Meiyu Shen

U.S. Food and Drug Administration | FDA · Center for Drug Evaluation and Research

Multivariate equivalence testing is needed in a variety of scenarios for drug development. For example, drug products obtained from natural sources may contain many components for which the individual effects and/or their interactions on clinical efficacy and safety cannot be completely characterized. Such lack of sufficient characterization poses...

On October 27–28, 2022, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop titled “Best Practices for Utilizing Modeling Approaches to Support Generic Product Development.” This report summarizes the presentations and panel discussions for a session titled “Development o...

In vitro dissolution profile has been shown to be correlated with the drug absorption and has often been considered as a metric for assessing in vitro bioequivalence between a test product and corresponding reference one. Various methods have been developed to assess the similarity between two dissolution profiles. In particular, similarity factor...

FDA’s experience to date has shown that completion of stability data requirements is one of the most observed challenges for applicants of New Drug Applications (NDAs) with an expedited review designation. Since NDAs submitted under these expedited pathways often have limited available real-time stability data from the primary batches, Modeling App...

Background: Currently, screening cut point (CP) calculated from an assay validation with replicates are applied to an immunogenicity study with nonreplicates, for which the antidrug antibodies rate is determined. IID treats the replicate of a sample as coming from another independent sample. AVE uses average results from each sample across runs but...

The 14 th edition of the Workshop on Recent Issues in Bioanalysis (14 th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14 th WRIB included three Main Worksho...

Proper adhesion plays a critical role in maintaining a consistent, efficacious, and safe drug delivery profile for transdermal and topical delivery systems (TDS). As such, in vivo skin adhesion studies are recommended by regulatory agencies to support the approval of TDS in new drug applications (NDAs). A draft guidance for industry by the US Food...

On page 5, in the second paragraph, the authors inadvertently included inaccurate information for the description of the analytical method.

PEGylated recombinant human granulocyte colony stimulating factor (pegfilgrastim) is used clinically to accelerate immune reconstitution following chemotherapy and is being pursued for biosimilar development. One challenge to overcome in pegfilgrastim biosimilar development is establishing pharmacokinetic (PK) similarity, which is partly due to the...

Non-inferiority comparison between binary response rates of test and reference treatments is often performed in clinical studies. The most common approach to assess non-inferiority is to compare the difference between the estimated response rates with some margin. Previous methods use a variety of margins, including fixed margin, step-wise constant...

FDA recommends a stepwise approach for obtaining the totality-of-the-evidence for assessing biosimilarity between a proposed biosimilar product and its corresponding reference biologic product being considered (US Food and Drug Administration.: Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. U...

The purpose of uniformity of dosage unit test is to determine the degree of uniformity in the amount of drug substance among dosage units in a batch. Recently, there are several nonparametric methods including the large sample counting approach proposed in European Pharmacopeia 8.1 (EU Option 2). All nonparametric methods specify a maximum number o...

Adaptive sample size re-estimation (SSR) methods have been widely used for designing clinical trials, especially during the past two decades. We give a critical review for several commonly used two-stage adaptive SSR designs for superiority trials with continuous endpoints. The objective, design and some of our suggestions and concerns of each desi...

For the reference scaled equivalence hypothesis to reduce the deficiency of the current practice in analytical equivalence assessment, the Wald test with Constrained Maximum Likelihood Estimate (CMLE) of the standard error was proposed to improve the efficiency when the sample sizes of test and reference product lots are small, and variances are un...

The equivalence test in analytical similarity assessment uses a margin of 1.5 times of the standard deviation of a reference product. In the current practice, the standard deviation , estimated from study data, is considered as a fixed constantin the margin. The impact of such a practice leads to the inflation of type I error rate and the reduction...

Particle size distribution (PSD) is an important property of particulates in drug products. In the evaluation of generic drug products formulated as suspensions, emulsions, and liposomes, the PSD comparisons between a test product and the branded product can provide useful information regarding in vitro and in vivo performance. Historically, the FD...

To evaluate the analytical similarity between the proposed biosimilar product and the US-licensed reference product, a working group at Food and Drug Administration (FDA) developed a tiered approach. This proposed tiered approach starts with a criticality determination of quality attributes (QAs) based on risk ranking of their potential impact on p...

Bioequivalence studies are an essential part of the evaluation of generic drugs. The most common in-vivo bioequivalence study design is the two-period two-treatment crossover design. The observed drug concentration-time profile for each subject from each treatment under each sequence can be obtained. AUC (the area under the concentration-time curve...

In the evaluation of the analytical similarity data, an equivalence testing approach for most critical and quantitative quality attributes, that are assigned to Tier 1 in their proposed three-tier approach, was proposed (Tsong, Dong, and Shen, 2016). Food and Drug Administration (FDA) has recommended the proposed equivalence testing approach to spo...

Bioequivalence (BE) studies are an essential part of the evaluation of generic drugs. The most common in vivo BE study design is the two-period two-treatment crossover design. AUC (area under the concentration-time curve) and Cmax (maximum concentration) are obtained from the observed concentration-time profiles for each subject from each treatment...

