Scaled Average Bioequivalence Research Articles

A Fully Replicate, Cross-over, Bioequivalence Study to Compare Two Prolonged Release, Multi-matrix Tablet Formulations of Budesonide in Healthy Indian Adults

Introduction: Budesonide is a synthetic, non halogenated corticosteroid, structurally related to 16α-hydroxyprednisolone, which is approved as first-line therapy for various gastrointestinal disorders. Budesonide prolonged-release tablets incorporating multi-matrix technology {Cortiment® 9 mg: Reference product (R)} were approved in India for induction of remission in adult patients with mild-to-moderate active ulcerative colitis. Aim: To assess the bioavailability, safety and tolerability of a single dose of generic budesonide prolonged-release tablets 9 mg {CortirowaTM OD; Test product (T)} and demonstrate their bioequivalence to Reference product (R) in healthy Indian adults under fasting conditions. Materials and Methods: In this randomised, open-label, single-dose, balanced, 2-treatment, 2-sequence, 4-period, fully replicate, cross-over bioequivalence study conducted from 12 July 2021 to 08 August 2021 at Ecron Acunova Limited, Manipal, India, 56 participants were randomly allocated (1:1) to treatment sequences Test-Reference-Test-Reference (TRTR) or Reference-Test-Reference-Test (RTRT). After a 10-hour overnight fast, participants were administered a single oral dose of T or R along with 240 mL of water. After each dose, a total of 26 venous blood samples (each 4 mL) were collected from each participant, at hourly intervals until 20 hours, and at 24, 30, 36, 48, and 72 hours. Plasma budesonide concentrations were analysed using a validated Liquid ChromatographyTandem-Mass Spectrometry (LC-MS/MS) method. Based on the randomisation sequences, the treatment periods were defined as test product treatment Period-1 (T1), test product treatment Period-2 (T2), reference product treatment Period-1 (R1), and reference product treatment Period-2 (R2). The primary pharmacokinetic parameters were peak plasma concentration (Cmax) and area under the concentration-time curve from time zero to the last sample with quantifiable concentration (AUC0-t). Results: Test and reference products were comparable in terms of mean (standard deviation) Cmax {pg/mL: T1=2163.0 (1423.9) and T2=2456.25 (1346.035) vs R1=2301.59 (1582.995) and R2=2437.62 (1437.665)} and AUC0-t {hr.pg/mL: T1=27938.0 (16431.23) and T2=33629.58 (18407.253) vs R1=25882.41 (17250.267) and R2=33146.25 (19350.222)}. As the within-subject Standard Deviation (SD) of R (SWR) for Cmax and AUC0-t was ≥0.294, the reference-Scaled Average Bioequivalence (SABE) approach was used. The bioequivalence criteria prespecified using the Scaled Average Bioequivalence (SABE) approach were met as the 95% upper confidence bound for (μT-μR)2 - θs2 WR of Cmax (-0.255371831) and AUC0-t (-0.445865013) were both ≤0, and the point estimate (T/R) geometric mean ratio of Cmax (0.97) and AUC0-t (1.06) were both within 0.80 and 1.25. While 10 Adverse Events (AEs) were reported in the study, all were of mild intensity. Conclusion: CortirowaTM OD was bioequivalent to Cortiment® 9 mg in healthy Indian adults under fasting conditions. Both the products were found to be well tolerated.

Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial.

BackgroundAlthough the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, “brand”) product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant.Methods and findingsFrom December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11–15.81) and the concentration maximum (Cmax) (range 17.96–24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%–118.13% and 80.00%–125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study.ConclusionsUsing an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other.Trial registrationClinicalTrials.gov NCT01889758.

