Bioequivalence Approach Research Articles

Assessment of comparative bioavailability of Itraconazole capsule 100 mg under fasting conditions by average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE) approaches

The assessment of interchangeability (prescribability and switchability) is one of the debatable topics in the generic drug industry. Currently, the question is whether we have an adequate assessment system for the evaluation of generic drug products. The objective of the study is to assess the comparative oral bioavailability of Itraconazole capsule 100mg after administering single dose to adult, healthy, human subjects in fasted state by different bioequivalence approaches like average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE) and to monitor the safety of study subjects. An open-label, balanced, randomized, two-treatment, two-sequence, four-period, crossover, single-dose comparative oral bioavailability study was conducted in sixteen healthy, adult, human subjects in a fasted state. Test formulation, Itraconazole capsule 100mg, and reference formulation, SPORANOX® (Itraconazole) capsule 100mg, were administered in a fasted state. The test formulation, Itraconazole capsule 100mg, showed bio-inequivalent against reference SPORANOX® (Itraconazole) capsule 100mg in study subjects under a fasted state. Also, the test formulation exhibited a similar safety and tolerability profile compared to the reference formulation. There was no report of serious adverse events (SAEs) and deaths in the study. The test formulation was found to be bio-inequivalent to reference formulation in the study subjects under a fasted state by estimating different bioequivalence approaches like average bioequivalence, population bioequivalence, and individual bioequivalence.

A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin.

A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10mg adefovir-dipivoxil (OAT1; renal clearance (CLR )), 100mg sitagliptin (OAT3; CLR ), 500mg metformin (several renal transporters; CLR ), 2mg pitavastatin (OATP1B1; clearance/F), and 0.5mg digoxin (intestinal P-gp, renal P-gp, and OATP4C1; peak plasma concentration (Cmax ) and CLR ). Using a randomized six-period, open change-over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80-1.25). Primary metrics supported the absence of relevant interactions, whereas secondary metrics suggested that mainly adefovir was a victim of minor drug-drug interactions (DDIs). All drugs were well tolerated. This cocktail may be another useful tool to assess transporter-based DDIs invivo.

Cascade Impactor Equivalence Testing: Comparison of the Performance of the Modified Chi-Square Ratio Statistic (mCSRS) with the Original CSRS and EMA's Average Bioequivalence Approach.

The performances of three statistical approaches for assessing in vitro equivalence was evaluated with a set of 55 scenarios of realistic test (T) and reference (R) cascade impactor (CI) profiles (originally employed by the Product Quality Research Institute to evaluate the chi-square ratio statistic: CSRS) by comparing the outcomes against experts' opinion (surrogate for the truth). The three methods were (A) a stepwise aerodynamic particle size distribution (APSD) equivalence test integrating population bioequivalence (PBE) testing of impactor-sized mass (ISM) with the CSRS (PBE-CSRS approach), previously suggested by the USFDA; (B) the combination of PBE testing of single actuation content and ISM with the newly suggested modified CSRS (PBE-mCSRS approach), a method employing reference variance scaling; and (C) EMA's average bioequivalence (ABE approach). Based on Monte-Carlo simulations, both PBE-CSRS and ABE approaches resulted in high misclassification rates, the former with highest false-pass rate and the latter with highest false-fail rate at both ≥ 50% and ≥ 80% classification threshold values (the % of simulations or experts necessary to judge a given scenario as equivalent). Based on DeLong's tests, the PBE-mCSRS approach showed significantly better overall agreement with experts' opinion compared to the other approaches. Comparison of CSRS with mCSRS (both without PBE) suggested that the more discriminatory characteristics of the mCSRS method is based on the integration of variance scaling into the mCSRS method. Contrary to the ABE approach, the application of PBE-mCSRS approach for assessing APSD profiles of three dry powder inhaler (DPI) formulations supported the pharmacokinetic bioequivalence assessment of these formulations.

Controlling type I error in the reference-scaled bioequivalence evaluation of highly variable drugs.

Reference-scaled average bioequivalence (RSABE) approaches for highly variable drugs are based on linearly scaling the bioequivalence limits according to the reference formulation within-subject variability. RSABE methods have type I error control problems around the value where the limits change from constant to scaled. In all these methods, the probability of type I error has only one absolute maximum at this switching variability value. This allows adjusting the significance level to obtain statistically correct procedures (that is, those in which the probability of type I error remains below the nominal significance level), at the expense of some potential power loss. In this paper, we explore adjustments to the EMA and FDA regulatory RSABE approaches, and to a possible improvement of the original EMA method, designated as HoweEMA. The resulting adjusted methods are completely correct with respect to type I error probability. The power loss is generally small and tends to become irrelevant for moderately large (affordable in real studies) sample sizes.