The nonclinical statistics teams in the Center of Drug Review and Research of the Food and Drug Administration (FDA) conduct regulatory reviews, statistical consultation, and statistical methodology development in nonclinical regulations. In this chapter, we provide a brief description of the two teams and provide two examples in statistical resear...

To evaluate the analytical similarity between the proposed biosimilar product and the US-licensed reference product, U.S. Food and Drug Administration (FDA) statisticians collaborated with Chemistry, Manufacturing and Control (CMC) scientists at FDA in order to develop a three-tier approach. The proposed tiered approach starts with a criticality de...

The number of subjects in a pharmacokinetic two-period two-treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one-sided tests procedure. No explicit mathematical formula for the power function in the context of the two one-sided tests procedure exis...

This article reflects the views of the authors and should not be construed to be those of the US Food and Drug Administration. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Bioequivalence studies are an essential part of the evaluation of generic drugs. The most common in-vivo bioequivalence (BE) study design is the two-period two-treatment crossover design. AUC (area under the concentration-time curve) and Cmax (maximum concentration) are obtained from the observed concentration-time profiles for each subject from ea...

ABSTRACT In quality control of drug products, tolerance intervals are commonly used methods to assure a certain proportion of the products covered within a pre-specified acceptance interval. Depending on the nature of the quality attributes, the corresponding acceptance interval could be one-sided or two-sided. Thus, the tolerance intervals can als...

ABSTRACT According to ICH Q6A (1999), a specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. For drug products, specifications usually consist of test methods and acceptance criteria for Assay, Impurities,...

Abstract The delivered dose uniformity is one of the most critical requirements for dry powder inhaler and metered dose inhaler products. In 1999, Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation and recomm...

ABSTRACT Cut point of the immunogenicity screening assay is the level of response of the immunogenicity screening assay at or above which a sample is defined to be positive and below which it is defined to be negative. Food and Drug Administration Guidance for Industry on Assay Development for Immunogenicity Testing of Therapeutic recommends the cu...

The European Union (EU) test for uniformity of dosage units using large sample sizes was published in European Pharmacopoeia 7.7 in 2012. There are 2 alternative tests. Option 1 is a parametric two-sided tolerance interval-based method modified with an indifference zone and counting units outside of (0.75 M, 1.25 M) (here, M is defined by sample me...

Abstract A test treatment is considered to be interchangeable with its reference treatment if they are equivalent and expected to produce the same clinical result in any given patient. To assess interchangeability, FDA Draft Guidance (1999), Guidance for Industry (2001, 2003) recommend using individual bioequivalence (IBE) and population bioequival...

Paired and multiple-to-one matched data have often been collected in clinical trials and epidemiological safety studies. When the response is binary, the sample size and power are determined by the discordant pairs or matched sets. Fixed sample size determination in assessing response rate difference of superiority, noninferiority, and equivalence...

To determine if cascade impactor (CI) measurement of drug in small particles from aqueous nasal sprays, described in FDA's 2003 draft Nasal Bioavailability/Bioequivalence Guidance, can be optimized to reduce measurement variability. To examine the influence of flow rate configurations and number of impactor stages on CI deposition and explore the i...

Complaints from healthcare providers that the adhesive on the Daytrana™ methylphenidate transdermal drug delivery system (TDDS) adhered to the release liner to such an extent that the release liner could not be removed prompted this study. Daytrana™ has a packaging system consisting of a moisture-permeable pouch contained within a sealed tray conta...

The USP harmonized dose content uniformity (DCU) sampling acceptance plan is the standard for the compendium. It consists of a two-tier sampling acceptance plan that uses the tolerance interval with an additional indifference zone concept. Other parametric tolerance interval-based DCU plans such as the parametric two-sided tolerance interval (PTSTI...

A release liner removal test is a valuable test for assessing the quality of a transdermal drug delivery system (i.e., TDDS, patch). This test measures the force required to remove the release liner from a patch. The objective of the present study was to establish sample preparation and instrument parameters for measuring release liner removal adhe...

This paper gives marine propeller load characteristic simulation system of electric propulsion as an example, the shaft structures of real propulsion system and simulation system are compared. Based on the detailed mathematical deduction of simulation principle and original research, and with the control strategy of simulation system, dynamic regul...

In a previous study on peel adhesion for medical tapes, it was shown that a stainless steel (SS) substrate better discriminated among medical tapes than a high-density polyethylene (HDPE) substrate. The objective of this study was to determine if a SS substrate would also better distinguish among transdermal drug delivery systems (TDDSs). Five TDDS...

As part of a method development for peel testing, an interlaboratory comparison among Food and Drug Administration-Center for Drug Evaluation and Research, Food and Drug Administration-Center for Devices and Radiological Health and Southwest Research Institute was conducted using medical tapes. The aim was to determine which readily available subst...

The objective of this study was to examine the effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powders measured by the ASTM D 6940-04 segregation tester using design of experiments (DOE) approaches. The test blends consisted of 4% aspirin (ASP) and 96% microcrystalline cellulose (MCC) with and w...

