The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

The role of partial area under the curve and maximum concentrations in assessing the bioequivalence of long-acting injectable formulation of exenatide_A sensitivity analysis.

To ensure therapeutic equivalence between the long-acting injectable (LAI) products, additional PK metrics other than Cmax and AUC were considered necessary. However, regarding the selection of additional PK metrics for bioequivalence (BE) assessment of exenatide LAI, a discrepancy existed between EMA's and USFDA's product-specific guidance. The EMA recommends that both the maximum plasma concentration in the initial-release phase (Cmax,1) and the extended-release phase (Cmax,2) should be determined. Nevertheless, the USFDA recommends the use of the partial area under the curve (i.e., the area under the curve from week 4 to the last sampling point; pAUC4w-t). The focus of this study was to compare the sensitivity of different PK metrics, including Cmax,1, Cmax,2, pAUC4w-t, early and late pAUC metrics truncated at different time points (three, four, five, six and seven weeks), to formulation-related parameters and pharmacodynamic (PD) markers of glycemic control. A sensitivity analysis was conducted using the published PK/PD model of exenatide LAI. The results indicated that Cmax,1 and Cmax,2 exhibited comparable sensitivities. AUC4w-t was sensitive to changes in detecting the differences in formulation-related parameters and PD markers of glycemic control, but did not provide superior sensitivity performance compared to Cmax,1 and Cmax,2. Among all tested PK metrics, AUC7w-t was found to be the most sensitive. The optimal cut-off time point for the pAUC should be set at the time of maximum plasma concentration in the extended-release phase (approximately 6-7 weeks). These results may provide useful insights into the selection of appropriate PK metrics for BE determination of exenatide LAI.

A Survey of Population Pharmacokinetic Reports Submitted to the USFDA: An Analysis of Common Issues in NDA and BLA from 2012 to 2021.

BACKGROUND AND OBJECTIVE: Population pharmacokinetic (PopPK) analysis is one of the important components of regulatory submission. The purpose of this study was to survey PopPK analysis reports in new drug applications (NDAs) and biological licensing applications (BLAs) submitted to the US Food and Drug Administration (FDA) and to retrieve the information regarding PopPK-related issues in the US FDA review reports. METHODS: We surveyed NDAs and BLAs over the period from 2012 to 2022 from Drug@FDA databases and extracted the review reports from the website. We explored the issues identified in these reports and sorted them into four categories: (i) data used for PopPK analysis, (ii) base model development, (iii) final model development, and (iv) model evaluation. The percentage of the issues in each category and the total issues were calculated. RESULTS: Data from a total of 317 applications were analyzed. Of these, 122 applications had at least one PopPK-related issue, and the count went up to 168 issues. The proportion of issues for each category was ranked as follows: model evaluation (39%, 65 of 168), final model development (34%, 57 of 168), data used for PopPK analysis (14%, 24 of 168), and base model development (13%, 22 of 168). The most common issues were related to the goodness-of-fit plots, covariate selection, and high shrinkage of ETA, accounting for 17.9%, 15.5%, and 11.3% of the total issues, respectively. CONCLUSION: The findings from this study may help the applicant understand the FDA's thinking on the PopPK analysis.

A Survey of the Criteria Used for the Selection of Alternative Comparator Products by Participating Regulators and Organizations of the International Pharmaceutical Regulators Programme.

The safety and efficacy of a generic product are partly based on demonstrating bioequivalence to the innovator product; however, when the innovator product is no longer available as a comparator product, a survey conducted within the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP) indicated that the criteria for selecting an alternative comparator product varies. For most members of the BEWGG, an existing marketed generic that was approved based on a comparison with the locally registered innovator product can be used, contingent on criteria that ranges from allowing any generic to be used, to allowing only specific criteria-defined generics to be used. Notwithstanding the acceptability of a generic as an alternative comparator, it is not always the preferred comparator for several jurisdictions. Some jurisdictions require the use of a locally sourced alternative innovator comparator (e.g., the same medicinal ingredient manufactured by a different company) or a foreign innovator comparator. Unlike the other members of the BEWGG, the European Union (EU) has no such options available, rather mechanisms are in place to allow manufacturers to develop a new comparator. The criteria described herein regarding the use of an alternative comparator product can also be applied to scenarios where a specific strength of a series of strengths or an innovative fixed dose combination are discontinued. The results of the survey demonstrate that while criteria for selecting alternative comparator products are not harmonized among the BEWGG participants, the common concern for all jurisdictions is to select a comparator product that meets the safety and efficacy standards of the original innovator product.

