The question of how individual patient data from cohort studies or historical clinical trials can be leveraged for designing more powerful, or smaller yet equally powerful, clinical trials becomes increasingly important in the era of digitalisation. Today, the traditional statistical analyses approaches may seem questionable to practitioners in light of ubiquitous historical covariate information.
Several methodological developments aim at incorporating historical information in the design and analysis of future clinical trials, most importantly Bayesian information borrowing, propensity score methods, stratification, and covariate adjustment. Recently, adjusting the analysis with respect to a prognostic score, which was obtained from some machine learning procedure applied to historical data, has been suggested and we study the potential of this approach for randomised clinical trials.
In an idealised situation of a normal outcome in a two-arm trial with 1:1 allocation, we derive a simple sample size reduction formula as a function of two criteria characterising the prognostic score: (1) The coefficient of determination $R^2$ on historical data and (2) the correlation $ρ$ between the estimated and the true unknown prognostic scores. While maintaining the same power, the original total sample size $n$ planned for the unadjusted analysis reduces to $(1 - R^2 ρ^2) \times n$ in an adjusted analysis. Robustness in less ideal situations was assessed empirically. We conclude that there is potential for substantially more powerful or smaller trials, but only when prognostic scores can be accurately estimated.
In clinical trials, identification of prognostic and predictive biomarkers is essential to precision medicine. Prognostic biomarkers can be useful for the prevention of the occurrence of the disease, and predictive biomarkers can be used to identify patients with potential benefit from the treatment. Previous researches were mainly focused on clinical characteristics, and the use of genomic data in such an area is hardly studied. A new method is required to simultaneously select prognostic and predictive biomarkers in high dimensional genomic data where biomarkers are highly correlated. We pro…
Enhancing Longitudinal Clinical Trial Efficiency with Digital Twins and Prognostic Covariate-Adjusted Mixed Models for Repeated Measures (PROCOVA-MMRM)
Data-Adaptive and Model-Robust Covariate Adjustment for Time-to-Event Outcomes in Stratified Randomized Trials
Cornell Tech, Cornell University（康奈尔科技校区，康奈尔大学）；Department of Biostatistics, Department of Population Health, New York University School of Medicine（纽约大学医学院生物统计学系、人口健康系）
Randomized clinical trials are often designed to assess whether a test treatment prolongs survival relative to a control treatment. Increased patient heterogeneity, while desirable for generalizability of results, can weaken the ability of common statistical approaches to detect treatment differences, potentially hampering the regulatory approval of safe and efficacious therapies. A novel solution to this problem is proposed. A list of baseline covariates that have the potential to be prognostic for survival under either treatment is pre-specified in the analysis plan. At the analysis stage, u…
In randomized trials, appropriately adjusting for baseline variables and short-term outcomes can lead to increased precision and reduced sample size. We examine the impact of such adjustment in group sequential designs, i.e., designs with preplanned interim analyses where enrollment may be stopped early for efficacy or futility. We address the following questions: how much precision gain can be obtained by appropriately adjusting for baseline variables and a short-term outcome? How is this precision gain impacted by factors such as the proportion of pipeline participants (those who enrolled bu…
Prognosis on the occurrence of relapses in individuals with Relapsing-Remitting Multiple Sclerosis (RRMS), the most common subtype of Multiple Sclerosis (MS), could support individualized decisions and disease management and could be helpful for efficiently selecting patients in future randomized clinical trials. There are only three previously published prognostic models on this, all of them with important methodological shortcomings. We aim to present the development, internal validation, and evaluation of the potential clinical benefit of a prognostic model for relapses for individuals with…
Knockoffs provide a general framework for controlling the false discovery rate when performing variable selection. Much of the Knockoffs literature focuses on theoretical challenges and we recognize a need for bringing some of the current ideas into practice. In this paper we propose a sequential algorithm for generating knockoffs when underlying data consists of both continuous and categorical (factor) variables. Further, we present a heuristic multiple knockoffs approach that offers a practical assessment of how robust the knockoff selection process is for a given data set. We conduct extens…
