Application of Model-informed Drug Development (MIDD) in Regulatory Submissions for Drug Approval in Japan

doi:10.21203/rs.3.rs-4615728/v1

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Application of Model-informed Drug Development (MIDD) in Regulatory Submissions for Drug Approval in Japan

https://doi.org/10.21203/rs.3.rs-4615728/v1

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Model-informed drug development (MIDD) is an approach to improve the efficiency of drug development. To promote awareness and application of MIDD in Japan, the Data Science Expert Committee of the Drug Evaluation Committee in the Japan Pharmaceutical Manufacturers Association established a task force, which surveyed MIDD applications for approved products in Japan. This study aimed to reveal the trends and challenges in the use of MIDD by analyzing the survey results.

A total of 322 cases approved in Japan between January 2020 and March 2022 as medical products were included in the survey. Modeling analysis was performed in approximately half of the cases (47.8% [154/322]) and formed a major basis for the selection or justification of dosage and administration in approximately one-fourth of the cases [24.2% (78/322)]. Modeling analysis/model-based dose selection was frequently conducted in cases involving monoclonal antibodies, first indication, orphan drugs, and multi-regional trials. Moreover, the survey results indicated that modeling analyses contributed to dose optimization throughout the developmental phases, including changing dose levels from phase II to phase III and dose adjustment in special populations. Japanese data were included in most cases in which modeling analysis was used for dosage selection. Thus, modelling analysis may also address ethnic factors introduced in the ICH E5 and/or E17 guidelines. In summary, this survey is useful for understanding the current status of MIDD use in Japan and for future drug development.

MIDD

Japan

JPMA

dose selection

pharmacometrics

According to the Japan Pharmaceutical Manufacturers Association (JPMA) survey (2003–2022), the probability of successful drug development is low and worsening further, at approximately 1/20,000–1/30,000 as a proportion of regulatory approved/synthesized compounds [1]. The median drug development costs and clinical development periods reported are $1141.7 million (2009–2018) [2] and 8.3 years (2010–2020) [3], respectively. Therefore, the efficiency and probability of successful drug development must be improved. Model-informed drug development (MIDD) is an approach used to address these challenges. MIDD is a development strategy involving mathematical modeling to characterize the relationships among pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety endpoints, thereby providing information and guiding quantitative decision-making in drug development. MIDD consists of repeated “Learning and Confirming” steps during the various phases of drug development, including the non-clinical stage, to collate the various information and improve the prediction accuracy of the model as drug development progresses [4–6]. The resulting aggregated information is used for decision making with quantified uncertainty.

Although the use of MIDD has been advocated after the year 2000 [5, 6], the pharmaceutical industry and regulatory agencies have recently made attempts to accelerate its use. In 2016, the European Federation of Pharmaceutical Industries and Associations (EFPIA) issued a “Model-informed Drug Discovery and Development” white paper [4], systematically summarizing more than 100 cases in each phase of drug development, from the non-clinical to the post-marketing period. The US Food and Drug Administration (FDA) adopted MIDD as an activity for the Prescription Drug User Fee Act (PDUFA) VI (2018–2022) [7] and implemented a pilot program for MIDD-paired meetings, a consultation dedicated to MIDD [8]. This program will continue in the subsequent years of PDUFA VII (2023–2027) [9], promoting collaboration between sponsors and agencies on the use of MIDD from an early stage of development. In Japan, guidelines related to MIDD, such as population PK/PD, exposure-response (E-R), and physiologically based pharmacokinetic (PBPK) modeling analyses, were issued in 2019–2020 [10–12]. The Japanese regulatory agency, Pharmaceuticals and Medical Devices Agency (PMDA) sponsored MIDD workshops and introduced trends in MIDD use for approved products in Japan [13]. In addition, international harmonization was initiated, and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) adopted MIDD as M15 in 2022 [14], and published a concept paper [15], business plan [16], and work plan [17].

Recently, high-impact utilization such as using model-based simulations has been reported instead of conducting clinical trials for drugs requiring urgent development [e.g., drugs for coronavirus disease (COVID-19) [18]] or those for which it is difficult to obtain actual clinical data (e.g., pediatric patients with rare diseases [19]). In addition, MIDD is expected to associate with several emerging areas, such as real-world evidence (RWE), quantitative systems pharmacology (QSP), machine learning, and artificial intelligence (AI) [9, 20].

However, there is a limited report which systematically summarizes the application of MIDD on drug development in Japan. To promote MIDD in Japan, the Data Science Expert Committee of the Drug Evaluation Committee of the JPMA established a task force in spring of 2022. This task force surveyed MIDD applications for approval products in Japan from various perspectives, such as drug characteristics, therapeutic areas, and the presence of data from Japan to capture the trends and challenges in applying MIDD to drug development in Japan. Additionally, case studies of unique applications have been discussed.

Approval cases in Japan between January 2020 and March 2022 as medicinal products were investigated based on published assessment reports and submission dossiers (i.e. common technical document) available on the PMDA website (https://www.pmda.go.jp/PmdaSearch/iyakuSearch/). Cases of PBPK modeling from special populations/drug interactions were excluded from the survey. In the absence of sufficient information on the PMDA website, we investigated other data sources, such as published articles, assessment reports by other regulatory agencies [the European Medical Agency (EMA) and FDA], and submission dossiers available on the Health Canada website.

The following information was obtained for all cases surveyed:

Mode of action (MoA)
First-in-class (FIC) or not
Drug modality
Therapeutic area
Indication
First indication or not
The presence of any special notices related to the approval (e.g., priority reviews, orphan drugs)
Existence of multi-regional clinical trials (MRCTs) in the clinical data package

The following data were collected for each approval case to identify whether several modeling analyses were included in a single approval case (e.g., dose selection or justification for the proposed dose).

Any modeling analyses performed
Development phase
Rationale for dose selection for the next phase
Number of doses selected

In addition, for cases in which modeling analyses were performed, the following additional information was obtained.

Any dose selection and/or dose modification using the model
Purpose of the modeling analysis
Data used for the modeling analysis
The kind of modeling analysis performed
Conclusions of the modeling analysis
The application of the modeling analysis in drug development
The inclusion of Japanese data in the modeling analysis
Any mitigation undertaken in the absence of Japanese data in the modeling analysis
The presence of modeling results specific to Japanese patient and its potential discussion (e.g., higher exposure in Japanese patients than that in patients from other regions)
Comments from regulatory authorities

Using the survey results, the following metrics were calculated overall and for each category:

$$Percentage of modelling analyses performed \left(PMAP\right)=100\times \frac{number of cases with any kind of modeling analysis conducted}{total number of cases}$$ $$Percentage ofdose/dosageselection by modelling analysis \left(PDSM\right)=100\times \frac{number of cases withdose/dosageselection by modeling analysis}{ total number of cases}$$

PMAP is a measure that conveys whether modeling supports approval, and PDSM is a measure that conveys whether modeling plays a critical role in dose/dosage selection.