Investigation of the discriminatory ability of analytes for the bioequivalence assessment of ezetimibe: Parent drug, metabolite, total form, and combination of parent drug and total form.

The analysis of parent drug is usually the design of choice for a bioequivalence (BE) study. However, there is a controversy regarding the choice of analytes between EMA and USFDA for the BE study of ezetimibe (EZE). The EMA recommends measuring the total form alone, that means the sum of the concentration of "parent" EZE and "metabolite" ezetimibe-glucuronide (EZEG), as the BE determination. On the other hand, the USFDA recommends measuring not only total form but also EZE. The aim of this study was to employ a simulation approach to determine which analyte (e.g., EZE alone, EZEG alone, total form alone, or combination of EZE and total form) was more appropriate for use as a BE indicator. The previously published pharmacokinetic model of EZE and EZEG with enterohepatic circulation was used to generate virtual BE studies. Eight different scenarios were performed with changes in the rate of absorption of EZE and EZEG. Five hundred virtual BE studies were generated for each scenario. In addition, the discriminatory ability of selected analytes for detecting differences in the rate of absorption of EZE and EZEG was evaluated based on power curve performance. The results obtained through simulations indicated that none of the single analytes (EZE alone, EZEG alone, and total form alone) could have clear advantages in terms of discriminatory ability. Therefore, it was recommended that a combination of EZE and total form should be used in the BE assessment.

Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

This article describes an overview of waivers of in vivo bioequivalence studies for additional strengths in the context of the registration of modified release generic products and is a follow-up to the recent publication for the immediate release solid oral dosage forms. The current paper is based on a survey among the participating members of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Program (IPRP) regarding this topic. Most jurisdictions consider the extrapolation of bioequivalence results obtained with one (most sensitive) strength of a product series as less straightforward for modified release products than for immediate release products. There is consensus that modified release products should demonstrate bioequivalence not only in the fasted state but also in the fed state, but differences exist regarding the necessity of additional multiple dose studies. Fundamental differences between jurisdictions are revealed regarding requirements on the quantitative composition of different strengths and the differentiation of single and multiple unit dosage forms. Differences in terms of in vitro dissolution requirements are obvious, though these are mostly related to possible additional comparative investigations rather than regarding the need for product-specific methods. As with the requirements for immediate release products, harmonization of the various regulations for modified release products is highly desirable to conduct the appropriate studies from a scientific point of view, thus ensuring therapeutic equivalence.

A Survey of the Regulatory Requirements for the Waiver of In Vivo Bioequivalence Studies of Generic Products in Certain Dosage Forms by Participating Regulators and Organisations of the International Pharmaceutical Regulators Programme.

The requirements to waive in vivo bioequivalence studies for immediate release solid oral dosage forms based on the Biopharmaceutics Classifications System (BCS) are well known, and biowaivers[1] for other types of oral dosage forms based on pre-defined criteria may also be acceptable. Similarly, biowaivers for dosage forms such as injectable products may also be allowed if certain criteria are met. The current paper summarises the biowaiver requirements for oral solutions and suspensions, soft gelatin capsules and injectable products (intravenous injections, subcutaneous and intramuscular injections, emulsions for injection and micellar solutions for injection) among the participants of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP). A review of the requirements indicated that there was a trend towards convergence when the dosage form became less complex; however, the most common approach used by each of the jurisdictions was a case-by-case approach given that most jurisdictions do not have well defined guidelines to support all possible scenarios. Even in the simplest case of intravenous solutions, the acceptability of qualitative changes in excipients differ between the IPRP members.  Notwithstanding the differences, the dissemination of the information is a first step towards regulatory convergence regarding biowaivers for certain dosage forms and should be useful for pharmaceutical companies currently developing generic medicinal products for IPRP jurisdictions.

Model-based simulation to support the extended dosing regimens of atezolizumab.

