FDA simultaneously announced the revision of several hundred draft product-specific guidances (PSGs) for immediate-release oral drug products to align with the M13A guidance. FDA will hold a webinar on Nov. 21 to discuss the final guidance, and seeks comments on the draft PSGs by Dec. 30.

FDA recently final guidance on “M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms,” as well as Q&A guidance of the same name, which provides recommendations on conducting bioequivalence (BE) studies during both development and post-approval phases for orally administered immediate-release (IR) solid oral dosage forms that are designed to deliver drugs to systemic circulation, such as tablets, capsules, and granules/powders for oral suspension.

The final guidance mostly resembles the draft version of the same name from January 2023, which it replaces, with one significant difference regarding fasting and fed study conditions. Alongside the final guidance, FDA also announced several hundred revised draft product-specific guidances (PSGs), which offer recommendations on the design of BE studies to support abbreviated new drug applications (ANDAs), to align with the M13A guideline.

Most notably, the final guidance and revised PSGs recommend that ANDA applicants may conduct just one bioequivalence study – for products with a non-high risk of bioinequivalence due to food effect – under either fasting or fed conditions. This upends FDA’s long-standing convention of requiring two bioequivalence studies: one BE study under fasting conditions, and one BE study conducted under fed conditions, which the agency historically requested in order to demonstrate that there is no difference in food-effect on the rate and extent of release of the active ingredient from the formulation. Now, FDA’s guidance states:

“For orally administered IR solid dosage forms, single-dose BE studies conducted under fasting conditions typically provide greater discrimination between the PK profiles of two drug products than studies conducted under fed conditions. Therefore, for the majority of these drug products, BE may be demonstrated in a single study conducted under fasting conditions.”

The guidance further specifies that, if safety permits, the following is recommended:

• for a drug product that is labeled to be taken only under fasting conditions or can be taken under fasting or fed conditions, a single BE study conducted under fasting conditions is recommended;

• for a drug product that is labeled to be taken only with food due to PK reasons, a single BE study conducted under fed conditions is recommended; and

• for a drug product that is labeled to be taken only with food due to tolerability reasons, a single BE study conducted under either fasting or fed conditions is acceptable.

Generic drug sponsors have long argued that in vivo fed BE studies, which require a drug to be tested when taken with food, are unnecessary for most IR oral products.

FDA writes in the final guidance, “food can have a differential, formulation-dependent impact on the absorption of drug substances from drug products with special characteristics that result in a higher risk of bioinequivalence due to food effects”; these are drug products that FDA calls “high-risk.” FDA said it will continue to require studies under fed conditions to demonstrate BE for these products.

FDA has scheduled a webinar for November 21 to discuss the agency’s implementation of the final guidance. The agency has also invited comments on the revised PSGs through December 30, 2024. If you wish to submit a comment, or have any questions on FDA’s requirements for demonstrating BE, please contact either of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.