Using mechanistic models to support development of complex generic drug products: European Medicines Agency perspective
2023; Nature Portfolio; Volume: 12; Issue: 5 Linguagem: Inglês
10.1002/psp4.12906
ISSN2163-8306
AutoresEfthymios Manolis, Alfredo García‐Arieta, Anders Lindahl, Evangelos Kotzagiorgis, Jobst Limberg, Øyvind Holte, Paulo Paixão, Carolien H.M. Versantvoort, Flora T. Musuamba, Kevin Blake, Michiel van den Heuvel,
Tópico(s)Innovative Microfluidic and Catalytic Techniques Innovation
ResumoCPT: Pharmacometrics & Systems PharmacologyEarly View PERSPECTIVEOpen Access Using mechanistic models to support development of complex generic drug products: European Medicines Agency perspective Efthymios Manolis, Corresponding Author Efthymios Manolis [email protected] European Medicines Agency, Amsterdam, The Netherlands Correspondence Efthymios Manolis, European Medicines Agency, Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands. Email: [email protected]Search for more papers by this authorAlfredo García-Arieta, Alfredo García-Arieta orcid.org/0000-0002-9702-6973 Spanish Agency of Medicines and Medical Devices, Madrid, SpainSearch for more papers by this authorAnders Lindahl, Anders Lindahl Swedish Medical Products Agency, Uppsala, SwedenSearch for more papers by this authorEvangelos Kotzagiorgis, Evangelos Kotzagiorgis European Medicines Agency, Amsterdam, The NetherlandsSearch for more papers by this authorJobst Limberg, Jobst Limberg Federal Institute of Drugs and Medical Devises, Bonn, GermanySearch for more papers by this authorØyvind Holte, Øyvind Holte Norwegian Medicines Agency, Oslo, NorwaySearch for more papers by this authorPaulo Paixao, Paulo Paixao INFARMED - National Authority of Medicines and Health Products, Lisbon, PortugalSearch for more papers by this authorCarolien Versantvoort, Carolien Versantvoort Medicines Evaluation Board, Utrecht, The NetherlandsSearch for more papers by this authorFlora Musuamba Tshinanu, Flora Musuamba Tshinanu Federal Agency for Medicines and Health Products, Brussels, BelgiumSearch for more papers by this authorKevin Blake, Kevin Blake European Medicines Agency, Amsterdam, The NetherlandsSearch for more papers by this authorMichiel Van Den Heuvel, Michiel Van Den Heuvel Medicines Evaluation Board, Utrecht, The NetherlandsSearch for more papers by this author Efthymios Manolis, Corresponding Author Efthymios Manolis [email protected] European Medicines Agency, Amsterdam, The Netherlands Correspondence Efthymios Manolis, European Medicines Agency, Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands. Email: [email protected]Search for more papers by this authorAlfredo García-Arieta, Alfredo García-Arieta orcid.org/0000-0002-9702-6973 Spanish Agency of Medicines and Medical Devices, Madrid, SpainSearch for more papers by this authorAnders Lindahl, Anders Lindahl Swedish Medical Products Agency, Uppsala, SwedenSearch for more papers by this authorEvangelos Kotzagiorgis, Evangelos Kotzagiorgis European Medicines Agency, Amsterdam, The NetherlandsSearch for more papers by this authorJobst Limberg, Jobst Limberg Federal Institute of Drugs and Medical Devises, Bonn, GermanySearch for more papers by this authorØyvind Holte, Øyvind Holte Norwegian Medicines Agency, Oslo, NorwaySearch for more papers by this authorPaulo Paixao, Paulo Paixao INFARMED - National Authority of Medicines and Health Products, Lisbon, PortugalSearch for more papers by this authorCarolien Versantvoort, Carolien Versantvoort Medicines Evaluation Board, Utrecht, The NetherlandsSearch for more papers by this authorFlora Musuamba Tshinanu, Flora Musuamba Tshinanu Federal Agency for Medicines and Health Products, Brussels, BelgiumSearch for more papers by this authorKevin Blake, Kevin Blake European Medicines Agency, Amsterdam, The NetherlandsSearch for more papers by this authorMichiel Van Den Heuvel, Michiel Van Den Heuvel Medicines Evaluation Board, Utrecht, The NetherlandsSearch for more papers by this author First published: 11 January 2023 https://doi.org/10.1002/psp4.12906 All authors contributed equally to the manuscript. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Model-informed drug development (MIDD) approaches receive wide regulatory acceptance in the European Medicines Agency (EMA) to support new drug development. For generic drugs, the European regulators have not reached a common position on how to use these methods. This commentary expands on the existing EMA regulatory framework for bioequivalence and physiological based pharmacokinetic (PBPK) modeling to propose conditions where mechanistic models could support or potentially waive clinical bioequivalence (BE)/bioavailability (BA) studies. SCOPE The focus is on the use of mechanistic models and specifically PBPK modeling in a complex generic drug development. The US Food and Drug Administration (FDA) defines complex generics as products that have complex active ingredients, formulations, dosage forms, or routes of administration or are complex drug–device combination