Major categories investigated with the corresponding hypothesis are summarized as follows:

Drug modality: Drug modalities with a clear target/MoA [e.g., monoclonal antibody (mAb) showed higher PMAP/PDSM than those of other modalities].
FIC or not: Non-FIC cases showed higher PMAP/PDSM than those of FIC cases because data and models from other similar drugs could be (re-)used for modeling.
First indication: Non-first indication drugs showed a higher PMAP/PDSM than that of first indication drugs, because data from first indication can be utilized for modeling.
Clinical data package: The data package with MRCTs showed higher PMAP/PDSM than those for cases without MRCTs, as the effect of intrinsic and extrinsic factors may have to be investigated via modeling for dose selection.
Development Phase: Study in early development phase shows higher PDSM due to its exploratory nature of the study.
Therapeutic areas: Infectious diseases, oncology, immunology, cardiovascular, and metabolic diseases show higher PMAP/PDSM than those of other therapeutic indications.
- PK/PD is relatively established and well recognized by stakeholders (infectious diseases)
- Target and MoA are clear (oncology and immunology)
- Data from competitors are available; thus, constructing and accessing platform models, such as disease progression models (metabolic and cardiovascular diseases), are relatively easy.

In addition, we surveyed modeling cases for dose setting and categorized them into the following four groups: (i) cases where different dosages and administrations were applied between phase II and phase III studies, (ii) cases where different dosages and administrations were recommended for new drug applications (NDAs) from those in the phase III study, (iii) cases where the validity of dose selection was explained primarily using modeling works without conducting formal proof-of-concept (PoC) and/or dose-finding studies, and (iv) cases where MIDD was applied for dose adjustment in special populations.

Graphical and other analyses were performed using Microsoft® Excel® for Microsoft 365 or R version 4.3.1 (https://cran.r-project.org/).

Overall Analysis

A total of 322 cases were approved in Japan between January 2020 and March 2022 as medicinal products. Table 1 summarizes the background information of the analyzed cases. Majority of the modalities considered were small molecules, followed by mAbs, other biologics, and other modalities. Of these, 83 cases (25.8%) were classified as FIC and 127 cases (39.4%) were approved as the first indication. Regarding therapeutic areas, oncology (solid) was prevalent as a single therapeutic area, followed by immunology, and oncology (non-solid).

Figure 1 shows the overall PMAP and PDSM. Modeling analysis was performed in approximately half of the cases (47.8%), and approximately one-fourth of the cases (24.2%) involved changes in the dosage and administration based on modeling analysis. Among the 154 cases in which model analysis was performed, dose selection/modification was performed in approximately half (50.6%) of the cases using modeling analysis.

Drug Characteristics/Therapeutic Areas

Table 2 summarizes the PMAP and PDSM stratified by the prespecified categories (see METHODS). The PMAP and PDSM were higher in FIC cases than those in non-FIC cases. In addition, PMAP and PDSM were higher in cases as the first indication than those in cases that did not qualify as the first indication. Cases with MRCTs showed remarkably higher PMAP and PDSM than those for cases without MRCTs.

Figure 2 shows the PMAP and PDSM according to drug modality and therapeutic area. PDSM values were higher in mAbs than those in small molecules or other biologics. Regarding therapeutic areas, while the number of cases was limited, the central nervous system (CNS) drugs showed the highest PMAP and PDSM values, followed by those in metabolic disease and oncology (solid).

A total of 73 (22.7%) orphan drug designations were included in the survey. Orphan diseases showed higher PMAP and PDSM values [PMAP = 58.9% (43/73), PDSM = 28.8% (21/73)] than those for non-orphan diseases [PMAP = 44.6% (111/249), PDSM = 22.9% (57/249)]. Figure 3 shows the acceptability of dose selection by the regulatory agency using modeling analysis. The percentage of regulatory acceptability of dose selection using modeling analysis was marginally higher in cases for treating orphan diseases [Yes + partially Yes = 74.1% (20/27)] than those in cases for non-orphan diseases [55.3% (42/76)].

Development Phase

The PDSM during the developmental phase is summarized in Figure 4. Model-based dose selection was more likely to be reported in the dose recommendation/justification for NDA (end of phase III) than that in the dose findings for the phase III study (end of phase II).

Model-informed dose selection: Proposed different dose regimens for a phase III study from those in the phase II study

In six cases of the survey, phase III studies were conducted at dosage regimens different from those in the phase II study. All these cases were approved by Japanese authorities. Table 3 shows the details for each case (semaglutide, rabrizumab, galcanezumab, belotralstat hydrochloride, gefapixant citrate, and nemolizumab). Overall, different types of dose selections were observed, such as the selected dose within the range of dose levels tested in the phase II study, meeting PK/efficacy and PK/safety targets, transition from a fixed-dose regimen (mg/body) to a weight-band dose (mg/kg) and vice versa, and application of the loading dose.

Model-informed dose selection: Proposed different dose regimens for NDA from those in phase III study

A total of 11 cases were identified from the survey results in which MIDD was applied to recommend a different dose regimen for NDA in a phase III study (Table 4). Of the 11 cases, seven were accepted by the Japanese authorities, among which six involved dose modifications based on exposure matching, which is relatively straightforward for explaining similar efficacy or safety even with dose modification. The one remaining case was that of fremanezumab for chronic migraine, in which a loading dose of 675 mg was judged unnecessary from the E-R analysis after the phase III study. Meanwhile, of the 11 cases, four were not accepted by the Japan authorities, although the dose modification of paliperidone palmitate was accepted in the United States. No specific/common reason(s) of “unacceptance” could be identified for any of the four cases. The four unaccepted cases also included those in which exposure matching was applied. The reasons for unacceptance were presumably related to the lack of investigation of the modified dose regimen in clinical trials (paliperidone palmitate, simapacitan, and molidustat sodium) and the benefit of no dose modification for proper use (paliperidone palmitate) or early induction of remission (paliperidone palmitate).

Dose selection using modeling works without conducting PoC and/or dose-finding studies

In two cases, the validity of dose selection was explained by the results of the model analysis in the absence of formal PoC and dose-finding studies. Table 5 lists the key points of MIDD in each case .

Model-informed dose adjustments for special populations

In nine cases, population PK and E-R analyses were used to adjust the dosage in special populations. Weight-based dosage adjustment for pediatric patients was the most frequently used method (four/nine cases, details are avaialble on Table 6).

