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In 2016, the US Food and Drug Administration (FDA) approved the first Abbreviated New Drug Application for Mometasone Furoate Nasal Suspension Spray. To establish the bioequivalence of this generic nasal suspension spray with the reference listed drug product (RLD), Nasonex®, a "weight-of-evidence" approach was utilized by the applicant that included formulation and device similarities, equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition to these testing for comprehensive evaluation of the drug product, FDA also considered supportive data generated by a novel in vitro method, Morphologically-Directed Raman Spectroscopy (MDRS), to characterize the particle size distribution (PSD) of active pharmaceutical ingredient (API) in the drug product. In this case, MDRS data eliminated the need for a comparative clinical endpoint bioequivalence study. The approval of the first generic Mometasone Furoate Nasal Suspension Spray is precedent-setting and paves a new pathway to establish bioequivalence for generic nasal suspension sprays. This approval also exemplifies FDA's commitment to advance regulatory science for evaluation of generic drug products.

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The FDA guidance on application of the biopharmaceutics classification system (BCS) for waiver of in vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created worldwide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry toward its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided. Results show that greater than 160 applications were approved, or tentatively approved, based on the BCS approach across multiple therapeutic areas; an additional significant finding was that at least 50% of these approvals were in the central nervous system (CNS) area. These findings indicate a robust utilization of the BCS approach toward reducing unnecessary in vivo BE studies and speeding up availability of high quality pharmaceutical products. The article concludes with a look at the adoption of this framework by regulatory and health policy organizations across the globe, and FDA's current thinking on areas of improvement of this guidance.

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Administration of proton pump inhibitors (PPIs) through nasogastric tubes may present risks. If the PPI drug products are not prepared properly, clogging or obstruction of nasogastric tubes can pose a safety concern. In addition, the integrity of the enteric coating of the drug product may be damaged resulting in reduced bioavailability of the active moiety. From the perspective of administration of generic PPIs when compared to the reference drug product, differences in formulation can potentially result in a greater relative risk for the generic drug product. As part of the assessment of bioequivalence, the Office of Generic Drugs (OGD) has developed a suite of in vitro testing to compare the delivery of the generic and reference products via nasogastric tubes. These in vitro tests assess essential attributes associated with the likelihood of clogging and maintenance of the enteric coating. These in vitro tests include studies evaluating sedimentation, granule size distribution, drug recovery, and acid resistance. One of the challenges is that while the administration of PPIs through nasogastric tubes is common in clinical practice, this issue is not uniformly addressed in the FDA approved label of the reference drug products. This paper discusses the design and rationale for in vitro testing of PPI formulations with respect to bioequivalence via nasogastric tube administration and in addition, it summarizes commonly occurring deficiencies in the in vitro nasogastric tube testing of 14 recent Abbreviated New Drug Applications (ANDA) submitted for five generic PPI drug products.

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Oral modified-release (MR) products are dosage forms administered through the mouth and designed to release drug in a controlled manner to achieve maximum efficacy, minimal side effects, and better patient compliance. With significant progress in pharmaceutical technologies and favored therapeutic benefit, more and more oral MR products including the generic versions of these products are being developed, marketed, and used in the USA. Because different types of MR products may exhibit unique drug release modes and specific pharmacokinetic profiles, a better understanding of the regulation and evaluation of these generic MR products can help development and marketing of generic MR products that are therapeutically equivalent to the corresponding reference product. This review summarizes the general regulatory requirements for establishing bioequivalence between generic and reference oral MR products. In addition, some special regulatory considerations for bioequivalence evaluation are highlighted with examples of specific oral MR drug products.

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Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00-125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD's within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion.