Decision Science for Generic Drug Development and Review.

Decision Science for Generic Drug Development and Review.

Bioequivalence Guidelines Requirements for Orally Administered Generics (IR Products) in Gulf Cooperation Council Countries, European Union and United States of America

The importance of the bioequivalence requirements is increasing in the GCC (Gulf Cooperation Council) region pertaining towards the growth of generic drug market. GCC bioequivalence guidelines describes the requirements for bioequivalence study as per this region regulatory requirements. This review article mainly focuses on bioequivalence study requirements in the Gulf Cooperation Council countries, European union countries and the United States of America that needs to be fulfilled in order to successfully submit a generic application. This comparison includes the bioequivalence approaches such as study design, sample size, study condition, pharmacokinetic parameters, statistical analysis, narrow therapeutic index drugs, highly variable drug products and BCS based bio waiver requirements. The rationale for this article is to give prompt overview on the bioequivalence requirements in these region and in comparison with well-established regulatory such as USFDA and EMA. In addition, it also highlights the possibilities for harmonization.

Scientific Considerations for an In Vitro Bioequivalence Approach for Ultrasound Contrast Agent Products: How Size Distribution and Total Volume of Microbubbles Affect Its Echogenicity

Scientific Considerations for an In Vitro Bioequivalence Approach for Ultrasound Contrast Agent Products: How Size Distribution and Total Volume of Microbubbles Affect Its Echogenicity

Drug Interchangeability of Generic and Brand Products of Fixed Dose Combination Tablets of Sofosbuvir and Ledipasvir (400/90mg): Employment of Reference Scaled Average Bioequivalence Study on Healthy Egyptian Volunteers.

The purpose of this study was to apply the reference-scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence and to investigate the pharmacokinetic properties of two formulations of fixed dose combination (FDC) tablet of sofosbuvir (SOF) and ledipasvir (LED) (400/90mg) in 36 healthy Egyptian volunteers. The study was performed in single-dose, randomized-sequence, open-label, reference-replicated, 3-period crossover design (RTR, TRR, RRT), with a washout period of 2weeks. A rapid and simple LC-MS/MS method was developed and validated for the simultaneous estimation of SOF and LED using eplerenone as an internal standard (IS). The results showed that the 90% confidence intervals (CIs) for natural log-transformed ratios of Cmax, AUClast and AUC∞ of SOF (89.95-115.31, 98.77-109.75 and 98.79-109.75) were within the RSABE acceptance limits. The 90% CIs for natural log-transformed ratios of Cmax and AUClast of LED (87.33-115.15 and 83.82-112.26) were within the FDA bioequivalence limits (80.00-125.00). In addition, the in vitro dissolution study was done and both formulations released>85% of drug within 15min in the proposed dissolution medium. In conclusion, bioequivalence between the two fixed-dose combination products was demonstrated for both active ingredients.

Risk-Based Bioequivalence Recommendations for Antiepileptic Drugs.

This review summarizes the current FDA practice in developing risk- and evidence-based product-specific bioequivalence guidances for antiepileptic drugs (AEDs). FDA's product-specific guidance (PSG) for AEDs takes into account the therapeutic index of each AED product. Several PSGs for AEDs recommend fully replicated studies and a reference-scaled average bioequivalence (RS-ABE) approach that permit the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The PSGs for AEDs published by FDA reflect the agency's current thinking on the bioequivalence studies and approval standards for generics of AEDs. Bioequivalence between brand and generic AED products demonstrated in controlled studies with epilepsy patients provides strong scientific support for the soundness of FDA bioequivalence standards.

Do patients trust the FDA?: a survey assessing how patients view the generic drug approval process.

Skepticism about the safety and effectiveness of certain generic drugs remains, particularly related to generic drugs that are approved by the Food and Drug Administration (FDA) using product-specific bioequivalence studies that differ from the standard testing pathway. The current study was designed to assess patient knowledge and perceptions of the generic drug approval process. We conducted a survey of patients with 10 different chronic diseases. We recruited survey participants from the CVS Advisor Panel, a proprietary database of 124621 CVS customers pre-consented to participate in online research activities. We created a survey to collect data on patients' perceptions of the FDA's generic drug approval process, as well as their experiences with generic drugs approved using modified bioequivalence approaches used to treat their chronic medical conditions. Our survey of 753 patients with chronic diseases (65% response rate) showed that most (74%) expressed little familiarity with FDA's approval process for generic drugs, but nearly all (89%) believed that FDA approval ensures the safety and effectiveness of generic drugs. About one-fifth of respondents reported hearing concerns about their generic drugs, most commonly from physicians (35-36%) and the Internet (32-38%), but there were no differences in patients' reports of concerns about generic versions of the six study drugs approved using product-specific pathways versus comparator drugs. Patients have little knowledge about the generic drug approval system, but positive belief in the safety and effectiveness of generic drugs. Patients do not appear to have greater concern about generic drugs approved via product-specific pathways. Copyright © 2017 John Wiley & Sons, Ltd.

