Bioequivalence Testing Research Articles

Performance Testing for Dry Powder Inhaler Products: Towards Clinical Relevance

It is well established that the critical performance metrics for aerosol products are aerodynamic particle size distribution (APSD) and delivered dose uniformity (DDU). In broad terms, these performance characteristics dictate the efficiency and reproducibility with which an aerosol is administered clinically. However, these properties alone do not support in-vitro, in-vivo correlations. There have been numerous publications attempting to more directly link product performance testing to physiological relevance or further to draw direct correlations of relevance to bioequivalence testing for the development of generic products. While these novel methods have been employed in product development activity, their suitability for compendial testing has yet to be established. This paper explores the potential to establish biologically relevant compendial standards for dry powder inhaler products while maintaining accuracy and reproducibility of data collected to support the quality and performance of the product.

A cross-sectional study on knowledge and perceptions of generic medicines among MBBS and nursing students at a tertiary care hospital in Maharashtra

Background: Access to health-care facilities and essential medicines still remains a worldwide problem, particularly in developing countries. Greater awareness among health-care professional regarding generic drugs may translate into the increased consumption of generic drugs and reduction in healthcare costs wild maintaining the safety efficacy and quality off health-care system. Aim and Objectives: This study was conducted to analyze the knowledge and perception of generic medicines among MBBS and Nursing students in a medical teaching institute. Materials and Methods: A questionnaire-based cross-sectional study was conducted among 260 students (172 MBBS, 88 Nursing course) in Government Medical College Jalgaon, to assess knowledge and attitude of students for generic medicines. Descriptive statistics and Kruskal–Wallis test were used to analyze the responses. Results: Most respondents from MBBS (86%) and nursing course (89%) agree to need more information about how bioequivalence test are conducted for generic medicine. Perception about branded medicines requiring high quality standards as compared to generic medicines was high in both courses’ students with 69.3% of nursing students and 43.6% of MBBS students having wrong perception. About 77.4% of MBBS students and 42% of nursing students responded positively to the statement about generic medicines being cheaper than branded drugs. Conclusion: Students from both the courses showed eagerness to have more information, were lacking in the knowledge, and had confused attitude toward generic medicines. Proper education and training may impart proper knowledge and change the attitude among students toward the generic medicines.

A Feasibility Study on Re-establishing the Bioavailability/Bioequivalence Unit of the Department of Pharmacology and Toxicology, College of Medicine-University of the Philippines Manila.

The Bioavailability/Bioequivalence Unit (BA/BE Unit) of the Department of Pharmacology and Toxicology, College of Medicine, University of the Philippines Manila which has not been operational since 2012, is due for renewal of its accreditation. To date, there are only three Philippine Food and Drug Administration-accredited laboratories that perform bioequivalence studies in the Philippines. One of the prerequisites of registering specific generic medicines is the conduct of Bioequivalence (BE) studies which are performed to ensure that the generic drug is at par with the innovator drug. Thus, this study aimed to determine the feasibility of re-establishing the BA/BE Unit as a bioequivalence testing center. The feasibility study done is a qualitative descriptive analysis based on expansive literature review and performance of SWOT analysis within the BA/BE unit. Literatures were selected based on its assessed relevance to the study. The databases checked were PubMed and Google Scholar. The terms used were from the Medical Subject Heading (MeSH) including feasibility studies, therapeutic equivalency, and generic drugs. Literature review was performed on the factors affecting the four types of feasibility studies (market, technical, financial, and organizational). A SWOT analysis of the BA/BE Unit was done through the review of records and documents of previous BE studies and focus group discussion among the BA/BE Unit team members. The BA/BE Unit conducted 24 bioequivalence studies from 2006-2009 and still receives inquiries from drug companies. It implements its QMS throughout the pre-analytical, analytical, and post-analytical stages of the workflow. Its organizational structure consists of qualified professionals with updated GCP and GLP certificates. Because of the adequately equipped facility, lower honoraria for government-employed personnel, and lower expenses for laboratories and in-patient admissions, the cost of conducting a bioequivalence study in the BA/BE Unit will be lower than in other BE centers. Based on the SWOT analysis and market, technical, financial, and organizational considerations, re-establishing the BA/BE Unit as a bioequivalence testing center is feasible.

