Target trial emulation in oncology: current use and future directions

Hui-Yao Huang; Le Wang; Sheng Xu; Shuo-Peng Jia; Dan-Dan Kong; Xue-Jing Zhang; Si-Qi Wang; Han-Qing He; Hao-Ran Chen; Lu-Zhu Xia; Lan-Wei Guo; Yu Tang; Ling-Bin Du; Ning Li

doi:10.1186/s40779-026-00685-9

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Target trial emulation in oncology: current use and future directions

PERSPECTIVE | Updated：2026-08-20

- Target trial emulation in oncology: current use and future directions
- Target trial emulation in oncology: current use and future directions
- Military Medical Research 2026年13卷第7期页码：1033-1041
- Affiliations：
  
  Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
  Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
  Global Statistics and Data Science, BeiGene, Shanghai 200001, China
  School of Statistics, Renmin University of China, Beijing 100872, China
  School of Public Health, Qingdao University, Qingdao 266071, Shandong, China
  Minzu University of China, Beijing 100081, China
  Department of Clinical Research Management, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
- Author bio：
  
  * Ning Li ncctrials@cicams.ac.cn
- Funds：
  
  the National Natural Science Foundation of China(82303955);the Beijing Nova Program(20230484277)
- DOI：10.1186/s40779-026-00685-9
  中图分类号：
- 收稿：2025-07-13，
  
  录用：2026-01-28，
  
  网络首发：2026-02-24，
  
  纸质出版：2026-07
- Accepted：
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Hui-Yao Huang, Le Wang, Sheng Xu, 等. Target trial emulation in oncology: current use and future directions[J]. Military Medical Research, 2026,13(7):1033-1041.

Hui-Yao Huang, Le Wang, Sheng Xu, et al. Target trial emulation in oncology: current use and future directions[J]. Military Medical Research, 2026, 13(7): 1033-1041.
Hui-Yao Huang, Le Wang, Sheng Xu, 等. Target trial emulation in oncology: current use and future directions[J]. Military Medical Research, 2026,13(7):1033-1041. DOI： 10.1186/s40779-026-00685-9.

Hui-Yao Huang, Le Wang, Sheng Xu, et al. Target trial emulation in oncology: current use and future directions[J]. Military Medical Research, 2026, 13(7): 1033-1041. DOI： 10.1186/s40779-026-00685-9.

摘要

Abstract

Target trial emulation (TTE) has demonstrated popularity because of its ability to improve the reliability of causal inference from observational data. Nevertheless

knowledge about the current use

potential challenges

and insights of target trials in oncology is scarce. A total of 90 TTE studies in cancer areas were identified through systematic reviews in PubMed and Embase. Among the 54 applications in cancer treatment

registry databases (44.4%) and overall survival (OS

63.0%) were predominantly used as data sources and primary endpoints

respectively. Approximately 30 (55.6%) of the included TTE cases were associated with immortal time bias

and 21 (38.9%) were associated with prevalent user bias. Among the 21 trials from 13 studies that aimed to calibrate the results from preexisting randomized controlled trials (RCTs)

only 42.9% met both statistical agreement and estimate agreement. The availability of fit-for-purpose data sources and uncertainty about result concordance were the main hurdles limiting the quantity and quality of TTE in oncology areas. Promoting regulatory acceptance by initiating special projects could be crucial for the expanded application of real-world data (RWD) using TTE. Potential solutions

such as the integration of electronic medical records at the regional or country level

linkage with insurance claims databases

the modernization of eligibility criteria

the use of OS as the primary endpoint

and other best practices

were recommended for improving the feasibility and quality of oncology TTE.

关键词

Keywords

references

Tannock IF , Amir E , Booth CM , Niraula S , Ocana A , Seruga B , et al . Relevance of randomised controlled trials in oncology . Lancet Oncol . 2016 ; 17 ( 12 ): e560 – 7 .

Sheldrick RC . Randomized trials vs real-world evidence: how can both inform decision-making? . JAMA . 2023 ; 329 ( 16 ): 1352 – 3 .

Booth CM , Karim S , MacKillop WJ . Real-world data: towards achieving the achievable in cancer care . Nat Rev Clin Oncol . 2019 ; 16 ( 5 ): 312 – 25 .

Koole SN , Huisman AH , Timmers L , et al . Lessons learned from postmarketing withdrawals of expedited approvals for oncology drug indications . Lancet Oncol . 2024 ; 25 ( 3 ): e126 – 35 .

McGranahan N , Swanton C . Biological and therapeutic impact of intratumor heterogeneity in cancer evolution . Cancer Cell . 2015 ; 27 ( 1 ): 15 – 26 .