Presence of Japanese Data

Figure 5 presents the percentage of cases, including Japanese data in the submission dossiers, that involved at least one modeling analysis for dosage selection. Overall, Japanese data were included in 84.6% (66/78) of the cases. Most cases without Japanese data aimed at selecting the dose/dosage for subsequent clinical trials, including Japanese participants (i.e., dose selection for phase II or phase III studies) based on data from studies without Japanese data. One case without Japanese data was used for selecting the dose for approval (lasmiditan); however, this was considered as an exception because PK sampling was not feasible owing to the dosage (administered only when a migraine attack occurred). The other exceptional case demonstrated exposure similarity among different doses/dosages (25 mg once daily vs. 50 mg once in two days) in public knowledge-based applications, and no additional clinical study was conducted (clomiphene). The remaining 10 cases involving modeling analysis without Japanese data provided a major rationale for dosage selection in the Japanese population (Table 7).

In this study, a survey of MIDD utilization revealed that modeling analysis supported approximately half of the approved cases. Regarding the new molecular entities (NME: referred to as cases with first indication), the number of approval products with modeling analysis per year from April 2014 to March 2021 have been reported by Kijima et al [21]. The reported numbers (approximately 60–80% each year for NME) are consistent with our cases with first indication (62.7%). We further investigated the numbers (including those for NME) from several product backgrounds and investigated how the modeling analysis contributed to dose/dosage selection as a PDSM. In approximately one-fourth of all the approved cases, modeling analysis was the major basis for dose/dosage selection. Considering that several (mainly exploratory) modeling analyses were performed but not reported in the assessment reports or submission dossiers, the percentage shown here should be treated as the minimum number of actual uses of modeling analysis.

Among the different modalities, mAbs showed higher PMAP and PDSM values than those for other modalities. This is reasonable because the MoA is relatively clear for mAbs, and MIDD integrates various information, including the drug MoA, to enhance model reliability. MIDD could be potentially used for a drug of non-FIC or non-first indication depending on the availability of information from other drugs with the same MoA or from data obtained in the development of prior indications. However, this hypothesis was contradicted by the survey results (PMAP and PDSM values were marginally higher in the FIC/first indication). One possible explanation could be that modeling work was more relied on in the absence of rich data in FIC/first indications. Among the FIC cases for which the dose/dosage was selected based on modeling, QSP was utilized in two cases (Nirmatrelvir [18] and Olipudase Alfa [22]; none of the non-FIC cases used QSP). This may be attributed to the high affinity of QSP for FIC drugs with new MoAs. QSP can be used not only to determine dose/dosage for clinical trials but also to confirm the drug target, identify the MoA, and explore biomarkers [23]. In addition, even when data from clinical trials are lacking, data from nonclinical in vitro and in vivo studies can be directly used to set parameter values in QSP models [24]; however, the credibility of such models needs to be carefully assessed depending on the context of use [25–27]. There was one case of non-FIC in which the dose/dosage of the phase II trial was selected by applying a model-based meta-analysis using the published data of other drugs (Tildrakizumab) [28].

In terms of the therapeutic area, the original hypothesis was that MIDD is most likely applicable to the areas of infectious diseases, oncology, immunology, cardiovascular diseases, and metabolic diseases. In these areas, the application of PK/PD is relatively established and well-recognized by stakeholders (e.g., infectious diseases), the MoA is clear (e.g., oncology and immunology), and constructing and accessing platform models such as disease progression models (e.g., metabolic and infectious diseases) are comparatively simple. Although metabolic diseases constituted a high proportion, the overall percentage did not differ greatly from that of infectious diseases, immune diseases, and oncology. Contrary to the original speculation, PMAP and PDSM values were remarkably high for CNS drugs, despite the limited number of cases (23). CNS drugs include anti-epileptic/psychiatric medications, which are often administered as part of a combination therapy, and drug interactions are often a clinical issue [29, 30]; hence, dosage adjustment based on modeling analysis might be performed more frequently.

The use of modeling tended to be more frequent for orphan diseases than that for non-orphan diseases, and the analysis results tended to have higher regulatory acceptance. This observation could be attributed to the following reasons. 1) In some orphan diseases, the relationship between the target disease and treatment is straightforward, and, therefore, model development using biomarkers based on the MoA is relatively easy. 2) Actual clinical data is difficult to obtain owing to the limited number of patients. Although not included in this survey, in some cases, the dose was selected by simulation-based extrapolation (Burosumab [31]) for the younger age group (< 1 year of age), which has not been investigated in clinical trials. Additionally, there were cases in which biomarker results have been used as confirmatory evidence of efficacy based on the exposure-biomarker relationship analysis (Fosdenopteri [32]). In addition, some studies attempted to optimize clinical trial design by analyzing the real-world data at the literature level [20, 33]. Thus, MIDD may contribute more to orphan diseases than to non-orphan diseases [34]. Early patient access to innovative drugs is strongly desired globally, and drug lag or drug loss has been discussed for a long time in Japan [35]. Considering the difficulty in obtaining actual clinical data of patients with orphan diseases, MIDD could be an approach to accelerate patient access where limited data are available based on scientifical justifications.

MRCTs have been used globally for the simultaneous development of drugs in different regions. This survey suggested that cases with MRCTs showed a remarkably high percentage of use of modeling analyses. In development programs using MRCTs, new drug applications are often submitted to more than one region based on the same or very similar clinical data package; thus, dose selection needs to be investigated considering the effects of intrinsic and extrinsic factors, which can be addressed using MIDD.

In addition, in the development program with MRCTs, the dosage and administration in Japan are usually based on (direct or indirect) ethnic factors and the evaluation of data outside Japan, as well as those obtained in Japan. Therefore, the presence of Japanese data in the modeling analysis was investigated. Most model analyses included Japanese data for dose selection. Even if Japanese data were not included in the modeling analysis, ethnic differences in PK were evaluated by comparing the phase I results directly between Japanese and non-Japanese participants in most cases and/or by conducting population PK analysis, inclusive of Japanese participants, after phase III studies separately from the model analysis for dose selection. Some other frameworks may involve the application of ICH E5 (i.e., a bridging strategy) [36] or E17 guideline [37]. In the case of ICH E17, exploring effect modifiers (i.e., covariates which would cause apparent ethnic differences) is crucial. MIDD will therefore have an important role in completing the framework. Iwasa et al. reported a model-informed dose justification for the use of the antifungal compound, posaconazole in Japanese patients [38]. They developed a population PK model for posaconazole and identified body weight and age as the primary contributors to posaconazole exposure. In a clinical study, Japanese patients showed higher exposure to posaconazole (approximately 2.5-fold higher than that in other populations), and the covariates identified in population PK analysis explained the higher observed exposures in Japanese patients. They also reported no major safety concerns in Japanese patient, based on E-R analysis. This information justified the use of the same dosing regimen in Japanese patients as in foreign patients.

