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. 2024 Oct 24;17(10):e70050. doi: 10.1111/cts.70050

Asia‐inclusive drug development leveraging principles of ICH E5 and E17 guidelines: Case studies illustrating quantitative clinical pharmacology as a foundational enabler

Hong Lu 1,✉, Lena Klopp‐Schulze 2, Jatinder Kaur Mukker 3, Dandan Li 1, Yoshihiro Kuroki 4, Jayaprakasam Bolleddula 3, Nadia Terranova 5, Kosalaram Goteti 3, Wei Gao 3, Rainer Strotmann 2, Jennifer Dong 3, Karthik Venkatakrishnan 3,✉
PMCID: PMC11500040  PMID: 39445632

Abstract

With the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guidelines in effect from 2018, the design of Asia‐inclusive multiregional clinical trials (MRCTs) has been streamlined, thereby enabling efficient simultaneous global development. Furthermore, with the recent regulatory reforms in China and its drug administration joining the ICH as a full regulatory member, early participation of China in the global clinical development of novel investigational drugs is now feasible. This would also allow for inclusion of the region in the geographic footprint of pivotal MRCTs leveraging principles of the ICH E5 and E17. Herein, we describe recent case examples of model‐informed Asia‐inclusive global clinical development in the EMD Serono portfolio, as applied to the ataxia telangiectasia and Rad3‐related inhibitors, tuvusertib and berzosertib (oncology), the toll‐like receptor 7/8 antagonist, enpatoran (autoimmune diseases), the mesenchymal–epithelial transition factor inhibitor tepotinib (oncology), and the antimetabolite cladribine (neuroimmunological disease). Through these case studies, we illustrate pragmatic approaches to ethnic sensitivity assessments and the application of a model‐informed drug development toolkit including population pharmacokinetic/pharmacodynamic modeling and pharmacometric disease progression modeling and simulation to enable early conduct of Asia‐inclusive MRCTs. These examples demonstrate the value of a Totality of Evidence approach where every patient's data matter for de‐risking ethnic sensitivity to inter‐population variations in drug‐ and disease‐related intrinsic and extrinsic factors, enabling inclusive global development strategies and timely evidence generation for characterizing benefit/risk of the proposed dosage in Asian populations.

INTRODUCTION

In recent years, the pharmaceutical industry has witnessed a significant shift in drug development strategies, particularly with inclusivity and global reach. Although implementation of the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E5 (ethnic bridging) guidelines 1 is common, drug development programs initiated in the Western region have traditionally included Asian populations at later timepoints due to regulatory and administrative barriers. 2 This has led to delays in bringing new therapies to Asian regions. With the recent regulatory reform in China and its drug administration joining the ICH, early participation in global clinical development is now feasible due to substantial streamlining of regulatory processes and application of ICH E17 principles for efficient design and analysis of multiregional clinical trials (MRCTs). 3

This paradigm shift has paved the way for Asia‐inclusive drug development, where countries such as Japan and China have emerged as key players in early clinical development. Complementing ICH E5 and E17 guidelines is the proposed ICH M15 guideline for implementing model‐informed drug development (MIDD). 4 MIDD enhances quantitative understanding of variability in dose/exposure–response and should, therefore, enable a scientifically rigorous approach to Asia‐inclusive drug development aligned with ICH E17, that is, consideration of drug‐ and disease‐related intrinsic and extrinsic factors in the design of MRCTs. 5

Herein, we share recent case examples illustrating application of these concepts for Asia‐inclusive drug development across therapeutic areas (oncology, neurology, and immunology) in the EMD Serono portfolio from early through late‐stage clinical development. These cases illustrate application of population pharmacokinetic (PK) (tuvusertib, enpatoran, tepotinib, berzosertib), PK/pharmacodynamic (PD) (tuvusertib, enpatoran, cladribine), and disease progression (enpatoran) modeling and simulation to assess consistency in the drug‐ and/or disease‐related intrinsic and extrinsic factors and support dosage for Asian populations. We aim to demonstrate the value of MIDD and a Totality of Evidence approach enabling timely Asia‐inclusive MRCTs in the context of a global phase I (tuvusertib), phase II (enpatoran and berzosertib), or pivotal registrational (tepotinib) clinical trial, and as a key component of evidence generation for characterizing benefit/risk of a drug in Asian populations (cladribine).

