As a reaction to the pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a multitude of clinical trials for the treatment of SARS-CoV-2 or the resulting corona disease (COVID-19) are globally at various stages from planning to completion. Although some attempts were made to standardize study designs, this was hindered by the ferocity of the pandemic and the need to set up trials quickly. We take the view that a successful treatment of COVID-19 patients (i) increases the probability of a recovery or improvement within a certain time interval, say 28 days; (ii) aims to expedite favourable events within this time frame; and (iii) does not increase mortality over this time period. On this background we discuss the choice of endpoint and its analysis. Furthermore, we consider consequences of this choice for other design aspects including sample size and power and provide some guidance on the application of adaptive designs in this particular context.
The COVID-19 pandemic continues to affect the conduct of clinical trials globally. Complications may arise from pandemic-related operational challenges such as site closures, travel limitations and interruptions to the supply chain for the investigational product, or from health-related challenges such as COVID-19 infections. Some of these complications lead to unforeseen intercurrent events in the sense that they affect either the interpretation or the existence of the measurements associated with the clinical question of interest. In this article, we demonstrate how the ICH E9(R1) Addendum o…
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…
Very recently the new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified and the coronavirus disease 2019 (COVID-19) declared a pandemic by the World Health Organization. The pandemic has a number of consequences for the ongoing clinical trials in non-COVID-19 conditions. Motivated by four currently ongoing clinical trials in a variety of disease areas we illustrate the challenges faced by the pandemic and sketch out possible solutions including adaptive designs. Guidance is provided on (i) where blinded adaptations can help; (ii) how to achieve type I error r…
Clinical trials of a vaccine during an epidemic face particular challenges, such as the pressure to identify an effective vaccine quickly to control the epidemic, and the effect that time-space-varying infection incidence has on the power of a trial. We illustrate how the operating characteristics of different trial design elements may be evaluated using a network epidemic and trial simulation model, based on COVID-19 and individually randomised two-arm trials with a binary outcome. We show that "ring" recruitment strategies, prioritising participants at high risk of infection, can result in s…
Introduction: Endpoint choice for randomized controlled trials of treatments for COVID-19 is complex. A new disease brings many uncertainties, but trials must start rapidly. COVID-19 is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks and can end in death. While improvement in mortality would provide unquestionable evidence about clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical. Furthermore, patient states in between "cure" and "death" represent meaningful distinctions.…
Knowing the true effect size of clinical interventions in randomised clinical trials is key to informing the public health policies. Vaccine efficacy is defined in terms of the relative risk or the ratio of two disease risks. However, only approximate methods are available for estimating the variance of the relative risk. In this article, we show using a probabilistic model that uncertainty in the efficacy rate could be underestimated when the disease risk is low. Factoring in the baseline rate of the disease, we estimate broader confidence intervals for the efficacy rates of the vaccines rece…
Clinical trials disruption has always represented a non negligible part of the ending of interventional studies. While the SARS-CoV-2 (COVID-19) pandemic has led to an impressive and unprecedented initiation of clinical research, it has also led to considerable disruption of clinical trials in other disease areas, with around 80% of non-COVID-19 trials stopped or interrupted during the pandemic. In many cases the disrupted trials will not have the planned statistical power necessary to yield interpretable results. This paper describes methods to compensate for the information loss arising from…
Efficient estimation of cumulative incidence curves via data fusion with surrogates: application to integrated analysis of vaccine trial and immunobridging data
In the search for effective treatments for COVID-19, initial emphasis has been on re-purposed treatments. To maximise the chances of finding successful treatments, novel treatments that have been developed for this disease in particular, are needed. In this manuscript we describe and evaluate the statistical design of the AGILE platform, an adaptive randomized seamless Phase I/II trial platform that seeks to quickly establish a safe range of doses and investigates treatments for potential efficacy using a Bayesian sequential trial design. Both single agent and combination treatments are consid…
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 …