Determining bioequivalence possibilities of long acting injectables through population PK modelling

Long acting injectables (LAI) products are a popular intervention for treating a number of chronic conditions, with their long drug release reducing the administration frequency and thus improving patient adherence. The extended release, however, can provide a major challenge to bioequivalence (BE) testing since the long absorption half-life results in a long washout period, meaning that a traditional BE study can be many months or years in length. The unique PK profile for LAI products also means that it is critical to have appropriate metrics to summarise the plasma concentration profile. In this work, we use paliperidone as a case study to demonstrate how Population PK modelling can be utilised to explore sensitivity of summary metrics to different products. We also determine a range of products that are bioequivalent after both multiple dosing and single dosing. Finally, we show how the modelling can be used in a (virtual) PK study as an alternative approach to determining bioequivalence. This work demonstrates the potential for Population PK modelling in bioequivalence assessment, opening doors to more streamlined product development.

Reconstructed Human Epidermis: An Alternative Approach for In Vitro Bioequivalence Testing of Topical Products.

The use of in vitro human skin permeation tests is of value when addressing the quality and equivalence of topical drug products in Europe and the US. Human skin is the membrane of choice for these studies. The use of human skin as a membrane is hindered by limited access, high variability of results, and limited applicability for drugs with low skin permeability. Reconstructed human epidermis (RhE) models are validated as skin surrogates for safety tests and have been explored for percutaneous absorption testing. Clotrimazole poorly permeates human skin and is widely available for topical treatments. In this study, clotrimazole creams were used to test the ability of RhE to be used as biological membrane for bioequivalence testing, based on the Draft Guideline on Quality and Equivalence of Topical Products (CHMP/QWP/708282/2018) using a discriminative and modified in vitro permeation test (IVPT). To fulfill the validation of a discriminatory method, Canesten® 10 mg/g cream was compared with a test product with the same drug strength, along with two “negative controls” dosed at a 50% and 200% drug strength. Products were compared in finite dose conditions, regarding maximal flux (Jmax) and the total amount of drug permeated (Atotal). The results showed the discriminatory power of the method among the three drug strengths with no interference of the placebo formulation. The study design and validation complied with the requirements established in the guideline for a valid IVPT. This new test system allowed for the equivalence comparison between test and comparator product. Higher permeability of the RhE compared to human skin could be observed. This arose as a strength of the model for this modified IVPT bioequivalence testing, since comparing permeation profiles among products is envisaged instead of drawing absolute conclusions on skin permeation extent. These results may support the acceptance of RhE as biological membranes for modified IVPT in bioequivalence testing of topical products.

Development of a Sensitive and Rapid HPLC-MS Method for Dihydrocodeine and Dihydromorphine: Application to Bioequivalence Studies.

A ultraperformance liquid chromatography-tandem mass spectrometry method has been developed to determine dihydrocodeine (DHC) and dihydromorphine (DHM) in human plasma using dihydrocodeine-d6 and desomorphine as internal standards (IS). Acetonitrile-water-ammonium format was used as the mobile phase, in gradient elution on a C18 column. The concentration of DHC and DHM was determined in the positive ionization mode of mass spectrometry. The total chromatogram run time was 3.2min, and the linear ranges of DHC and DHM were 1.000-400.0ng/mL and 0.050-20.00ng/mL, respectively. The method was fully validated concerning precision, accuracy, selectivity, linearity, recovery, stability and matrix effect. The method had been successfully applied to the bioequivalence test. In addition, we found that a high-fat diet impacts the Tmax and t1/2 of DHC.

Improving access to medicines by popularising generics: a study of ‘India’s People’s Medicine’ scheme in two districts of Maharashtra