CASE STUDIES

Tuvusertib

Tuvusertib is a potent, selective, orally administered ataxia telangiectasia, and Rad3‐related (ATR) protein kinase inhibitor being evaluated as an anticancer drug in phase I and II trials as monotherapy and in combination settings. 6 , 7

In part A1 (monotherapy dose escalation) of an open‐label, first‐in‐human (FIH) phase I trial (NCT04170153), tuvusertib (5–270 mg once daily [q.d.]) was evaluated in patients with advanced solid tumors (N = 55). 6 Tuvusertib was tolerated up to 180 mg q.d.: the maximum tolerated dose (MTD) under continuous dosing. The most frequently reported dose‐limiting toxicity (DLT) was anemia during the dose‐escalation phase, which was dose‐ and exposure‐related. 6 Tuvusertib was rapidly absorbed with dose‐proportional PK up to 180 mg, and a mean half‐life (t 1/2) from ~1.2 to 5.6 h, with minimum accumulation following q.d. administration. Exposure‐related target engagement, that is >80% inhibition of ɤ‐H2AX in blood, was attained at doses ≥130 mg. 6 Tuvusertib 180 mg q.d. administered in a 2‐week on/1‐week off schedule demonstrated a favorable safety profile and was declared the recommended dose for the expansion for monotherapy.

A preliminary assessment of ethnic sensitivity of tuvusertib was performed based on ICH E5 principles and available clinical PK and safety data in the dose escalation phase. Based on the in vitro studies, aldehyde oxidase (AO) is expected to be the primary enzyme that metabolizes tuvusertib. In vitro and clinical PK data from drugs metabolized by AO indicate no relevant ethnic differences in AO function. 8 , 9 , 10 In the ongoing Western phase I trial, consistency in tuvusertib exposure in Asian (N = 5) and non‐Asian (N = 50) populations was ascertained by overlaying individual area under the concentration–time curve during dosing interval at steady state (AUCτ,ss) values for patients of Asian origin over the 90% prediction interval (PI) of the dose–AUCτ,ss relationship for the study population, estimated using a power model based on full population (Figure 1a). The effect of tuvusertib on hemoglobin (Hb) was characterized in a longitudinal semi‐mechanistic, multivariate population PK/PD model to predict the time course of reticulocytes, red blood cells, and Hb. Model‐based simulations of multicycle tuvusertib treatment indicated that Hb reduction in patients of Asian origin was within the 90% PI of Hb reduction in patients of non‐Asian origin at the corresponding doses, suggesting no evidence of difference in Hb reduction between Asian and non‐Asian populations (Figure 1b).

FIGURE 1.

FIGURE 1

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Assessment of ethnic sensitivity in exposure and safety of tuvusertib in Asian and non‐Asian patients with advanced solid tumors. (a) Dose–AUCτ,ss relationship. Relationship between tuvusertib doses and AUCτ,ss was assessed using a power model. Symbols represent individual patients (Asian patients in blue, non‐Asian patients in gray); the solid black line and the shaded gray area represent the power model‐predicted relationship and 95% prediction interval, respectively. (b) Hemoglobin reduction. Observed Hb reductions in Asians in comparison with simulated Hb levels for 4 cycles of tuvusertib treatment and various doses of interest. The dashed black line and the shaded gray area represent median and 5th–95th percentiles, respectively. The horizontal dashed black line represents Hb levels of 80 g/L. The blue symbols are for the individual Asian patients. AUCτ,ss , area under the curve; Hb, hemoglobin; q.d., once daily; w, week.

