Use of the Same Model or Modeling Strategy Across Multiple Submissions: Focus on Complex Drug Products.

Evidence shows that there is an increasing use of modeling and simulation to support product development and approval for complex generic drug products in the USA, which includes the use of mechanistic modeling and model-integrated evidence (MIE). The potential for model reuse was the subject of a workshop session summarized in this review, where the session included presentations and a panel discussion from members of the U.S. Food and Drug Administration (FDA), academia, and the generic drug product industry. Concepts such as platform performance assessment and MIE standardization were introduced to provide potential frameworks for model reuse related to mechanistic models and MIE, respectively. The capability of models to capture formulation and product differences was explored, and challenges with model validation were addressed for drug product classes including topical, orally inhaled, ophthalmic, and long-acting injectable drug products. An emphasis was placed on the need for communication between FDA and the generic drug industry to continue to foster maturation of modeling and simulation that may support complex generic drug product development and approval, via meetings and published guidance from FDA. The workshop session provided a snapshot of the current state of modeling and simulation for complex generic drug products and offered opportunities to explore the use of such models across multiple drug products.

Principles and Experimental Considerations for In Vitro Transporter Interaction Assays.

Drug transporters are universally acknowledged as important determinants of the absorption, distribution, metabolism, and excretion of both endogenous and exogenous compounds. Altered transporter function, whether due to genetic polymorphism, DDIs, disease, or environmental factors such as dietary constituents, can result in changes in drug efficacy and/or toxicity due to changes in circulating or tissue levels of either drugs or endogenous substrates.Prediction of whether and to what extent the biological fate of a drug is influenced by drug transporters, therefore, requires in vitro test systems that can accurately predict the risk and magnitude of clinical DDIs. While these in vitro assessments appear simple in theory, practitioners recognize that there are multiple factors that can influence experimental outcomes. A better understanding of these variables, including test compound characteristics, test systems, assay formats, and experimental design, will enable clear, actionable steps and translatable outcomes that may avoid unnecessary downstream clinical engagement. This chapter will delineate the role of these variables in improving in vitro assay outcomes.

Case Study 7: Transporters Case Studies-In Vitro Solutions for Translatable Outcomes.

Assessing the interactions of a new drug candidate with transporters, either as a substrate, inhibitor, or inducer, is no simple matter. There are many clinically relevant transporters, as many as nine to be evaluated for an FDA submission and up to 11 for the EMA as of 2020. Additionally, it is likely that if a compound is a substrate or inhibitor of one transporter, it will be so for other transporters as well. There are practically no specific substrates or inhibitors, presumably because the specificities of drug transporters are so broad and overlapping, and even fewer clinically relevant probes that can be used to evaluate transporter function in humans. In the case of some transporters, it is advisable to evaluate an NCE with more than one test system and/or more than one probe substrate in order to convince oneself (and regulatory authorities) that a clinical drug interaction study is not warranted. Finally, each test system has its own unique set of advantages and disadvantages. One has to appreciate the nuances of the available tools (test systems, probe substrates, etc.) to select the most relevant tools for the study and design the optimal in vitro experiment. In this chapter, several examples are used to illustrate the successful interpretation of in vitro data for both efflux and uptake transporters. Some data presented in this chapter are unpublished at the time of the compilation of this book. It has been included in this chapter to provide a sense of the complexities in transporter kinetics to the reader.

Public Workshop Summary Report on Fiscal Year 2021 Generic Drug Regulatory Science Initiatives: Data Analysis and Model-Based Bioequivalence.

On May 4, 2020, the US Food and Drug Administration (FDA) hosted an online public workshop titled "FY 2020 Generic Drug Regulatory Science Initiatives Public Workshop" to provide an overview of the status of the science and research priorities and to solicit input on the development of Generic Drug User Fee Amendments fiscal year 2021 priorities. This report summarizes the podium presentations and the outcome of discussions along with innovative ways to overcome challenges and significant opportunities related to model-based approaches in bioequivalence assessment for breakout session 4 titled, "Data analysis and model-based bioequivalence (BE)." This session focused on the application of model-based approaches in the generic drug development, with a vision of accelerating regulatory decision making for abbreviated new drug application assessments. The session included both podium presentations and panel discussions with three topics of interest: (i) in vitro study evaluation methods and their clinical relevance, (ii) challenges in model-based BE, (iii) emerging expertise and tools in implementing new BE approaches.

