Highly Variable Drugs: Observations from Bioequivalence Data Submitted to the FDA for New Generic Drug Applications

Abstract

Introduction. It is widely believed that acceptable bioequivalence studies of drugs with high withinsubject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied the scope of this issue within US generic drug regulatory submissions. Materials and Methods. We collected data from all in vivo bioequivalence studies reviewed at FDA's Office of Generic Drugs (OGD) from [2003][2004][2005]. We used the ANOVA root mean square error (RMSE) from bioequivalence statistical analyses to estimate within-subject variability. A drug was considered highly variable if its RMSE for C max and/or AUC was ≥0.3. To identify factors contributing to high variability, we evaluated drug substance pharmacokinetic characteristics and drug product dissolution performance. Results and Discussion. In 2003-2005, the OGD reviewed 1,010 acceptable bioequivalence studies of 180 different drugs, of which 31% (57/180) were highly variable. Of these highly variable drugs, 51%, 10%, and 39% were either consistently, borderline, or inconsistently highly variable, respectively. We observed that most of the consistent and borderline highly variable drugs underwent extensive first pass metabolism. Drug product dissolution variability was high for about half of the inconsistently highly variable drugs. We could not identify factors causing variability for the other half. Studies of highly variable drugs generally used more subjects than studies of lower variability drugs. Conclusion. About 60% of the highly variable drugs we surveyed were highly variable due to drug substance pharmacokinetic characteristics. For about 20% of the highly variable drugs, it appeared that formulation performance contributed to the high variability.

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

“…For example, in a two-way crossover design, two products with identical bioavailability may require 40 subjects to demonstrate BE with 90% power if the intra-subject variability is 30% but the number of subjects increases to approximately 140 at intra-subject variability of 60% (26). Similar analysis of BE data by Food and Drug Administration (FDA) for new generic drug applications showed that generally studies of highly variable drugs (root mean square error (RMSE)≥0.3) used more subjects than BE studies of drugs with lower variability (RMSE<0.3) (27). For drugs that had high variability in C max , the number of study subjects ranged from 18 to 134, with an average of 46 subjects per study.…”

Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/Bioequivalence

“…(FDA) discussed two approaches acceptable to the FDA for bioequivalence studies of highly variable generic drug products (21). The first is the reference-scaled average bioequivalence approach, whereby the BE acceptance limits are scaled to the variability of the reference product.…”

The basic regulatory considerations and prospects for conducting bioavailability/bioequivalence (BA/BE) studies &ndash; an overview

“…Using this BCS approach, a highly permeable, highly soluble drug substance formulated into a rapidly dissolving drug product may need only in vitro dissolution studies to establish BE. 20 In addition, in vitro approaches to document BE for nonbioproblem drugs approved before 1962 remain acceptable as per FDA regulations. Dissolution tests can also be used to reduce the number of in vivo studies in other circumstances, and to i) assess batch-to-batch quality and support batch release; ii) provide process control and quality assurance; and iii) assess the need for further BE studies relative to minor post-approval changes, where they function as a signal of bioinequivalence.…”

“…Dissolution tests can also be used to reduce the number of in vivo studies in other circumstances, and to i) assess batch-to-batch quality and support batch release; ii) provide process control and quality assurance; and iii) assess the need for further BE studies relative to minor post-approval changes, where they function as a signal of bioinequivalence. 20 The broad spectrum of BA/BE in vitro studies specifications were provided by each regulatory authority.…”

“…Bioanalysis [15][16][17][18][19][20][21][22][23][24][25][26][34][35][36] In a general prospective of BA/BE studies, bioanalysis should be the subsequent step following clinical operations of the study (as shown in Figure 3), and it should be executed with strict adherence to good laboratory practices, standard operating procedures, and specific regulatory requirements. Bioanalysis is a term generally used to describe the quantitative measurement of a compound (drug) or its metabolite in biological fluids, primarily blood, plasma, serum, urine, or tissue extracts.…”