BackgroundIn spite of being the ‘pharmacy of the world’, access to essential medicines for a large majority of Indians is constrained by both physical and financial reasons. According to an estimate, medicines account for 69% of household out-of-pocket spending on health care. To make quality generic medicine affordable, India’s People’s Medicine Scheme (Jan Aushadhi) was launched in 2008 and then revamped and rebranded as Pradhan Mantri Bhartiya Jan Ausadhi Pariyojana (PMBJP) in 2015. The current study focuses on the availability, affordability and acceptability aspects of PMBJP essential medicines.MethodsWe have used a mixed-methods approach, with the survey-based quantitative component supplemented by a qualitative component consisting of in-depth interviews (IDIs). The survey was conducted in 11 PMBJP pharmacies in Mumbai and Palghar. Data were gathered on the availability, stock-outs, price and affordability of 35 essential medicines and 2 consumables.ResultsApart from the limited coverage of essential medicines and the significant presence of Fixed dose combinations (FDCs) in the PMBJP medicine list, the availability of surveyed essential drugs was also found to be low (47%) in PMBJP outlets. Across Mumbai and Palghar districts, around 50% and 42% of medicines were found to be out of stock for the period of 3–6 months respectively. The cost of generic medicines of PMBJP outlets for treating various conditions range from 0.01 days’ wages to 0.47 days’ wages for the lowest paid unskilled worker in Maharashtra.ConclusionsThe study findings show that PMBJP’s unbranded generics offer great opportunities for substantial cost savings. But, in order to fully realise the potential of this scheme, some policy actions are urgently required. First, the PMBJP drug list must include all essential drugs that feature in NLEM. Second, BPPI should procure only those drugs that pass the bioequivalence test. Third, compulsory de-branding of generics should be done in a phased manner. Fourth, PMBJP’s medicine procurement and distribution policies must be reviewed to address the supply chain issues. Moreover, there is a need for major pharmaceutical policy reforms to promote generic medicines in a big way. Regulations to support mandatory generic prescribing and generic substitution by pharmacists are needed.

Barriers to Worldwide Access for Paxlovid, a New Treatment for COVID-19.

Pfizer and the Medicines Patent Pool (MPP) have reached a voluntary licensing agreement for Paxlovid (nirmatrelvir+ritonavir), a novel antiviral for coronavirus disease 2019 (COVID-19) taken orally in the first 5 days from symptom onset. The Pfizer-MPP deal enables 95 low- and middle-income countries (L/MICs) to access affordable biosimilars. Generics are delayed awaiting bioequivalence testing and may be ineffective in L/MICs with reduced testing capacity, which comprise only 10% of global diagnoses. Thirty-nine percent of diagnoses originate in MICs forced to pay high prices due to exclusion from the Pfizer-MPP deal. The cost-effectiveness of Paxlovid could be limited compared with the creation of sustainable vaccine infrastructure in these nations, delaying socioeconomic pandemic recovery. Furthermore, Paxlovid may not be cost-effective in vaccinated populations, and concerns remain over ritonavir drug interactions with COVID-19 comorbidity medications. We call for expanded coverage by the Paxlovid-MPP deal and greater access to testing.

The structural diversity of ibuprofen sustained-release pellets on the same goal of bioequivalence consistency

The consistency evaluation, which is largely unexplored is crucial in regulating the quality and efficacy of generic drugs. In this report, after generic ibuprofen (IBU) sustained-release pellets were developed and validated as bioequivalent to the reference list drug (RLD) in 48 healthy human volunteers (p < 0.001***), three-dimensional (3D) structures of generic IBU pellets from bioequivalence tests, along with RLD were investigated and compared for architecture using Micro-computed tomography (Micro-CT). The surface and internal architectures of the pellets, sphericity, pellet volume, core volume and gray value have been evaluated in both static and dynamic conditions. The material distribution and composition of IBU pellets were characterized using synchrotron radiation-FTIR mapping. Although the structures of RLD and the generic products were not similar dynamically, identical release profiles and bioequivalence were obtained. Overall, micro-CT could be very useful for characterization of internal structure, material design and development of new dosage form.

Final year pharmacy students’ knowledge and perceptions towards generic medicines: A survey-based pilot study from Eastern province, Saudi Arabia

Objective: A prospective cross-sectional survey-based pilot study was conducted amongst final year pharmacy students at a private pharmacy college in Eastern Province, Saudi Arabia, to evaluate the knowledge and perception toward generic medicines. Methods: This online survey-based study was carried out amongst all final year students enrolled in the pharmacy programme between 1 February and 30 April 2020. Results: The response rate was 95.56%. Most participants (66.27%) agreed that generic products are therapeutically equivalent to the innovator brand product, and 75.57% reported the need for more information on how bioequivalence tests are conducted for generic medicines. Furthermore, 34.88% agreed that generic medicines are of inferior quality to brand drugs and 73.24% reported the need for more information on the issues pertaining to the safety and efficacy of generic medicines. Conclusion: This study showed that fifth-year pharmacy students had a basic knowledge of generic medicines, with an ambivalent perception of generics’ quality and safety standards. A number of collaborative initiatives should be planned and executed to equip future pharmacists with broad knowledge concerning generic medications.