Results from clinical trials can be susceptible to bias if investigators choose their analysis approach after seeing trial data, as this can allow them to perform multiple analyses and then choose the method that provides the most favourable result (commonly referred to as 'p-hacking'). Pre-specification of the planned analysis approach is essential to help reduce such bias, as it ensures analytical methods are chosen in advance of seeing the trial data. However, pre-specification is only effective if done in a way that does not allow p-hacking. For example, investigators may pre-specify a cer…
We present a general framework for using existing data to estimate the efficiency gain from using a covariate-adjusted estimator of a marginal treatment effect in a future randomized trial. We describe conditions under which it is possible to define a mapping from the distribution that generated the existing external data to the relative efficiency of a covariate-adjusted estimator compared to an unadjusted estimator. Under conditions, these relative efficiencies approximate the ratio of sample size needed to achieve a desired power. We consider two situations where the outcome is either fully…
Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes measured over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem ha…
Debiasing hazard-based, time-varying vaccine effects using vaccine-irrelevant infections: An observational extension of a pivotal Phase 3 COVID-19 vaccine efficacy trial
In many randomized clinical trials of therapeutics for COVID-19, the primary outcome is an ordinal categorical variable, and interest focuses on the odds ratio (active agent vs. control) under the assumption of a proportional odds model. Although at the final analysis the outcome will be determined for all subjects, at an interim analysis, the status of some participants may not yet be determined, e.g., because ascertainment of the outcome may not be possible until some pre-specified follow-up time. Accordingly, the outcome from these subjects can be viewed as censored. A valid interim analysi…
Mila, Quebec Artificial Intelligence Institute（米拉-魁北克人工智能研究所）；University of Montreal（蒙特利尔大学）；Fontbonne University（方邦大学）；Heidelberg University（海德堡大学）；Stony Brook Medicine（石溪医学中心）；Vector Institute（矢量研究所）；University of Toronto（多伦多大学）
Purpose: The need to streamline patient management for COVID-19 has become more pressing than ever. Chest X-rays provide a non-invasive (potentially bedside) tool to monitor the progression of the disease. In this study, we present a severity score prediction model for COVID-19 pneumonia for frontal chest X-ray images. Such a tool can gauge severity of COVID-19 lung infections (and pneumonia in general) that can be used for escalation or de-escalation of care as well as monitoring treatment efficacy, especially in the ICU. Methods: Images from a public COVID-19 database were scored retrospecti…
Predicting interactions among heterogenous graph structured data has numerous applications such as knowledge graph completion, recommendation systems and drug discovery. Often times, the links to be predicted belong to rare types such as the case in repurposing drugs for novel diseases. This motivates the task of few-shot link prediction. Typically, GCNs are ill-equipped in learning such rare link types since the relation embedding is not learned in an inductive fashion. This paper proposes an inductive RGCN for learning informative relation embeddings even in the few-shot learning regime. The…
School of Computer Science and Engineering, Hunan University（湖南大学计算机科学与工程学院）；AWS Shanghai AI Lab（亚马逊云科技上海人工智能实验室）；Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic（克利夫兰诊所勒纳研究所基因组医学研究所）；New York University Shanghai（上海纽约大学）；AWS AI（亚马逊云科技人工智能部门）；University of Minnesota（明尼苏达大学）；Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University（凯斯西储大学克利夫兰诊所勒纳医学院分子医学系）；Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine（凯斯西储大学医学院凯斯综合癌症中心）
There have been more than 850,000 confirmed cases and over 48,000 deaths from the human coronavirus disease 2019 (COVID-19) pandemic, caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), in the United States alone. However, there are currently no proven effective medications against COVID-19. Drug repurposing offers a promising way for the development of prevention and treatment strategies for COVID-19. This study reports an integrative, network-based deep learning methodology to identify repurposable drugs for COVID-19 (termed CoV-KGE). Specifically, we built a comprehe…
The problem of skewness is common among clinical trials and survival data which has being the research focus derivation and proposition of different flexible distributions. Thus, a new distribution called Extended Rayleigh Lomax distribution is constructed from Rayleigh Lomax distribution to capture the excessiveness of some survival data. We derive the new distribution by using beta logit function proposed by Jones (2004). Some statistical properties of the distribution such as probability density function, cumulative density function, reliability rate, hazard rate, reverse hazard rate, momen…
Assessing Vaccine Effectiveness in Observational Studies via Nested Trial Emulation
Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill（北卡罗来纳大学教堂山分校吉林斯全球公共卫生学院生物统计系）；Nuffield Department of Population Health, University of Oxford（牛津大学努菲尔德人口健康系）
The usual development cycles are too slow for the development of vaccines, diagnostics and treatments in pandemics such as the ongoing SARS-CoV-2 pandemic. Given the pressure in such a situation, there is a risk that findings of early clinical trials are overinterpreted despite their limitations in terms of size and design. Motivated by a non-randomized open-label study investigating the efficacy of hydroxychloroquine in patients with COVID-19, we describe in a unified fashion various alternative approaches to the analysis of non-randomized studies. A widely used tool to reduce the impact of t…
