Toshimitsu Hamasaki

RESEARCH:

Patient-Centric Benefit–Risk Evaluation Through the Desirability of Outcome Ranking Methodology

The Desirability of Outcome Ranking Methodology (DOOR) methodology provides a novel paradigm for the design, monitoring, analysis, reporting, and interpretation of clinical trials through a patient-centric framework for benefit:risk evaluation. Unlike traditional approaches that assess efficacy and safety as separate outcomes, DOOR integrates multiple clinical outcomes into a single interpretable ranking that reflects the overall desirability of a patient’s clinical course. Our research has established the statistical foundation for DOOR, including rigorous approaches for hypothesis testing, confidence interval estimation, stratified analysis, covariate adjustment, statistical monitoring, meta-analysis, graphical presentation, and sample size determination for DOOR-based endpoints. We have also developed methods to address key challenges in applying DOOR to complex clinical research settings, including longitudinal outcomes, survival outcomes, and missing data. These methodological advances provide investigators with statistically rigorous and clinically meaningful approaches for comparing therapeutic strategies based on outcomes that better capture patient experiences. In addition, we have developed publicly available web-based tools that facilitate implementation of DOOR methods by clinical investigators and biostatisticians, supporting broader dissemination and adoption of this framework. The DOOR methodology has been implemented in clinical studies conducted through the ARLG and in other collaborative clinical research studies across diverse disease areas, demonstrating its applicability beyond the initial development setting. Collectively, these contributions have advanced the science of patient-centric benefit:risk evaluation and provided innovative statistical tools for improving the design, analysis, and interpretation of clinical trials and other medical research studies.

1. He Y, Wu Q, Ge L, Evans SR, Hamasaki T. Rank-based analysis of the desirability of outcome ranking methodology: confidence intervals and hypothesis testing. Commun. Stat.-Simul. Comput. 1–23. (First published online on 04 July 2024 as doi:10.1080/03610918.2026.2694561)
2. Evans SR, Wu Q, Hamasaki T. Patient-centric pragmatic clinical trials: Opening the DOOR. Stat Med. 2026; 45:e70328.
3. Hamasaki T, He Y, Wu Q, Howard-Anderson J, Boucher HW, Doernberg SB, Holland TL, Powers JH 3rd, Wang J, Diao G, van Duin D, Fowler VG Jr, Chambers HF, Evans SR. A patient-centric paradigm and tool for clinical research: the DOOR is open. Antimicrob Agents Chemother. 2026; 70:e0147825.
4. Shu S, Diao G, Hamasaki T, Evans SR. Longitudinal benefit:risk analysis through the desirability of outcome ranking (DOOR) with application to ACTT-1 trial. Stat Biopharm Res. 2025; 17:488–495.
5. Follmann D, Fay M, Hamasaki T, Evans SR. Analysis of ordered composite endpoints. Stat Med. 2020; 39:602-616.

Design and Analysis of Complex Clinical Trials

Our research has advanced statistical methodology for the design, analysis, and monitoring of complex clinical trials, including multi-regional clinical trials, bridging studies, adaptive designs, and precision medicine approaches. We have developed statistical frameworks addressing challenges in global medical product development, including evaluation of treatment effects across diverse populations, assessment of regional consistency, and integration of evidence across geographic regions. These contributions have supported rigorous approaches for generating evidence applicable across populations and regulatory

settings. We have developed innovative trial designs, including Sequential Multiple Assignment Randomized Trial (SMART) designs, to evaluate treatment strategies and decision rules guiding empiric and definitive therapy choices, particularly in antibiotic trials. We have also developed precision medicine methods for identifying patient subgroups with differing prognoses among long-term survivors, supporting individualized risk assessment and treatment strategies. We have developed statistical methods tor multi-objective trials, including trials with multiple endpoints and arms, group-sequential designs, and adaptive designs. These approaches provide rigorous and flexible frameworks for addressing complex trial objectives while maintaining statistical validity and interpretability. Collectively, these contributions have advanced clinical trial methodology by providing statistical tools for global evidence generation, personalized medicine, and complex therapeutic evaluation.