Phase 1, Open-Label, Randomized, Bioequivalence Study of 2 Bendamustine Hydrochloride Formulations; A Ready-to-Dilute Low-Volume, Rapid Infusion Solution and a Lyophilized Powder Formulation

Introduction: This phase 1, open-label, randomized, crossover study assessed the bioequivalence (BE) and safety of an investigational, ready-to-dilute, rapid infusion, low-volume solution of bendamustine hydrochloride (test product [T]) and the approved bendamustine lyophilized powder formulation (reference product [R]). [CT.gov ID NCT02162888]Methods: Eligible patients (Pts) were aged 18 years or older with relapsed or refractory solid tumors or hematologic malignancies excluding chronic lymphocytic leukemia. All Pts received bendamustine 120 mg/m2 intravenously as T (in 50 mL; 0.9% NaCl) over 10 min, and as R (in 500 mL; 0.9% NaCl) over 60 min on days 1 and 2 of two consecutive 28-day cycles. Patients were randomly assigned to 1 of 3 treatment sequences defining the first 3 doses of study drug: TRR, RTR, RRT. T was given to all Pts at cycle 2, day 2. For the first 3 doses, blood samples were collected prior to infusion; mid-infusion (T 5 min, R 30 min); at 5, 15, 30, and 45 min, and at 1, 1.5, 2, 3, 4, 5, and 8 h postinfusion; and 24 h from the start of infusion on day 1 of both cycles. The pharmacokinetic (PK) endpoints for BE were area under plasma concentration-vs-time curve (AUC) from time 0 to the last quantifiable sample collected (AUC0-t) and from time 0 to infinity (AUC0-oo), which were evaluated using a scaled average BE (SABE) method, appropriate for high variability drugs. Other PK endpoints were maximum plasma concentration (Cmax), time to Cmax (tmax), and elimination half-life (t1/2). Safety was assessed by reported adverse events (AEs), Eastern Cooperative Oncology Group performance status, physical examination, and laboratory values throughout the 56-day study period.Results: A total of 83 Pts were randomized to the 3 treatment sequences; 81 received at least one dose of study drug and comprised the safety population; 60 received 3 doses (required for BE analysis). BE analyses were conducted for AUC in this population, and for other patient subsets based on dosing and sample collections deemed evaluable and complete. Here, PK results are presented for the 38 Pts meeting all BE inclusion criteria (Table 1). The BE of T and R was assessed by Reference-SABE for AUC as intra-subject variability for R (SWR) was >0.3 (Table 2). Mean concentration-vs-time is presented in the Figure. The AUC and t1/2 were similar in Pts treated with T and R. Cmax was higher and tmax was shorter in Pts treated with T, consistent with the faster infusion of bendamustine. The overall safety profiles of T and R were similar (Table 3), with serious AEs (SAEs) in 28% of Pts and 6 deaths (all attributable to disease progression). AEs occurring within 24 h of treatment were similar in type and frequency; the only AEs occurring in ≥3% of Pts with either treatment during this period were nausea (R 11%, T 9%), fatigue (R 8%, T 9%), vomiting (R 3%, T 4%), and constipation (R 4%, T 3%).Conclusions: BE of the two bendamustine formulations was demonstrated for AUCs as the upper critical values were <0 and the point estimates of T/R geometric mean ratio fell within 0.80 to 1.25 inclusive. Differences in Cmax and tmax were anticipated from the different infusion rates for the T and R. The safety profile of the two drugs was comparable with no new safety signals. Reported AEs were either known effects of bendamustine or presumed to be related to underlying disease.Sponsor: Eagle Pharmaceuticals, Inc.Table 1Summary of PK ParametersParameterTn = 38Rn = 38AUC0-t, ng·h/mL (% CV)10339.21 (49.3)10514.87 (55.9)AUC0-¥, ng·h/mL (% CV)10369.74 (49.2)10527.76 (55.8)tmax, h (range)0.18 (0.1-0.4)1.0 (0.5-1.3)Cmax, ng/mL (% CV)19158.16 (33.5)8868.42 (47.4)t1/2, h (% CV)0.65 (37.3)0.60 (30.3)CV: coefficient of variationTable 2Bioequivalence Analyses Results (n = 38)AUC(ng·h/mL)GM1 Test (T)GM1 Reference (R)T/R90%Confidence IntervalsSwrUpper Critical ValueAUC0-t9143.729047.811.010.898-1.1450.403-0.09AUC0--¥9173.019062.771.020.899-1.1460.402-0.09GM: geometric mean, Swr: within-patient standard deviation of the reference product1 by SABETable 3Summary of AEsPatientsn (%)Tn = 73Rn = 81Totaln = 81OverallAEs49 (67)60 (74)76 (94)SAEs12 (16)12 (15)23 (28)Deaths*5 (7)1 (1)6 (7)Occurring within 24 h of infusionAEs23 (32)34 (42)49 (61)SAEs2 (3)2 (3)4 (5)Deaths000*All attributable to disease progression [Display omitted] DisclosuresEdenfield:Novartis, Astellas/Medivation: Speakers Bureau. Anthony:Eagle Pharmaceuticals, Inc.: Research Funding. Mutch:Eagle Pharmaceuticals, Inc.: Employment. Chanas:Eagle Pharmaceuticals, Inc.: Employment. Smith:Eagle Pharmaceuticals, Inc.: Employment.

