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Randomized controlled trials (RCTs) are the gold standard for assessing drug safety and efficacy. However, RCTs have some drawbacks which have led to the use of single-arm studies to make certain internal drug development and regulatory…

Randomized clinical trials (RCTs) are widely considered the gold standard for evaluating the effectiveness of new treatments or interventions in drug development. Still, they may not be feasible in certain cases, such as with rare diseases…

Methodology · Statistics 2025-08-05 Di Ran , Fanni Zhang , Sima Shahsavari , Kristine Broglio , Alasdair Henderson , Binbing Yu

Augmenting randomized controlled trials (RCTs) with external real-world data (RWD) has the potential to improve the finite sample efficiency of treatment effect estimators. We describe using adaptive targeted maximum likelihood estimation…

Methodology · Statistics 2025-01-30 Sky Qiu , Jens Tarp , Andrew Mertens , Mark van der Laan

Clinical trials with a hybrid control arm (a control arm constructed from a combination of randomized patients and real-world data on patients receiving usual care in standard clinical practice) have the potential to decrease the cost of…

Methodology · Statistics 2021-08-20 Joanna Harton , Brian Segal , Ronac Mamtani , Nandita Mitra , Rebecca Hubbard

As clinical decision-making increasingly moves toward individualized and context-specific treatment recommendations, reliance on any single evidence source, randomized or observational, may be insufficient. Principled integration of…

Randomized controlled trials (RCTs) face inherent limitations, such as ethical or resource constraints, which lead to a limited number of study participants. To address these limitations, recent research endeavors have sought to incorporate…

Methodology · Statistics 2025-02-20 Peijin Wang , Hwanhee Hong , Kyungeun Jeon , Laine Elliott Thomas

PURPOSE Providing rapid answers and early acces to patients to innovative treatments without randomized clinical trial (RCT) is growing, with benefit estimated from single-arm trials. This has become common in oncology, impacting the…

Randomized controlled trials (RCTs) are the gold standard for evaluating causal effects but are often costly and difficult to scale; consequently, they are frequently augmented with auxiliary external controls in many applications. Prior…

Methodology · Statistics 2026-05-28 Jiawei Shan , Yiteng Tu , Guanbo Wang , Chao Ying , Jiwei Zhao

While randomized controlled trials (RCTs) are the gold standard for estimating treatment effects in medical research, there is increasing use of and interest in using real-world data for drug development. One such use case is the…

Methodology · Statistics 2021-10-11 Devin Incerti , Michael T Bretscher , Ray Lin , Chris Harbron

A/B testing, a widely used form of Randomized Controlled Trial (RCT), is a fundamental tool in business data analysis and experimental design. However, despite its intent to maintain randomness, A/B testing often faces challenges that…

Methodology · Statistics 2024-08-13 Zihao Zheng , Carol Liu

In recent years, real-world external controls have grown in popularity as a tool to empower randomized placebo-controlled trials, particularly in rare diseases or cases where balanced randomization is unethical or impractical. However, as…

Methodology · Statistics 2024-11-14 Chenyin Gao , Shu Yang , Mingyang Shan , Wenyu Ye , Ilya Lipkovich , Douglas Faries

Hybrid randomized controlled trials (hybrid RCTs) integrate external control data, such as historical or concurrent data, with data from randomized trials. While numerous frequentist and Bayesian methods, such as the test-then-pool and…

Methodology · Statistics 2025-10-07 Han Chang Chiam , Franz König , Martin Posch

We develop a method for hybrid analyses that uses external controls to augment internal control arms in randomized controlled trials (RCT) where the degree of borrowing is determined based on similarity between RCT and external control…

Methodology · Statistics 2023-05-11 Evan Kwiatkowski , Jiawen Zhu , Xiao Li , Herbert Pang , Grazyna Lieberman , Matthew A. Psioda

In situations where it is difficult to enroll patients in randomized controlled trials, external data can improve efficiency and feasibility. In such cases, adaptive trial designs could be used to decrease enrollment in the control arm of…

Methodology · Statistics 2020-10-02 Brian D. Segal , W. Katherine Tan

Randomized experiments play a major role in data-driven decision making across many different fields and disciplines. In medicine, for example, randomized controlled trials (RCTs) are the backbone of clinical trial methodology for testing…

Applications · Statistics 2016-08-30 Andrew W. Correia

External controls (ECs) from historical trials or real-world data have gained increasing attention as a way to augment hybrid and single-arm trials, especially when balanced randomization is infeasible. While most existing work has focused…

Methodology · Statistics 2025-12-15 Yujing Gao , Xiang Zhang , Shu Yang

Leveraging external controls -- relevant individual patient data under control from external trials or real-world data -- has the potential to reduce the cost of randomized controlled trials (RCTs) while increasing the proportion of trial…

Methodology · Statistics 2022-07-13 Yanyao Yi , Ying Zhang , Yu Du , Ting Ye

Randomized Controlled Trials (RCTs) are the gold standard for evaluating the effect of new medical treatments. Treatments must pass stringent regulatory conditions in order to be approved for widespread use, yet even after the regulatory…

Machine Learning · Statistics 2025-03-13 Omer Noy Klein , Alihan Hüyük , Ron Shamir , Uri Shalit , Mihaela van der Schaar

Randomized controlled trials (RCTs) have been the cornerstone of clinical evidence; however, their cost, duration, and restrictive eligibility criteria limit power and external validity. Studies using real-world data (RWD), historically…

Methodology · Statistics 2025-11-26 Shu Yang , Margaret Gamalo , Haoda Fu

Randomized controlled trials (RCTs) are widely regarded as the gold standard for causal inference in biomedical research. For instance, when estimating the average treatment effect on the treated (ATT), a doubly robust estimation procedure…

Methodology · Statistics 2025-09-26 Chi-Shian Dai , Chao Ying , Yang Ning , Jiwei Zhao
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