Sample Size Determination

1. Sugimoto T, Hamasaki T, Evans SR, Sozu T. Sizing clinical trials when comparing bivariate time-to-event outcomes. Stat Med. 2017; 36:1363-1382.
2. Hamasaki T, Sugimoto T, Evans SR, Sozu T. Sample size determination for clinical trials with co-primary outcomes. Exponential event-times. Pharm Stat 2013; 12:28-34.
3. Sugimoto T, Sozu T, Hamasaki T, Evans SR. A logrank test-based method for sizing clinical trials with two co-primary time-to-events endpoints. Biostatistics. 2013; 14:409-421.
4. Sozu T, Sugimoto T, Hamasaki T. Sample size determination in clinical trials with multiple co-primary endpoints including mixed continuous and binary variables. Biom J. 2012; 54:716-729.
5. Sozu T, Sugimoto T, Hamasaki T. Sample size determination in clinical trials with multiple co-primary binary endpoints. Stat Med. 2010; 29: 2169-2179.

Group-sequential clinical trials

1. Diao G, Zhang Q, Hamasaki T, Evans SR. Group sequential design and monitoring of clustered data in randomized eye trials.  Stat Biopharm Res 2026; 18:471-480.
2. Hamasaki T, Hung HMJ, Hsiao CF, Evans SR. On selecting the critical boundary functions in group-sequential trials with two time-to-event outcomes. Contemp Clin Trials. 2021; 101:106244.
3. Sugimoto T, Hamasaki T, Evans SR, Halabi S. Group-sequential logrank methods for trial designs using bivariate non-competing event time outcomes. Lifetime Data Anal. 2020; 26:266–291.
4. Hamasaki T, Evans SR, Asakura K. Design, data monitoring and analysis of clinical trials with co-primary endpoints: A review. J Biopharm Stat. 2018; 28:28-51.
5. Hamasaki T, Asakura K, Evans SR, Sugimoto T, Sozu T. Group sequential strategies for clinical trials with multiple co-primary endpoints. Stat in Biopharm Res 2015; 7:36-54.

Clinical trials with adaptive features

1. Dimairo M, Pallmann P, Wason J, Todd S, Jaki T, Julious SA, Mander AP, Weir CJ, König F, Walton MK, Nicholl JP, Coates E, Biggs K, Hamasaki T, Proschan MA , Scott JA, Ando Y, Hind D, Altman DG. The adaptive designs CONSORT extension (ACE) statement: A checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. BMJ. 2020; 369:m115
2. Dimairo M, Coates E, Pallmann O, Todd S, Julious SA, Jaki T, Wason J, Mander AP, Weir CJ, König F, Walton MK, Biggs K, Nicholl J, Hamasaki T, Proschan MA, Scott JA, Ando Y, Hind D, Altman DG. Development of a consensus-driven CONSORT extension for randomised trials using an adaptive design. BMC Med. 2018; 16:210.
3. Sozu T, Sugimoto T, Hamasaki T. Reducing unnecessary measurements in clinical trials with multiple primary endpoints. J Biopharm Stat. 2016; 26:631-643.
4. Asakura K, Hamasaki T, Sugimoto T, Hayashi K, Evans SR, Sozu T. Sample size determination in group-sequential clinical trials with two co-primary endpoints. Stat Med 2014; 33:2897-2913.
5. Sugitani T, Hamasaki T, Hamada C. Partition testing in confirmatory adaptive designs with structured objectives. Biom J. 2013; 55:341-359.