products. An established definition is not available in the European regulatory system. Complex generics are submitted to the EMA as generic (e.g., systemically acting products such as long-acting injectables) or hybrid (e.g., locally acting products such as orally inhaled products or semisolid cutaneous products) applications under Article 10(1) or 10(3) of Directive 2001/83/EC as amended, respectively. Other MIDD approaches, such as virtual bioequivalence and population pharmacokinetic (PK) model-based bioequivalence, although relevant, are not elaborated in this article for the sake of brevity. PBPK REGULATORY FRAMEWORK The PBPK guideline1 represents the current thinking of the EMA on PBPK models. Regulators are more familiar with the use of PBPK in predicting drug–drug interactions (DDIs) and pediatric PK. The extent of PBPK modeling use is expanding in other areas, such as the setting of clinically relevant drug product specifications. However, there is still a limited number of real case studies where PBPK absorption models have been used in European Union regulatory submissions. The requirements for model reporting, evaluation, and qualification are highlighted in the guideline document. They follow a broader risk-based framework for model assessment, where models are graded as low, medium, or high impact according to the weight they carry in regulatory review and decision making.2 Recently, the credibility matrix was proposed to facilitate model evaluation.3 For high-impact PBPK models, which would be the case for the models expected to waive clinical PK BE studies, platform qualification is required. The EMA has not yet issued a public qualification opinion on a PBPK platform for a specific context of use. Nevertheless, PBPK models have had a high impact in regulatory review4 supported on a case-by-case basis by relevant data at submission, for example, for a new cytochrome P450 (CYP) 3A4 substrate investigational drug, it has been accepted to inform the label on the risk of DDIs with a moderate or weak CYP3A4 inhibitor based on a clinical DDI study with a strong inhibitor and PBPK modeling to simulate the clinically untested scenarios. BIOWAIVER (IN VITRO–BASED BIOEQUIVALENCE) The EMA recommendations for the need and design of human PK bioequivalence studies are summarized in several published guidelines,5-7 including the framework and conditions for waiving these studies. In the ICH M9 Guideline on Biopharmaceutics Classification System-Based Biowaivers,8 the Biopharmaceutics Classification System (BCS)–based biowaiver framework is defined. A biowaiver is applicable only for oral immediate-release drug products belonging to BCS Class I (high solubility and complete absorption) and BCS Class III (high solubility and limited absorption), meeting specific requirements on dissolution and excipient composition. In the Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms,6 the in vitro–in vivo correlation (IVIVC) framework is elaborated. For a biowaiver (in later stages of development or after authorization), a validated Level A correlation is generally a prerequisite. PBPK models are acknowledged in the guideline as one approach of IVIVC modeling. Emphasis is put on the model qualification, predictability assessment and reporting. The establishment of an IVIVC requires a thorough understanding of in vitro drug release and drug absorption in vivo. The same guideline examines different scenarios for bioequivalence assessment of prolonged release formulations. Safety (with regard to the conduct of the studies in healthy volunteers) and feasibility are additional factors to be considered, offering some flexibility regarding biowaivers. The guideline on the requirements for clinical documentation for orally inhaled products (OIP)9 describes a set of conditions that need to be met for basing the approval of an abridged OIP only on in vitro data as the first step of the European stepwise approach (in vitro [Step 1], pulmonary deposition [Step 2], and therapeutic equivalence studies [Step 3]) in contrast to the weight-of-evidence approach employed by the US FDA. These requirements are restrictive or overdiscriminative to ensure that those in vitro differences do not translate into relevant in vivo differences. The efficacy and safety of the medicinal product is conditional to the amount of active substance that reaches the lung and on the deposition pattern in the lungs. In addition, the safety will also be influenced by the rate and extent of systemic absorption from the lungs and the gastrointestinal tract. PBPK–BIOWAIVER FRAMEWORK PBPK models have several inherent characteristics that make them an attractive tool in support of PK BE/BA and biowaivers. For example, for orally administered products, they offer the possibility of predicting the rate and extent of systemic exposure by modeling absorption from the physiological gut compartment; describing distribution and elimination by mirroring relevant physiological processes such as blood flows and