13A changes, the agency should “provide a scientific justification for doing so and discuss the change in approach with the applicant.”
The group also sought clarity on other aspects of the ICH guidance, including the study population, sample sizes, comparator and test products, and fasting and fed conditions.
FDA released the guidance for public consultation on 1 February after the draft guidance reached Step 2 of the ICH process last December. (RELATED: ICH releases draft guideline proposing harmonized bioequivalence testing, Regulatory Focus 3 January 2023).
M13A may conflict with PSGs
FDA should ensure alignment between the ICH guideline and the agency’s own PSGs, AAM said. “Before issuing any final guidance, AAM is concerned that in some cases, this ICH guideline may be inconsistent with existing PSGs or advice provided to applicants, and that as a result, FDA could question ANDAs developed in accordance with those PSGs or advice,” AAM said. One disconnect that AAM highlighted is that some PSGs may only recommend a fasting study while the ICH guideline recommends both fed and fasting studies.
PSGs provide product-specific recommendations on the design of BE studies to support generic drug approval. The agency has so far issued more than 2,000 PSGs, many of which are for complex products. (RELATED: FDA releases FY 2022 generic drug research summary, Regulatory Focus 31 January 2023).
AAM states that “although in general, FDA should ensure alignment between PSGs and ICH M13A, it must be cautious about applying the final M13A retroactively in a way that could delay ongoing ANDA development programs and approvals of pending applications. If FDA decides to apply ICH M13A changes to ongoing development programs or pending applications, it should provide a scientific justification for doing so and discuss the change in approach with the applicant.”
AAM wants more flexibility in study designs
AAM also called for more flexibility in the design of BE studies. The guidance states that “subjects should be at least 18 years of age and preferably have a Body Mass Index between 18.5 and 30.0 70 kg/m2. If a drug product is intended for use in both sexes, it is recommended the study include male and female subjects.”
AAM state that “it should be acceptable to run bioequivalence (BE) studies in any population, irrespective of ethnic origin, age, gender or other characteristics, unless there is a known impact on PK in a subpopulation.”
High-risk products should be better defined
AAM also suggested the definition of a high-risk product for purposes of be better defined. The product’s risk class affects the design of BE studies.
The guidance defines high-risk products as “those where the complexity of the formulation design or manufacturing process leads to an increased likelihood that in vivo performance will be impacted differently by varying gastrointestinal (GI) conditions between the fasted and fed states.”
AAM said that the definition of a high-risk product should be amended to reflect additional characteristics, such as the drug substance, in addition to the complexity of the formulation design or manufacturing process.
The group suggested that high-risk products be defined as “those in which the drug substance characteristics in combination with the complexity of the formulation design or manufacturing process leads to an increased likelihood that in vivo performance will be impacted differently by varying gastrointestinal (GI) conditions between the fasted and fed states.”
Change suggested for low-solubility drugs
AAM also suggested changes in the section on designing BE studies for low-solubility drugs. The guidance states that “if the test product uses a substantially different manufacturing technology or particle size control method from the comparator, or if substantially different excipients are used in the test and comparator that are likely to impact dissolution, solubility, or permeability, this may warrant the need for BE studies under fasting and fed conditions.”
AAM said that “this sentence is very broad and may result in fast and fed studies for almost every low solubility drug.”
The group called for the text be amended to state that “if the test product is a complex product (complex formulation and/or manufacturing method) and uses a substantially different manufacturing technology or particle size control method from the comparator, and or if substantially different excipients are used in the test and comparator that are likely to impact dissolution, solubility, or permeability, this may warrant the need for BE studies under fasting and fed conditions.”
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