Overview

In 2024, Bioavailability/Bioequivalence (BA/BE) studies remained pivotal in generic drug approvals and certain new formulation evaluations by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). This report summarizes clinical trial outcomes, regulatory decisions, submission highlights, and key trends based on official FDA and EMA sources.

USFDA Highlights

• ANDA Approvals: FDA approved 694 Abbreviated New Drug Applications (ANDAs) and provided tentative approval for 162 generics in FY2024. Notably, 70 were first-time generics demonstrating successful BA/BE.
• Adoption of ICH M13A Guideline: FDA adopted the final version of the ICH M13A guideline "Bioequivalence for Immediate-Release Solid Oral Dosage Forms" in July 2024, releasing guidance in October 2024. It standardizes BE study design globally, simplifying studies for non-high-risk oral products by requiring just one pivotal BE study (fed or fasting), instead of two.
• Data Integrity Issue (Synapse Labs): FDA invalidated BA/BE studies from Synapse Labs due to serious data integrity concerns, requiring approximately 20 affected generics to redo studies. Applications based solely on Synapse data had their therapeutic equivalence rating changed to BX (insufficient evidence) until new data is submitted.

Table 1: Select USFDA BA/BE Study Outcomes (2024)

This table summarizes notable Abbreviated New Drug Applications (ANDAs) reviewed by the USFDA, highlighting key bioequivalence study outcomes and regulatory decisions.

EMA Highlights

• Generics Approved: EMA's CHMP recommended approval for 17 generics in 2024, including drugs for multiple sclerosis, oncology, and chronic illnesses.
• Product-specific BE Guidance: EMA continued offering detailed, product-specific bioequivalence guidance, supporting applicants in successful generic submissions.
• Implementation of ICH M13A: EMA facilitated the transition from its existing BE guidelines to align with ICH M13A, providing clarity on conducting BE studies under harmonized international standards.
• Data Integrity Issue (Synapse Labs): Similar to FDA's actions, EMA suspended approximately 100 generics due to unreliable BA/BE studies from Synapse Labs. Affected sponsors were mandated to repeat studies at compliant facilities. Around 35 medicines avoided suspension due to having additional acceptable BE studies.

Table 2: Select EMA BA/BE Study Outcomes (2024)

This table highlights significant generic drug marketing authorization applications (MAAs) reviewed by EMA's CHMP, focusing on bioequivalence study outcomes and regulatory decisions.

Key Trends and Regulatory Insights

• Clinical Outcomes: BA/BE studies predominantly showed bioequivalence, validating their use as a surrogate for clinical efficacy and safety.
• Regulatory Actions: Both FDA and EMA issued approvals swiftly upon satisfactory BE evidence but actively addressed cases requiring further clarification or additional data through rejections, withdrawals, or CRLs.
• Integrity Enforcement: Both agencies intensified scrutiny of data integrity, as evidenced by the high-profile Synapse Labs case, signaling a zero-tolerance policy for compromised studies.
• Guideline Harmonization: The adoption of ICH M13A by FDA and EMA marked significant progress toward international regulatory harmonization in bioequivalence standards, promoting global consistency and efficiency in generic drug development.

In 2024, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) conducted global inspections focusing on Bioavailability (BA) and Bioequivalence (BE) studies. These inspections aimed to ensure the integrity and reliability of data submitted in support of drug approvals. Key findings from these inspections include:​

FDA Findings

• Data Integrity Concerns: The FDA identified significant data integrity issues during in vivo BA and BE studies. In April 2024, the FDA released a draft guidance titled "Data Integrity for In Vivo Bioavailability and Bioequivalence Studies," highlighting the importance of maintaining accurate and reliable data throughout the study process. The guidance provides recommendations to applicants and testing site management on achieving and maintaining data integrity for both clinical and bioanalytical portions of BA and BE studies. ​
• Sample Handling and Retention: The FDA emphasized proper handling and retention of testing samples in BA and BE studies. In March 2024, the agency issued draft guidance outlining procedures for distributing test articles and reference standards to testing facilities, random selection of samples for testing, and retention of reserve samples. This guidance aims to ensure compliance with regulatory requirements and maintain the integrity of study samples.

EMA Findings

• Harmonization of BE Study Designs: The EMA, through its Good Clinical Practice Inspectors Working Group (GCP IWG), worked towards harmonizing BE study designs. A survey conducted by the International Pharmaceutical Regulators Programme Bioequivalence Working Group (IPRP BEWGG) collected recommendations from various participants regarding the design and analysis of BE studies for immediate-release solid oral dosage forms. The findings highlighted the need for standardized study designs to facilitate global acceptance of BE studies.
• Product-Specific BE Guidance: The EMA continued to provide product-specific bioequivalence guidance, summarizing relevant study design principles for demonstrating bioequivalence. This guidance assists applicants in meeting regulatory expectations for generic applications across all submission routes.

These findings underscore the commitment of both agencies to uphold the quality and reliability of BA and BE studies, ensuring that generic medicines meet the necessary standards for safety and efficacy.

Conclusion

In 2024, FDA and EMA continued rigorous enforcement of bioequivalence standards while streamlining requirements through the harmonization of global guidelines. The year highlighted substantial generic drug approvals based on robust BA/BE evidence alongside critical regulatory interventions ensuring data integrity and patient safety.

References

• FDA Generic Drug Approvals and Submissions Data (2024). Available at: www.fda.gov
• FDA Guidance on ICH M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms (2024). Available at: www.fda.gov
• EMA CHMP Recommendations (2024). Available at: www.ema.europa.eu
• EMA Product-Specific Bioequivalence Guidance (2024). Available at: www.ema.europa.eu
• EMA Implementation of ICH M13A Guideline (2024). Available at: www.ema.europa.eu
• FDA and EMA Notices on Data Integrity Issues related to Synapse Labs (2024). Available at: www.fda.gov, www.ema.europa.eu