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

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

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Over the years, incurred sample (IS) reanalysis (ISR) has become a tool to confirm the reliability of bioanalytical measurements. The recommendation for ISR acceptance criterion for small molecules is at least 67% of ISR samples that have reanalyzed concentrations within 20% of their original concentrations when normalized to their means. To understand the relevance of the ISR acceptance criterion and sample size requirements, simulated ISR studies evaluated the probability of ISR studies passing the acceptance criterion (ISR pass rate) as a function of IS imprecision and sample size. When IS imprecision (percent coefficient of variation: %CV) is low (≤ 10 or 1-10% CV), high ISR pass rate (≥ 99%) is attained with <50 samples. At intermediate IS imprecision (e.g., 12% CV or 7-12% CV range), 80-160 samples are required for a high ISR pass rate. When IS imprecision is at the higher end of the acceptance limit, ISR pass rate decreases significantly, and increasing sample size fails to achieve high ISR pass rate. The effect of systematic bias (e.g., instability, interconversion) on ISR pass rate is strongly dependent on sample size at intermediate IS imprecision. The results provide an understanding of the effect of IS imprecision on ISR pass rates and a framework for selection of ISR sample sizes.

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Establishing bioequivalence (BE) of drugs indicated to treat cancer poses special challenges. For ethical reasons, often, the studies need to be conducted in cancer patients rather than in healthy volunteers, especially when the drug is cytotoxic. The Biopharmaceutics Classification System (BCS) introduced by Amidon (1) and adopted by the FDA, presents opportunities to avoid conducting the bioequivalence studies in humans. This paper analyzes the application of the BCS approach by the generic pharmaceutical industry and the FDA to oncology drug products. To date, the FDA has granted BCS-based biowaivers for several drug products involving at least four different drug substances, used to treat cancer. Compared to in vivo BE studies, development of data to justify BCS waivers is considered somewhat easier, faster, and more cost effective. However, the FDA experience shows that the approval times for applications containing in vitro studies to support the BCS-based biowaivers are often as long as the applications containing in vivo BE studies, primarily because of inadequate information in the submissions. This paper deliberates some common causes for the delays in the approval of applications requesting BCS-based biowaivers for oncology drug products. Scientific considerations of conducting a non-BCS-based in vivo BE study for generic oncology drug products are also discussed. It is hoped that the information provided in our study would help the applicants to improve the quality of ANDA submissions in the future.

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BACKGROUND: The US FDA published A Guidance for Industry: Bioanalytical Method Validation in May 2001. Despite the publication of the guidance, companies continue to submit bioequivalence studies with bioanalytical deficiencies that preclude Abbreviated New Drug Application approval. The Divisions of Bioequivalence in the FDA's Office of Generic Drugs conducted a survey of the bioequivalence submissions over a 10-year period (2001-2011) to identify the most commonly occurring bioanalytical deficiencies. RESULTS: Data from a total of 4028 Abbreviated New Drug Application submissions were collected to identify bioanalytical deficiencies. Of the three categories of bioanalytical deficiencies (method, validation and report), the majority of the deficiencies were from the bioanalytical method validation section. Globally, the percentage of bioanalytical method validation deficiencies was 62%. CONCLUSIONS: The approval of generic drugs would be accelerated if these deficiencies were avoided by generic companies by adhering to the guidance and therefore submitting a more complete application.

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The demonstration of bioequivalence (BE) between the test and reference products is an integral part of generic drug approval process. A sound BE study design is pivotal to the successful demonstration of BE of generic drugs to their corresponding reference listed drug product. Generally, BE of systemically acting oral dosage forms is demonstrated in a crossover, single-dose in vivo study in healthy subjects. The determination of BE of solid oral anticancer drug products is associated with its own unique challenges due to the serious safety risks involved. Unlike typical BE study in healthy subjects, the safety issues often necessitate conducting BE studies in cancer patients. Such BE studies of an anticancer drug should be conducted without disturbing the patients' therapeutic dosing regimen. Attributes such as drug permeability and solubility, pharmacokinetics, dosing regimen, and approved therapeutic indication(s) are considered in the BE study design of solid anticancer drug products. To streamline the drug approval process, the Division of Bioequivalence posts the Bioequivalence Recommendations for Specific Products guidances on the FDA public website. The objective of this article is to illustrate the scientific and regulatory considerations in the design of BE studies for generic solid oral anticancer drug products through examples.

