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There has been a growing trend that activities relating to clinical trials take place at locations other than traditional trial sites (hence decentralized clinical trials or DCTs), some of which are at settings of real-world clinical practice. Although there are numerous benefits of DCTs, this also brings some implications on a number of issues relating to the design, conduct, and analysis of DCTs. The Real-World Evidence Scientific Working Group of the American Statistical Association Biopharmaceutical Section has been reviewing the field of DCTs and provides in this paper considerations for decentralized trials from a statistical perspective. This paper first discusses selected critical decentralized elements that may have statistical implications on the trial and then summarizes regulatory guidance, framework, and initiatives on DCTs. More discussions are presented by focusing on the design (including construction of estimand), implementation, statistical analysis plan (including missing data handling), and reporting of safety events. Some additional considerations (e.g., ethical considerations, technology infrastructure, study oversight, data security and privacy, and regulatory compliance) are also briefly discussed. This paper is intended to provide statistical considerations for decentralized trials of medical products to support regulatory decision-making.

Real-world data (RWD) and real-world evidence (RWE) have been increasingly used in medical product development and regulatory decision-making, especially for rare diseases. After outlining the challenges and possible strategies to address the challenges in rare disease drug development (see the accompanying paper), the Real-World Evidence (RWE) Scientific Working Group of the American Statistical Association Biopharmaceutical Section reviews the roles of RWD and RWE in clinical trials for drugs treating rare diseases. This paper summarizes relevant guidance documents and frameworks by selected regulatory agencies and the current practice on the use of RWD and RWE in natural history studies and the design, conduct, and analysis of rare disease clinical trials. A targeted learning roadmap for rare disease trials is described, followed by case studies on the use of RWD and RWE to support a natural history study and marketing applications in various settings.

Developing drugs for rare diseases presents unique challenges from a statistical perspective. These challenges may include slowly progressive diseases with unmet medical needs, poorly understood natural history, small population size, diversified phenotypes and geneotypes within a disorder, and lack of appropriate surrogate endpoints to measure clinical benefits. The Real-World Evidence (RWE) Scientific Working Group of the American Statistical Association Biopharmaceutical Section has assembled a research team to assess the landscape including challenges and possible strategies to address these challenges and the role of real-world data (RWD) and RWE in rare disease drug development. This paper first reviews the current regulations by regulatory agencies worldwide and then discusses in more details the challenges from a statistical perspective in the design, conduct, and analysis of rare disease clinical trials. After outlining an overall development pathway for rare disease drugs, corresponding strategies to address the aforementioned challenges are presented. Other considerations are also discussed for generating relevant evidence for regulatory decision-making on drugs for rare diseases. The accompanying paper discusses how RWD and RWE can be used to improve the efficiency of rare disease drug development.

Multiple imputation (MI) models can be improved by including auxiliary covariates (AC), but their performance in high-dimensional data is not well understood. We aimed to develop and compare high-dimensional MI (HDMI) approaches using structured and natural language processing (NLP)-derived AC in studies with partially observed confounders. We conducted a plasmode simulation study using data from opioid vs. non-steroidal anti-inflammatory drug (NSAID) initiators (X) with observed serum creatinine labs (Z2) and time-to-acute kidney injury as outcome. We simulated 100 cohorts with a null treatment effect, including X, Z2, atrial fibrillation (U), and 13 other investigator-derived confounders (Z1) in the outcome generation. We then imposed missingness (MZ2) on 50% of Z2 measurements as a function of Z2 and U and created different HDMI candidate AC using structured and NLP-derived features. We mimicked scenarios where U was unobserved by omitting it from all AC candidate sets. Using LASSO, we data-adaptively selected HDMI covariates associated with Z2 and MZ2 for MI, and with U to include in propensity score models. The treatment effect was estimated following propensity score matching in MI datasets and we benchmarked HDMI approaches against a baseline imputation and complete case analysis with Z1 only. HDMI using claims data showed the lowest bias (0.072). Combining claims and sentence embeddings led to an improvement in the efficiency displaying the lowest root-mean-squared-error (0.173) and coverage (94%). NLP-derived AC alone did not perform better than baseline MI. HDMI approaches may decrease bias in studies with partially observed confounders where missingness depends on unobserved factors.