Taken together, the Totality of Evidence supported an expectation of low ethnic sensitivity. Hence, a common dosage of tuvusertib aligned with the recommended dose for the expansion, established in the Western population, was thus selected (during A1) for further evaluation in China and Japan dose confirmation cohorts (country‐specific A4 and A5), as an early enabler for Asia‐inclusive drug development in future global studies. Cohorts 4 and 5 (six to nine patients each) were aimed to confirm consistency in safety and PK in Asian patients for monotherapy. Importantly, the above‐described initial assessment of low risk for ethnic sensitivity was instrumental in enabling an Asia‐inclusive FIH MRCT where both Japan and China could join dose confirmation cohorts without the need for a dose escalation design. Of note, the associated clinical trial applications filed with the Pharmaceutical and Medical Devices Agency (PMDA) in Japan and the Center for Drug Evaluation (CDE) in China were supported by the above‐discussed ethnic sensitivity assessments, leveraging data from the dose escalation phase. Notably, we also leveraged the regulatory reforms in China, enabling China to join clinical development as early as completion of the dose escalation phase of the FIH study.

Enpatoran

Enpatoran is a novel, highly selective, and potent dual toll‐like receptor (TLR) 7/8 inhibitor currently under development for the treatment of autoimmune disorders including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and myositis. 11 Completed phase I and phase II studies evaluated the PK, PD, and safety of enpatoran in healthy volunteers and patients with coronavirus disease 2019 (COVID‐19). 12 , 13 The Western FIH, phase I study (NCT03676322) in healthy participants demonstrated that orally administered enpatoran was well tolerated, with dose‐proportional PK and a t 1/2 of 6.8 to 10.6 h. 12 PD results showed effective TLR7/8 target modulation demonstrated by exposure‐dependent inhibition of ex vivo‐stimulated cytokine (interleukin‐6 and interferon‐α) release. 12 PK and PD data from this study were used to develop population PK/PD models, which, in combination with safety data in humans and preclinical efficacy and PK/PD data, supported the investigation of enpatoran 25, 50, and 100 mg twice a day in patients with SLE or CLE. 14

The ongoing, 24‐week, phase II study (WILLOW; NCT05162586) is evaluating enpatoran in patients with SLE or CLE. 11 To enable patients from Japan and China to be a part of the global WILLOW study, a holistic integration of drug and disease knowledge using quantitative clinical pharmacology methods was performed based on the results from an ethno‐bridging study (NCT04880213) and expanding on previously published population PK/PD data and SLE disease trajectory modeling (DTM) results. 15 The ethno‐bridging study in Caucasian and Japanese healthy subjects matched by body weight, height, and sex demonstrated comparable PK/PD properties for enpatoran in represented Asian and Caucasian subjects across single 100, 200, and 300 mg orally administered doses. DTM suggested no significant differences in SLE disease trajectory for patients of Asian and non‐Asian origin. 16 While a quantitative DTM was performed in this case, also aligned with broader contexts of use of such a MIDD framework, alternate approaches (e.g., systematic review of the literature) are recommended when investment in development of such pharmacometric models is not feasible. AO is considered to be a key contributor to enpatoran metabolism, 15 and in vitro and clinical PK data from marketed drugs metabolized by AO indicate no relevant ethnic differences in AO function. 9 , 10 Enpatoran absorption or disposition is not expected to be influenced by drug transporters. Based on Totality of Evidence principles (Figure 2), inclusion of Japanese and Chinese patients in MRCTs was supported. The data and integrative analyses presented were foundational for regulatory review by the Health Authorities (the PMDA in Japan and the CDE in China), and enabled the inclusion of Asian patients in the ongoing global phase II WILLOW study, confirmed by the respective regulatory consultations. China could join the global phase II study without the need to conduct a dedicated Chinese bridging study. Designing this phase II trial as an Asia‐inclusive MRCT should enable timely learning regarding the efficacy, safety, and associated exposure–response relationships of enpatoran in the target patient populations to further evaluate consistency across global patient populations and enable seamless globalization of potential late‐stage trials following proof‐of‐concept.

FIGURE 2.

