Session Title
Chairs:
Wanjie Sun, PhD (FDA)
Fairouz Makhlouf, PhD, (FDA)
Abstract: This session presents three cutting-edge statistical methodologies addressing critical challenges in generic drug development and equivalence testing. The presentations showcase the application of hybrid trial designs in equivalence settings, novel approaches to bioequivalence assessment and comparative testing for complex drug delivery systems.
Dr. Ethan Cao will present “Utility of Hybrid Controlled Trials in Equivalence Studies,” exploring the application of hybrid controlled trial designs that incorporate external real-world controls in equivalence settings. Through simulation-based studies, Dr. Cao will compare various statistical approaches for handling external controls.
Dr. Wanjie Sun will present “Bridging Methods in PK Bioequivalence Studies,” introducing an innovative statistical framework for establishing pharmacokinetic bioequivalence when traditional reference standards are unavailable due to Reference Listed Drug discontinuation. This bridging methodology has already informed two FDA product-specific guidances, demonstrating its practical impact on facilitating generic drug development and improving patient access to affordable medications.
Dr. Meiyu Shen will discuss “Comparison of In-Vitro Release Rates for Vaginal Systems,” addressing the unique challenges of evaluating chemistry, manufacturing, and controls changes in complex drug-device delivery systems. Dr. Shen will propose an equivalence testing approach that ensures critical daily release amounts are maintained consistently throughout the product lifecycle.
Dr. Stella Grosser from the FDA will serve as the session discussant, providing expert commentary and facilitating discussion on the methodological innovations and regulatory implications presented across all three talks.
Speaker: Ethan Cao, PhD (Sandoz)
Title: Utility of Hybrid Controlled Trials in Equivalence Studies
Abstract: In recent years, various statistical methodologies have been proposed for analyzing hybrid controlled trials that incorporate external real-world controls. These methods aim to provide unbiased estimates of the average treatment effect. However, most discussions have focused on superiority trials. Our paper investigates the utility of hybrid controlled trials in equivalence settings through a simulation-based study. We compare different statistical approaches for handling external controls, including propensity-score matching, a two-step approach—matching followed by down-weighting—and other selective borrowing methods.
Speaker: Wanjie Sun, PhD (FDA)
Title: Bridging Methods in PK Bioequivalence Studies
Abstract: For most generic drugs, pharmacokinetic (PK) bioequivalence (BE) must be demonstrated using a reference standard (RS), which is typically the Reference Listed Drug (RLD) or, in some cases, an approved generic product. Challenges arise when the RLD has been discontinued for reasons unrelated to safety or efficacy and no approved generic product is available to serve as the RS.
In this work, we propose an innovative statistical approach to establish PK BE between a test product and its discontinued RLD through bridging methods utilizing one or more alternative comparators. These are usually approved drug products containing the same active pharmaceutical ingredient but differing in dosage form, leveraging publicly available historical data to create a scientifically robust pathway. Under the constancy assumption, we propose a bridging method to extrapolate the confidence interval of the geometric mean ratio for the test product vs the discontinued RLD product leveraging data across historical and current studies, under homogeneity or heterogeneity, which is tested by a F test. This statistical approach provides a scientifically sound and practical alternative pathway for generic drug development when traditional BE methods are unavailable due to RLD discontinuation. Two FDA product-specific guidances were published based on this bridging method, which facilitates generic drug development and improves patient access to affordable medications.
Speaker: Meiyu Shen, PhD (FDA)
Title: Comparison of In-vitro Release Rates for Vaginal System
Abstract: Vaginal systems (VSs) or intravaginal rings are flexible, polymer-based, drug-device delivery systems used for release of one or more drugs directly to the vaginal-cervical tissues for an extended period. These complex products can undergo chemistry, manufacturing, and controls (CMC) changes. Comparative in vitro release testing between pre-change and post-change product can be used to support minor/moderate CMC changes. Due to long drug release period, the cumulative profile may be insensitive to visualize release rates’ trend over time. Any summary statistic, e.g., the similarity factor f2 for dissolution profiles’ comparison, may hide a large deviation at some time points since a summary statistic is equivalent to comparing the mean difference between two profiles averaged over time. This is problematic since the amount released per day is critical to ensure maintaining product quality and product performance consistently. Therefore, a summary statistic does not fit for the use. Another way to compare two profiles is to compare estimated parameters after fitting the data to a curve which can be described by a few parameters. However, due to irregularity of these curves with limited number of time points, modeling approach, resulting in a large deviation at some points, isn’t practical. In addition, specifications on in-vitro release rates of drug product at several pre-selected time points are generally recommended when a batch is released to the market and through the stability. We propose an equivalence testing approach for comparing in-vitro release rates between the pre-change and the post-change VS at each of pre-selected time points.
Discussant: Stella Grosser, PhD (FDA)