Recognizing the importance of real-world data (RWD) for regulatory purposes, the United States (US) Congress passed the 21st Century Cures Act1 mandating the development of Food and Drug Administration (FDA) guidance on regulatory use of real-world evidence. The Forum on the Integration of Observational and Randomized Data (FIORD) conducted a meeting bringing together various stakeholder groups to build consensus around best practices for the use of RWD to support regulatory science. Our companion paper describes in detail the context and discussion carried out in the meeting, which includes a recommendation to use a causal roadmap for complete pre-specification of study designs using RWD. This article discusses one step of the roadmap: the specification of a procedure for sensitivity analysis, defined as a procedure for testing the robustness of substantive conclusions to violations of assumptions made in the causal roadmap. We include a worked-out example of a sensitivity analysis from a RWD study on the effectiveness of Nifurtimox in treating Chagas disease, as well as an overview of various methods available for sensitivity analysis in causal inference, emphasizing practical considerations on their use for regulatory purposes.

The American Statistical Association Biopharmaceutical Section (ASA BIOP) working group on real-world evidence (RWE) has been making continuous, extended effort towards a goal of supporting and advancing regulatory science with respect to non-interventional, clinical studies intended to use real-world data for evidence generation for the purpose of medical product development and evaluation (i.e., RWE studies). In 2023, the working group published a manuscript delineating challenges and opportunities in constructing estimands for RWE studies following a framework in ICH E9(R1) guidance on estimand and sensitivity analysis. As a follow-up task, we describe the other issue in RWE studies, sensitivity analysis. Focusing on the issue of unmeasured confounding, we review availability and applicability of sensitivity analysis methods for different types unmeasured confounding. We discuss consideration on the choice and use of sensitivity analysis for RWE studies. Updated version of this article will present how findings from sensitivity analysis could support regulatory decision-making using a real example., Comment: 17 pages, 2 figures

A Real-World Evidence (RWE) Scientific Working Group (SWG) of the American Statistical Association Biopharmaceutical Section (ASA BIOP) has been reviewing statistical considerations for the generation of RWE to support regulatory decision-making. As part of the effort, the working group is addressing estimands in RWE studies. Constructing the right estimand -- the target of estimation -- which reflects the research question and the study objective, is one of the key components in formulating a clinical study. ICH E9(R1) describes statistical principles for constructing estimands in clinical trials with a focus on five attributes -- population, treatment, endpoints, intercurrent events, and population-level summary. However, defining estimands for clinical studies using real-world data (RWD), i.e., RWE studies, requires additional considerations due to, for example, heterogeneity of study population, complexity of treatment regimes, different types and patterns of intercurrent events, and complexities in choosing study endpoints. This paper reviews the essential components of estimands and causal inference framework, discusses considerations in constructing estimands for RWE studies, highlights similarities and differences in traditional clinical trial and RWE study estimands, and provides a roadmap for choosing appropriate estimands for RWE studies.

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized controlled trials with outcomes assessed using RWD to fully observational studies. Yet many RWE study proposals lack sufficient detail to evaluate adequacy, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to pre-specify analytic study designs; it addresses a wide range of guidance within a single framework. By requiring transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on pre-specified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers, with companion papers demonstrating application of the Causal Roadmap for specific use cases., Comment: 51 pages, 2 figures, 4 tables

Purpose: The Targeted Learning roadmap provides a systematic guide for generating and evaluating real-world evidence (RWE). From a regulatory perspective, RWE arises from diverse sources such as randomized controlled trials that make use of real-world data, observational studies, and other study designs. This paper illustrates a principled approach to assessing the validity and interpretability of RWE. Methods: We applied the roadmap to a published observational study of the dose-response association between ritodrine hydrochloride and pulmonary edema among women pregnant with twins in Japan. The goal was to identify barriers to causal effect estimation beyond unmeasured confounding reported by the study's authors, and to explore potential options for overcoming the barriers that robustify results. Results: Following the roadmap raised issues that led us to formulate alternative causal questions that produced more reliable, interpretable RWE. The process revealed a lack of information in the available data to identify a causal dose-response curve. However, under explicit assumptions the effect of treatment with any amount of ritodrine versus none, albeit a less ambitious parameter, can be estimated from data. Conclusion: Before RWE can be used in support of clinical and regulatory decision-making, its quality and reliability must be systematically evaluated. The TL roadmap prescribes how to carry out a thorough, transparent, and realistic assessment of RWE. We recommend this approach be a routine part of any decision-making process., Comment: 13 pages, 4 figures

