Activity and perspective on quantitative modeling and simulation in Japan: Update from the Pharmaceuticals and Medical Devices Agency

Abstract

JFY, Japanese fiscal year; NDAs, new drug applications; NMEs, new molecular entities; PPK analysis, population pharmacokinetic analysis; PPK/PD (ER) analysis, population pharmacokinetic/pharmacodynamics analysis or exposure-response analysis; PBPK modeling: physiologically-based pharmacokinetic modeling In Japanese Fiscal Year (JFY) 2020, reports on PPK and PPK/PD or ER analyses were submitted for ~70% (29/43) and 50% (22/43) of NMEs, respectively. [...]empirical models, such as PPK, PPK/PD, and ER analysis, are generally used for drug development, indicating their new role as an essential tool for NDAs in Japan. The change in the frequency of submission of PBPK modeling in Japan indicates a trend similar to that observed in the US Food and Drug Administration (FDA) report on the utilization of PBPK modeling in NDAs in the United States. 3 M&SPT IN PMDA The PMDA launched the M&SPT in April 2016 to address the increasing number of M&S submissions in recent years and is strengthening the framework for using and sharing knowledge and experience with M&S. Currently, the M&SPT supports the scientific assessment and decision of each product with the review team, internally sharing the knowledge and experience and external communication of M&S, and cooperating with overseas agencies. 10 These guidelines serve as a common communication tool among pharmaceutical companies and Japanese regulatory agency and are expected to facilitate the appropriate utilization of M&S in drug development in Japan. The PMDA has been promoting the utilization of M&S in drug development in Japan through various activities, including M&SPT. [...]capacity building to assess and utilize M&S needs to be maintained and expanded in the PMDA, and international harmonization should be promoted in the future.

Quantitative modeling and simulation (M&S) have become increasingly important in drug development worldwide. The number of M&S applications submitted to the regulatory agency in Japan is steadily growing. In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) promotes the utilization of M&S in drug development by supporting the review team provided by the modeling and simulation project team (M&SPT), international harmonization through activities via the International Conference on Harmonization (ICH), and the development of local M&S-related guidelines.

BACKGROUND

In recent years, M&S has gained considerable attention in drug development. M&S involves development of mathematical model relevant to pharmacokinetics (PKs), pharmacological response, and efficacy or safety data relationships to inform study designs when study designs and/or the optimal dosage and administration are considered and estimates the progress from drug administration to the onset of clinical efficacy. In Japan, the M&S results have been increasingly utilized as the rationale for optimal drug dosing and M&S results support safe use instructions in package inserts for new drug applications (NDAs). We previously reported the status of M&S applications (population analysis and physiologically-based pharmacokinetic [PBPK] modeling) submitted to the regulatory agency in NDAs in Japan.^1,2

In this paper, we introduce the updated status of M&S applications in Japan. Additionally, we detail the current status of M&SPT activities that support the resolution of M&S-related issues and international harmonization activities within the PMDA.

M&S SUBMISSION IN JAPAN

Regarding the utilization of M&S in NDA documents for new molecular entities (NMEs) submitted to the PMDA, the NDA documents for approved NMEs (288 cases) were investigated in terms of population analysis (population pharmacokinetics [PPKs], population pharmacokinetics/pharmacodynamics [PPK/PDs], and exposure-response [ER] analyses), and PBPK modeling between April 2014 and March 2021 (Figure 1).

In Japanese Fiscal Year (JFY) 2020, reports on PPK and PPK/PD or ER analyses were submitted for ~70% (29/43) and 50% (22/43) of NMEs, respectively. Thus, empirical models, such as PPK, PPK/PD, and ER analysis, are generally used for drug development, indicating their new role as an essential tool for NDAs in Japan.

PBPK modeling was performed for ~10% of the NMEs from JFY 2014 to JFY 2017. PBPK modeling has gained momentum since JFY 2018, increasing to ~25% of NDAs from JFY 2019 to JFY 2020 (9/36 in JFY 2019 and 10/43 in JFY 2020). It should be noted that modalities other than low-molecular-weight compounds, such as biologics, were included in this percentage. When limited to small molecules, the percentage from JFY 2019 to JFY 2020 was ~40% (9/25 in JFY 2019 and 9/23 in JFY 2020). PBPK modeling is more commonly used for small molecules at the NDA proposal. This is probably because PBPK modeling is now widely utilized to predict drug–drug interactions. The change in the frequency of submission of PBPK modeling in Japan indicates a trend similar to that observed in the US Food and Drug Administration (FDA) report on the utilization of PBPK modeling in NDAs in the United States.³

M&SPT IN PMDA

The PMDA launched the M&SPT in April 2016 to address the increasing number of M&S submissions in recent years and is strengthening the framework for using and sharing knowledge and experience with M&S. Currently, the M&SPT supports the scientific assessment and decision of each product with the review team, internally sharing the knowledge and experience and external communication of M&S, and cooperating with overseas agencies. The review team requests the M&SPT to support evaluating adequacy of modeling strategy, verification and validation (V&V) of the model, and simulation scenarios.

