Article -> Article Details

The Regulatory Framework: ANDA and Bioequivalence

For oral solid dosage forms like tablets and capsules, approval is obtained via the Abbreviated New Drug Application (ANDA). Applicants do not need to submit Phase I, II, or III clinical trials for safety and efficacy re-proofs but must demonstrate bioequivalence to the Reference Listed Drug (RLD) through in vivo pharmacokinetic studies conducted in healthy volunteers, focusing on two key parameters.

For bioequivalence, the 90% confidence intervals for AUC and Cmax must be within the 80–125% acceptance range compared to the reference product.

The ICH M13A Update:

A significant change took place in January 2025 with the implementation of the ICH M13A guideline on bioequivalence for immediate-release solid oral dosage forms, adopted by both the FDA and EMA. This guideline establishes globally harmonized bioequivalence standards for oral drugs, including tablets and capsules.

Key Changes Under ICH M13A

1.     Single Study Instead of Dual Fasting/Fed Studies

Manufacturers of non-high-risk drugs may now conduct only one bioequivalence study, rather than requiring studies under both fasting and fed conditions, leading to reduced development time and lower clinical study costs.

2.     Structured Tiered Study Design Framework

ICH M13A provides a framework for bioequivalence (BE) studies, assisting companies in choosing appropriate study designs, analytical methods, and statistical techniques that meet both local and global regulatory requirements.

3. Methods to Handle Data Variability

The guidance outlines strategies to handle pharmacokinetic variability in absorption, essential for complex oral formulations, facilitating accurate assessments of generic products against bioequivalence standards.

4. Global Harmonization

ICH M13A standardizes bioequivalence study requirements across ICH regions, including the US and EU, minimizing regulatory redundancies and expediting access to safe and effective generic drugs globally.

5. Additional Strengths Biowaivers

Generic applicants under ICH M13B can receive approval for various drug strengths without extensive in vivo testing if they satisfy certain scientific criteria.

WHO Requirements for Global Markets

Manufacturers targeting markets outside the US and EU must ensure that BE study reports in product dossiers comply with World Health Organization (WHO) guidance for bioequivalence studies and Good Clinical Practice guidelines.

Key WHO requirements include:

• Completion of a Bioequivalence Trial Information Form (BTIF) for each BE study submitted
•  Demonstration that multisource (generic) products satisfy the same standards as originator products
• Compliance with WHO Good Clinical Practices for Trials on Pharmaceutical Products
• The WHO acknowledges that in vivo bioequivalence may be waived for immediate-release products showing rapid in vitro dissolution characteristics similar to the reference product.
• Data Integrity: Regulatory inspections are emphasizing data integrity practices, with the FDA’s April 2024 guidance detailing expectations for data integrity in in vivo bioavailability and bioequivalence studies. All clinical trial studies initiated after December 17, 2016, must submit data in CDISC-compliant format.