Comparison of Scaled-average, Population, and Individual Bioequivalence on 2 Tablets of Pitavastatin Calcium: A 3-Period, Reference-replicated, Crossover Study in Healthy Chinese Volunteers

BackgroundPitavastatin, a fully synthetic β-hydroxy-β-methylglutaryl–coenzyme A reductase inhibitor, is potent for the treatment of primary hyperlipidemia and mixed dyslipidemia. Recently, the original product and some generic products of pitavastatin calcium have become available in China. However, the intrasubject variability and interchangeability of this newly developed generic product and the branded innovator product have rarely been investigated in the Chinese population. PurposeThe aim of this study is to develop and compare the scaled-average, population, and individual bioequivalence (BE) of pitavastatin calcium tablets in healthy Chinese volunteers. This study will be used to allow for the interchangeability (switchability and prescribability) of the 2 products in clinical medication in China. MethodsA single-dose, reference-replicated, 3-period crossover BE study was conducted in 36 healthy male volunteers. Plasma samples were collected before and after oral administration of 2-mg test or reference tablets. A LC-MS/MS method was used to determine the concentration of pitavastatin calcium. A noncompartmental method was used to investigate the pharmacokinetic parameters. The ANOVA and 90% CIs of ln(AUC0–t) and ln(Cmax) were used for statistical analysis of scaled-average BE. A nonparametric test (Wilcoxon signed rank test) was performed to Tmax. The analyses of population BE and individual BE were used to assess the switchability and prescribability of the 2 products. FindingsThirty-six volunteers were enrolled in this clinical research; 33 volunteers completed the 3 treatment periods. The mean (SD) relative bioavailability calculated from the ratios (T/R) of AUC0–t was 101.3% (19.7%). The mean ln(AUC0–t) and ln(Cmax) were 98.64 (90% CI, 93.44–104.13) and 98.68 (90% CI, 91.88–105.99) within previously stipulated ranges recommended by the US Food and Drug Administration and the China Food and Drug Administration (CFDA). The intrasubject %CVs of AUC0–t and Cmax were 12.0% and 18.0% for the reference tablet and 13.0% and 17.0% for the test tablet. No significant differences were found among Tmax (0.742 ± 0.276, 0.674 ± 0.202, and 0.689 ± 0.226, respectively) for reference tablet 1, reference Supplemental Table II in the online version at 10.1016/j.clinthera.2014.06.21, and test tablet by a Wilcoxon test (P > 0.05). For ln(AUC0–t) and ln(Cmax), the statistical test-reference ratios were 99.13% and 98.95%, respectively. After inspecting the results for reference and mixed scaling, all the upper confidence limits were <0; therefore, population and individual BE were given. ImplicationsIn the healthy Chinese males, the generic and branded name tablets of pitavastatin calcium are bioequivalent at the rate and extent of absorption after a comparison of scaled-average, population, and individual BE and thus may be used interchangeably. Both the formulations are generally well tolerated. Chinese Clinical Trial identifier: ChiCTR-TTRCC-13003973.