PURPOSE: The currently recommended dosages of atezolizumab for patients with non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC) is 840 mg every 2 weeks, 1200 mg every 3 weeks (q3w), and 1680 mg every 4 weeks (q4w). However, it has been argued that these dosages may not be optimal. This study aimed to explore the feasibility of extended dosing regimens by population pharmacokinetics (PK) simulations and exposure-response (E-R) relationships. METHODS: All simulations were conducted based on the established population PK and E-R model for safety (i.e., adverse events of special interest, AESI) and efficacy (i.e., objective response rate, ORR) for patients with NSCLC or UC. The PK, AESI, and ORR profiles of the following dosing regimens were simulated: (i) 840 mg q4w, (ii) 1200 mg every 6 weeks (q6w), and (iii) 1680 mg q8w. These regimens were compared with those of the 1200 mg q3w standard regimen. RESULTS: The simulation revealed that the ranking of efficacy for different extended dosing regimens were 1680 mg q8w ≅ 1200 mg q3w ≅ 1200 mg q6w > 840 mg q4w based on the predicted probability of ORR in patients with NSCLC and UC, and this ranking order was similar to that of the safety outcome of the AESI. The minimum serum concentration at steady-state (Cmin,ss) values for all dosing regimens was all higher than the target effective concentration of 6 µg/mL. CONCLUSION: The findings from this simulation suggest that extended dosing regimens are unlikely to significantly impair clinical outcomes and may provide more therapeutic benefits to patients in terms of safety.

Analysis of Pharmacokinetic and Pharmacodynamic Parameters in EU- Versus US-Licensed Reference Biological Products: Are In Vivo Bridging Studies Justified for Biosimilar Development?

BACKGROUND: Bridging studies are mandatory in the EU and USA if the reference biological product used in the biosimilar comparability exercise is foreign sourced. However, it has been argued that the duplication of bridging studies may limit biosimilar development. OBJECTIVE: The aim of the study was to explore whether it is necessary to conduct pharmacokinetic (PK)/pharmacodynamic (PD) bridging studies for biosimilars. This study examines similarities and differences between EU- and US-licensed reference biological products, based on literature-reported PK and/or PD data. METHODS: We searched PubMed, Drugs@FDA, and European Medicines Agency (EMA) databases to identify biosimilar bridging studies designed to evaluate similarities between EU- and US-licensed reference biological products. PK and/or PD parameters were retrieved; the ratio of the parameter value of the EU-licensed product to that of the US-licensed product and its corresponding 90% confidence intervals (CIs) were calculated. Similarity was declared if the 90% CIs for the ratios of the PK or PD parameters were within the range of 80-125%. RESULTS: Thirty-one bridging studies were identified for 11 biosimilars, including adalimumab (n = 10), bevacizumab (n = 4), epoetin alfa (n = 1), etanercept (n = 2), filgrastim (n = 1), infliximab (n = 3), insulin glargine (n = 1), insulin lispro (n = 1), PEGfilgrastim (n = 2), rituximab (n = 2), and trastuzumab (n = 4). Most studies showed PK and/or PD similarities between the EU- and US-licensed reference biological products. However, among the 31 studies, only three studies (accounting for two biologics, PEGfilgrastim and adalimumab) showed dissimilarity between the EU and US reference products. Although one bridging study on PEGfilgrastim (Sandoz) indicated dissimilar PKs (maximum observed plasma concentration [Cmax] and area under the concentration-time curve [AUC]) between the reference products, the other study (Mylan) demonstrated similar PK. Moreover, two of ten studies involving adalimumab failed to demonstrate similarities between the reference products. However, for both cases, PK similarities were later confirmed in the follow-up bridging studies with larger sample sizes. CONCLUSION: Our analysis reveals that, in most cases, the reference biological products originated from the EU and those from the USA are almost indistinguishable in terms of PK/PD properties. Additional in vivo bridging studies between reference products from different global regions may not be required if similar physicochemical and structural properties are evident in vitro.

Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017.