Monitoring clinical trials

1. Zeng L, Hamasaki T, Evans SR. Data monitoring committee reports: Telling the data’s story. Ther Innov Regul Sci. 2025; 59:222-233.
2. Ge L, Hamasaki T, Evans SR. Inside the mind of the DMC: A review of principles and issues with case studies. Ther Innov Regul Sci. 2025; 59:234-244
3. Zeng L, Hamasaki T, Ge L, He Y, Evans SR. Benefit:risk assessments during clinical trials: a prediction approach using the desirability of outcome ranking (DOOR). In Biostatistics in Biopharmaceutical Research and Development: 80-Years of contributions and Dedications from the Deming Conference, Chen DG. (ed), Chapter 5, 161-180, Cham: Springer, 2024.
4. Asakura K, Evans SR, Hamasaki T. Interim monitoring for futility in clinical trials with two co-primary endpoints using prediction. Stat Biopharm Res 2020; 12:164-175.
5. Asakura K, Hamasaki T, Evans SR. Interim evaluation of efficacy or futility in group-sequential trials with multiple co-primary endpoints. Biom J. 2017; 59:703-731.

Multi-regional clinical trials

1. Hamasaki T, Wu YJ, Hsiao CF. Multiple endpoints in multiregional clinical trials, Chap17, In Simultaneous Global New Drug Development; Multi-Regional Clinical Trials after ICH E17, eds by: Gang Li et al. London, 2021, CRC Press.
2. Huang WS, Hung NH, Hamasaki T, Hsiao CF. Sample size determination for a specific region in multiregional clinical trials with multiple co-primary endpoints. PLoS ONE 2017; 12:e01804052017.
3. Ando Y, Hamasaki T. Practical issues and lessons learned from multi-regional clinical trials via case examples. A Japanese perspective. Pharm Stat. 2010; 9:190-200.
4. Goto M, Hamasaki T. Practical issues and observations on the use of foreign clinical data in the drug development. J Biopharm Stat 2002; 12: 369-384.
5. Hamasaki T, Isomura T, Baba M, Goto M. Statistical approaches to detecting dose-response relationships. Drug Inform J. 2000; 34:579-590.

Clinical Trials for Precision Medicine

1. Yin X, Hamasaki T, Evans SR. Sequential multiple assignment randomized trials for comparing personalized antibiotic strategies (SMART COMPASS): Design considerations. Stat Biopharm Res. 2021;13:181-191.
2. Evans SR, Follmann D, Liu Y, Holland T, Doernberg SB, Rouphael N, Hamasaki T, Jiang Y, Lok JL, Tran TTT, Harris AD, Fowler, Jr. VG, Boucher H, Kreiswirth BN, Bonomo RA, van Duin D, Paterson DL, Chambers H. Sequential Multiple Assignment Randomized Trials for COMparing Personalized Antibiotic StrategieS (SMART-COMPASS). Clin Infect Dis. 2019; 68:1961-1967.
3. Arano I, Sugimoto T, Hamasaki T, Ohno Y. Practical application of cure mixture model to long-term censored survivor data from a withdrawal clinical trial of patients with major depressive disorder. BMC Med Res Methodol. 2010; 10:33.

Other Statistical Methodologies

We have developed several statistical methodologies including confined and censored data, survival data.

1. Bebu I, Diao G, Hamasaki T. Generalized fiducial inference for the restricted mean survival time. Stat Meth Med Res. 2023; 32:1010-1020
2. Hamasaki T, Kim SY. Box and Cox power-transformation to confined and censored nonnormal responses in regression. Comput Stat Data Anal. 2007; 51:3788-3799.
3. Sugimoto T, Hamasaki T. Properties of estimators for baseline hazard functions in a semiparametric cure model. Ann Inst Stat Math 2006; 58:647-674.

PUBLICATIONS:

Selected Papers

Howard-Anderson J, Hamasaki T, Ge L, Collyar D, Rubin D, Nambiar S, Kinamon T, Leister-Tebbe H, Hill C, Geres H, Holland TL, Doernberg SB, Chambers HF, Fowler VG Jr, Evans SR, Boucher HW, on behalf of the Antibacterial Resistance Leadership Group. Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Acute Bacterial Skin and Skin Structure Infection. Open Forum Infect Dis. 2026; 13:ofag320. Editor’s choice

Hamasaki T, He Y, Wu Q, Howard-Anderson J, Boucher HW, Doernberg SB, Holland TL, Powers JH 3rd, Wang J, Diao G, van Duin D, Fowler VG Jr, Chambers HF, Evans SR. A patient-centric paradigm and tool for clinical research: the DOOR is open. Antimicrob Agents Chemother. 2026; 70:e0147825. Editor’s Pick

