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Shein-chung Chow - One of the best experts on this subject based on the ideXlab platform.
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Practical Statistical Issues in Evaluation of Average Bioequivalence
Journal of biometrics & biostatistics, 2019Co-Authors: Shein-chung Chow, Mo LiuAbstract:For approval of generic drug products, the United States Food and Drug Administration (FDA) has published several regulatory guidance to assist the sponsors in preparing documents, which provide substantial evidence for demonstration of Bioequivalence between a generic (test) product and its innovative (reference) product (e.g., FDA, 1992, 2003) through the conduct of bioavailability and Bioequivalence studies. Bioavailability and Bioequivalence studies are usually conducted under crossover designs such as a standard 2x2 crossover design or a higher-order crossover design. Under a crossover design, Bioequivalence is commonly evaluated using a two one-sided tests procedure (each at a 5% level of significance) or a 90% confidence interval approach. Bioequivalence is claimed if the constructed 90% confidence interval for the geometric mean ratio falls entirely within the Bioequivalence limit of (80%, 125%). Statistical methods for Bioequivalence evaluation are well established and widely accepted in the pharmaceutical industry since the publication of the FDA guidance in 2003. However, several practical issues are commonly encountered during the review of regulatory submissions of generic drug products. In this article, these issues are described. In addition, some recommendations for possible clarification and/or resolutions are made.
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bioavailability and Bioequivalence in drug development
Wiley Interdisciplinary Reviews: Computational Statistics, 2014Co-Authors: Shein-chung ChowAbstract:Bioavailability is referred to as the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action. The relative bioavailability in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. In 1984, the United States Food and Drug Administration (FDA) was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act based on evidence of average Bioequivalence in drug absorption through the conduct of bioavailability and Bioequivalence studies. This article provides an overview (from an American point of view) of definition of bioavailability and Bioequivalence, Fundamental Bioequivalence Assumption, regulatory requirements, and process for Bioequivalence assessment of generic drug products. Basic considerations including criteria, study design, power analysis for sample size determination, and the conduct of Bioequivalence trial, and statistical methods are provided. Practical issues such as one size-fits-all criterion, drug interchangeability and scaled average criteria for assessment of highly variable drug products are also discussed.
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In vivo and In vitro Bioequivalence Testing
Journal of Bioequivalence & Bioavailability, 2014Co-Authors: Shein-chung Chow, Shichen ZhuAbstract:For approval of generic drug products, the FDA requires that evidence of average Bioequivalence in drug absorption be provided through the conduct of Bioequivalence studies. As indicated in 21CFR320.24, Bioequivalence may be established by in vivo (e.g., pharmacokinetic, pharmacodynamic, or clinical) and in vitro studies or with suitable justification by in vitro studies alone. In this presentation, an overview of statistical considerations including study design, criteria, and statistical methods for assessment of Bioequivalence will be provided. For in vivo Bioequivalence testing, in addition to average Bioequivalence, the concept of population Bioequivalence and individual Bioequivalence for addressing drug interchangeability will also be discussed. For in vitro Bioequivalence testing, an overview regarding some in vitro tests such as dose or spray content uniformity through container’s life, droplet and drug particle size distribution, spray pattern, plume geometry, priming and repriming, and tail off profile that are commonly employed for local action drug products such as nasal aerosols and nasal sprays products will be provided. Recent development and future research topics will also be discussed.
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Statistical Issues in Bioavailability/Bioequivalence Studies
Journal of Bioequivalence & Bioavailability, 2011Co-Authors: Shein-chung Chow, Laszlo Endrenyi, Eric Chi, Lan-yan Yang, Laszlo TothfalusiAbstract:For the approval of generic drug products, bioavailability/Bioequivalence studies are often conducted to demonstrate that the drug absorption profiles in terms of the extent and rate of absorption of test products are bioequivalent to those of the innovative drug product. The bioavailability/Bioequivalence studies are often conducted under a standard two-sequence, two-period (2x2) crossover design. Under the standard 2x2 crossover design, statistical methods are well established for the assessment of Bioequivalence. However, it is a concern whether approved generic drug products can be used safely and interchangeably. In this article, drug interchangeability under a replicated crossover bioavailability/Bioequivalence study is discussed. Several controversial statistical issues that are commonly encountered in the assessment of Bioequivalence are discussed. In addition, some frequently asked questions during regulatory submissions are reviewed. Recommendations regarding possible resolutions are made whenever possible. Some concluding remarks on the feasibility of the application of current methods for Bioequivalence to the assessment of biosimilarity of follow-on biologics are also presented.
