Historically, and in most cases, industry knows that it will certainly be required to perform both fasting and fed bioequivalence studies on solid oral immediate-release products or it may have an option to seek a waiver of in-vivo bioequivalence requirements for BCS Class 1 drugs. However, a few days ago, the FDA published a listing of over 825 Product Specific Guidances (PSGs) that it plans to revise to remove the requirement for the conduct of a fed bioequivalence study. This comports with the newly issued ICH M13A (here), which goes into effect on January 1, 2025. The date for revision of the guidances, however, is planned for October 2024, which is right around the corner.
While the FDA has historically recognized that fasting studies are the most sensitive for determining bioequivalence of products, it is a monumental change for the FDA to drop the fed study requirement for most products and acknowledge that fed studies should be reserved for certain high-risk and complex products. This obviously means that the change does not apply to all products. The guidance indicates that removal of the fed study requirement is not appropriate for what are termed “high risk” or complex products, defined in the guidance as products for which “the drug substance characteristics in combination with the complexity of the formulation design or manufacturing process lead to an increased likelihood that in vivo performance will be impacted differently by varying gastrointestinal (GI) conditions between the fasted and fed conditions. For these drug products, performance differences related to differences in formulation and/or manufacturing process may not be detected with a single BE study, i.e., results from a fasting BE study may not be extrapolated to predict fed BE study outcome or vice versa, thus both fasting and fed BE studies should be conducted. For example, some drug products containing low solubility drug substances (as defined by the BCS low solubility criterion described in ICH M9) have complex formulation and/or manufacturing methods, such as solid dispersions, microemulsions, co-processed drug substances, lipid-based formulations, nanotechnologies, or other specialized technologies, to ensure sufficient solubility of the drug substance and dissolution of the drug substance from the drug product or to manage the impact of food. For these high-risk products, BE studies should be conducted under both fasting and fed conditions, irrespective of the drug product labelling with regard to food intake, if safety permits” (see section 2.1.5 of the M13A guidance).
It’s apparent from the number of PSGs planned for revision to remove the fed-study requirement that the FDA has determined these products are not classified as high-risk or complex. Each of the products in this category has a statement indicating that the guidance is being revised as a “Minor Revision to Remove recommendations on fed BE study to align with ICH M13A.”
This change in policy was designed, among other reasons, to reduce unnecessary human testing, which, by the way, was one of the tenets of the original Hatch-Waxman Act. The impact on industry will also be considerable and will reduce development costs by hundreds of thousands of dollars. This is welcome news as generic drug user fees continue to rise.
This change does, however, raise several questions that still need to be answered – and quickly! For instance, for those of us who have asked the FDA about bioequivalence requirements for non-high-risk/non-complex products through meetings or controlled correspondences and have been instructed to perform both fasting and fed bioequivalence studies, will it be necessary to submit another controlled correspondence asking the FDA to adjust its recommendations? Or will it be sufficient to rely on the revised guidance and move forward? In addition, how should a firm approach a scenario where it has previously conducted bioequivalence studies under both fasting and fed conditions and the fed study has marginally failed? What should a firm do if it is about to conduct studies under both fasting and fed studies based on previous PSG recommendations for a non-high risk or non-complex product? Should it obtain permission from the FDA to drop the fed study or should it just do it on its own? What should a firm do if a fed study was just started and now that study is no longer required? Is it permissible to stop the study? Does a firm have to wait until the guidance documents are revised in October 2024? What if some of the guidances take longer than projected to be formally revised? I’m sure there are many other scenarios that could be postulated so it would be nice if the FDA would provide guidance on its expectations as this is, as mentioned before, a monumental change in requirements for certain products! Perhaps the Agency could provide a quick Q&A document covering the most likely scenarios?