Ahmad TA , Gopal DP , Chelala C , Dayem Ullah AZ , Taylor SJ . Multimorbidity in people living with and beyond cancer: a scoping review . Am J Cancer Res . 2023 ; 13 ( 9 ): 4346 – 65 .

Tan YY , Papez V , Chang WH , Mueller SH , Denaxas S , Lai AG . Comparing clinical trial population representativeness to real-world populations: an external validity analysis encompassing 43,895 trials and 5,685,738 individuals across 989 unique drugs and 286 conditions in England . Lancet Healthy Longev . 2022 ; 3 ( 10 ): e674 – 89 .

Azoulay L . Rationale, strengths, and limitations of real-world evidence in oncology: a Canadian review and perspective . Oncologist . 2022 ; 27 ( 9 ): e731 – 8 .

Dahabreh IJ , Bibbins-Domingo K . Causal inference about the effects of interventions from observational studies in medical journals . JAMA . 2024 ; 331 ( 21 ): 1845 – 53 .

Hernán MA , Robins JM . Using big data to emulate a target trial when a randomized trial is not available . Am J Epidemiol . 2016 ; 183 ( 8 ): 758 – 64 .

Hernán MA , Wang W , Leaf DE . Target trial emulation: a framework for causal inference from observational data . JAMA . 2022 ; 328 ( 24 ): 2446 – 7 .

U. S. Food & Drug Administration : Real-world data: assessing electronic health records and medical claims data to support regulatory decision-making for drug and biological products . https://www.fda.gov/regulatory-information/search-fda-guidance-documents/real-world-data-assessing-electronic-health-records-and-medical-claims-data-support-regulatory . Accessed 30 Oct 2025 .

Miller K , Wang M , Gralow J , Dickler M , Cobleigh M , Perez EA , et al . Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer . N Engl J Med . 2007 ; 357 ( 26 ): 2666 – 76 .

Antoine A , Pérol D , Robain M , Delaloge S , Lasset C , Drouet Y . Target trial emulation to assess real-world efficacy in the Epidemiological Strategy and Medical Economics metastatic breast cancer cohort . J Natl Cancer Inst . 2023 ; 115 ( 8 ): 971 – 80 .

Yadav K , Lewis RJ . Immortal time bias in observational studies . JAMA . 2021 ; 325 ( 7 ): 686 – 7 .

Li Y , Zhu L , Ma J , Wang Y , Lin Y , Ye Y , et al . Metronomic chemotherapy of paclitaxel plus cisplatin in patients with metastatic breast cancer: a target trial emulation study . Ther Adv Med Oncol . 2025 ; 17 : 17588359251384228 .

Thill M , Zahn MO , Welt A , Nusch A , Zaiss M , Engelken K , et al . Head-to-head comparison of palbociclib and ribociclib in first-line treatment of HR-positive/HER2-negative metastatic breast cancer with real-world data from the OPAL registry . Int J Cancer . 2025 ; 156 ( 9 ): 1770 – 82 .

Merola D , Campbell U , Lenis D , Schneeweiss S , Wang S , Madsen A , et al . Calibrating observational health record data against a randomized trial . JAMA Netw Open . 2024 ; 7 ( 9 ): e2436535 .

Jourdain H , Di Meglio A , Mansouri I , Desplas D , Zureik M , Haddy N . Real-world efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine and tucatinib as second-line and third-line treatments for HER2-positive metastatic breast cancer: two target trial emulation studies . Lancet Reg Health Eur . 2025 ; 58 : 101455 .

Westerberg M , Garmo H , Robinson D , Stattin P , Gedeborg R . Target trial emulation using new comorbidity indices provided risk estimates comparable to a randomized trial . J Clin Epidemiol . 2024 ; 174 : 111504 .

Chen HJ , Cheng WC , Tu CY , Hsia TC , Lin YS , Fang HY , et al . Stereotactic ablative radiotherapy versus conventional fractionated radiotherapy for clinical early-stage non-small-cell lung cancer: a population-based study . Thorac Cancer . 2024 ; 15 ( 24 ): 1779 – 91 .

Boyne DJ , Cheung WY , Hilsden RJ , Sajobi TT , Batra A , Friedenreich CM , et al . Association of a shortened duration of adjuvant chemotherapy with overall survival among individuals with stage III colon cancer . JAMA Netw Open . 2021 ; 4 ( 3 ): e213587 .

Ernandez J , Kaul S , Fleishman A , Korets R , Chang P , Wagner A , et al . Adjuvant chemotherapy plus radiotherapy versus chemotherapy alone for locally advanced bladder cancer after radical cystectomy . Bladder Cancer . 2022 ; 8 ( 4 ): 405 – 17 .