Model-Based Equivalent Dose Optimization to Develop New Donepezil Patch Formulation.

Donepezil patch was developed to replace the original oral formulation. To accurately describe the pharmacokinetics of donepezil and investigate compatible doses between two formulations, a population pharmacokinetic model for oral and transdermal patches was built based on a clinical study. Plasma donepezil levels were analyzed via liquid chromatography/tandem mass spectrometry. Non-compartmental analyses were performed to derive the initial parameters for compartmental analyses. Compartmental analysis (CA) was performed with NLME software NONMEM assisted by Perl-speaks-NONMEM, and R. Model evaluation was proceeded via visual predictive checks (VPC), goodness-of-fit (GOF) plotting, and bootstrap method. The bioequivalence test was based on a 2 × 2 crossover design, and parameters of AUC and Cmax were considered. We found that a two-compartment model featuring two transit compartments accurately describes the pharmacokinetics of nine subjects administered in oral, as well as of the patch-dosed subjects. Through evaluation, the model was proven to be sufficiently accurate and suitable for further bioequivalence tests. Based on the bioequivalence test, 114 mg/101.3 cm2–146 mg/129.8 cm2 of donepezil patch per week was equivalent to 10 mg PO donepezil per day. In conclusion, the pharmacokinetic model was successfully developed, and acceptable parameters were estimated. However, the size calculated by an equivalent dose of donepezil patch could be rather large. Further optimization in formulation needs to be performed to find appropriate usability in clinical situations.

Review: Application of Bioequivalence Testing of Medicines in Peru

Review: Application of Bioequivalence Testing of Medicines in Peru

Bioequivalence of a Preparation of Tulathromycin in Cattle

Testing the quality of antibacterial pharmaceutical preparations that can be regarded as generic is of utmost importance to ensure sustainable medical practices. Hence, comparative pharmacokinetics studies become necessary. In this trial, a new pharmaceutical preparation of tulathromycin (TTM) was submitted to a bioequivalence test, taking the reference preparation of this macrolide derivative as control i.e., the commercial preparation of TTM containing 100 mg of the drug Pisadrax ® , manufactured by PiSA Agropacuaria S.A. de C.V. and the reference brand of TTM Draxxin ® (Zoetis, Mexico). Twenty-four young steers Charolais/Brahman randomly divided into two groups of twelve animals each, received a single injection of 2.5 mg/kg subcutaneously of either preparation. A validated HPLC-masses analytical technique of plasma concentrations of tulathromycin was used to determine TTM plasma concentrations at fixed intervals for 240 h. The key pharmacokinetic parameters were obtained by compartmental and non-compartmental analysis. Results show that the experimental preparation of tulathromycin (Pisadrax ® ) can be regarded as bioequivalent to the reference one (Draxxin ® ) in steers, given that AUC0-240, MRT, and K½el values from both preparations resulted statistically indistinguishable and with confidence interval &gt; 95%.

Model-Based Approach for Designing an Efficient Bioequivalence Study for Highly Variable Drugs.

The statistical procedures as outlined by the European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) guidelines for bioequivalence testing of highly variable drugs (HVDs) are complex. Additionally, the sample size is affected by clinical study designs or practical real-world problems, such as dropout rate or study budget. To overcome these difficulties, we propose a model-based approach for the selection of a study design with a sample size that satisfies the bioequivalence criteria using simulation studies based on a pharmacokinetic (PK) model. The designed approach was implemented using a simulation procedure considering some conventionally measured factors, such as geometric mean ratio and within-subject coefficient of variation, with various PK information important in determining bioequivalence. All simulation results were assessed according to the EMA and FDA guidelines. Furthermore, power calculations from simulation results were interpreted with regard to PK characteristics and compared among 2 × 2, 3 × 3, and 2 × 4 crossover designs to determine the efficient design considering appropriate sample size and duration of the clinical study. The proposed approach can be applied to bioequivalence studies of all drugs. However, the current study was targeted at HVDs, which are highly likely to require detailed decision making for sample size and study design.