Joint modelling of time-dependent biomarker variability and time-to-event outcomes, a two-step approach
Erasmus University Medical Center（伊拉斯姆斯大学医学中心）；European Organisation for Research and Treatment of Cancer（欧洲癌症研究与治疗组织）；Julius Center for Health Sciences and Primary Care, University Medical Center UtrechtUtrecht University（乌得勒支大学医学中心朱利叶斯健康科学与初级保健中心）
Estimating causal effects from randomized experiments is central to clinical research. Reducing the statistical uncertainty in these analyses is an important objective for statisticians. Registries, prior trials, and health records constitute a growing compendium of historical data on patients under standard-of-care that may be exploitable to this end. However, most methods for historical borrowing achieve reductions in variance by sacrificing strict type-I error rate control. Here, we propose a use of historical data that exploits linear covariate adjustment to improve the efficiency of trial…
Historical data about disease outcomes can be integrated into the analysis of clinical trials in many ways. We build on existing literature that uses prognostic scores from a predictive model to increase the efficiency of treatment effect estimates via covariate adjustment. Here we go further, utilizing a Bayesian framework that combines prognostic covariate adjustment with an empirical prior distribution learned from the predictive performances of the prognostic model on past trials. The Bayesian approach interpolates between prognostic covariate adjustment with strict type I error control wh…
Bayesian adaptive designs have gained popularity in all phases of clinical trials with numerous new developments in the past few decades. During the COVID-19 pandemic, the need to establish evidence for the effectiveness of vaccines, therapeutic treatments and policies that could resolve or control the crisis emphasized the advantages offered by efficient and flexible clinical trial designs. In many COVID-19 clinical trials, due to the high level of uncertainty, Bayesian adaptive designs were considered advantageous. Designing Bayesian adaptive trials, however, requires extensive simulation st…
Conditional power calculations are frequently used to guide the decision whether or not to stop a trial for futility or to modify planned sample size. These ignore the information in short-term endpoints and baseline covariates, and thereby do not make fully efficient use of the information in the data. We therefore propose an interim decision procedure based on the conditional power approach which exploits the information contained in baseline covariates and short-term outcomes. We will realise this by considering the estimation of the treatment effect at the interim analysis as a missing dat…
The present paper deals with the problem of allocating patients to two competing treatments in the presence of covariates or prognostic factors in order to achieve a good trade-off among ethical concerns, inferential precision and randomness in the treatment allocations. In particular we suggest a multipurpose design methodology that combines efficiency and ethical gain when the linear homoscedastic model with both treatment/covariate interactions and interactions among covariates is adopted. The ensuing compound optimal allocations of the treatments depend on the covariates and their distribu…
Covariate adjustment and methods of incorporating historical data in randomized clinical trials (RCTs) each provide opportunities to increase trial power. We unite these approaches for the analysis of RCTs with binary outcomes based on the Cochran-Mantel-Haenszel (CMH) test for marginal risk ratio (RR). In PROCOVA-CMH, subjects are stratified on a single prognostic covariate reflective of their predicted outcome on the control treatment (e.g. placebo). This prognostic score is generated based on baseline covariates through a model trained on historical data. We propose two closed-form prospect…
We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to obtain equal or better asymptotic precision compared to traditional estimators. Under regularity conditions and random censoring within strata of treatment and baseline variables, the proposed estimator has the following features: (i) it is interpretable under violations of the proportional hazards assumption; (ii) it is consistent and at least as precise as the …
University Hospital, University of Zurich（苏黎世大学医院）；Leiden University Medical Center（莱顿大学医学中心）；University of Groningen, University Medical Center Groningen（格罗宁根大学医学中心）；Erasmus MC Cancer Institute, University Medical Center Rotterdam（鹿特丹大学医学中心伊拉斯谟MC癌症研究所）；University Medical Center Utrecht（乌得勒支大学医学中心）；Maastricht Radiation Oncology Clinic（马斯特里赫特放射肿瘤诊所）；Medisch Spectrum Twente（特文特医疗集团）；Radiotherapiegroep（放射治疗集团）