Establishment of in vitro–in vivo equivalence of highly variable drugs – a generic product development perspective

In vivo equivalence of highly variable drugs (HVD) has always been a subject of great concern, in terms of both safety and efficacy, for regulatory agencies. Successful demonstration of their bioequivalence thus presents the most crucial component of a generic application, significantly contributing toward the cost and time of development. For poorly soluble drugs, such as telmisartan, dissolution represents the rate-limiting step in the gastric region and in many cases may not be complete, thereby contributing to low and highly variable bioavailability. Consequently, simulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of drug formulations. In this study, we evaluated usefulness of physiologically relevant dissolution method over commonly used acidic media to forecast comparable in vivo performance of telmisartan formulation to that of reference samples. In the present study, telmisartan was classified as a HVD and a partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability has been presented. The design has effectively decreased sample size, without increasing patient risk. Results from this project suggest that scaled average bioequivalence (SABE) provides a good approach for evaluating the bioequivalence of HVD, meeting the need for international guidelines for bioequivalence.

Estimating product bioequivalence for highly variable veterinary drugs

The occurrence of drugs and drug formulations associated with large intrasubject pharmacokinetic (PK) variability has been well described in humans and is likewise encountered in veterinary medicine. The scaled average bioequivalence (SABE) approach adopted by CDER of the FDA for the determination of bioequivalence (BE) of highly variable drugs (HVD) needs to be considered when applied to veterinary dosage forms. However, because of some of the unique challenges that are encountered within the framework of veterinary medicine, variations of CDER's approach are presented. The present manuscript discusses HVD and highly variable veterinary drugs (HVVD) from the perspective of possible alternative approaches to support the assessment of product BE in veterinary medicine. Limitations in the use of 3- and 4-way crossover study designs are enumerated. In addition to a need for a statistical analysis of HVVD when using a parallel study design, the use of the secondary criteria (test-to-reference ratio), definition of σ(0) , and average BE with expanding limits are raised. A number of the details need to be finalized, from the selection of a regulatory constant to the determination of 'highly variable' in a veterinary drug product. Academicians, industrial scientists, and regulators should continue this discussion and resolve these details.

변이가 큰 약물의 생물학적 동등성 평가에 관한 연구

This paper reviews the definition of highly variable drug(HVD), the present regulatory recommendations and the approaches proposed in the literature to deal with the bioequivalence issues of HVD. The concept and the statistical approach of scaled average bioequivalence(SABE) is introduced and discussed with the current regulatory methods. The recommendations for SABE approach are proposed and the further study topics related to HVDs are also presented.

Viewpoint: observations on scaled average bioequivalence

The two one-sided test procedure (TOST) has been used for average bioequivalence testing since 1992 and is required when marketing new formulations of an approved drug. TOST is known to require comparatively large numbers of subjects to demonstrate bioequivalence for highly variable drugs, defined as those drugs having intra-subject coefficients of variation greater than 30%. However, TOST has been shown to protect public health when multiple generic formulations enter the marketplace following patent expiration. Recently, scaled average bioequivalence (SABE) has been proposed as an alternative statistical analysis procedure for such products by multiple regulatory agencies. SABE testing requires that a three-period partial replicate cross-over or full replicate cross-over design be used. Following a brief summary of SABE analysis methods applied to existing data, we will consider three statistical ramifications of the proposed additional decision rules and the potential impact of implementation of scaled average bioequivalence in the marketplace using simulation. It is found that a constraint being applied is biased, that bias may also result from the common problem of missing data and that the SABE methods allow for much greater changes in exposure when generic-generic switching occurs in the marketplace.

Comparison of average, scaled average, and population bioequivalence methods for assessment of highly variable drugs: An experience with doxifluridine in beagle dogs

Several strategies for overcoming the challenge of establishing bioequivalence (BE) for highly variable drugs (HVDs; drugs having within-subject variability >0.3) have been considered in recent years. Within-subject variability of the area under the curve (AUC 4 h ) and peak concentration ( C max) of doxifluridine in the minimal group ( n = 24) were 0.444 and 0.491, respectively, meeting the criteria for an HVD. For the large group ( n = 60), within-subject variability of the AUC 4 h and C max were 0.431 and 0.493, respectively. The 90% confidence interval for the AUC 4 h and C max of the ratio of the test drug to the reference drug exceeded the acceptable BE limits (0.80–1.25) of the ABE (average bioequivalence), in both the minimal and large groups. However, the 90% CI fell within the extended BE limits (0.61–1.64) of the SABE (scaled average bioequivalence), calculated using within-subject variability. The 95% CI of the AUC 4 h and C max of the ratio of test to reference drug were within the extended BE limit (<1.73) of the PBE (population bioequivalence), calculated using total variance. Our results suggest that the SABE method may be useful for evaluating the BE of HVDs and for meeting the need for international guidelines for BE.