Northeastern University（东北大学）；Brigham and Women’s Hospital（布莱根妇女医院）；Harvard Medical School（哈佛医学院）；Harvard University（哈佛大学）；Scipher Medicine；Sabanci University（萨班哲大学）；Boston University（波士顿大学）；Central European University（中欧大学）
The current pandemic has highlighted the need for methodologies that can quickly and reliably prioritize clinically approved compounds for their potential effectiveness for SARS-CoV-2 infections. In the past decade, network medicine has developed and validated multiple predictive algorithms for drug repurposing, exploiting the sub-cellular network-based relationship between a drug's targets and disease genes. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity, tasking each of them to rank 6,340 drugs for their expected efficacy against SAR…
The COVID-19 pandemic due to the novel coronavirus SARS CoV-2 has inspired remarkable breakthroughs in development of vaccines against the virus and the launch of several phase 3 vaccine trials in Summer 2020 to evaluate vaccine efficacy (VE). Trials of vaccine candidates using mRNA delivery systems developed by Pfizer-BioNTech and Moderna have shown substantial VEs of 94-95%, leading the US Food and Drug Administration to issue Emergency Use Authorizations and subsequent widespread administration of the vaccines. As the trials continue, a key issue is the possibility that VE may wane over tim…
Win Time In Favor of Treatment (WINFT) for Hierarchical Endpoints
North Carolina State University（北卡罗来纳州立大学）；Duke Clinical Research Institute, Duke University（杜克大学杜克临床研究所）；Department of Biostatistics and Bioinformatics, Duke University（杜大学生统计与生物信息系）；Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison（威斯康星大学麦迪逊分校医学院公共卫生学院生物统计与医学信息系）
A key issue for all observational causal inference is that it relies on an unverifiable assumption - that observed characteristics are sufficient to proxy for treatment confounding. In this paper we argue that in medical cases these conditions are more likely to be met in cases where standardized treatment guidelines do not yet exist. One example of such a situation is the emergence of a novel disease. We study the case of early COVID-19 in New York City hospitals and show that observational analysis of two important thereapeutics, anti-coagulation and steroid therapy, gives results that agree…
A recent cluster trial in Bangladesh randomized 600 villages into 300 treatment/control pairs, to evaluate the impact of an intervention to increase mask-wearing. Data was analyzed in a generalized linear model and significance asserted with parametric tests for the rate of the primary outcome (symptomatic and seropositive for COVID-19) between treatment and control villages. In this short note we re-analyze the data from this trial using standard non-parametric paired statistics tests on treatment/village pairs. With this approach, we find that behavioral outcomes like physical distancing are…
Based on the information communicated in press releases, and finally published towards the end of 2020 by Pfizer, Moderna and AstraZeneca, we have built up a simple Bayesian model, in which the main quantity of interest plays the role of {\em vaccine efficacy} (`$ε$'). The resulting Bayesian Network is processed by a Markov Chain Monte Carlo (MCMC), implemented in JAGS interfaced to R via rjags. As outcome, we get several probability density functions (pdf's) of $ε$, each conditioned on the data provided by the three pharma companies. The result is rather stable against large variations of the…
MedBravo；Hospital General Universitario de Alicante (HGUA)（阿利坎特综合大学医院（HGUA））；Institute for Health and Biomedical Research, Alicante, Spain (ISABIAL)（阿利坎特健康与生物医学研究所（ISABIAL））；Hospital Universitario San Juan de Alicante（阿利坎特圣胡安大学医院）；San Juan University Hospital（圣胡安大学医院）
Introduction: Real-world data generated from clinical practice can be used to analyze the real-world evidence (RWE) of COVID-19 pharmacotherapy and validate the results of randomized clinical trials (RCTs). Machine learning (ML) methods are being used in RWE and are promising tools for precision-medicine. In this study, ML methods are applied to study the efficacy of therapies on COVID-19 hospital admissions in the Valencian Region in Spain. Methods: 5244 and 1312 COVID-19 hospital admissions - dated between January 2020 and January 2021 from 10 health departments, were used respectively for t…
Randomized control trials (RCTs) have been the gold standard to evaluate the effectiveness of a program, policy, or treatment on an outcome of interest. However, many RCTs assume that study participants are willing to share their (potentially sensitive) data, specifically their response to treatment. This assumption, while trivial at first, is becoming difficult to satisfy in the modern era, especially in online settings where there are more regulations to protect individuals' data. The paper presents a new, simple experimental design that is differentially private, one of the strongest notion…
ALL-IN meta-analysis for flexibility and validity in prospective and retrospective evidence synthesis
Amsterdam UMC（阿姆斯特丹大学医学中心）；NWO-I institute CWI（荷兰皇家艺术与科学院下属信息研究所）；University Hospital Basel and University of Basel（巴塞尔大学医院与巴塞尔大学）；Oslo University Hospital（奥斯陆大学医院）；Bristol Medical School, University of Bristol（布里斯托大学布里斯托医学院）；Diakonhjemmet Hospital（迪阿孔赫梅特医院）；Faculty of Medicine, University of Oslo（奥斯陆大学医学院）