Innovative in vitro methodologies for establishing therapeutic equivalence.

To improve the quality of pharmaceutical products in their markets, several Latin American countries have begun to require that new generic products demonstrate bioequivalence against innovator or reference products. However, given the number of products involved, it is not feasible to rely on clinical studies to comply with this requirement. Instead, it makes sense to adopt or develop strategies that are appropriate to the characteristics of the region. To streamline drug development and accelerate patients' access to quality drug products, 15 years ago the United States Food and Drug Administration (FDA) decided to grant exemptions from clinical bioequivalence studies (i.e., biowaivers) for certain types of drug products based on the Biopharmaceutics Classification System (BCS). Biowaivers can significantly reduce development time and cost and can also prevent unnecessary human exposure to potentially dangerous drugs while providing a robust, consistent standard for therapeutic equivalence of generic drug products. In addition, the limited success of translating in vitro dissolution data into in vivo performance can be enhanced using innovative tools such as the in vitro dissolution and absorption systems (IDAS). By integrating in vitro dissolution and permeability tests, these systems can provide useful insights for formulation development. A thorough assessment of the potential of in vitro techniques, along with formalization of their use through regulatory science initiatives when appropriate, may lead to cost-effective tools to help address some of the quality and regulatory challenges faced in the Latin American and Caribbean region.

Innovative in vitro methodologies for establishing therapeutic equivalence / Métodos in vitro innovadores para determinar la equivalencia terapéutica

To improve the quality of pharmaceutical products in their markets, several Latin American countries have begun to require that new generic products demonstrate bioequivalence against innovator or reference products. However, given the number of products involved, it is not feasible to rely on clinical studies to comply with this requirement. Instead, it makes sense to adopt or develop strategies that are appropriate to the characteristics of the region. To streamline drug development and accelerate patients’ access to quality drug products, 15 years ago the United States Food and Drug Administration (FDA) decided to grant exemptions from clinical bioequivalence studies (i.e., biowaivers) for certain types of drug products based on the Biopharmaceutics Classification System (BCS). Biowaivers can significantly reduce development time and cost and can also prevent unnecessary human exposure to potentially dangerous drugs while providing a robust, consistent standard for therapeutic equivalence of generic drug products. In addition, the limited success of translating in vitro dissolution data into in vivo performance can be enhanced using innovative tools such as the in vitro dissolution and absorption systems (IDAS). By integrating in vitro dissolution and permeability tests, these systems can provide useful insights for formulation development. A thorough assessment of the potential of in vitro techniques, along with formalization of their use through regulatory science initiatives when appropriate, may lead to cost-effective tools to help address some of the quality and regulatory challenges faced in the Latin American and Caribbean region.

Para mejorar la calidad de los productos farmacéuticos comercializados en su mercado, varios países latinoamericanos han empezado a exigir que se demuestre la bioequivalencia de los nuevos medicamentos genéricos frente a los medicamentos innovadores o de referencia. Sin embargo, dado el gran número de medicamentos, resulta, poco factible realizar estudios clínicos para cumplir con este requisito pero tiene sentido incorporar o elaborar estrategias que sean acordes a las características de la región. Para simplificar el desarrollo de fármacos y optimizar el acceso de los pacientes a medicamentos de buena calidad, hace 15 años la Administración de Alimentos y Medicamentos de los Estados Unidos de América (FDA) decidió conceder exenciones a la realización de estudios clínicos de bioequivalencia (es decir, bioexenciones) a algunos tipos de medicamentos conforme al Sistema de Clasificación Biofarmacéutica. Las bioexenciones reducen significativamente el tiempo y el costo de desarrollo, y también evitan la exposición innecesaria de seres humanos a medicamentos que podrían ser nocivos, a la vez que constituyen una norma robusta y uniforme que garantiza la equivalencia terapéutica de los medicamentos genéricos. Por otra parte, los métodos innovadores, como los sistemas de disolución y absorción in vitro, permiten ampliar los resultados limitados obtenidos al aplicar los datos de disolución in vitro para simular los efectos in vivo. Dado que combinan las pruebas de disolución in vitro con las de permeabilidad, estos sistemas brindan conocimientos útiles para el desarrollo galénico. Es probable que la evaluación meticulosa del potencial de las técnicas in vitro, junto con su formalización mediante iniciativas de normalización científica cuando corresponda, permita concebir métodos eficaces en función de los costos que ayuden a encarar algunos de los retos relativos a la calidad y la regulación de los medicamentos que enfrentan América Latina y el Caribe.