Randomized controlled trials (RCTs) are considered as the gold standard for testing causal hypotheses in the clinical domain. However, the investigation of prognostic variables of patient outcome in a hypothesized cause-effect route is not feasible using standard statistical methods. Here, we propose a new automated causal inference method (AutoCI) built upon the invariant causal prediction (ICP) framework for the causal re-interpretation of clinical trial data. Compared to existing methods, we show that the proposed AutoCI allows to efficiently determine the causal variables with a clear diff…
The rapid finding of effective therapeutics requires the efficient use of available resources in clinical trials. The use of covariate adjustment can yield statistical estimates with improved precision, resulting in a reduction in the number of participants required to draw futility or efficacy conclusions. We focus on time-to-event and ordinal outcomes. A key question for covariate adjustment in randomized studies is how to fit a model relating the outcome and the baseline covariates to maximize precision. We present a novel theoretical result establishing conditions for asymptotic normality …
Due to the heterogeneity of the randomized controlled trial (RCT) and external target populations, the estimated treatment effect from the RCT is not directly applicable to the target population. For example, the patient characteristics of the ACTG 175 HIV trial are significantly different from that of the three external target populations of interest: US early-stage HIV patients, Thailand HIV patients, and southern Ethiopia HIV patients. This paper considers several methods to transport the treatment effect from the ACTG 175 HIV trial to the target populations beyond the trial population. Mos…
A treatment regime is a deterministic function that dictates personalized treatment based on patients' individual prognostic information. There is a fast-growing interest in finding optimal treatment regimes to maximize expected long-term clinical outcomes of patients for complex diseases, such as cancer and AIDS. For many clinical studies with survival time as a primary endpoint, a main goal is to maximize patients' survival probabilities given treatments. In this article, we first propose two nonparametric estimators for survival function of patients following a given treatment regime. Then,…
Towards Best Practices for Covariate Adjustment in Regulatory Trials: From Fixed to Data-Adaptive Approaches
University of California Berkeley（加州大学伯克利分校）；Division of Biometrics IV, OB/OTS/CDER/FDA（美国食品药品监督管理局药物评价与研究中心生物统计学第四处）；Harvard T.H. Chan School of Public Health（哈佛大学陈曾熙公共卫生学院）；Beth Israel Deaconess Hospital（贝斯以色列女执事医疗中心）；Novo Nordisk A/S（诺和诺德公司）；Pfizer Inc.（辉瑞公司）；Northeastern University（东北大学）；Gilead Sciences（吉利德科学公司）；National Center for the Advancement of Translational Science, National Institutes of Health（美国国立卫生研究院转化科学促进国家中心）；Section of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark（南丹麦大学流行病学、生物统计学和生物人口学系）；Forum for Collaborative Research, School of Public Health, University of California Berkeley（加州大学伯克利分校公共卫生学院合作研究论坛）；OncoBrain Inc（OncoBrain 公司）；Moffitt Cancer Center（莫菲特癌症中心）；Department of Biostatistics, University of Michigan（密歇根大学生物统计学系）；Department of Mathematics, Computer Science and Statistics, Ghent University（根特大学数学、计算机科学和统计系）；Department of Mathematics and Data Science, Vrije Universiteit Brussel（布鲁塞尔自由大学数学与数据科学系）
Observing the unobserved confounding through its effects: toward randomized trial-like estimates from real-world survival data
Operations Research Center, Massachusetts Institute of Technology（麻省理工学院运营研究中心）；Sloan School of Management, Massachusetts Institute of Technology（麻省理工学院斯隆管理学院）；Department of Surgery, Memorial Sloan Kettering Cancer Center（纪念斯隆凯特琳癌症中心外科部）；Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin（柏林夏里特医学院，柏林自由大学和洪堡大学联合成员）
Covariate-adaptive randomization is popular in clinical trials with sequentially arrived patients for balancing treatment assignments across prognostic factors which may have influence on the response. However, existing theory on tests for treatment effect under covariate-adaptive randomization is limited to tests under linear or generalized linear models, although covariate-adaptive randomization has been used in survival analysis for a long time and its main application is in survival analysis. Often times, practitioners would simply adopt a conventional test such as the log-rank test or sco…
Calibrated Transfer Learning for Survival Prediction and Treatment Inference
University of Louisville（路易斯维尔大学）；University of Louisville School of Medicine（路易斯维尔大学医学院）；Louisville Clinical and Translational Research Center, University of Louisville（路易斯维尔大学路易维尔临床转化研究中心）；Takeda Pharmaceuticals（武田制药）；Bristol Myers Squibb（百时美施贵宝）
Estimating Causal Treatment Effects in Placebo-Controlled Randomized Clinical Trials When High Placebo Response is Anticipated
Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center（贝斯以色列女医生医疗中心心脏结局研究史密斯中心）；Department of Statistics, SungKyunKwan University（成均馆大学统计系）；Biostatistics Department, Boston University（波士顿大学生物统计学系）