In principle, approval of a modified-release (MR) drug product is based on evidence from pharmacokinetic (PK) and/or pharmacodynamic studies and clinical efficacy/safety studies. The purpose of this survey is (i) to explore the number of new drug applications (NDAs) of MR drug products, approved by the FDA, employ the PK study as a bridge to already-approved immediate-release drug products without conducting their own clinical efficacy/safety studies; and (ii) to understand the type of PK studies are required for such NDAs. To this end, we surveyed the approved records of MR drug products from 2008 to 2017 from the Drug@FDA website, and filtered pertinent information from FDA's assessment reports. A total of five out of 79 products were found. A single dose PK study was conducted to investigate the underlying drug release mechanisms in four of these products. For these products, the applicants also performed multiple dose PK equivalence studies, but the PK parameters used to support the equivalence were different among studies. Information regarding the exposure-response relationship was available for all selected products, which is fundamental for such cases. Although the difference in PK curve shapes is recognized as being critical for the clinical effectiveness, this evaluation was not performed in all selected cases, as indicated in FDA's assessment reports.

Investigation of the Discriminatory Ability of Pharmacokinetic Metrics for the Bioequivalence Assessment of PEGylated Liposomal Doxorubicin.

PURPOSE: The purpose of the study was to construct a population pharmacokinetic model for pegylated liposomal doxorubicin and use the final model to investigate the discrimination performance of pharmacokinetic metrics (e.g., Cmax, AUC and partial AUC) of various analytes (e.g., liposome encapsulated doxorubicin, free doxorubicin and total doxorubicin) for the identification of formulation differences by means of Monte Carlo simulations. METHODS: A model was simultaneously built to characterize the concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin using NONMEM. The different scenarios associated with changes in release rate (Rel) were simulated based on the final parameters. 500 simulated virtual bioequivalence (BE) studies were performed for each scenario, and power curves for the probability of declaring BE were also computed. RESULTS: The concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin were well described by a one- and two-compartment model, respectively. pAUC0-24 h and pAUC0-48 h of free doxorubicin was most responsive to changes in the Rel when the Rel (test)/Rel (reference) ratios decreased. In contrast, when the Rel (test) increased, AUC0-t of liposome-encapsulated doxorubicin was the most responsive metric. CONCLUSIONS: In addition to the traditional metrics, partial AUC should be included for the BE assessment of pegylated liposomal doxorubicin.

Evaluating the Feasibility of Use of a Foreign Reference Product for Generic Drug Applications: A Retrospective Pilot Study.

BACKGROUND AND OBJECTIVES: The adoption of a domestic reference product in bioequivalence (BE) studies for generic drug applications is required by some countries. The objective of this study is to assess the feasibility of this by investigating whether innovative products from different countries are bioequivalent. METHODS: Data were collected from all generic drug applications received by the Taiwan regulatory authority 2012-2016. If a submission package contained BE studies, that generic product was compared separately with different reference products, and the resulting data included in this analysis. A method of adjusted indirect comparison was used to evaluate the BE of reference products from different sources. The relationship between in vitro dissolution and in vivo BE was also explored. RESULTS: The present study included 10 drugs and a total of 11 comparisons. Seven comparisons for maximum concentration (C max) (63.6%) and all comparisons (100.0%) for area under the curve up to last measurable time point (AUC) complied with the BE criterion. Similar in vitro dissolution profiles were observed in all comparisons. Among the comparisons that failed to demonstrate BE, only one was considered to be possibly related to product difference, with point estimates of indirect comparison for C max significantly greater than unity (22%). Discordance between in vitro and in vivo observations was probably due to either drugs with highly variable properties or a lack of discriminatory dissolution testing method. CONCLUSIONS: Although this retrospective analysis only included a few drugs and product formulation types, i.e., immediate release, delayed release, and orally disintegrating tablet, these preliminary results suggest that using a foreign reference product in BE studies for generic drug applications could be a feasible approach, but with some restrictions: comparable dissolution profiles, same innovator company, same size, weight, and type of coating as the domestic reference product, etc. Further investigations for other complex formulations are required.