distribution in different organs or hepatic, renal, or other elimination routes; and combining systems knowledge, population characteristics, and product-specific in vitro/in vivo PK absorption, distribution, metabolism, and excretion data.10 They provide an intermediate step between an in vitro biowaiver and a clinical PK BE study to assess BE. The narrow scope of BCS-based biowaivers could be widened to more BCS subclasses (e.g., IIa) or to accept larger dissolution differences (e.g., for BCS Class III drugs) if this is supported by fit-for-purpose PBPK models with physiologically relevant in vitro dissolution testing/parameters. For the regulatory acceptance of such models to support a biowaiver, model/PBPK platform qualification would be necessary. In addition to the demonstration of the predictive performance of the model for the PK of drug substance/formulation, the applicant should demonstrate consistency of predictions (BE, no BE) between the PBPK platform and the in vivo BE in a safe space that encompasses the physicochemical and formulation properties of the two products to be compared. Likewise, PBPK coupled with computational fluid dynamics models offer the possibility to characterize all the processes from aerosolization to lung deposition and systemic PK. Thus, they can be valuable tools in the assessment of the BE of inhaled products. When these models are used for high regulatory impact applications, for example, to widen in vitro acceptance criteria (Step 1) and thus waiving drug deposition (Step 2) and therapeutic equivalence studies (Step 3), model/platform qualification is needed. For this qualification, predictive performance of the platform compared with in vivo data should be demonstrated in a safe space defined by, for example, different types of dosage forms/devices (dry powders/pressurized metered dose inhalers and solutions/suspension for nebulization) and substances with different physicochemical and absorption properties. The requirements in terms of numbers of experiments and acceptance criteria for the evaluation of the predictive performance of the drug/formulation model and for platform qualification in the context of waiving a BE study have not been fully established. The qualification of a PBPK platform to support a biowaiver may be seen as a high hurdle to overcome in a setting where a clinical PK BE study is easily done and can provide an undisputed answer. This speaks for the need of a collaborative effort instead of stand-alone submissions and for a shift of the focus to a more integrated regulatory setting. For complex generics, clinical PK BE/BA studies may be challenging or not fully informative, for example, systemic PK BE for a locally applied/acting product if the absorption into systemic circulation does not occur from the site of action or if the absorption from the site of action is saturated. In these cases, PBPK and other models can offer valuable solutions. Of note, the use of physiologically based biopharmaceutic modeling (PBBM) to support formulation development and internal decision making is not considered a high-impact application for regulators and as such not subject to the same scrutiny as in the case of biowaiver. CONCLUSIONS The EMA's experience in assessing PBPK approaches to support or even waive BE is limited, but there is a willingness to engage in a discussion regarding the utility and qualification of these models. As a first step, it is recommended to focus on a clinical setting where regulators would likely be more open in accepting model-based BE (MBBE), that is, where clinical PK BE studies are hindered by feasibility constrains or are not fully informative. The EMA qualification procedure11 represents a suitable forum to drive regulatory requirements and acceptance forward. The topic of MBBE is already on the radar of European regulators and of the newly formed methodology working party in particular. The EMA, with the aim to build expertise and achieve consensus on the use of PBPK absorption models, joined an IQ Consortium collaboration initiative on PBBM with other regulatory agencies. Where there is a will, there is a way! FUNDING INFORMATION The authors received no funding for this work. CONFLICT OF INTEREST The authors declared no competing interests for this work. DISCLAIMER The article reflects the personal views of the authors and does not represent the official position of the European Medicines Agency or its committees and working parties. REFERENCES 1 Committee for Medicinal Products for Human Use (CHMP). Guideline on the reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation. EMA/CHMP/458101/2016. 13 December 2018. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation_en.pdf. Accessed November 14, 2022. 2Manolis E, Rohou S, Hemmings R, Salmonson T, Karlsson M, Milligan P. The role of modeling and simulation in development and registration of medicinal products: output from the EFPIA/EMA modeling and simulation workshop. 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