The PDSM was higher for the dose recommendation/justification for NDA (end of phase III) than that in the dose findings for the phase III study (end of phase II). However, the value at the end of phase II might be underestimated as the rationale of the dose selection for phase III is less often discussed in CTDs and review reports.

Regarding the development phase, we surveyed modeling cases for dose setting and categorized them into the i to iV categories (See METHODS). This survey revealed that MIDD contributed to dose optimization throughout the developmental phases, including when using doses different from those of the previous phase (categories i–iii) and dose adjustment in special populations (category iv). For (i), as all the six submitted cases were accepted by the Japanese authorities, model-informed dose selection would be acceptable to propose different dose regimens for a phase III study from those in the phase II study during drug development in Japan. For (ii), only seven of the 11 cases were accepted by the Japanese authorities. Common factors could not be identified in the remaining four unaccepted cases; however, unacceptance was attributed to the lack of investigation of the modified dose regimen in clinical trials for three of the four cases. This indicates that proposing different dose regimens for NDA from those in the phase III study is more difficult than proposing different dose regimens for a phase III study from those in the phase II study. For (iii), there were only two cases; however, it is suggested that under special conditions (e.g. rare diseases and special approval), such limited clinical data could be mitigated with model-informed results. Cases of MIDD application in the absence of PoC and/or dose-finding studies were identified for an orphan drug and a product with urgent approval for which data acquisition by clinical studies was considered difficult. These two cases involved relatively well-established PD markers (B cells and viral load), which may be one of the reasons for accepting dose-finding via modeling analysis. Thus, depending on the status/circumstance of the drug candidates of interest, model analyses may be more acceptable for providing key information or even an alternative to dose-finding studies.

This survey provided organized information on the application of MIDD on drug development in Japan. MIDD plays a key role in cases where the MoA is clear (mAbs), obtaining actual data is challenging (orphan drug designation), and dose setting is complicated (e.g., package with MRCTs). Also, the application of MIDD at each development phase is well characterized. The limitation of this study is that the survey is only subjected to approvals of approximately two years in Japan. Thus, further investigation using upcoming cases could support our findings. MIDD applications incorporating new technologies such as machine learning, AI, and RWE is also anticipated, although no such cases were included in this survey, requiring further progress in MIDD utilization for drug development.

A survey on the utilization of MIDD was conducted for 322 cases approved in Japan from January 2020 to March 2022 as medicinal products. Approximately half of the approved cases were supported by modeling analysis, and in approximately one-fourth of the approved cases, this was the major basis for dose/dosage selection. Modeling analysis/model-based dose selection was frequently conducted in cases involving mAbs, first indication, orphan drug designation, and MRCTs. Moreover, the survey results indicated that modeling analyses contributed to dose optimization throughout the developmental phases, including changing dose levels from phase II to phase III and dose adjustment in special populations. Japanese data were included in most cases in which modeling analysis was used for dosage selection. This survey provided organized information on the application of MIDD on drug development in Japan and could be useful for planning future drug development strategy.

Author Contribution

T.S and T.K wrote the main manuscript text and prepared figures and tables. All authors reviewed the manuscript.

Acknowledgement

We would like to thank Honyaku Center Inc. for English language editing.

CONFLICT OF INTEREST

The authors have no competing interests to declare. All authors are employees of the organizations listed in the author affiliations.

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Tanaka M, Idei M, Sakaguchi H, Kato R, Sato D, Sawanobori K et al (2021) Evolving landscape of new drug approval in Japan and lags from international birth dates: Retrospective regulatory analysis. Clin Pharmacol Ther 109:1265–1273
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Iwasa T, de Almeida C, Fauchet F, Winchell GA, de Greef R, Hasegawa C et al (2023) Model-informed dose justifications of posaconazole in Japanese patients for prophylaxis and treatment against fungal infection. J Clin Pharmacol 63:421–434

Table 1 Background Information for the Analyzed Data

Metrics	Category	Number of Cases (%)
Total	-	322 (100%)
Drug Modality	Small Molecule	169 (52.5%)
	Monoclonal Antibody	78 (24.2%)
	Other Biologics¹	54 (16.8%)
	Others	21 (6.52%)
First-in-class	Yes	83 (25.8%)
First-in-class	No	239 (74.2%)
First Indication	Yes	127 (39.4%)
First Indication	No	195 (60.6%)
Therapeutic Area	Oncology (Solid)	77 (23.9%)
	Oncology (Non-solid)	30 (9.32%)
	Immunology	43 (13.4%)
	Infectious Disease	26 (8.07%)
	Central Nervous System Disease	23 (7.14%)
	Cardiovascular/renal Disease	20 (6.21%)
	Metabolic Disease	17 (5.28%)
	Respiratory Disease	4 (1.24%)
	Others	82 (25.5%)
Special Notices	Orphan Drug Designation	73 (22.7%)
Special Notices	Accelerated Review	15 (4.66%)
MRCTs in Package	Yes	142 (44.1%)
MRCTs in Package	No	180 (55.9%)
Sponsor	Japanese Domestic Company	157 (48.8%)
Sponsor	Multi-national Company	165 (51.2%)

MRCT = multi-regional clinical trial

¹ Other biologics include biologics other than monoclonal antibodies such as enzymes and peptides.

Table 2 Summary of Percentage of Modeling Analyses Performed (PMAP) and Percentage of Dose Selection and Dosage Modification using the Modeling Analysis (PDSM) Stratified by Categories

Metrics	Category	PMAP	PDSM
Total	n = 322	154 (47.8%)	78 (24.2%)
First-in-class	Yes (n = 83)	50 (60.2%)	26 (31.3%)
First-in-class	No (n = 239)	104 (43.5%)	52 (21.8%)
First Indication	Yes (n = 127)	80 (63.0%)	39 (30.7%)
First Indication	No (n = 195)	74 (37.9%)	39 (20.0%)
Special Notices	Orphan Drug Designation (n = 73)	43 (58.9%)	21 (28.8%)
Special Notices	Accelerated Review (n = 15)	9 (60.0%)	3 (20.0%)
MRCTs in Package	Yes (n = 142)	104 (73.2%)	57 (40.1%)
MRCTs in Package	No (n = 180)	50 (27.8%)	21 (11.7%)
Sponsor	Japanese Domestic Company (n = 157)	56 (35.7%)	28 (17.8%)
Sponsor	Multi-National Company (n = 165)	98 (59.4%)	50 (30.3%)