Bharadwaj M , Kaul S , Fleishman A , Korets R , Chang P , Wagner A , et al . Adjuvant chemotherapy versus observation following radical cystectomy for locally advanced urothelial carcinoma of the bladder . Urol Oncol . 2022 ; 40 ( 6 ): 274.e15 - 274.e23 .

Antoine A , Pérol D , Robain M , Bachelot T , Choquet R , Jacot W , et al . Assessing the real-world effectiveness of 8 major metastatic breast cancer drugs using target trial emulation . Eur J Cancer . 2024 ; 213 : 115072 .

Merola D , Young J , Schrag D , Lin KJ , Alwardt S , Schneeweiss S . Effectiveness research in oncology with electronic health record data: a retrospective cohort study emulating the PALOMA-2 trial . Pharmacoepidemiol Drug Saf . 2023 ; 32 ( 4 ): 426 – 34 .

Petito LC , García-Albéniz X , Logan RW , Howlader N , Mariotto AB , Dahabreh IJ , et al . Estimates of overall survival in patients with cancer receiving different treatment regimens: emulating hypothetical target trials in the surveillance, epidemiology, and end results (SEER)-medicare linked database . JAMA Netw Open . 2020 ; 3 ( 3 ): e200452 .

Voelskow V , Garcia-Albeniz X , Berglund A , Feychting M , Kurth T , Matthews AA . Trastuzumab in early curative breast cancer: a target trial emulation benchmarked against two randomized clinical trials . PLoS Med . 2025 ; 22 ( 7 ): e1004661 .

Fang Q , Fung CY , Wang J , Lai WH , Wong RSM , Kho BCS , et al . Hypomethylating agent versus venetoclax combination: an electronic health records-based target trial emulation among Asian elderly patients with newly diagnosed acute myeloid leukaemia in Hong Kong . Ther Adv Hematol . 2025 ; 16 : 20406207251346910 .

Wang SV , Schneeweiss S , Franklin JM , Desai RJ , Feldman W , et al . Emulation of randomized clinical trials with nonrandomized database analyses: results of 32 clinical trials . JAMA . 2023 ; 329 ( 16 ): 1376 – 85 .

Garcia S , Bisen A , Yan J , Xie XJ , Ramalingam S , Schiller JH , et al . Thoracic oncology clinical trial eligibility criteria and requirements continue to increase in number and complexity . J Thorac Oncol . 2017 ; 12 ( 10 ): 1489 – 95 .

Huang H , Miao H , Tang J , Li N . Reflections and insights into the evolution of restrictive eligibility criteria for cancer clinical trials in China and beyond . Cancer Commun . 2025 ; 45 ( 6 ): 673 – 6 .

U. S. Food & Drug Administration : Clinical trial endpoints for the approval of cancer drugs and biologics . https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-endpoints-approval-cancer-drugs-and-biologics . Accessed 30 Oct 2025 .

Desai RJ , Wang SV , Sreedhara SK , et al . Process guide for inferential studies using healthcare data from routine clinical practice to evaluate causal effects of drugs (PRINCIPLED): considerations from the FDA Sentinel innovation center . BMJ . 2024 ; 384 : e076460 .

CERBOT : https://certbot.eff.org/ . Accessed 30 Oct 2025 .

Cashin AG , Hansford HJ , Hernán MA , Swanson SA , Lee H , Jones MD , et al . Transparent reporting of observational studies emulating a target trial-the TARGET statement . JAMA . 2025 ; 334 ( 12 ): 1084 – 93 .

Seewald NJ , McGinty EE , Stuart EA . Target trial emulation for evaluating health policy . Ann Intern Med . 2024 ; 177 ( 11 ): 1530 – 8 .

European Medicines Agency : Reflection paper on the use of real-world data in non-interventional studies to generate real-world evidence . https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-use-real-world-data-non-interventional-studies-generate-real-world-evidence_en.pdf . Accessed 30 Oct 2025 .

U. S. Food & Drug Administration : Considerations for the use of real-world data and real-world evidence to support regulatory decision-making for drug and biological products . https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-real-world-data-and-real-world-evidence-support-regulatory-decision-making-drug . Accessed 30 Oct 2025 .

U. S. Food & Drug Administration : Calibrating real-world evidence studies in oncology against randomized trials: ENCORE . https://www.fda.gov/about-fda/oncology-center-excellence/calibrating-real-world-evidence-studies-oncology-against-randomized-trials-encore . Accessed 30 Oct 2025 .

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