Suppose we are interested in the effect of a treatment in a clinical trial. The efficiency of inference may be limited due to small sample size. However, external control data are often available from historical studies. Motivated by an application to Helicobacter pylori infection, we show how to borrow strength from such data to improve efficiency of inference in the clinical trial. Under an exchangeability assumption about the potential outcome mean, we show that the semiparametric efficiency bound for estimating the average treatment effect can be reduced by incorporating both the clinical trial data and external controls. We then derive a doubly robust and locally efficient estimator. The improvement in efficiency is prominent especially when the external control dataset has a large sample size and small variability. Our method allows for a relaxed overlap assumption, and we illustrate with the case where the clinical trial only contains a treated group. We also develop doubly robust and locally efficient approaches that extrapolate the causal effect in the clinical trial to the external population and the overall population. Our results also offer a meaningful implication for trial design and data collection. We evaluate the finite-sample performance of the proposed estimators via simulation. In the Helicobacter pylori infection application, our approach shows that the combination treatment has potential efficacy advantages over the triple therapy.
In many clinical trials, individuals in different subgroups have experience differential treatment effects. This leads to individualized differences in treatment benefit. In this article, we introduce the general concept of predictive directions, which are risk scores motivated by potential outcomes considerations. These techniques borrow heavily from sufficient dimension reduction (SDR) and causal inference methodology. Under some conditions, one can use existing methods from the SDR literature to estimate the directions assuming an idealized complete data structure, which subsequently yields…
Individualized treatment rules (ITRs) tailor treatments according to individual patient characteristics. They can significantly improve patient care and are thus becoming increasingly popular. The data collected during randomized clinical trials are often used to estimate the optimal ITRs. However, these trials are generally expensive to run, and, moreover, they are not designed to efficiently estimate ITRs. In this paper, we propose a cost-effective estimation method from an active learning perspective. In particular, our method recruits only the "most informative" patients (in terms of learn…
Phase III randomized clinical trials play a monumentally critical role in the evaluation of new medical products. Because of the intrinsic nature of uncertainty embedded in our capability in assessing the efficacy of a medical product, interpretation of trial results relies on statistical principles to control the error of false positives below desirable level. The well-established statistical hypothesis testing procedure suffers from two major limitations, namely, the lack of flexibility in the thresholds to claim success and the lack of capability of controlling the total number of false pos…
Conditional (European Medicines Agency) or accelerated (U.S. Food and Drug Administration) approval of drugs allow earlier access to promising new treatments that address unmet medical needs. Certain post-marketing requirements must typically be met in order to obtain full approval, such as conducting a new post-market clinical trial. We study the applicability of the recently developed harmonic mean Chi-squared test to this conditional or accelerated approval framework. The proposed approach can be used both to support the design of the post-market trial and the analysis of the combined evide…
Recently, the strategy for dose optimization in oncology has shifted to conduct Phase 2 randomized controlled trials with multiple doses. Optimal biologic dose selection from Phase 1 trial data to determine candidate doses for Phase 2 trials has been gaining attention. This study proposes a novel adaptive cohort size determination method for optimal biologic dose-finding to accelerate trials. The cohort size expansion is determined adaptively depending on the toxicity and efficacy data of the ongoing trial. In a simulation, the proposed method shortened the trial duration and maintained accura…
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…
Medical research has evolved conventions for choosing sample size in randomized clinical trials that rest on the theory of hypothesis testing. Bayesians have argued that trials should be designed to maximize subjective expected utility in settings of clinical interest. This perspective is compelling given a credible prior distribution on treatment response, but Bayesians have struggled to provide guidance on specification of priors. We use the frequentist statistical decision theory of Wald (1950) to study design of trials under ambiguity. We show that ε-optimal rules exist when trials have la…
An early phase clinical trial is the first step in evaluating the effects in humans of a potential new anti-disease agent or combination of agents. Usually called "phase I" or "phase I/II" trials, these experiments typically have the nominal scientific goal of determining an acceptable dose, most often based on adverse event probabilities. This arose from a tradition of phase I trials to evaluate cytotoxic agents for treating cancer, although some methods may be applied in other medical settings, such as treatment of stroke or immunological diseases. Most modern statistical designs for early p…
Intensity-based multistate models provide a useful framework for characterizing disease processes, the introduction of interventions, loss to follow-up, and other complications arising in the conduct of randomized trials studying complex life history processes. Within this framework we discuss the issues involved in the specification of estimands and show the limiting values of common estimators of marginal process features based on cumulative incidence function regression models. When intercurrent events arise we stress the need to carefully define the target estimand and the importance of av…