Lodise TP, Turner NA, Hamasaki T, Fishbane N, Ghazaryan V, Wall A, Ge L, Wu Q, Zeng L, Riccobene T, Patel R, Zaharoff S, Rappo U, Evans S, Fowler VG Jr, Chambers HF, Holland TL; Antibacterial Resistance Leadership Group. Pharmacokinetics of dalbavancin in complicated staphylococcus aureus bacteremia: A secondary analysis of the DOTS randomized clinical trial JAMA Network Open 2026; 9:e2611652.

Turner NA, Hamasaki T, Doernberg SB, Lodise TP, King HA, Ghazaryan V, Cosgrove SE, Jenkins TC, Liu C, Sharma S, Zaharoff Z, Wahid L, Renard VJ, Cook P, Raad I, Hachem R, Chaftari AM, Sims M, DeMarco C, Miller LG, McCarthy MW, Morse CG, Lucasti C, Forrest GN, Cherabuddi K, Polk C, Fazili T, Rupp ME, Thompson GR, Kim K, Strnad L, Schnee AE, McKinnell JA, Ramesh M, Silveira FP, McCarty TP, Lee TC, McDonald EG, Paolino K, Wiegand K, Wall A, Riccobene T, Patel R, Rappo U, Evans SR, Chambers HF, Fowler VG Jr,. Holland TL, on behalf of the Antibacterial Resistance Leadership GroupDalbavancin as an option for treatment of staphylococcus aureus bacteremia: The DOTS randomized clinical trial. JAMA 2025;334:866-877.

Evans SR, Pennello G, Zhang S, YLi Y, Wang Y, Cao Q, Komarow L, Hamasaki T, Petrides V, Meier K, Galicia NP, Fowler VG, Boucher HW, Doernberg SB, Banerjee R, Rigatto MH, Kreiswirth KN, Bonomo RA, Chambers HF, Patel RIntention-to-diagnose and distinct research foci in diagnostic accuracy studies. Lancet Infect Dis. 2025; 25:e472 - e481

Howard-Anderson J, Hamasaki T, Dai W, Collyar D, Rubin D, Nambiar S, Kinamon T, Leister-Tebbe H, Hill C, Geres H, Holland TL, Doernberg SB, Chambers HF, Fowler VG Jr, Evans SR, Boucher HW, on behalf of the Antibacterial Resistance Leadership Group. Moving beyond mortality: Development and application of a desirability of outcome ranking (DOOR) endpoint for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis 2024; 78:259-268.

Howard-Anderson J, Hamasaki T, Dai W, Collyar D, Rubin D, Nambiar S, Kinamon T, Hill C, Gelone SP, Mariano D, Baba T, Holland TL, Doernberg SB, Chambers HF, Fowler VG Jr, Evans SR, Boucher HW, on behalf of the Antibacterial Resistance Leadership Group. Improving traditional registrational trial endpoints: Development and application of a desirability of outcome ranking (DOOR) endpoint for complicated urinary tract infection clinical trials. Clin Infect Dis. 2023 76:e1157-e1165. Editor’s choice

Evans SR, Hamasaki T. Weighing evidence: robustness vs. quantity. J Natl Cancer Inst. 2022 ;115: djac186.

Koga M, Yamamoto H, Inoue M, Asakura K, Aoki J, Hamasaki T, Kanzawa T, Kondo R, Ohtaki M, Itabashi R, Kamiyama K, Iwama T, Nakase T, Yakushiji Y, Igarashi S, Nagakane Y, Takizawa S, Okada Y, Doijiri R, Tsujino A, Ito Y, Ohnishi H, Inoue T, Akagi Y, Hasegawa Y, Shiokawa Y, Sakai N, Osaki M, Uesaka Y, Yoshimura S, Urabe T, Ueda T, Ihara M, Kitazono T, Sasaki M, Oita A, Yoshimura S, Fukuda-Doi M, Miwa K, Kimura K, Minematsu K, Toyoda KThrombolysis with alteplase at 0.6 mg/kg for stroke with unknown time of onset: a randomized controlled trial. Stroke. 2020; 51:1530–1538.