The M&SPT has addressed more than 150 M&S applications between JPY 2016 and JPY 2020; the details are shown in Figure 2. M&SPT supports the assessment of M&S applications for individual products based on the request of the review team (i.e., it does not support the assessment of all M&S applications). In the credibility assessment of M&S applications, the M&SPT primarily assesses the validity and results of the V&V plan, and the review team reaches a final decision on the acceptability of M&S.

Approximately two-thirds of the support for the M&SPT for assessing individual products was provided during the clinical trial consultation. The most common objective of M&S is dose finding/setting especially for phase III trials and drug applications, followed by the assessment of QT-prolongation risk, drug–drug interactions, and utilization in pediatric drug development. Regarding the model type, the number of requests for support for PBPK modeling and concentration-QTc (C-QTc) modeling was similar to that for PPK and ER analyses. The absolute number of PBPK modeling and C-QTc modeling to be submitted at NDA submission was smaller than that of the PPK and ER analyses. Nevertheless, the number of requests for support was similar. This can be explained by the high percentage of requests for supporting when PBPK modeling and C-QTc modeling were submitted. The review team seemed to utilize the support of the M&SPT when relatively new and less-experienced techniques were used. This information suggests that the M&SPT plays a pivotal role in addressing the utilization of relatively new techniques in the PMDA, and this activity of the PMDA plays an important role in promoting the utilization of M&S in drug development in Japan.

The FDA and European Medicines Agency (EMA) have proposed a framework for the credibility assessment of model-informed drug development (MIDD) based on the American Society of Mechanical Engineers (ASME) V&V 40.^4,5 The support of the M&SPT enables the assessment of M&S using the latest M&S-related knowledge, such as incorporating the concept of risk-informed model credibility assessment with reference to V&V 40.

INTERNATIONAL COLLABORATIONS

International harmonization through activities such as the ICH of Technical Requirements for Pharmaceuticals for Human Use is an important activity related to international collaboration. In the ICH, the E11A (pediatric extrapolation), the M12 (drug–drug interactions), and the M15 (general considerations MIDD) guidelines discuss issues related to M&S.⁶ The PMDA experts also participate in discussing guidelines regarding these topics and promoting the international harmonization of important topics in drug development using M&S.

In addition, a cluster meeting on pharmacometrics is held as an activity related to international collaborations.⁷ The PMDA, the FDA, the EMA, Health Canada, and the Therapeutic Goods Administration participate in meetings and hold web meetings four times annually. The purpose of these meetings is to discuss best practices and product development matters concerning pharmacometrics (M&S) and to exchange information and perspectives on pharmacometrics, including guidelines, workshops, publications, and products under parallel assessment.

DISCUSSION

The FDA and the EMA have developed guidance or guidelines related to M&S. Guidelines for M&S have also been developed for Japan. The Japanese regulatory agency has published general matters that remain scientifically valid in accordance with three guidelines released from 2019 to 2020: “Guideline on population pharmacokinetic and pharmacodynamic analysis,”⁸ “Guideline for exposure-response analysis of drugs,”⁹ and “Guidelines for analysis reports involving physiologically based pharmacokinetic models.”¹⁰ These guidelines serve as a common communication tool among pharmaceutical companies and Japanese regulatory agency and are expected to facilitate the appropriate utilization of M&S in drug development in Japan.

The importance of international harmonization will continue growing, considering that the topic of the MIDD has been considered as M15 in ICH, and the framework for credibility assessment of MIDD based on the ASME V&V 40 has been proposed by the FDA and the EMA.

The PMDA has been promoting the utilization of M&S in drug development in Japan through various activities, including M&SPT. Moreover, capacity building to assess and utilize M&S needs to be maintained and expanded in the PMDA, and international harmonization should be promoted in the future.

ACKNOWLEDGMENTS

The authors thank all the M&SPT members.

FUNDING INFORMATION

No funding was received for this work.

CONFLICT OF INTEREST

The authors declared no competing interests for this work.

DISCLAIMER

The views presented in this paper are those of authors and do not necessarily reflect the official position of the Pharmaceuticals and Medical Devices Agency.