This paper presented a new multi-modular PWM converter. A novel Interleaved SVPWM (ISVPWM) technique is introduced to reduce the harmonic component of AC current. Simultaneously, a parallel control scheme, which is simple and easy to implement, is proposed based on the study of mathematical model and equivalent circuit of the converter. The theoret...

The delivery dose uniformity is one of the most critical requirements of dry powder inhaler and metered dose inhaler products. In 1998, the U.S. Food and Drug Administration recommended a two-tier acceptance sampling plan in the Draft Guidance of Metered Dose Inhaler and Dry Powder Inhaler Drug Products Chemistry, Manufacturing and Controls. The tw...

The ICH (20057. ICH ( 2005 ). ICH (E14) Guidance. The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs. International Conference on Harmonization, May 2005, in Geneva, Switzerland . View all references) defined drug-induced prolongation of QT interval, i.e., the duration of depolarization a...

The paper proposes a novel energy-fed traction power supply system of railways, which bases three-phase voltage source PWM rectifier. The merits include bidirectional energy flow, high power factor, low harmonic current and good stability of DC voltage. Through building the model of the traction power supply system, the difference between the diode...

In the paper, a novel traction power supply system of railways is proposed, which bases on three-phase voltage source PWM rectifier. The merits include energy saving, high power factor, low harmonic current, easy modularization and easy redundancy design. The circuit topology, PWM rectifier control scheme, a novel parallel control scheme and the IS...

The paper proposes a novel subway traction power supply system (DC 1500 V) based on three-level voltage source PWM rectifier. It has many merits, such as energy saving, high power factor, low harmonic current, easy modularization and easy redundancy design. The paper mainly introduces the circuit topology, parallel control scheme, and three-level r...

In order to assess the equivalence of two treatments, clinical trials are designed to test against the null hypothesis that the difference (or ratio) of two means (proportions) is either smaller than a pre-specified lower equivalence limit or larger than a pre-specified upper equivalence limit. For example, in generic drug evaluation, such approach...

The United States Pharmacopeia (USP) content uniformity sampling acceptance plan consisting of a two-stage sampling plan with criteria on sample mean and number of out-of-range tablets is the standard for compendium. It is, however, often used mistakenly for lot quality assurance. In comparison to the Japan Phamacopeia (JP) procedure, USP procedure...

In order to improve line side current quality of energy-fed PWM rectifier connected to the AC mains, this paper adopts synchronous current PI control technique. Engineering design techniques including software filter, anti-integrated-saturation PI control, simple dead-time compensation and unity power factor (PF) control are described in detail, as...

The U.S. Pharmacopoeia (USP) general monograph provides a standard for dissolution compliance with the requirements as stated in the individual USP monograph for a tablet or capsule dosage form. The USP monograph sets performance limit on dissolution in terms of a specific percentage Q that the drug product is required to be dissolved at a specifie...

To characterize the pharmacokinetics of the anticancer agent cisplatin, and explore the influence of patient covariates and interoccasion variability on drug disposition. Data were obtained from 285 patients (519 complete curves; 3483 plasma samples) who received the drug as a 3-h intravenous infusion at a mean dose of 144 mg (range 75-210 mg). The...

Objective: By means of a nonlinear mixed effect modeling technique, a population pharmacokinetic (PK) model was developed to evaluate the effects of a variety of covariates on clearance and other pharmacokinetic parameters of ultrafilterable carboplatin administered in high-dose combination regimens with peripheral blood stem cell support. In addi...

The important characteristics of a gas-promoted oil agglomeration process for cleaning coal particles in an aqueous suspension were determined. Numerous agglomeration tests with scale-model mixing systems of different sizes with controlled amounts of air were conducted. The tests were conducted on high- and medium-volatile bituminous coals using ei...

Coal cleaning by selective agglomeration of an aqueous suspension of coal particles was demonstrated on a laboratory scale by employing a colloidal dispersion of microscopic gas bubbles as an agglomerant. The microbubbles were produced by saturating water with gas under pressure and then releasing the pressure as the water was agitated. The formati...

The development of two modified agglomeration processes for coal beneficiation is presented separately in Parts I and II of this dissertation. Part I is based on research which was conducted to study the mechanism and characteristics of a gas-promoted oil agglomeration process. Part II is based on research which was carried out to develop a newer a...

The preliminary laboratory-scale development of a gas-promoted, oil agglomeration; process for cleaning coal was carried out with scale model mixing systems in which aqueous; suspensions of ultrafine coal particles were treated with a liquid hydrocarbon and a small; amount of air. The resulting agglomerates were recovered by screening. During a bat...

Coal beneficiation is achieved by suspending coal fines in a colloidal suspension of microscopic gas bubbles in water under atmospheric conditions to form small agglomerates of the fines adhered by the gas bubbles. The agglomerates are separated, recovered and resuspended in water. Thereafter, the pressure on the suspension is increased above atmos...