FIGURE 2

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Ethnic sensitivity assessment of enpatoran to inform Asia‐inclusive development in patients with systemic and cutaneous lupus erythematosus. ADME, absorption, distribution, metabolism, and excretion; AO, aldehyde oxidase; BICLA, British Isles Lupus Assessment Group [BILAG]‐based Composite Lupus Assessment; DDI, drug–drug interaction; DTM, disease trajectory modeling; IL, interleukin; MoA, mechanism of action; PD, pharmacodynamics; PK, pharmacokinetics; SoC, standard of care; SLE, systemic lupus erythematosus; TLR, toll‐like receptor. Graphs for BICLA response probability over time show median predicted values (represented by solid lines), with 95% prediction intervals represented by shaded areas.

Berzosertib

Berzosertib is an intravenously administered ATR inhibitor that was under evaluation for multiple cancer types as monotherapy or in combination with chemotherapeutics. 17 Berzosertib is also currently being evaluated in combination with lurbinectedin and sacituzumab govitecan. 18 , 19 Berzosertib has moderate to high clearance (~60 L/h), high volume of distribution (V d; ~1250 L), and t 1/2 of 17 h. 20 Berzosertib PK is dose‐linear (18–480 mg/m2) and unchanged upon coadministration of combination drugs. It is generally well tolerated as monotherapy with no DLTs at doses up to 480 mg/m2 (Data on file). A population PK analysis was performed on data from 240 patients in the Western clinical trials. 17 This dataset included five patients of Asian race (non‐Japanese). Graphical explorations of demographic covariate variables against between‐subject random effects estimates for clearance and V d showed that neither race nor ethnicity had relevant relationships, indicating expectation of lack of relevant differences in berzosertib PK in Asian versus non‐Asian patients. 17 In addition, berzosertib is dosed on a body surface area‐adjusted basis, which should help bridge demographic differences in body size for Asian versus Western patients. Taken together, it was considered that berzosertib is likely not sensitive to ethnic factors. In an investigator‐initiated study (NCT02487095), the combination of berzosertib and topotecan was evaluated in patients with relapsed SCLC. The recommended phase II dose (RP2D) of this combination was topotecan 1.25 mg/m2 (Days 1–5) and berzosertib 210 mg/m2 (Days 2 and 5) in 21‐day cycles. 21 An objective response rate (ORR) of 36% was observed. 22 Subsequently, a global phase II pivotal trial of the berzosertib–topotecan combination in patients with relapsed, platinum‐resistant SCLC (NCT04768296) including Japan and China was designed (Figure 3a). 23 Since no data were available on berzosertib in Japanese patients and the RP2D of topotecan/berzosertib was considered the MTD, 21 a Japan‐only safety run‐in part with two dose levels (DL, DL1: 105 mg/m2 berzosertib [Days 2 and 5] + 1.25 mg/m2 topotecan [Days 1–5]; DL2: 210 mg/m2 berzosertib [Days 2 and 5] + 1.25 mg/m2 Topotecan [Days 1–5]) was included. 23 A total of three to nine Japanese patients with advanced solid tumors were to receive DL1. If DL1 was tolerated, patients were to receive DL2. If DL2 was tolerated, patients were to be enrolled into the main part of the study.

FIGURE 3.

FIGURE 3

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Multiregional clinical trial designs and ethnic sensitivity assessment of berzosertib and tepotinib. (a) Multiregional clinical trial design of berzosertib and topotecan in patients with relapsed, platinum‐resistant small cell lung cancer. (b) PK parameters of berzosertib in Japanese and non‐Japanese patients with relapsed, platinum‐resistant small cell lung cancer. (c) Multiregional clinical trial design of tepotinib in patients with advanced NSCLC and METex14 skipping alterations. (d) Distribution of tepotinib AUCτ,ss in Asian and Caucasian patients based on the population pharmacokinetic model. The horizontal line in the box indicates the median value, the box edges represent the 25th and 75th percentiles, and the whiskers extend from the box to the furthest data points still within a distance of 1.5 times the interquartile range from the box. Data points, which are jittered in the horizontal direction, show the individually predicted AUCss values. ALK, anaplastic lymphoma kinase; AUCinf, area under the plasma concentration–time curve extrapolated to infinity; C max, maximum serum concentration; D, dose; DL, dose level; DLT, dose‐limiting toxicity; DNA, deoxyribonucleic acid; DoR, duration of response; EGFR, epidermal growth factor receptor; HRQoL, health‐related quality of life; LBx, liquid biopsy; METex14, mesenchymal–epithelial transition factor exon 14; NSCLC, non‐small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression‐free survival; PK, pharmacokinetics; q.d., once daily; RNA, ribonucleic acid; SCLC, small cell lung cancer; TBx, tissue biopsy.