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a comparison of moment based and probability based criteria for assessment of follow on biologics
Journal of Biopharmaceutical Statistics, 2009Co-Authors: Shein-chung Chow, Tsungcheng Hsieh, Jun YangAbstract:For approval of generic drugs, the U.S. Food and Drug Administration (FDA) requires the evidence of Bioequivalence in average bioavailability from the bioavailability/Bioequivalence studies. The criterion for assessment of Bioequivalence adopted by the FDA is a moment-based criterion evaluating log-transformed pharmacokinetic responses such as area under the blood or plasma concentration–time curve (AUC) or maximum concentration (Cmax). Unlike traditional small molecule drug products, the characteristics and development of biologic products are more complicated and sensitive to many factors. Thus, it is of concern to know whether the current Bioequivalence criterion is applicable to the assessment of biosimilarity between biologic products. In this article, we compare the moment-based criterion with a probability-based criterion proposed by Tse et al. (2006) for assessment of Bioequivalence or biosimilarity between two drug products in terms of consistency/inconsistency for correctly concluding bioequival...
Liang Zhao - One of the best experts on this subject based on the ideXlab platform.
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Risk-Based Bioequivalence Recommendations for Antiepileptic Drugs
Current Neurology and Neuroscience Reports, 2017Co-Authors: Zhichuan Li, Wenlei Jiang, Lanyan Fang, Liang ZhaoAbstract:Purpose of Review This review summarizes the current FDA practice in developing risk- and evidence-based product-specific Bioequivalence guidances for antiepileptic drugs (AEDs). Recent Findings 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. Summary 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.
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Risk-Based Bioequivalence Recommendations for Antiepileptic Drugs.
Current neurology and neuroscience reports, 2017Co-Authors: Lanyan Fang, Wenlei Jiang, Myong-jin Kim, Liang ZhaoAbstract: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.
Philippe Ravaud - One of the best experts on this subject based on the ideXlab platform.
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quality of reporting of Bioequivalence trials comparing generic to brand name drugs a methodological systematic review
PLOS ONE, 2011Co-Authors: Amelie Van Der Meersch, Agnès Dechartres, Philippe RavaudAbstract:Background Generic drugs are used by millions of patients for economic reasons, so their evaluation must be highly transparent. Objective To assess the quality of reporting of Bioequivalence trials comparing generic to brand-name drugs. Methodology/Principal Findings PubMed was searched for reports of Bioequivalence trials comparing generic to brand-name drugs between January 2005 and December 2008. Articles were included if the aim of the study was to assess the bioequivalency of generic and brand-name drugs. We excluded case studies, pharmaco-economic evaluations, and validation dosage assays of drugs. We evaluated whether important information about funding, methodology, location of trials, and participants were reported. We also assessed whether the criteria required by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) to conclude Bioequivalence were reported and that the conclusions were in agreement with the results. We identified 134 potentially relevant articles but eliminated 55 because the brand-name or generic drug status of the reference drug was unknown. Thus, we evaluated 79 articles. The funding source and location of the trial were reported in 41% and 56% of articles, respectively. The type of statistical analysis was reported in 94% of articles, but the methods to generate the randomization sequence and to conceal allocation were reported in only 15% and 5%, respectively. In total, 65 articles of single-dose trials (89%) concluded Bioequivalence. Of these, 20 (31%) did not report the 3 criteria within the limits required by the FDA and 11 (17%) did not report the 2 criteria within the limits required by the EMA. Conclusions/Significance Important information to judge the validity and relevance of results are frequently missing in published reports of trials assessing generic drugs. The quality of reporting of such trials is in need of improvement.
Lanyan Fang - One of the best experts on this subject based on the ideXlab platform.
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Risk-Based Bioequivalence Recommendations for Antiepileptic Drugs
Current Neurology and Neuroscience Reports, 2017Co-Authors: Zhichuan Li, Wenlei Jiang, Lanyan Fang, Liang ZhaoAbstract:Purpose of Review This review summarizes the current FDA practice in developing risk- and evidence-based product-specific Bioequivalence guidances for antiepileptic drugs (AEDs). Recent Findings 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. Summary 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.
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Risk-Based Bioequivalence Recommendations for Antiepileptic Drugs.
Current neurology and neuroscience reports, 2017Co-Authors: Lanyan Fang, Wenlei Jiang, Myong-jin Kim, Liang ZhaoAbstract: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.
Walter W. Hauck - One of the best experts on this subject based on the ideXlab platform.