Comparability of Pharmacodynamics Profiles with an Application to a Biosimilar Study

It is often interest of comparing two pharmacodynamics (PD) profiles in drug development. Currently the common practice is borrowing the bioequivalence (BE) rule in pharmacokinetics analysis for pharmacodynamics comparison in terms of the area under the effect curve (AUEC) of the pharmacodynamics profile. However, this may not be a feasible and sensitive enough approach since the bioequivalence approach is based on the summarized parameter of the pharmacodynamics profile rather than on directly comparison of the whole pharmacodynamics profile. In this paper, a simple but efficient and pragmatic pharmacodynamics comparability index is proposed to evaluate the comparability of pharmacodynamics profiles by comparing the whole pharmacodynamics profiles directly. Different biological products have different variability and the CV% can be in a very large range. The PD comparability index can take account of the reference knowledge into consideration in assessment but the AUEC BE type approach ignores the reference variability. The good properties of the proposed approach are illustrated through simulated data and a real dataset.

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects

The aim of this study was to apply the reference-scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence of 2 formulations of agomelatine, and to investigate the pharmacokinetic properties of agomelatine in Chinese healthy male subjects. This was performed in a single-dose, randomized-sequence, open-label, four-way crossover study with a one-day washout period between doses. Healthy Chinese males were randomly assigned to receive 25mg of either the test or reference formulation. The formulations were considered bioequivalent if 90% confidence intervals (CIs) for the log-transformed ratios and ratio of geometric means (GMR) of AUC and Cmax of agomelatine were within the predetermined bioequivalence range based on RSABE method. Results showed that both of the 90% CIs for the log-transformed ratios of AUC and Cmax of 7-desmethyl-agomelatine and 3-hydroxy-agomelatine were within the predetermined bioequivalence range. The 90% CIs for natural log-transformed ratios of Cmax, AUC0–t and AUC0–∞ of agomelatine (104.42–139.86, 101.33–123.83 and 97.90–117.94) were within the RSABE acceptance limits, and 3-hydroxy-agomelatine (105.55–123.03, 101.95–109.10 and 101.72–108.70) and 7-desmethyl-agomelatine (104.50–125.23, 102.36–111.50 and 101.62–110.64) were within the FDA bioequivalence definition intervals (0.80–1.25 for AUC and 0.75–1.33 for Cmax). The RSABE approach was successful in evaluating the bioequivalence of these two formulations.

Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products.

The pharmacokinetic approach has accelerated the development of high-quality generic medicines with extraordinary cost savings, transforming the pharmaceutical industry and healthcare system in the USA. While this is true for systemically absorbed drug products, the availability of generic versions of topical dermatological products remains constrained due to the limited methods accepted for bioequivalence evaluation of these products. The current review explores the possibility of developing appropriate bioequivalence approaches based on pharmacokinetic principles for topical dermatological products. This review focuses on the strengths and limitations of the three most promising pharmacokinetics-based methods to evaluate the performance and bioequivalence of topical dermatological products, which include in vivo skin stripping, in vivo microdialysis, and in vitro permeation testing (IVPT) with excised human skin. It is hoped that recent advances in pharmaceutical and regulatory science will facilitate the development of robust bioequivalence approaches for these dosage forms, enable more efficient methodologies to compare the performance of new drug products in certain pre-approval or post-approval change situations, and promote the availability of high-quality generic versions of topical dermatological products.

From Bioequivalence to Biosimilarity: The Rise of a Novel Regulatory Framework.