In clinical trials, response-adaptive randomization (RAR) has the appealing ability to assign more subjects to better-performing treatments based on interim results. The traditional RAR strategy alters the randomization ratio on a patient-by-patient basis; this has been heavily criticized for bias due to time-trends. An alternate approach is blocked RAR, which groups patients together in blocks and recomputes the randomization ratio in a block-wise fashion; the final analysis is then stratified by block. However, the typical blocked RAR design divides patients into equal-sized blocks, which is…
In current clinical trial development, historical information is receiving more attention as it provides utility beyond sample size calculation. Meta-analytic-predictive (MAP) priors and robust MAP priors have been proposed for prospectively borrowing historical data on a single endpoint. To simultaneously synthesize control information from multiple endpoints in confirmatory clinical trials, we propose to approximate posterior probabilities from a Bayesian hierarchical model and estimate critical values by deep learning to construct pre-specified strategies for hypothesis testing. This featur…
Clinical trials are an instrument for making informed decisions based on evidence from well-designed experiments. Here we consider adaptive designs mainly from the perspective of multi-arm Phase II clinical trials, in which one or more experimental treatments are compared to a control. Treatment allocation of individual trial participants is assumed to take place according to a fixed block randomization, albeit with an important twist: The performance of each treatment arm is assessed after every measured outcome, in terms of the posterior distribution of a corresponding model parameter. Diffe…
The use of information from real world to assess the effectiveness of medical products is becoming increasingly popular and more acceptable by regulatory agencies. According to a strategic real-world evidence framework published by U.S. Food and Drug Administration, a hybrid randomized controlled trial that augments internal control arm with real-world data is a pragmatic approach worth more attention. In this paper, we aim to improve on existing matching designs for such a hybrid randomized controlled trial. In particular, we propose to match the entire concurrent randomized clinical trial (R…
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…
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…
The analysis and planning methods for competing risks model have been described in the literatures in recent decades, and non-inferiority clinical trials are helpful in current pharmaceutical practice. Analytical methods for non-inferiority clinical trials in the presence of competing risks were investigated by Parpia et al., who indicated that the proportional sub-distribution hazard model is appropriate in the context of biological studies. However, the analytical methods of competing risks model differ from those appropriate for analyzing non-inferiority clinical trials with a single outcom…
Most clinical trials involve the comparison of a new treatment to a control arm (e.g., the standard of care) and the estimation of a treatment effect. External data, including historical clinical trial data and real-world observational data, are commonly available for the control arm. Borrowing information from external data holds the promise of improving the estimation of relevant parameters and increasing the power of detecting a treatment effect if it exists. In this paper, we propose to use Bayesian additive regression trees (BART) for incorporating external data into the analysis of clini…
[Invited Discussion] Randomization Tests to Address Disruptions in Clinical Trials: A Report from the NISS Ingram Olkin Forum Series on Unplanned Clinical Trial Disruptions
Confusion often arises when attempting to articulate target estimand(s) of a clinical trial in plain language. We aim to rectify this confusion by using a type of causal graph called the Single-World Intervention Graph (SWIG) to provide a visual representation of the estimand that can be effectively communicated to interdisciplinary stakeholders. These graphs not only display estimands, but also illustrate the assumptions under which a causal estimand is identifiable by presenting the graphical relationships between the treatment, intercurrent events, and clinical outcomes. To demonstrate its …
Historical data from previous clinical trials, observational studies and health records may be utilized in analysis of clinical trials data to strengthen inference. Under the Bayesian framework incorporation of information obtained from any source other than the current data is facilitated through construction of an informative prior. The existing methodology for defining an informative prior based on historical data relies on measuring similarity to the current data at the study level and does not take advantage of individual patient data (IPD). This paper proposes a family of priors that uti…
Comparative effectiveness evidence from randomized trials may not be directly generalizable to a target population of substantive interest when, as in most cases, trial participants are not randomly sampled from the target population. Motivated by the need to generalize evidence from two trials conducted in the AIDS Clinical Trials Group (ACTG), we consider weighting, regression and doubly robust estimators to estimate the causal effects of HIV interventions in a specified population of people living with HIV in the USA. We focus on a non-nested trial design and discuss strategies for both poi…
A new approach to adaptive design of clinical trials is proposed in a general multiparameter exponential family setting, based on generalized likelihood ratio statistics and optimal sequential testing theory. These designs are easy to implement, maintain the prescribed Type I error probability, and are asymptotically efficient. Practical issues involved in clinical trials allowing mid-course adaptation and the large literature on this subject are discussed, and comparisons between the proposed and existing designs are presented in extensive simulation studies of their finite-sample performance…