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An individual Bioequivalence criterion: regulatory considerations†
Statistics in medicine, 2000Co-Authors: Mei-ling Chen, Walter W. Hauck, Rabindra Patnaik, Donald J. Schuirmann, Terry Hyslop, Roger L. WilliamsAbstract:Over the years, concerns have been raised regarding the appropriateness of using the average Bioequivalence approach for evaluation of comparability between formulations. In lieu of average Bioequivalence, scientists from academia, industry and regulatory agencies have spent considerable effort and time in exploring the concepts of population and individual Bioequivalence, and developing the statistical methods to assess the bioavailability metrics using these approaches. Recently, the Food and Drug Administration (FDA) has published a preliminary draft guidance entitled 'In vivo Bioequivalence studies based on population and individual Bioequivalence approaches'. The concept of prescribability and switchability underscores the difference between the population and individual Bioequivalence approaches. The most important consideration for individual Bioequivalence, the focus of this paper, rests on the assurance that products deemed bioequivalent can be used interchangeably in the target population (switchability). In addition to the comparison of averages, the individual Bioequivalence approach compares within-subject variabilities and assesses subject-by-formulation interaction. The proposed criterion represents substantial departure from the current practice and thus has resulted in extensive public discussion. In contrast to the current average Bioequivalence procedure, the proposed individual Bioequivalence approach offers flexible equivalence criteria based on the individual therapeutic window and variability of the reference drug product. The proposed criterion rewards manufacture of less variable drug products, allows scaling criteria for highly variable/narrow therapeutic range drugs, and promotes the use of subjects from the general population in Bioequivalence studies. The FDA is currently considering various approaches for resolution of issues raised from the public debate on the subject-by-formulation interaction term, statistical methods and resource implications.
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Measuring switchability and prescribability: When is average Bioequivalence sufficient?
Journal of pharmacokinetics and biopharmaceutics, 1994Co-Authors: Walter W. Hauck, Sharon AndersonAbstract:Recent work, beginning with that of Anderson and Hauck in 1990, has led to a general acceptance of the need to ensure switchability in Bioequivalence testing for approval of generic drugs. In other applications of Bioequivalence testing, prescribability may be sufficient. However, there is less acceptance of the need to change statistical procedures and study designs from those currently used to assess the current criterion of average Bioequivalence. We propose easily interpreted measures of switchability and prescribability. These measures provide bases for assessing conditions under which average Bioequivalence is not sufficient to ensure switchability and prescribability, and hence for which a procedure for individual or population Bioequivalence is required. The required conditions are sufficiently tight that they cannot be presumed to hold. Thus, there are reasonable conditions for which current practice is not sufficient. An outcome of this development is a connection between two current approaches for assessing individual Bioequivalence.
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Types of Bioequivalence and related statistical considerations.
International journal of clinical pharmacology therapy and toxicology, 1992Co-Authors: Walter W. Hauck, Sharon AndersonAbstract:Approval of a generic alternative to an existing formulation carries the implication that the two formulations are "equivalent". However, there are many notions of equivalent. Current practice in Bioequivalence studies defines equivalence solely in terms of average (or median) measures of bioavailability. Current methods for this average Bioequivalence approach are commonly based on the two one-sided tests principle. Average Bioequivalence is the special case of population Bioequivalence, where the entire distribution of bioavailabilities is considered. Statistical approaches for population Bioequivalence are suggested. Population Bioequivalence is an improvement over average Bioequivalence, because average Bioequivalence does not consider the variabilities of the formulations. However, population Bioequivalence is still not sufficient to ensure that an individual will respond similarly to the two formulations; that requires individual Bioequivalence. Again, statistical approaches are suggested, one of which, a tolerance interval approach, appears to directly address the clinical question of switchability of formulations. We conclude that population Bioequivalence is sufficient for marketing approval, but that individual Bioequivalence is necessary for switchability.
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Individual Bioequivalence: what matters to the patient.
Statistics in medicine, 1991Co-Authors: Walter W. Hauck, Sharon AndersonAbstract:Current procedures for assessing the Bioequivalence of two formulations are based on the concept of average Bioequivalence. That is, they assess whether the average responses between individuals on the two formulations are similar. We show first that average Bioequivalence is not sufficient to assure that an individual patient could be expected to respond similarly to the two formulations. To have such reasonable assurance requires a different notion of Bioequivalence; individual (or within-subject) Bioequivalence. Second, we propose a simple statistical procedure for assessing individual Bioequivalence. This decision rule, TIER (test of individual equivalence ratios) requires the specification of the minimum proportion of subjects in the applicable population for which the two formulations being tested must be bioequivalent (a regulatory decision). The TIER rule is summarized in terms of the minimum number of subjects with bioavailability ratios falling within the specified equivalence interval necessary to be able to claim Bioequivalence for given sample size and type I error. We recommend that the corresponding lower bounds (one-sided confidence intervals) for the proportion of bioequivalent subjects be calculated.