Miyoshi T, Maeno Y, Hamasaki T, Inamura N, Yasukochi S, Kawataki M, Horigome H, Yoda H, Taketazu M, Nii M, Hagiwara A, Kato H, Shimizu W, Shiraishi I, Sakaguchi H, Ueda K, Katsuragi S, Yamamoto H, Sago H, Ikeda T, on behalf of the Japan Fetal Arrhythmia Group. Antenatal antiarrhythmic treatment for fetal tachyarrhythmias: a prospective multicentre trial. J Am Coll Cardiol. 2019; 74:874-885. JACC Editor-in-Chief Selected the Top 100 Papers in 2019

Kinoshita T, Yamakawa K, Matsuda H, Yoshikawa Y, Wada D, Hamasaki T, Ono K, Nakamori Y, Fujimi S. The survival benefit of a novel trauma workflow that includes immediate whole-body computed tomography, surgery, and interventional radiology, all in one trauma resuscitation room: A retrospective historical control study. Ann Surg. 2019; 269:370-376.

Asakura M, Kim J, Asanuma H, Nakama Y, Tsukahara K, Higashino Y, Ishikawa T, Koba S, Tsujimoto M, Himeno H, Maruyama Y, Ookusa T, Yoda S, Suzuki H, Okubo S, Shimizu M, Hashimoto Y, Satake K, Fujino S, Uzui H, Nagai Y, Kohno T, Mizuno S, Nakahama M, Kanaya H, Murohara T, Fukui K, Takase H, Ohte N, Shiono T, Fukunami M, Endo T, Sawada R, Fujii K Takeuchi M, Ikeda S, Mizuno K, Uematsu M, Matsubara T, Yano S, Takahashi J, Ueda K, Kinoshita Y, Tamita K, Hayashi H, Hamasaki T, Kitakaze M, and PPAR investigators. Cardiovascular outcomes in patients with previous myocardial infarction and mild diabetes mellitus following treatment with pioglitazone: Reports of a randomised trial from the Japan working group for the assessment whether pioglitazone protects DM patients against re-infarction (PPAR Study). EClinicalMedicine 2018; 4:10-24.

Nakamura M, Iijima R, Ako J, Shinke T, Okada H, Ito Y, Ando K, Anzai H, Tanaka H, Ueda Y, Takiuchi S, Nishida Y, Ohira H, Kawaguchi K, Kadotani M, Niinuma H, Omiya K, Morita T, Zen K, Yasaka Y, Inoue K, Ishiwata S, Ochiai M, Hamasaki T, Yokoi H on behalf of the NIPPON investigators. Dual antiplatelet therapy for 6 versus 18 months after biodegradable polymer drug eluting stent implantation. JACC: Cardiovasc Interv. 2017; 10:1189-1198.

Iida O, Nakamura M, Yamauchi Y, Fukunaga M, Yokoi Y, Yokoi H, Soga Y, Zen K, Suematsu N, Inoue N, Suzuki K, Hirano K, Shintani Y, Miyashita Y, Urasawa K , Kitano I, Tsuchiya T, Kawamoto K, Yamaoka T, Uesugi M, Shinke T, Oba Y, Ohura N, Uematsu M, Takahara M, Hamasaki T, Nanto S. 3-year outcomes of the OLIVE Registry, a prospective multi-center study of patients with critical limb ischemia: A prospective, multi-center, three-year follow-up study on endovascular treatment for intra-inguinal vessel in patients with critical limb ischemia. JACC: Cardiovasc Interv. 2015; 8:1493-1502.

Wataya-Kaneda M, Tanaka M, Yang L, Yang F, Tsuruta D, Nakamura A, Matsumoto S, Hamasaki T, Tanemura A, Katayama I. Clinical and histologic analysis of the efficacy of topical rapamycin therapy against hypomelanotic macules in tuberous sclerosis complex. JAMA Dermatol 2015; 151:722-730.