MRCT = multi-regional clinical trial. shown as number of cases (%)

Table 3 Cases of model-informed dose selection for proposed dose regimens for phase III studies different from those in phase II studies

Compound name [Therapeutic area]	Phase II doses	Phase III doses	Point of MIDD
Semaglutide [Metabolic disease]	2.5, 5, 10, 20, and 40 mg	3, 7, and 14 mg	Based on the data from a phase II study investigating five doses of oral semaglutide (2.5, 5, 10, 20, and 40 mg) versus placebo, E-R model was developed to describe the relationship between semaglutide C_avg and the change in HbA1c levels. Based on the simulated E-R curve, three doses of oral semaglutide as 3, 7, and 14 mg were selected for the phase III study.
Ravulizumab [Others]	400, 600, 800, 900, 1400, 1600, 1800, and 3000 mg	Initial dose of 2400 mg and maintenance dose of 3000 mg for body weight range of 40 to <60 kg; Initial dose of 2700 mg and maintenance dose 3300 mg for body weight range of 60 to <100 kg; Initial dose of 3000 mg and maintenance dose of 3600 mg for body weight of ≥100 kg	Population PK analysis was performed which showed that body weight affected PK of ravulizumab, with higher exposures in lighter-weight patients than those in heavier-weight patients, suggesting the need for weight-based dose adjustment. A PK-LDH model was also established for the inhibitory response to terminal complements (measured as the largest clinically relevant LDH response) and set a weight-based dosage regimen (weight band dose) in a phase III trial which was expected to be above target thresholds in all individuals by simulations.
Galcanezumab [CNS]	5, 50, 120, and 300 mg (no loading dose)	120 mg (240 mg once as a loading dose), 240 mg	Simulations using population PK modeling showed that the serum steady-state levels may be attained rapidly by setting 240 mg as a loading dose; hence, two groups were selected in the phase III study [120-mg group (240 mg once as a loading dose) and 240-mg group].
Belotralstat hydrochloride [Others]	55, 110, 218, and 300 mg	110 and 150 mg	Simulations were performed at each dose-level from 125–250 mg to estimate the percentage of participants meeting the same EC₅₀ target levels. Parameter estimates with linear regression were used to impute trough estimates for the selected dose. The simulations supported the selection of 150 mg.
Gefapixant citrate [Others]	7.5, 20, and 50 mg	15 and 45 mg	From E-R simulation (efficacy and safety), 15 mg was expected to provide a clinically meaningful effect, and approximately 80% of the participants may not exhibit adverse events. A dose level of 45 mg was predicted to maintain a low rate of discontinuation and achieve the greatest effect.
Nemolizumab [Others]	0.1, 0.5, and 2.0 mg/kg	60 mg	A dose of 60 mg/body was expected to be included within the range as those provided at 0.5–2.0 mg/kg, to be as effective as or better than this dosage in patients with a body weight of 30–120 kg. Therefore, the fixed dose was chosen in the phase III study considering convenience as well.

CNS, central nervous system; E-R, exposure-response; HbA1c, glycated hemoglobin; PK, pharmacokinetic; LDH, lactate dehydrogenase; MIDD, Model-Informed Drug Development

The therapeutic areas were categorized as oncology (solid), oncology (non-solid), immunology, infectious disease, central nervous system, cardiovascular/renal disease, metabolic disease, and respiratory disease.

Table 4 Cases of model-informed dose selection for proposed different dose regimens for new drug applications from those in the phase III study

(a) Cases accepted by the Japanese authority

Compound name [Therapeutic area]	Phase III study dose ¹	Proposed dose at submission	MIDD use points	Acceptance in USPI
Fremanezumab [CNS]	225 mg once every 4 weeks with a loading dose of 675 mg	225 mg once every 4 weeks without loading dose	Population PK and E-R analyses conducted at the time of review in Europe and the United States were analyzed again with additional data from the Japan-Korea joint studies (Studies 406-102-00001 and 406-102-00002), suggesting that Japanese patients with chronic migraine (chronic migraine) have similar efficacy 225 mg dose once every 4 weeks with and without the loading dose of 675 mg.	Yes
Durvalumab [Oncology (solid)]	In a phase III study (dose: 1500 mg Q3W/Q4W), participants with body weight ≤30 kg were excluded.	A single dose is 20 mg/kg if the body weight is below 30 kg	Exposure in patients with body weight of 30 kg at 20 mg/kg dose Q3W or Q4W was lower than that in patients with body weight of more than 30 kg at 1500 mg dose Q3W or Q4W, but was shown to overlap. There was no clear relationship between drug exposure and the occurrence of overall survival or adverse events in the exposure range at 1500 mg.	Yes
Pembrolizumab [Oncology (solid)]	200 mg Q3W	400 mg Q6W	The E-R relationship showed that efficacy and safety were consistent across doses and AUC ranging from 2 mg/kg Q3W to 10 mg/kg Q2W (>5-fold higher exposures), regardless of cancer type. In addition, exposures at 200 mg Q3W were covered within the range of those provided by the dose range above, where both efficacy and safety have been confirmed. The exposure (AUC) following 400 mg Q6W was predicted to be as efficacious and safe as 200 mg Q3W.	Yes
Nivolumab [Oncology (solid)]	Nivolumab 3 mg/kg and ipilimumab 1 mg/kg	Nivolumab 240 mg and ipilimumab 1 mg/kg	Although exposure to 240 mg nivolumab was expected to be higher than that to nivolumab 3 mg/kg, it was also expected to be lower than that of nivolumab at the dosage and administration (10 mg/kg Q2W), which was well tolerated in Japanese patients.	Yes
Nivolumab [Oncology (solid)]	240 mg Q2W	240 mg Q2W or 480 mg Q4W	Simulations using population PK and E-R models predicted that there would be no clear difference in efficacy and safety between nivolumab 480 mg Q4W and 240 mg Q2W, which is the approved dosage and administration of nivolumab. Overall survival and response rates of nivolumab 3 mg/kg treated with Q2W, 240 mg treated with Q4W, 480 mg treated with Q2W were not expected to differ clearly. Similarly, no clear difference was predicted between the dose regimens for the adverse events studied.	Yes
Adalimumab [Immunology]	0.6–2.4 mg/kg in a phase III study of moderate to severe ulcerative colitis patients aged from 4–17 years old	Setting the dosage from 20–160 mg based on weight category in pediatric patients	Simulations of fixed doses by body weight category and weight equivalent doses used in phase III studies showed similar pharmacokinetic profiles.	Yes²
Selpercatinib [Oncology (solid)]	160 mg BID in Study 17001 for patients aged ≥12 years	The following dose is set for patients aged ≥12 years according to body surface area category (approximately 92 mg/m² per dose): 80 mg BID for <2 m², 120 mg BID for 1.2 to <1.6 m², 160 mg BID for ≥1.6 m^2..	There was an identified risk of QT prolongation with increase in selpercatinib exposure, and 160 mg fixed dose can result in excess exposure in children. When doses were selected for each body surface area category in the simulation, the exposure of drug in each body surface area category was similar. In addition, a preliminary study of a multi-regional phase I/II study in patients with advanced solid cancers aged 6 months to 21 years with RET genetic aberrations showed that responders were observed in patients with thyroid cancer (including patients with medullary thyroid cancer) who received 92 mg/m² BID, and that the exposure of drug in pediatric patients who received 92 mg/m² BID was similar to that in adult patients who received 160 mg BID, supporting the appropriateness of dose-setting by body surface area category.	Partially yes³