The Pharmacy Student’s Knowledge And Perception About Generic Medicine: Web-based Cross-Sectional Study

Background: The promotion of generic medicines in developing nation like India plays a crucial role in the availability of essential drugs for everyone. The main objective of this survey is to understand the knowledge and perception of the pharmacy student about generic medicine along with its safety and efficacy profile. Methods: The web-based cross-sectional study was carried out from September 2020 to February 2021 utilizing the Google form. The google form had four questionnaire sections, i.e., socio-demographic section, overall knowledge section, knowledge regarding safety and efficacy section, and perception section. Results: Most students believe they require additional knowledge regarding how bioequivalence tests are performed for generic drugs. Of 463 students, 419 students (88%) agrees generic medicine is cheaper than branded medicines, and 339 students (73%) agrees wider use of generic medicines in India helps in decreasing health care cost whereas 215 students (45%) are not aware generics are only marketed after the patent expiry of the branded medicine. Of 441 students, 127 students (27%) wrongly agree that generic medicines are less effective than branded medicine, and 196 students (43%) wrongly agree that generic medicine costs less because they are inferior to branded medicine. Most pharmacy students believe doctors and patients should be given enough knowledge about generic medicine and that branded medicine use is influenced by advertisements. Conclusion: This study concludes that there is a gap in knowledge among pharmacy students about generic medicine. The responsible authorities should establish relevant curriculum revisions to increase students’ knowledge about generic medications.

Evaluation of area under the concentration curve adjusted by the terminal‐phase as a metric to reduce the impact of variability in bioequivalence testing

To quantify the utility of a terminal-phase adjusted area under the concentration curve method in increasing the probability of a correct and conclusive outcome of a bioequivalence (BE) trial for highly variable drugs when clearance (CL) varies more than the volume of distribution (V). Data from a large population of subjects were generated with variability in CL and V, and used to simulate a two-period, two-sequence crossover BE trial. The 90% confidence interval for formulation comparison was determined following BE assessment using the area under the concentration curve (AUC) ratio test, and the proposed terminal-phase adjusted AUC ratio test. An outcome of bioequivalent, nonbioequivalent or inconclusive was then assigned according to predefined BE limits. When CL varied more than V, the proposed approach enhanced the probability of correctly assigning bioequivalent or nonbioequivalent and reduced the risk of an inconclusive trial. For a hypothetical drug with between-subject variability of 35% for CL and 10% for V, when the true test-reference ratio of bioavailability was 1.15, a crossover study of n = 14 subjects analysed by the proposed method would have 80% or 20% probability of claiming bioequivalent or nonbioequivalent, compared to 22%, 46% or 32% probability of claiming bioequivalent, nonbioequivalent or inconclusive using the standard AUC ratio test. The terminal-phase adjusted AUC ratio test represents a simple and readily applicable approach to enhance the BE assessment of drug products when CL varies more than V.

Batch Selection via In Vitro/In Vivo Correlation in Pharmacokinetic Bioequivalence Testing.

Pharmacokinetic differences between manufacturing batches, well established for inhaled drug products, preclude control of patient risk in the customary two-way (single batch) pharmacokinetic bioequivalence crossover design if batches are randomly chosen. European regulators have recommended selecting a "typical" in vitro batch to represent each product in pharmacokinetic bioequivalence testing. We explored the feasibility of this approach to control patient risk (the "false equivalence", or Type I, error rate). The probability of achieving a Test/Reference 90% confidence interval within (0.80, 1.25) for a true (non-equivalent) value of 1.25 was simulated for a two-way crossover design using the median in vitro batch across a range of number of in vitro batches, in vitro/in vivo correlation (IVIVC) quality (correlation coefficient, r, of zero to one), and within-subject between-batch pharmacokinetic variability. Even under extremely optimistic conditions, e.g., r=0.95 and >100 batches per product screened in vitro, patient risk for typical between-batch variability levels remained at least threefold higher than the 5% regulatory expectation for the significance level (the false equivalence error rate) of the pharmacokinetic bioequivalence test. This elevated error rate in bioequivalence decision-making occurs because of incomplete confidence that the true product average has been identified, and, importantly, omission of this uncertainty from the bioequivalence confidence interval.