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The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association, Japan, Mexico, Singapore, South Korea, Switzerland, the USA, and the World Health Organization. We began with a comparison of how the various jurisdictions and organizations define a generic product and its corresponding reference product. We then compared the following bioequivalence approaches: recommended bioequivalence study designs, method of pharmacokinetic calculations and bioequivalence acceptance limits, recommendations for modifying bioequivalence study designs and limits for highly variable drugs and narrow therapeutic index drugs, provisions for waiving bioequivalence study requirements (granting biowaivers), and implementation of the Biopharmaceutics Classification System. We observed that, overall, there are more similarities than differences in bioequivalence approaches among the regulatory authorities surveyed.

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Demonstrating bioequivalence (BE) for nasal spray/aerosol products for local action has been very challenging because the relationship between the drug in systemic circulation and the drug reaching the nasal site of action has not been well established. Thus, the current BE standard for these drug/device combination products is based on a weight-of-evidence approach, which contains three major elements: equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition, formulation sameness and device similarity are evidences to support BE. This paper presents a comprehensive review of the scientific rationale of the current BE standard and their development history for nasal spray/aerosol products, as well as the Food and Drug Administration's review and approval status of generic nasal sprays/aerosols with the application of these BE standard.

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"For-cause" inspections are initiated during the review of bioequivalence (BE) data submitted to Abbreviated New Drug Applications when possible scientific misconduct and study irregularities are discovered. We investigated the common reasons for initiating "for-cause" inspections related to the clinical, analytical, and dissolution study sites associated with BE studies. This information may help the pharmaceutical industry to understand the root causes of compliance failures in BE studies and help them to improve compliance with FDA's regulations, thereby facilitating more rapid approval of safe and effective generic drugs.

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Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.

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The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submissions. To categorize solubility and intestinal permeability properties of generic drugs under development, we used a list of 61 drugs which were classified as BCS 1, 2, 3, and 4 drugs with certainty in the World Health Organization Model List of Essential Medicines. Applying this list to evaluation of 263 ANDA approvals of BCS drugs during the period of 2000 to 2011 indicated 110 approvals (41.8%) for Class 1 drugs (based on both biowaiver and in vivo bioequivalence studies), 55 (20.9%) approvals for Class 2 drugs, 98 (37.3%) approvals for Class 3 drugs, and no (0%) approvals for Class 4 drugs. The present data indicated a trend of more ANDA approvals of BCS Class 1 drugs than Class 3 or Class 2 drugs. Antiallergic drugs in Class 1, drugs for pain relief in Class 2 and antidiabetic drugs in Class 3 have received the largest number of approvals during this period.

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The purpose of this article is to document the discussions at the 2010 European Workshop on Equivalence Determinations for Orally Inhaled Drugs for Local Action, cohosted by the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Consortium on Regulation and Science (IPAC-RS). The article summarizes current regulatory approaches in Europe, the United States, and Canada, and presents points of consensus as well as ongoing debate in the four major areas: in vitro testing, pharmacokinetic and pharmacodynamic studies, and device similarity. Specific issues in need of further research and discussion are also identified.

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PURPOSE: A generic product must meet the standards established by the Food and Drug Administration (FDA) to be approved for marketing in the USA. FDA approves a generic product for marketing if it is proved to be therapeutically equivalent to the reference product. Bioequivalence (BE) between a proposed generic product and its corresponding reference product is one of the major components of therapeutic equivalence. These approvals may be delayed if the BE portion of the submission is determined to be deficient. Many of these BE deficiencies recur commonly and can be avoided. METHOD: We conducted a survey of the BE submissions to abbreviated new drug applications (ANDAs) over years 2001 to 2008 to identify the most commonly occurring BE deficiencies. RESULTS: Recurring deficiencies are found in a majority of the ANDAs reviewed by FDA's Division of Bioequivalence. The most common deficiencies were the two deficiencies related to dissolution (method and specifications) found in 23.3% of the applications and analytical method validation and/or report found in 16.5% of the applications. The approval of generic drugs would be greatly accelerated if these deficiencies could be avoided.

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