RET, rearranged during transfection; Q3W, every 3 weeks; Q6W, every 6 weeks; BID, twice daily; USPI, US prescribing information

1 Among the doses and administrations established in the phase III study, only those related to the changed or added dosage and administration at the time of application for approval are described.

2 The weight category of USPI differs from that of the domestic package insert.

3 For USPI, the dose is set according to body weight category rather than body surface area.

(b) Cases not accepted by the Japanese authority

Compound name [Therapeutic area]	Phase III dosage and administration ¹	Proposed dosage and administration	MIDD use points	Comment from Japan regulatory agency	Acceptance in USPI
Paliperidone palmitate [CNS]	12-week intervals	Once every 3 months	Exposure with Q13W treatment was similar to that with Q12W treatment.	Although the predicted PK parameters were similar, a dosing interval of 12 weeks was used in two phase III studies, and the efficacy and safety of continuous dosing other than 12-week intervals have not been investigated. In addition, a 12-week interval was considered appropriate as it adheres to the dosing interval in terms of promoting optimum use.	Yes
Somapacitan [Others]	The initial dosage was set at 1.5 mg for patients aged ≥60 years, 1.0 mg for over 60 years old, and 2.0 mg for female patients who were taking oral estrogen.	When switching from human somatotropic preparations to somapacitan in women, the Initial dose was set at 2.0 mg for ≤60 years, 1.5 mg for >60 years old, and 4.0 mg for female patients who were taking oral estrogen.	Based on the findings using population PK/PD analysis, a dose higher than the starting dose used in the phase III study was selected.	The starting dose used in the phase III studies is appropriate in terms of efficacy and safety.	No
Molidustat sodium [Metabolic disease]	Postprandial administration	No dietary restrictions	A simulated Hb level was determined, assuming that BA levels increase by 30% in the fasting state compared with those in the postprandial state. Changes in BA did not appear to significantly impact Hb levels. Hence, no restriction on the meal in the administration was observed.	The postprandial administration was appropriate owing to the following reasons: -PK of the phase I study showed an effect similar to that of food. -The effect of the exposure variation on Hb level was unclear. -The postprandial administration was set in the domestic phase III study.	-²
Adalimumab [Immunology]	For patients with moderate-to-severe ulcerative colitis aged 4–17 years, adalimumab was administered at Weeks 0, 1, 2, 4, and 6 during the run-in period (up to Week 8).	The dose at Week 1 was not set in pediatric patients. The dosing was set once every 2 weeks after the first dose. The same dose as that at Week 2 was administered at Weeks 4 and 6	Population PK indicated that the exposure did not change significantly in the absence of treatment at Week 1. In addition, E-R analysis showed that the same level of efficacy could be achieved by administering the fixed dosage and administration according to body weight category, regardless of the administration at Week 1.	Early induction of remission is important in active ulcerative colitis. To increase the possibility of remission, high serum levels must be maintained after the initiation of treatment with drug, and it is appropriate to set the dosage at Week 1.	No

1 Among the doses and administrations established in the phase III study, only those related to the changed or added dosage and administration at the time of application for approval are described.

2 It is not approved in US.

BA = bioavailability; Hb = hemoglobin; USPI = US prescribing information

Table 5 Cases of model-informed dose selection without conducting proof-of-concept (PoC) and/or dose-finding studies

Compound name

[Therapeutic area]

MIDD use points

Special Remarks

Inebilizumab

[Others]

PK/PD modeling was constructed based on the outcome of a phase I study (0.1–10 mg/kg single intravenous administration) in patients with other indications, without conducting a phase I study in patients who could be evaluated for PoM/PoC, and applied to the dosage regimen selection in the following study.

Orphan drug

Nirmatrelvir/
Ritonavir

[Infectious diseases]

Though dose-finding clinical studies were not performed, the validity of dose selection was explained

The phase II/III dose was selected as a dose of PK reaching in vitro EC₉₀ for severe acute respiratory syndrome coronavirus 2

Duration of phase II/III studies was set using QSP modeling.

Products subject to special approval

PoM, proof of mechanism; PoC, proof of concept; QSP, quantitative system pharmacology