Based on the above justification, alignment with PMDA on a safety run‐in strategy in Japan without a standalone phase I PK/safety assessment was achieved. The safety run‐in portion of the study was completed, and exposure (area under the plasma concentration–time curve extrapolated to infinity [AUCinf] and maximum serum concentration [C max]; Figure 3b) and safety data were consistent between Japanese and non‐Japanese patients. Based on these results, both Japan and China were able to join the primary/main cohort of the global phase II study directly. This example illustrates the participation of Asia in a global oncology pivotal study without a dedicated phase I PK/safety study.

Tepotinib

Tepotinib is a highly selective, potent, mesenchymal–epithelial transition factor (MET) inhibitor. Tepotinib 450 mg q.d. is approved for the treatment of non‐small cell lung cancer (NSCLC) with METex14 skipping alterations in many Asian and non‐Asian countries, based on efficacy data from a multiregional pivotal single‐arm phase II study (NCT02864992, VISION). 24 Tepotinib was first approved in Japan in March 2020 based on Cohort A of VISION, where it received SAKIGAKE designation and was the first global approval for a MET inhibitor. 25 In February 2021, the Food and Drugs Administration (FDA) approved tepotinib for the treatment of adult patients with metastatic NSCLC harboring METex14 skipping alterations.

Due to the regulatory reforms as an ICH country, China could join a global MRCT and use the totality of study results for drug registration in China instead of a dedicated regional study. After CDE consultation, to meet the registration requirement on sample size and also confirmed by statistical simulation that 20% of total patients in Cohort C provide adequate power to show treatment effect consistency with the global population, the VISION study protocol was amended for a China‐specific extension to allow more time for enrolment in China (Figure 3c). Enrolment in Cohorts A and C of VISION was completed as planned with 152 patients enrolled in Cohort A and 161 patients (including 30 mainland Chinese patients) enrolled in Cohort C.

During clinical development, PK of tepotinib was assessed in patients with cancer at doses of 30–1400 mg q.d. The PK properties of tepotinib, that is, t 1/2 of ~32 h and time‐independent clearance, support q.d. dosing. Population PK analysis indicated no relevant effects of race (Caucasian, Japanese, and other East Asian), age, sex, body weight, mild/moderate hepatic impairment, and mild/moderate renal impairment. 26 In addition, rich PK sampling from phase I study (NCT01832506) in Japanese patients with solid tumors confirmed similar exposure to that in the phase I study in Western patients. 25 , 26

All patients in VISION provided sparse PK data, and the effect of ethnic factors on the PK of tepotinib was further investigated by comparing individual popPK model‐predicted AUCτ,ss at the clinical dose of 450 mg q.d. and confirmed consistent clinical exposures across races/ethnic groups (Figure 3d). 26 This finding reinforces the rationale of the VISION study as an Asia‐inclusive MRCT following ICH E17 principles, which was accepted by the regulatory authorities across regions and countries as the primary source of evidence to support marketing approval, including the recent approval of tepotinib in China in December 2023.

Cladribine

Cladribine (2‐chloro‐2′‐deoxyadenosine) is a synthetic chlorinated analog of deoxyadenosine. It is converted to its active triphosphate form, 2‐chlorodeoxyadenosine 5′‐triphosphate upon phosphorylation by deoxycytidine kinase (DCK) and two additional kinases. 27 Due to the high constitutive expression of DCK in lymphocytes, the DCK to 5′‐nucleotidase ratio favors phosphorylation of cladribine. This leads to selective depletion of dividing and non‐dividing B and T cells. 27 Cladribine is indicated for the treatment of relapsing multiple sclerosis (RMS) in adult patients and is approved in >75 countries and regions (including Hong Kong, Taiwan, and South Korea). 27 Based on the data on Asian patients collected during global clinical development of cladribine and assessment of the impact of ethnic factors using ICH E5 principles, it is concluded that cladribine does not demonstrate ethnic sensitivity. 28