One of the most crucial issues in pharmacotherapy is to address the query if a patient can be switched from one product to another of the same active substance. For the conventional small-molecule drugs, there is a consensus on the required bioequivalence criteria. However, proving equivalence in the field of biologicals is an issue with no clear harmony. The aim of this review is to highlight the differences between the biologicals and the conventional chemical drugs, as well as, to present the different regulatory requirements for the placement of biosimilars on the market.Biologicals are substantially larger than chemical compounds, their manufacturing process is very complex, and their protein structure may trigger immune reactions. For this reason, the conventional bioequivalence approach is not adequate, but further emphasis should be placed on the quality of the manufacturing process and the risks of immunogenicity. The assessment procedure of biosimilars should encompass their comparison with the innovator product using all available evidence derived from the development process. The latter includes analytical and animal studies, pharmacokinetic and pharmacodynamic data, as well as, clinical trials focusing on immunogenicity. The US FDA has established a step-wise approach to demonstrate biosimilarity, while the EMA has already issued many guidelines referring either to all biosimilars or to specific products/classes. Overall, a case-by-case assessment procedure is considered by the regulatory authorities. In any case the placement of a biosimilar on the market does not necessarily imply interchangeability with the innovator drug.

Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes.

Generic drugs are approved on the basis of pharmaceutical equivalence and bioequivalence. Some drug products have unique structural or functional attributes, necessitating modified approaches to bioequivalence determinations. The aim of this systematic review was to identify studies that evaluated laboratory or clinical outcomes of six drugs approved via modified bioequivalence approaches. We conducted a systematic review of articles published through February 2014 in MEDLINE, EMBASE, and International Pharmaceutical Abstracts related to six recent drugs subject to modified regulatory approaches: venlafaxine extended release tablet (Effexor XR), acarbose (Precose), enoxaparin (Lovenox), vancomycin capsules (Vancocin), sodium ferric gluconate (Ferrlecit), and calcitonin salmon nasal spray (Miacalcin NS). We included all empirical evaluations (whether in vivo or in vitro) and excluded case studies, qualitative analyses, and pharmacoeconomic evaluations. Studies were summarized and evaluated on their methodological quality and assessed for bias using the Cochrane Risk of Bias Assessment Tool. Articles were divided into studies of US FDA-approved generics and non-FDA-approved generics available in non-US locations. We extracted drug(s) studied, study design, setting, sample size, population characteristics, study endpoints and results, and source of funding. After retrieving 1408 articles and searching through the full text of 106 articles, we found 26 articles that met our inclusion criteria-8 examining FDA-approved versions and 18 examining non-FDA-approved versions. Among FDA-approved generics, five studies of enoxaparin showed minor variations in biologic activities of unclear clinical importance, and no publications involved acarbose, venlafaxine ER, or vancomycin capsules. Among non-FDA-approved generics, nine studies of enoxaparin supported generic bioequivalence, despite three showing minor variations in drug activity. Four of six studies of venlafaxine ER supported generic bioequivalence, while two found a lack of bioequivalence with a Canadian generic version of the drug. Most studies were either highly susceptible to bias (12/26) or were not able to be assessed for bias (13/26), in part because eight studies were abstracts/posters without full reports. Pharmaceutical manufacturers sometimes raise scientific concerns related to potential generic versions of their drugs; however, in the six cases we reviewed, these companies did not follow up the pre-approval concerns they raised with any methodologically rigorous post-approval testing using clinical endpoints. Despite their pre-approval controversy, experience with these generic drugs provides reassurance of their clinical interchangeability. Systematized post-approval study of certain generic drug bioequivalence determinations is needed.

International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences.

International regulatory agencies have developed recommendations and guidances for bioequivalence approaches of orally inhaled drug products (OIDPs) for local action. The objective of this article is to discuss the similarities and differences among these approaches used by international regulatory authorities when applications of generic and/or subsequent entry locally acting OIDPs are evaluated. We focused on four jurisdictions that currently have published related guidances for generic and/or subsequent entry OIDPs. They are Therapeutic Goods Administration (TGA) in Australia, Health Canada (HC) in Canada, European Medicines Association (EMA) of European Union (EU), and the Food and Drug Administration (FDA) in the United States of America (USA). The comparisons of these bioequivalence (BE) recommendations are based on selection of reference products, formulation and inhaler device comparisons, and in vitro tests and in vivo studies, including pharmacokinetic (PK), pharmacodynamics (PD), and clinical studies. For the in vivo studies, the study design, choices of dose, subject inclusion/ exclusion criteria, study period, study endpoint, and equivalence criteria are elaborated in details. The bioequivalence on multiple-strength products and waiver options are also discussed.