Table 6 Cases of model-informed dose adjustments for special populations

Generic name [Disease area]	Alectinib hydrochloride [oncology (non-solid)]
Dose modulator	Pediatrics and body weight
MIDD use points	Dose-setting in pediatric phase II studies supported by the results of adult phase I studies and simulation
Analysis method	PK for pediatrics was predicted without the use of pediatric actual data. PK predictions for pediatrics were performed using the equation of allometry, which mathematically expresses the relationship of body weight to PK parameters in adults.¹
Analysis results	It was estimated that the trough levels of patients with body weight of 20 kg corresponding to pediatrics aged 6-years old were approximately 2.3 times higher than those of patients with body weight of 60 kg. The trough concentrations at 150 mg BID in pediatrics aged 6 years old were predicted to be similar to those of 300 mg BID in patients with body weight of 60 kg and decreased with increasing body weight. Based on E-R relationship and in vitro growth inhibitory activity, it was predicted that 150 mg BID may be effective in patients who may have relatively low trough concentration levels.
Japanese authority's view	Unknown because CTD and review report did not include Japanese authority’s opinion on the setting of dosage regimen for phase II studies.
Generic name [Therapeutic area]	Glucagon [metabolic disease]
Dose modulator	Japanese pediatrics
MIDD use points	Dose adequacy of Japanese pediatric patients was explained by model analysis (data from non-Japanese pediatric patients were utilized. No domestic clinical studies were conducted). Cases in which Japanese pediatrics could be extrapolated using population PK models and E-R models for Japanese adults, foreign adults, and foreign children
Analysis method	Data from patient populations including Japanese adult patients and non-Japanese pediatric patients aged 4 years or older were available for analysis. In population PK, allometric scaling was used, with body weight as a covariate. E-R analysis described the relationship between glucagon levels in blood and elevated glucose using an indirect response model. In the simulations, three different age groups were assumed (4 to <8 years, 8 to <12 years, and 12 to <18 years), and glucagon exposure and glucose response were simulated after 3 mg intranasal or intramuscular glucagon administration based on body weight (1 mg for body weight >25 kg, and 0.5 mg for body weight of ≤25 kg) in each age group.
Analysis results	The predicted BG_max of intranasal 3 mg glucagon administered to pediatrics and adults in each age-group resembled those predicted for intramuscular glucagon injections based on body weight. Simulations also predicted that in children and adolescents of three age-groups, the treatment success rate after administration of 3 mg glucagon nasal spray was more than 99%, which was similar to that after administration of glucagon injection.
Japanese authority's view	Although no clinical trials have been conducted in Japanese pediatric patients, successful treatment can be expected when 3 mg drug is administered nasally to Japanese pediatric patients based on the simulations. In the simulation, it was predicted that exposure with 3 mg intranasal glucagon in Japanese pediatric patients is higher than that observed in adult patients but is below C_max for intravenous glucagon 2 mg, the largest approved dose in the United States. In addition, considering that the safety profile of 3 mg nasal administration in adults was not significantly different between Japan and foreign countries, 3 mg may be selected as the intranasal administration dose of the drug in pediatrics, similar to that in foreign countries. However, the intranasal administration of 3 mg glucagon to Japanese pediatric patients with diabetes mellitus has not been investigated. Therefore, collecting post-marketing information on the safety and efficacy of drug administration to these patients is necessary.
Generic name [Therapeutic area]	Mepolizumab [immunology]
Dose modulator	Pediatrics and body weight
MIDD use points	Establishment of dosage and administration for pediatrics based on population PK: In a multi-national phase II study in pediatrics aged 6–11 years, doses were 40 mg for body weight <40 kg, 100 mg for body weight ≥ 40 kg and the doses were administered subcutaneously at 4-week intervals. Based on the subsequent population PK, 40 mg dose every 4 weeks was selected for pediatrics aged 6–11 years with severe asthma, regardless of body weight.
Analysis method	In population PK, the effect of body weight on PK was incorporated allometrically. In PK/PD (blood eosinophil count), an indirect response model, which included the production inhibition rate constant of eosinophils, was utilized.
Analysis results	Population PK analysis estimated that the expected dosage and administration in pediatrics aged 6–11 years with severe asthma was 40 mg every 4 weeks regardless of body weight to correspond exposure levels in patients aged ≥12 years with severe asthma. In clinical studies, drug exposure and the percentage reduction in blood eosinophil count after subcutaneous administration of the pediatric dose in patients with body weight of 40 kg were not significantly different from those after subcutaneous administration of 100 mg in patients aged 12 years or older with severe asthma. Simulated dose-response relationships between blood drug levels and blood eosinophil counts suggested that the exposure of drug and the rate of reduction in blood eosinophil counts after subcutaneous administration of 40 mg every 4 weeks in pediatric patients with severe asthma and body weight ≥40 kg were similar to those after subcutaneous administration of 100 mg in patients with severe asthma aged ≥12 years.
Japanese authority's view	It was considered acceptable to use 40 mg every 4 weeks subcutaneously. In the absence of results for this dosage and administration to pediatric patients with severe asthma and body weight ≥ 40 kg, the safety and efficacy of drug administration should be determined through post-marketing surveillance.
Generic name [Therapeutic area]	Azilsartan [metabolic disease]
Dose modulator	Pediatrics and body weight
MIDD use points	Dose selection for the phase III study (OCT-101 study)
Analysis method	A population PK analysis was performed using plasma drug concentrations in Japanese hypertensive patients aged from 6 to less than 16 years and healthy Japanese adults. The effects of body weight on CL/F and Vc/F were incorporated in an allometric manner.
Analysis results	Population PK analysis showed that the exposure in pediatrics with body weight of 50–80 kg to once-daily dose of 2.5–40 mg was similar to that in adults at the same dose, and exposure with the same dose in pediatrics with body weight of 20–49 kg was marginally less than twice compared to that of adults at the same dose. To ensure safety of the patients, the starting dose for OCT-101 study was 5 mg once daily, which was one fourth of the adult dose for body weight ≥ 50 kg and 2.5 mg once daily for body weight of <50 kg. Based on this estimation by population PK analysis, the maximum dose for pediatrics was 40 mg once daily for body weight ≥ 50 kg and 20 mg once daily for body weight <50 kg, which were doses that did not result in exposure at 40 mg once daily, which is the maximum dose for adults.
Japanese authority's view	The dosage and administration of drug established in OCT-101 study was considered appropriate from the viewpoint of obtaining exposures similar to or lower in Japanese pediatrics aged ≥6 years than those obtained when the approved dosage and administration of drug is administered to Japanese adults.
Generic name [Therapeutic area]	Gefapixant citrate [others]
Dose modulator	Renal function
MIDD use points	Dosage and administration in patients with renal impairment was selected based on population PK analysis.
Analysis method	Population PK analysis
Analysis results	A 1.46-fold increase in patients with moderate renal impairment and a 1.89-fold increase in patients with severe renal impairment were estimated, relative to patients with normal renal function. In addition, the steady-state C_max and AUC at 45 mg once daily in patients with severe renal impairment were predicted to be similar to those at 45 mg twice daily in patients with normal renal function. Based on these findings, the dosing regimen of 45 mg once daily was proposed in patients with severe renal impairment.
Authority's view	The explanation was accepted.
Generic name [Therapeutic area]	Sodium tolvaptan phosphate [others]
Dose modulator	Patients with difficulty in oral fluid intake
MIDD use points	Population PK and simulations to explain the starting dose in the special population at the proposed dose for NDA.
Analysis method	Population PK analysis
Analysis results	Estimated exposures to tolvaptan after intravenous administration of 2, 4, 8, and 16 mg and oral administration of 7.5 and 15 mg indicated that the dose of 8 mg provided similar exposure to that of the oral tolvaptan 7.5 mg and was half of the recommended drug dosing regimen. To reduce the risk due to excessive water diuresis immediately after the initiation of drug administration, it was recommended that drug administration should be started at a half-dose (8 mg) of the standard dose in patients with difficulty in oral intake.
Japanese authority's view	The applicant's policy to advise that it is desirable to start administration of drug at half-dose (8 mg) of the standard dosage is justified.
Generic name [Therapeutic area]	Nirmatrelvir and ritonavir [infectious diseases]
Dose modulator	Pediatrics and body weight
MIDD use points	Dosage regimen for pediatrics based on predictions using adult population PK model. Cases in which pediatric patients aged ≥12 years and body weight ≥ 40 kg could be extrapolated using a population PK model in adults and a distribution of body weight in pediatrics.
Analysis method	Prediction of exposure differences by body weight in population PK analysis
Analysis results	Plasma drug exposures to 300 mg nirmatrelvir and 100 mg ritonavir co-administered twice daily were predicted to be similar in pediatrics with body weight ≥ 40 kg and adults. The dosage and administration in pediatrics aged ≥12 years and body weight ≥ 40 kg was set at the same dosage and administration as that in adults.
Authority’s view	It is reasonable that the dosage and administration in pediatrics aged ≥ 12 years and body weight ≥40 kg should be set to the same dosage and administration as in adults. However, it is necessary to continue to collect post-marketing information on the efficacy and safety in pediatrics, including the results of clinical studies in pediatrics under planning, and to provide information to medical institutions as soon as new findings are obtained.
Generic name [Therapeutic area]	Valbenazine tosilate [central nervous system]
Dose modulator	Deficiency in CYP2D6 activity
MIDD use points	Dose selection for phase III studies and explaining the need for dose adjustments in patients with factors that increase exposure
Analysis method	Population PK analysis
Analysis results	In CYP2D6 poor metabolizer, the exposure of the metabolite NBI-98782 after drug administration was considered to increase approximately twofold. E-R analysis showed that the percentage change from baseline in the Abnormal Involuntary Movement Rating Scale total score and the change from baseline as well as the global impression-improvement score of tardive dyskinesia tended to improve with increasing exposure. The incidences of somnolence-related adverse events, parkinsonism-related adverse events, and akathisia-related adverse events were related to the exposure levels (C_max and AUC) of unchanged drug and NBI-98782.
Japanese authority’s view	The applicant’s belief that 40 mg should be administered to patients with genetically defective CYP2D6 activity and those with risk of the increased exposure, and that the dose should not be increased to 80 mg is acceptable.
Generic name [Therapeutic area]	Filgotinib maleate [immunology]
Dose modulator	Renal function
MIDD use points	Selection of proposed dose based on renal function
Analysis method	Population PK analysis
Analysis results	Dose adjustment for patients with ulcerative colitis (UC) with mild and moderate renal impairment was considered unnecessary for the following reasons: As a consequence of population PK, exposures (C_max and AUC_tau) of unchanged drug and major metabolite (GS-829845) in patients with UC and mild renal impairment were similar to those in patients with normal renal function. Exposure of unchanged drug was similar between patients with UC and moderate renal impairment and patients with normal renal function, and exposure of GS-829845 was 20–30% higher in those with UC and moderate renal impairment than in patients with normal renal function.
Japanese authority's view	Caution should be exercised for half the dose of drug in patients with moderate renal impairment for the following reasons: ² PK parameters between the approved indication (rheumatoid arthritis: RA) and the proposed indication (UC) were similar. The results of predictions for renal dysfunction in patients with UC were similar as those for renal dysfunction in patients with RA. Dedicated study assessing the effect of renal function suggested that exposure to GS-829845 in moderate renal impairment may be increased more than 2-fold.