Evaluation of Bioequivalence for Highly Variable Drugs with Scaled Average Bioequivalence

Bioequivalence studies are performed to demonstrate in vivo that two pharmaceutically equivalent products (in the US) or alternative pharmaceutical products (in the EU) are comparable in their rate and extent of absorption. By definition, for highly variable drugs (HVDs), the estimated within-subject variability is >30%. HVDs often fail to meet current regulatory acceptance criteria for average bioequivalence (ABE). The determination of the bioequivalence of HVDs has been a vexing problem since the inception of the current regulations. It is of concern not only to the generic industry but also to the innovator industry. This article reviews the definition of HVDs, the present regulatory recommendations and the approaches proposed in the literature to deal with the bioequivalence problems of HVDs. The approach of scaled ABE (SABE) is proposed as the most adequate procedure to solve the problem. It is demonstrated that SABE has firm theoretical foundations. In fact, statistical tests similar to SABE are used in various fields, such as psychology and quality control. Algorithms and numerical examples are presented to calculate SABE from the data in conventional two-period and replicate-design studies. The most important feature of SABE is that a fixed sample size is adequate to demonstrate bioequivalence regardless of within-subject variability. The conditions for reaching consistent regulatory decisions with SABE are discussed. The required sample size, for a given statistical power, depends on the regulatory criteria. Sample sizes with different criteria are demonstrated and compared with those arising from a recent informal US FDA proposal. Pragmatic considerations lead to modifications of the theoretical concept of SABE. Several modifications are proposed, including reference scaling, restriction on the estimated geometric mean ratios and possibly limiting SABE to only secondary bioequivalence metrics such as the maximum concentration. Each proposal has its own merit but is also a source of new controversy. Overall, the statistical evaluation of SABE is more complex than that of ABE, which means higher regulatory burden. Standardized open software could be very useful in this regard. A small program script is presented to calculate SABE confidence limits.

Regulatory and Study Conditions for the Determination of Bioequivalence of Highly Variable Drugs

The FDA Working Group on Highly Variable (HV) Drugs recently presented interim procedures and conditions for determining the bioequivalence (BE) of HV drug products. They included analysis by the method of scaled average BE (SABE), a switching coefficient of variation of CV S = 30% and a regulatory standardized variation of CV 0 = 25% for applying SABE, and the use of a secondary regulatory criterion restricting to 0.80-1.25 the point estimate for the ratio of estimated geometric means (GMR) of the two formulations. These conditions are scrutinized in the present communication. 3-period BE studies were simulated with various statistical and regulatory assumptions. Power curves, obtained by gradually increasing the true GMR, compared performances of the methods of SABE, a constrained point estimate of GMR (PE/GMR), and the composite of these two approaches. The consumer risk of each procedure was evaluated. With CV 0 = 30% and PE/GMR = 0.80-1.25, the composite criterion of BE relied on the confidence limits of SABE. In contrast, with CV 0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion approached almost completely the features of the GMR point estimate, especially at high within-subject variation. The consumer risk was near 5% with CV 0 = 30% but much higher when CV 0 = 25%. A constraint on GMR is difficult to justify scientifically. Still, if it is introduced then the condition of CV S = CV 0 = 30% and PE/GMR = 0.80-1.25 is recommended as a composite regulatory criterion. With alternative settings of the conditions, such as the recommended CV 0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion would reflect almost entirely the GMR point estimate. Also, with CV 0 = 25%, the BE limits are discontinuous at CVS = 30% and, as consequences, the consumer risk is substantially larger than 5%, and the regulatory uncertainty for making a decision about acceptance or rejection is enhanced. These would be undesirable outcomes.