Cladribine has a unique PK/PD profile with a short elimination t 1/2 (~1 day) relative to a prolonged PD effect on specific immune cells (most notably a reversible reduction in B and T lymphocyte counts). This results in a short intermittent dosing schedule (up to 20 days over 2 years of treatment). 27 Cladribine has dose‐linear PK following oral administration with a typical log‐normal distribution of apparent clearance, without evidence for skewness, bimodality, or outliers in the overall distribution of PK parameters. Global clinical studies were conducted primarily in Caucasian patients, in part due to the distinctly higher prevalence of RMS in Western regions. Although the participation of Asian patients in the development program was limited, reflecting the status of RMS as a rare disease in Asia due to the low prevalence of RMS in Asian populations, a Totality of Evidence approach was used to demonstrate favorable benefit/risk profile of cladribine for treatment of RMS in Asian patients. The absence of ethnic sensitivity and a common dosage of cladribine across Asian and non‐Asian patient populations was confirmed using population PD modeling and simulation of treatment‐related reduction in absolute lymphocyte count (ALC) (Figure 4), a PD biomarker of relevance for both safety and efficacy of cladribine. 28 Of 1318 patients in the phase III studies that contributed to population PD modeling of ALC dynamics, 24 were Asian. The time course of change in ALC following cladribine treatment in Asian patients could be quantitatively described well by the mechanism‐based population PD model developed from a global patient population without requiring any additional considerations of ethnicity or race. This example illustrates the value of holistic integration of available data using a MIDD approach and a Totality of Evidence mindset to evaluate ethnic sensitivity in support of Asia‐inclusive development and use of the drug in a rare disease in Asian populations.

FIGURE 4.

FIGURE 4

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(a) Likelihood assessment of ethnic sensitivity for cladribine based on ICH E5 principles. (b) Representative plots of model‐predicted ALC time course for 5 of 16 Asian patients receiving cladribine in various dosing regimens in CLARITY/CLARITY Extension and ORACLE‐MS studies. The graph shows median (black dashed line) and 2.5th and 97.5th percentiles (lower and upper solid black lines, respectively) of the individual predicted profile. The observed data (solid light blue line) are compared with the predicted 95% confidence interval of the simulated data (N = 500 profiles). The horizontal black solid line denotes the upper limit for lymphopenia of grade 1 (1.0 × 109 cells/L). The gray solid lines denote upper limits for lymphopenia of grades 2, 3, and 4 (0.8, 0.5, and 0.2 × 109 cells/L, respectively). ALC, absolute lymphocyte count; BCRP, breast cancer resistance protein; DDI, drug–drug interaction, ICH, International Conference on Harmonization; MoA, mechanism of action; PD, pharmacodynamics; PK, pharmacokinetics.

CONCLUSIONS

The pharmaceutical industry has recognized the need for a paradigm shift in global drug development strategies. The transition from bridging approaches to simultaneous global development, with a specific focus on Asia‐inclusive drug development, has become a priority. Supported by regulatory guidelines such as ICH E5 and E17, drug developers are equipped with a framework to consider ethnic factors, evaluate variability, and refine their approach to meet the needs of diverse populations.

China in addition to Japan has emerged as a significant contributor to Asia‐inclusive drug development due to its robust regulatory framework and growing market influence. By encouraging early‐phase development within its borders, China has provided opportunities to expedite clinical trials and generate valuable data on drug response in diverse populations, as illustrated here in case studies of China‐inclusive early‐phase MRCTs (e.g., tuvusertib FIH, enpatoran phase II). This inclusive approach has enabled pharmaceutical companies to gain insights into the efficacy and safety of investigational therapies in Asia, ultimately benefiting patients worldwide. While the examples reviewed here are for small molecules, the principles and strategies are equally applicable to biologics. Protein therapeutics like monoclonal antibodies are generally less sensitive to known sources of ethnic variability, although knowledge of inter‐population variability in target expression and disease burden are important considerations while evaluating the risk for potential ethnic sensitivity in PK/PD properties.