Pharmacokinetics of vancomycin in adults receiving extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: Extracorporeal membrane oxygenation (ECMO) alters the pharmacokinetics (PK) of vancomycin in neonates; but data on adults is limited. METHODS: This is a prospective, matched cohort, single center, pharmacokinetic study. For each adult patient who received vancomycin therapy in the ECMO group (with either centrifugal pump or roller pump), a control patient was matched by age (≥ 60 years or < 60 years), gender, and creatinine clearance (CLCr) in intensive care units. After vancomycin was administered for at least four doses, serial blood samples were drawn at 0.5 hours, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 11 hours, 23 hours, 35 hours, and 47 hours post vancomycin infusion according to the dosing intervals. The serum concentration-time profile was fitted to a noncompartment model and a nonlinear mixed effect model to determine the PK parameters. RESULTS: Twenty-two critically ill adults without renal replacement therapy were enrolled. There were no significant differences between the ECMO group and the matched group in demographics, renal function, and PK parameters. However, vancomycin clearance in the roller pump group was significantly lower than that in the matched control (0.83 ± 0.43 mL/min/kg vs. 0.97 ± 0.43 mL/min/kg, p = 0.002). CONCLUSION: Vancomycin clearance in patients receiving ECMO with a roller pump was significantly lower than that in the matched cohort. Vancomycin PK parameters in patients on ECMO with a centrifugal pump were comparable to those in the matched control group.

A statistical analysis to assess the most critical bioequivalence parameters for generic liposomal products.

OBJECTIVES: The purpose of the study was to identify the most sensitive analyte (i.e., encapsulated, free, and total forms) for assessing the bioequivalence (BE) of liposome drug products using Monte Carlo simulation. METHODS: We proposed a liposome classification system that divided liposome drug products into four classes according to the extent of reticuloendothelial system uptake and in vivo release rate: class I: low reticuloendothelial system uptake-rapid release rate; class II: low reticuloendothelial system uptake-slow release rate; class III: high reticuloendothelial system uptake-rapid release rate; Class IV: high reticuloendothelial system uptake-slow release rate. In conjunction with the proposed classification scheme, a variety of drug classes were simulated to determine which analyte provides the most sensitive measure of BE. All drug classes were investigated in single and multiple dose studies. The sensitivity of analytes for measuring BE was evaluated using the power curve. RESULTS AND CONCLUSIONS: Our simulations indicated the encapsulated form provides the most accurate assessment BE for liposome drug products with low reticuloendothelial system uptake (i.e., class I and II). For liposome drug products with high reticuloendothelial system uptake (i.e., class III and IV), the free form provides the best indication BE. Measurement of total drug form to assess BE was preferred only for liposome drug products with low reticuloendothelial system uptake and slow release rates (i.e., class II liposomal drug product). In general, a single dose form is sufficient for demonstrating the BE of liposome drug products.

Evaluation of etanercept dose reduction in patients with rheumatoid arthritis using pharmacokinetic/pharmacodynamic modeling and simulation.

OBJECTIVES: In this study, we attempt to explore the feasibility of alternative dosing regimens of etanercept in patients with rheumatoid arthritis (RA) using pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation. METHODS: All data used for estimation of PK/PD model parameters were collected from previously published literatures. American College of Rheumatology (ACR) 20/50/70 response rate and a disease activity score in 28 joints (DAS28) was selected as the principal clinical endpoint for further PK/PD modeling. The cumulative AUC (area under the concentration-time curve) of etanercept for different dosing regimens was calculated based on the final PK model and was then linked to the time course of clinical endpoints. Ten different dosing regimens were simulated in this study. RESULTS: The PK model that best fit the serum concentration-time data for etanercept was a one-compartment model with first order absorption and elimination. Based on the PK/PD analysis, the relationship between the predicted cumulative AUC of etanercept to the ACR 20/50/70 response rate and DAS28 score was well characterized by Emax logistic and inhibitory Emax model, respectively. In our simulations, the following dosing regimens that are equally effective to current recommended dosage of 25 mg twice weekly (b.i.w.): (1) 25 mg once weekly (q.w.); (2) 50 mg every 2 weeks (q2w); (3) 25 mg b.i.w. for 3 months and 25 mg q2w thereafter; and (4) 50 mg q.w. for 3 months and 50 mg q2w thereafter. CONCLUSION: In this study, the clinical data was well described by the models developed, and several alternative dosing regimens were proposed. Further clinical studies in patients are still needed to confirm our findings.