A quantitative approach for cardiovascular safety evaluation of a generic drug

In generic drug development, comparative pharmacokinetic (PK) studies are conducted to assess equivalence in pharmacokinetics and safety profiles between test and reference formulations. However, there is no established quantitative approach available for safety assessment. This study aimed to propose a method for drug safety evaluation in generic drug development, as assessed by drug influence on blood pressure and heart rate change. Data were taken from a randomized, open label, 2-way cross-over comparative PK study for megestrol conducted in 39 healthy male volunteers. Vital signs of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured at 0 (pre-dose), 4, 8, 12, 24, 48, 72, 96 and 120 hours after the dose. Safety parameters used in the analysis were area under vital sign change versus time curve to the last measured time (AUVlast) and maximum vital sign change (Vmax). Considering highly variable nature of vital signs, the scaled bioequivalence approach developed by US FDA was adopted as a decision rule for safety evaluation between formulations. With the FDA scaled approach, 90% confidence intervals of geometric mean ratio for DBP, 0.7969~1.0377 for Vmax and 0.7304~1.0660 for AUVlast, were both included in the equivalence ranges of 0.7694~1.2997 and 0.6815~1.4674, respectively, and similarly, those for HR were included in their respective scaled equivalence limits, while SBP satisfied the conventional equivalence criterion of 0.8-1.25. These results illustrate the feasibility of applying the suggested approach in cardiovascular safety evaluation in a generic drug.

Novel bioequivalence approach for narrow therapeutic index drugs

Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products.

Survey of international regulatory bioequivalence recommendations for approval of generic topical dermatological drug products.

The objective of this article is to discuss the similarities and differences in accepted bioequivalence (BE) approaches for generic topical dermatological drug products between international regulatory authorities and organizations. These drug products are locally applied and not intended for systemic absorption. Therefore, the BE approaches which serve as surrogates to establish safety and efficacy for topical dosage forms tend to differ from the traditional solid oral dosage forms. We focused on 15 different international jurisdictions and organizations that currently participate in the International Generic Drug Regulators Pilot Project. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association (EMA), Japan, Mexico, New Zealand, Singapore (a member of the Association of Southeast Asian Nations), South Africa, South Korea, Switzerland, the USA and the World Health Organization (WHO). Upon evaluation, we observed that currently only Canada, the EMA, Japan, and the USA have specific guidance documents for topical drug products. Across all jurisdictions and organizations, the three approaches consistently required are (1) BE studies with clinical endpoints for most topical drug products; (2) in vivo pharmacodynamic studies, in particular the vasoconstrictor assay for topical corticosteroids; and (3) waivers from BE study requirements for topical solutions. Japan, South Africa, the USA, and the WHO are also making strides to accept other BE approaches such as in vivo pharmacokinetic studies for BE assessment, in vivo dermatopharmacokinetic studies and/or BE studies with in vitro endpoints.

Bioequivalence study of two formulations of ibandronic acid 150-mg film-coated tablets in healthy volunteers under fasting conditions: a randomized, open-label, three-way, reference-replicated crossover study.

AimsThis bioequivalence study aimed to compare rate and extent of absorption of a generic medicinal product of ibandronic acid 150-mg film-coated tablet versus Bonviva®.MethodsThis was a single-centre, open-label, randomized, three-way, three-sequence, reference-replicated, crossover bioequivalence study, under fasting conditions. A single oral dose of ibandronic acid as one 150-mg film-coated tablet was administered in each study period. Each washout period lasted 14 days. Blood samples were collected according to a predefined sampling schedule and up to 48.0 hours after administraton in each period. Plasma concentrations of ibandronic acid were measured using a liquid chromatograph–mass spectrometry/mass spectrometry method. Bioequivalence between generic and reference medicinal products is acceptable if the 90 % confidence intervals (CI) of ratio of least-squares means between the test and the reference product of ln-transformed area under the serum concentration–time curve from time zero to time of last measurable concentration (AUC0–t) is within the 80.00–125.00 % interval. Prospectively, a scaled average bioequivalence approach for maximum serum concentration (C max) was established.Results153 healthy volunteers were enrolled and randomized. After the test formulation (T) and first and second Bonviva® (R) dosing, the C max was 96.71 ± 90.19 ng/mL, 92.67 ± 91.48 ng/mL and 87.94 ± 60.20 ng/mL and the AUC0–t was 390.83 ± 287.27 ng·h/mL, 388.54 ± 356.76 ng·h/mL and 383.53 ± 246.72, respectively. Ratios of T/R and 90 % CI were 100.92 % (94.35–107.94) for AUC0–t, 100.90 % (94.37–107.88) for AUC0–inf and 102.56 % (95.05–110.67) for C max.ConclusionsTest formulation of ibandronic acid is bioequivalent in rate and extent of absorption to Bonviva® following a 150-mg dose, under fasting conditions.