Performance of Multiple-Batch Approaches to Pharmacokinetic Bioequivalence Testing for Orally Inhaled Drug Products with Batch-to-Batch Variability

Batch-to-batch pharmacokinetic (PK) variability of orally inhaled drug products has been documented and can render single-batch PK bioequivalence (BE) studies unreliable; results from one batch may not be consistent with a repeated study using a different batch, yet the goal of PK BE is to deliver a product comparison that is interpretable beyond the specific batches used in the study. We characterized four multiple-batch PK BE approaches to improve outcome reliability without increasing the number of clinical study participants. Three approaches include multiple batches directly in the PK BE study with batch identity either excluded from the statistical model (“Superbatch”) or included as a fixed or random effect (“Fixed Batch Effect,” “Random Batch Effect”). A fourth approach uses a bio-predictive in vitro test to screen candidate batches, bringing the median batch of each product into the PK BE study (“Targeted Batch”). Three of these approaches (Fixed Batch Effect, Superbatch, Targeted Batch) continue the single-batch PK BE convention in which uncertainty in the Test/Reference ratio estimate due to batch sampling is omitted from the Test/Reference confidence interval. All three of these approaches provided higher power to correctly identify true bioequivalence than the standard single-batch approach with no increase in clinical burden. False equivalence (type I) error was inflated above the expected 5% level, but multiple batches controlled type I error better than a single batch. The Random Batch Effect approach restored 5% type I error, but had low power for small (e.g., <8) batch sample sizes using standard [0.8000, 1.2500] bioequivalence limits.

Safety and Systemic Exposure of Triamcinolone Acetonide Following Ultrasound-Guided Intra-Articular Injection of Triamcinolone Extended-Release or Standard Triamcinolone Acetonide in Patients with Shoulder Osteoarthritis: An Open-Label, Randomized Study.

Background and ObjectivesOsteoarthritis (OA) is a major public health burden. While knee and hip joints are most commonly affected, the glenohumoral (shoulder) joint is also frequently involved. We evaluated the pharmacokinetics and safety/tolerability of triamcinolone acetonide extended-release (TA-ER) and triamcinolone acetonide crystalline suspension (TAcs) in patients with shoulder OA.MethodsIn this phase 2, randomized, open-label, single-dose study (NCT03382262), adults with moderately-to-severely symptomatic shoulder OA for ≥ 6 months randomly received a single ultrasound-guided intra-articular (IA) injection of TA-ER 32 mg or TAcs 40 mg. Safety was evaluated throughout 12 weeks post-injection; blood samples for pharmacokinetic evaluations were collected pre-injection and through Day 85 post-injection.ResultsAmong 25 randomized patients, 12 received TA-ER and 13 received TAcs. Most patients were female (60%), and all had moderate (72%) or severe (28%) shoulder OA. Adverse events (AEs) were reported by four (33%) patients following TA-ER and three (23%) following TAcs injection. No AE was serious or led to study discontinuation. Systemic exposure following TAcs was approximately 1.5-fold higher than that following TA-ER injection (geometric mean [GM] AUC0–last 873,543 vs 557,602 h × pg/mL). GM Cmax was also higher in TAcs- than TA-ER-treated patients (2034 vs 1283 pg/mL). Bioequivalence testing confirmed lower systemic TA exposure following TA-ER than TAcs IA injection.ConclusionThese pharmacokinetic data confirm protracted release of TA from TA-ER following IA injection in patients with shoulder OA. Lower peak and systemic TA exposure following TA-ER suggests TA-ER could potentially confer an improved systemic safety profile over TAcs.Trial Registration NumberNCT03382262 (December 22, 2017 retrospectively registered).

In Silico Modeling and Simulation to Guide Bioequivalence Testing for Oral Drugs in a Virtual Population.

Model-informed drug discovery and development (MID3) shows great advantages in facilitating drug development. A physiologically based pharmacokinetic model is one of the powerful computational approaches of MID3, and the emerging field of virtual bioequivalence is well recognized to be the future of the physiologically based pharmacokinetic model. Based on the translational link between in vitro, in silico, and in vivo, virtual bioequivalence study can evaluate the similarity and potential difference of pharmacokinetic and clinical performance between test and reference formulations. With the aid of virtual bioequivalence study, the pivotal information of clinical trials can be provided to streamline the development for both new and generic drugs. However, a regulatory framework of virtual bioequivalence study has not reached its full maturity. Therefore, this article aims to present an overview of the current status of bioequivalence study, identify the framework of virtual bioequivalence studies for oral drugs, and also discuss the future opportunities of virtual bioequivalence in supporting the waiver and optimization of in vivo clinical trials.