CL/F, apparent total clearance; Vc/F, apparent volume of distribution in central compartment

¹ Biological rules for the relationship between organism function and size, represented by the equation Y = a × W^b (Y: variable representing organism function; W: variable representing organism size; a, b: constants). To predict pharmacokinetics, Y is used as a PK parameter, such as clearance and volume of distribution, and W is used as body weight. The constants a and b are derived from the relationship between PK parameters and body weight in existing data (often 0.75, clearance and 1.0 for volume of distribution, respectively) and predict the PK parameter at the desired body weight.

² It was not acceptable to the authorities to propose that no dosage adjustment of drug is required for UC with moderate renal impairment.

BG_max, maximum plasma glucose level; CTD, common technical document.

Table 7 Summary of Cases without Japanese Data in Which Modeling Analysis Provided Major Rationale for Dosage Selection

Compound Name	Approval Year in Japan	Indication	Development Phase	Application of Modeling Analysis
Ambrisentan	2021	Pulmonary arterial hypertension (Orphan)	End of Phase I	For selecting dose/dosage for multi-regional (including Japan) phase II study in pediatric patients using data from phase II/III study in adults conducted outside Japan.
Inebilizumab	2021	Neuromyelitis optica spectrum disorder (first indication, orphan)	End of Phase I	For selecting dose/dosage for multi-regional (including Japan) phase II/III study using data from phase I study conducted outside Japan.
Pemigatinib	2021	Cholangiocarcinoma with FGFR2 fusion or rearrangement (first indication, orphan)	End of Phase I	For selecting dose/dosage for multi-regional (including Japan) phase II study using data from phase I study conducted outside Japan.
Ixazomib	2021	Relapsed/Refractory Multiple myeloma	End of Phase II	For selecting dose/dosage for multi-regional (including Japan) phase III study using data from phase I/II study conducted outside Japan.
Perampanel	2020	Epilepsy	End of Phase II	For selecting dose/dosage for multi-regional (including Japan) phase III study in pediatric patients using data from phase II in pediatric patients and part of phase III in adults and adolescents conducted outside Japan.
Osilodorostat	2021	Cushing’s disease (first indication)	End of Phase II	For selecting dose/dosage for multi-regional (including Japan) phase III study using data from early-phase clinical studies conducted outside Japan.
Ofatumumab	2021	Multiple sclerosis (Orphan)	End of Phase II	For selecting dose/dosage for phase III (outside Japan) and multi-regional phase II (including Japan) study using data from phase II study conducted outside Japan.
Valbenazine	2022	Tardive dyskinesia (first indication)	End of Phase II	For selecting dose/dosage for phase III study (outside Japan) using data from phase II study conducted outside Japan. Domestic phase II/III study was separately conducted in Japan with the same dose as the phase III study determined by the analysis.
Lasmiditan	2022	Migraine (first indication)	End of Phase III	For selecting dose for approval using data from early-phase clinical trials conducted outside Japan. No PK sampling was done in late-phase clinical trials owing to its dosage (only administered for migraine attack).
Clomiphene	2022	Oligozoospermia	After launch	For demonstrating exposure similarity among different dose/dosage (25 mg once daily vs. 50 mg once in two days). Public knowledge-based application. No additional clinical study was conducted.

No competing interests reported.

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Application of Model-informed Drug Development (MIDD) in Regulatory Submissions for Drug Approval in Japan

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