The role of clinical pharmacology concepts and MIDD approaches cannot be understated in the pursuit of Asia‐inclusive drug development. Viewed from a broader perspective, reflecting on the examples presented here, we recommend timely quantitative characterization of (a) dose–exposure relationships, (b) ADME mechanisms, (c) therapeutic index based on exposure–response relationships for efficacy and safety, and (d) intrinsic and extrinsic sources of variability in disease biology and patient outcomes, as foundational pillars for ethnic sensitivity assessment to enable Asia‐inclusive drug development through MRCT design guided by ICH E5 and E17 principles. A robust understanding of ADME mechanisms and therapeutic index are particularly vital when dealing with complex modalities (e.g., antibody–drug conjugates) and in the setting of non‐linear PK. In this context, it is important to note that every patient's data matters, even when they represent the minority in the enrolled population and analysis dataset. We have demonstrated this across examples (tuvusertib FIH PK and safety analyses, berzosertib end of phase II population PK analysis, and cladribine phase III population PD modeling) where data in a limited number of Asian patients in global clinical trials were valuable in advancing Asia‐inclusive development. Furthermore, by building these considerations across the development plan, the design of studies can be adapted to address any questions of regional variability connected with statistical design principles (e.g., exchangeability/non‐exchangeability concepts) to enable confirmatory evidence generation.

In summary, the case studies presented here illustrate the successful implementation of ICH E5 and E17 principles for efficient Asia‐inclusive drug development and the importance of timely consideration of ethnic sensitivity through evaluation of drug‐ and disease‐related intrinsic and extrinsic factors in global drug development.

AUTHOR CONTRIBUTIONS

All authors contributed to writing various sections of the manuscript, critically reviewed the manuscript, and approved the final version before submission.

FUNDING INFORMATION

The study was funded by EMD Serono Research and Development Institute Inc., Billerica, Massachusetts, USA.

CONFLICT OF INTEREST STATEMENT

H.L. and D.L. are employees of Merck Serono Co., Ltd., Beijing, China, an affiliate of Merck KGaA, Darmstadt, Germany. L.K.‐S. and R.S. are employees of the healthcare business of Merck Healthcare KGaA, Darmstadt, Germany. Y.K. is an employee of Merck Biopharma Co., Ltd., Tokyo, Japan, an affiliate of Merck KGaA, Darmstadt, Germany. J.K.M., K.G., J.D., and K.V. are employees of EMD Serono, Billerica, MA, USA. N.T. is an employee of Ares Trading S.A., Lausanne, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany. J.B. and W.G. were employees of EMD Serono, Billerica, MA, USA, when the study was conducted.

ACKNOWLEDGMENTS

The medical writing and editorial support were provided by Preetinder Kaur of Certara, under the direction of the authors following Good Publication Practice guidelines (Ann Intern Med 2022;175:1298‐1304) and was funded by EMD Serono Research and Development Institute Inc., Billerica, Massachusetts, USA. All authors approved the final version of this article, including the authorship list.

Lu H, Klopp‐Schulze L, Mukker JK, et al. Asia‐inclusive drug development leveraging principles of ICH E5 and E17 guidelines: Case studies illustrating quantitative clinical pharmacology as a foundational enabler. Clin Transl Sci. 2024;17:e70050. doi: 10.1111/cts.70050

Contributor Information

Hong Lu, Email: hong.lu@merckgroup.com.

Karthik Venkatakrishnan, Email: karthik.venkatakrishnan@emdserono.com.

DATA AVAILABILITY STATEMENT

EMD Serono is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial‐level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research and will be provided following review and approval of a research proposal, statistical analysis plan, and execution of a data sharing agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered.

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Associated Data

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Data Availability Statement

EMD Serono is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial‐level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research and will be provided following review and approval of a research proposal, statistical analysis plan, and execution of a data sharing agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered.

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