Mabuchi S, Matsumoto Y, Kawano M, Minami K, Sasano T, Takahashi R, Kuroda H, Hisamatsu T, Kakigano A, Hayashi M, Sawada K, Seo Y, Hamasaki T, Morii E, Kurachi H, Matsuura N, Kimura T. Uterine cervical cancer displaying tumor-related leukocytosis: A distinct clinical entity with radioresistant feature. J. Natl. Cancer Inst 2014; 106:dju147.

Oze T, Hiramatsu N, Yakushijin T, Miyazaki M, Yamada A, Oshita M, Hagiwara H, Mita E, Ito T, Fukui H, Inui Y, Hijioka T, Inada M, Katayama K, Tamura S, Yoshihara H, Inoue A, Imai Y, Hayashi E, Kato M, Miyagi T, Yoshida Y, Tatsumi T, Kasahara A, Hamasaki T, Hayashi N, Takehara T. Significance of post-treatment alpha-fetoprotein levels for hepatocellular carcinoma incidence after interferon therapy. Clin Gastroenterol Hepatol. 2014; 12:1186-1195.

Matsumoto S, Sakata Y, Nakatani D, Suna S, Usami M, Hara M, Kitamura T, Hamasaki T, Nanto S, Kawahara Y, Komuro I. Circulating p53-responsive microRNAs are predictive Indicators of Heart Failure after acute myocardial infarction. Circ Res 2013; 113:322-326.

Iida O, Yokoi H, Soga Y, Inoue N, Suzuki K, Yokoi Y, Kawasaki D, Zen K, Urasawa K, Shintani Y, Miyamoto A, Hirano K, Miyashita Y, Tsuchiya T, Shinozaki N, Nakamura M, Isshiki T, Hamasaki T, Nanto S. Cilostazol reduces angiographic restenosis after endovascular therapy for femoropopliteal lesions in the sufficient treatment of peripheral intervention by cilostazol (STOP-IC) study. Circulation 2013; 127:2307-2315.

Iida O, Nakamura M, Yamauchi Y, Miyamoto A, Kawasaki D, Yokoi Y, Yokoi Y, Soga Y, Zen K, Hirano K, Suematsu N, Inoue N, Suzuki K, Shintani Y, Miyashita Y, Urasawa K, Kitano I, Yamaoka T, Murakami T, Uesugi M, Tsuchiya T, Shinke T, Oba Y, Ohura N, Hamasaki T, Nanto S, on behalf of the OLIVE investigators. Endovascular treatment for infrainguinal vessels in patients with critical limb ischemia. OLIVE registry, a prospective, multicenter study in Japan with 12-month Follow-up. Circ: Cardiovasc Interv 2013; 6:68-76.

Yamakawa K, S Fujimi, T Mohri, H Matsuda, Y Nakamori, T Hirose, Tasaki O, Ogura H, Kuwagata Y, Hamasaki T, Shimazu S. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study. Crit Care. 2011; 15:R123.

Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, Seguchi O, Myoishi M, Minamino T, Ohara T, Nagai Y, Nanto S, Watanabe K, Fukuzawa S, Hirayama A, Nakamura N, Kimura K, Fujii K, Ishihara M, Saito Y, J-Wind Study Group. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): Two randomised trials. The Lancet 2007; 370:1483-1493.

Sato T, Nakanishi T, Yamamoto Y, Andersen MP, Ogawa Y, Fukada K, Zhou Z, Aoike F, Sugai F, Nagano S, Hirata S, Ogawa M, Nakano R, Ohi T, Kato T, Nakagawa M, Hamasaki T, Shimizu A, Sakoda S. Rapid disease progression correlates with instability of mutant SOD1 in familial ALS. Neurology 2005; 65:1954-1957.

Interviews

Interview of Toshi Hamasaki by BIOP Report. ASA Biopharmaceutical Resport 2020; 27(2):20-22.

Episode 60: Toshimitsu Hamasaki. ASA Biopharm's Pocast, December 31, 2018.

Complete list available in Google Scholar

Complete list available in PubMed