The 21st Century Cures Act of 2016 includes a provision for the U.S. Food and Drug Administration (FDA) to evaluate the potential use of real-world evidence (RWE) to support new indications for use for previously approved drugs, and to satisfy post-approval study requirements. Extracting reliable evidence from real-world data (RWD) is often complicated by a lack of treatment randomization, potential intercurrent events, and informative loss to follow up. Targeted Learning (TL) is a sub-field of statistics that provides a rigorous framework to help address these challenges. The TL Roadmap offers a step-by-step guide to generating valid evidence and assessing its reliability. Following these steps produces an extensive amount of information for assessing whether the study provides reliable scientific evidence in support regulatory decision making. This paper presents two case studies that illustrate the utility of following the roadmap. We use targeted minimum loss-based estimation combined with super learning to estimate causal effects. We also compared these findings with those obtained from an unadjusted analysis, propensity score matching, and inverse probability weighting. Non-parametric sensitivity analyses illuminate how departures from (untestable) causal assumptions would affect point estimates and confidence interval bounds that would impact the substantive conclusion drawn from the study. TL's thorough approach to learning from data provides transparency, allowing trust in RWE to be earned whenever it is warranted., Comment: 34 pages (25 pages main paper + references, 9 page Appendix), 6 figures version 2 corrected minor typos, numbering errors, etc

Common tasks encountered in epidemiology, including disease incidence estimation and causal inference, rely on predictive modeling. Constructing a predictive model can be thought of as learning a prediction function, i.e., a function that takes as input covariate data and outputs a predicted value. Many strategies for learning these functions from data are available, from parametric regressions to machine learning algorithms. It can be challenging to choose an approach, as it is impossible to know in advance which one is the most suitable for a particular dataset and prediction task at hand. The super learner (SL) is an algorithm that alleviates concerns over selecting the one "right" strategy while providing the freedom to consider many of them, such as those recommended by collaborators, used in related research, or specified by subject-matter experts. It is an entirely pre-specified and data-adaptive strategy for predictive modeling. To ensure the SL is well-specified for learning the prediction function, the analyst does need to make a few important choices. In this Education Corner article, we provide step-by-step guidelines for making these choices, walking the reader through each of them and providing intuition along the way. In doing so, we aim to empower the analyst to tailor the SL specification to their prediction task, thereby ensuring their SL performs as well as possible. A flowchart provides a concise, easy-to-follow summary of key suggestions and heuristics, based on our accumulated experience, and guided by theory., Comment: A revised version of this article, which incorporates several modifications based on referees' suggestions, has been published in the International Journal of Epidemiology by Oxford University Press

Video Panoptic Segmentation (VPS) aims at assigning a class label to each pixel, uniquely segmenting and identifying all object instances consistently across all frames. Classic solutions usually decompose the VPS task into several sub-tasks and utilize multiple surrogates (e.g. boxes and masks, centres and offsets) to represent objects. However, this divide-and-conquer strategy requires complex post-processing in both spatial and temporal domains and is vulnerable to failures from surrogate tasks. In this paper, inspired by object-centric learning which learns compact and robust object representations, we present Slot-VPS, the first end-to-end framework for this task. We encode all panoptic entities in a video, including both foreground instances and background semantics, with a unified representation called panoptic slots. The coherent spatio-temporal object's information is retrieved and encoded into the panoptic slots by the proposed Video Panoptic Retriever, enabling it to localize, segment, differentiate, and associate objects in a unified manner. Finally, the output panoptic slots can be directly converted into the class, mask, and object ID of panoptic objects in the video. We conduct extensive ablation studies and demonstrate the effectiveness of our approach on two benchmark datasets, Cityscapes-VPS (\textit{val} and test sets) and VIPER (\textit{val} set), achieving new state-of-the-art performance of 63.7, 63.3 and 56.2 VPQ, respectively.