Principles and experimental considerations for in vitro transporter interaction assays.

Drug transporters are now universally acknowledged as important determinants of the absorption, distribution, metabolism and excretion of both endogenous and exogenous compounds. Altered transporter function, whether due to genetic polymorphism, DDIs, disease, or environmental factors such as dietary constituents, can result in changes in drug efficacy and/or toxicity due to changes in circulating or tissue levels of either drugs or endogenous substrates.Prediction of whether and to what extent the biological fate of a drug is influenced by drug transporters, therefore, requires in vitro test systems that can accurately predict the risk and magnitude of clinical DDIs. While these in vitro assessments appear simple in theory, practitioners recognize that there are multiple factors that can influence experimental outcomes. A better understanding of these variables, including test compound characteristics, test systems, assay formats, and experimental design will enable clear, actionable steps and translatable outcomes that may avoid unnecessary downstream clinical engagement. This chapter will delineate the role of these variables in improving in vitro assay outcomes.

Case study 6. Transporter case studies: in vitro solutions for translatable outcomes.

Assessing the interactions of a new drug candidate with transporters, either as a substrate or as an inhibitor, is no simple matter. There are many clinically relevant transporters, as many as nine to be evaluated for an FDA submission and up to eleven for the EMA as of 2013. Additionally, it is likely that if a compound is a substrate or inhibitor of one transporter, it will be so for other transporters as well. There are practically no specific substrates or inhibitors, presumably because the specificities of drug transporters are so broad and overlapping, and even fewer clinically relevant probes that can be used to evaluate transporter function in humans. In the case of some transporters, it is advisable to evaluate an NCE with more than one test system and/or more than one probe substrate in order to convince oneself (and regulatory authorities) that a clinical drug interaction study is not warranted. Finally, each test system has its own unique set of advantages and disadvantages. One has to really appreciate the nuances of the available tools (test systems, probe substrates, etc.) to select the best tools for the job and design the optimal in vitro experiment. In this chapter, several examples are used to illustrate the successful interpretation of in vitro data for both efflux and uptake transporters. Some data presented in this chapter is unpublished at the time of compilation of this book. It has been incorporated in this chapter to provide a sense of complexities in transporter kinetics to the reader.

Application of exogenous mixture of glutathione and stable isotope labeled glutathione for trapping reactive metabolites in cryopreserved human hepatocytes. Detection of the glutathione conjugates using high resolution accurate mass spectrometry.

Metabolites (including reactive metabolites) of troglitazone were generated by incubation with cryopreserved human hepatocytes and trapped in the presence of an exogenous mixture of unlabeled and stable isotope labeled (SIL: [1,2-(13)C, (15)N]-glycine) glutathione (GSH/SIL-GSH). The incubation samples were analyzed using liquid chromatography-high resolution accurate mass spectrometry (LC-HRAMS) implemented on a LTQ Orbitrap mass spectrometer. The GSH conjugates of the reactive metabolites were detected via a characteristic mono-isotopic pattern (peaks separated by 3.0037u). Analysis of the incubation samples led to detection of a number of previously described GSH conjugates, as well as two novel methylated GSH conjugates, which were partially characterized based on accurate mass measurements and MS/MS data. The addition of exogenous GSH led to an increase in the apparent level of detected GSH conjugates. Kinetic isotopic measurements showed that the rates of incorporation of exogenous GSH are conjugate-specific. In conclusion, this approach, based on the use of a mixture of GSH/SIL-GSH, allows facile capture and detection of reactive metabolites in human hepatocytes. Moreover, the data suggest that routine addition of glutathione to the assay medium may be advisable for experiments with cryopreserved hepatocytes.