Where there are a limited number of patients, such as in a rare disease, clinical trials in these small populations present several challenges, including statistical issues. This led to an EU FP7 call for proposals in 2013. One of the three projects funded was the Innovative Methodology for Small Populations Research (InSPiRe) project. This paper summarizes the main results of the project, which was completed in 2017. The InSPiRe project has led to development of novel statistical methodology for clinical trials in small populations in four areas. We have explored new decision-making methods f…
Marquette University（马凯特大学）；Oregon Clinical and Translational Research Institute（俄勒冈临床与转化研究所）；Oregon Health & Science University（俄勒冈健康与科学大学）
Explanatory studies, such as randomized controlled trials, are targeted to extract the true causal effect of interventions on outcomes and are by design adjusted for covariates through randomization. On the contrary, observational studies are a representation of events that occurred without intervention. Both can be illustrated using the Structural Causal Model (SCM), and do-calculus can be employed to estimate the causal effects. Pragmatic clinical trials (PCT) fall between these two ends of the trial design spectra and are thus hard to define. Due to its pragmatic nature, no standardized rep…
This paper focuses on statistical modelling and prediction of patient recruitment in clinical trials accounting for patients dropout. The recruitment model is based on a Poisson-gamma model introduced by Anisimov and Fedorov (2007), where the patients arrive at different centres according to Poisson processes with rates viewed as gamma-distributed random variables. Each patient can drop the study during some screening period. Managing the dropout process is of a major importance but data related to dropout are rarely correctly collected. In this paper, a few models of dropout are proposed. The…
This paper proposes a new method for analysis of adverse event data in clinical trials. The method is illustrated by application to data on 4 phase III clinical trials, two on breast cancer and two on diabetes mellitus.
Detection of interactions between treatment effects and patient descriptors in clinical trials is critical for optimizing the drug development process. The increasing volume of data accumulated in clinical trials provides a unique opportunity to discover new biomarkers and further the goal of personalized medicine, but it also requires innovative robust biomarker detection methods capable of detecting non-linear, and sometimes weak, signals. We propose a set of novel univariate statistical tests, based on the theory of random walks, which are able to capture non-linear and non-monotonic covari…
Clinical trials are considered as the golden standard for medical device validation. However, many sacrifices have to be made during the design and conduction of the trials due to cost considerations and partial information, which may compromise the significance of the trial results. In this paper, we proposed a model-based pre-clinical trial framework using statistical model checking. Physiological models represent disease mechanism, which enable automated adjudication of simulation results. Sampling of the patient parameters and hypothesis testing are performed by statistical model checker. …
Existing trials had not taken enough consideration of their population representativeness, which can lower the effectiveness when the treatment is applied in real-world clinical practice. We analyzed the eligibility criteria of Bevacizumab colorectal cancer treatment trials, assessed their a priori generalizability, and examined how it affects patient outcomes when applied in real-world clinical settings. To do so, we extracted patient-level data from a large collection of electronic health records (EHRs) from the OneFlorida consortium. We built a zero-inflated negative binomial model using a …
TWIN-GPT: Digital Twins for Clinical Trials via Large Language Model
School of Public Health, Zhejiang University（浙江大学公共卫生学院）；Rensselaer Polytechnic Institute（伦斯勒理工学院）；University of Illinois Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校）
Significant advancements have been made in recent years to optimize patient recruitment for clinical trials, however, improved methods for patient recruitment prediction are needed to support trial site selection and to estimate appropriate enrollment timelines in the trial design stage. In this paper, using data from thousands of historical clinical trials, we explore machine learning methods to predict the number of patients enrolled per month at a clinical trial site over the course of a trial's enrollment duration. We show that these methods can reduce the error that is observed with curre…
University of Cambridge（剑桥大学）；Newcastle University（纽卡斯尔大学）
High-dimensional biomarkers such as genomics are increasingly being measured in randomized clinical trials. Consequently, there is a growing interest in developing methods that improve the power to detect biomarker-treatment interactions. We adapt recently proposed two-stage interaction detecting procedures in the setting of randomized clinical trials. We also propose a new stage 1 multivariate screening strategy using ridge regression to account for correlations among biomarkers. For this multivariate screening, we prove the asymptotic between-stage independence, required for family-wise erro…
Centrality in Collaboration: A Novel Algorithm for Social Partitioning Gradients in Community Detection for Multiple Oncology Clinical Trial Enrollments
University of Toronto（多伦多大学）；University Health Network（大学健康网络）
Effective decision making from randomised controlled clinical trials relies on robust interpretation of the numerical results. However, the language we use to describe clinical trials can cause confusion both in trial design and in comparing results across trials. ACceptability Curve Estimation using Probability Above Threshold (ACCEPT) aids comparison between trials (even where of different designs) by harmonising reporting of results, acknowledging different interpretations of the results may be valid in different situations, and moving the focus from comparison to a pre-specified value to i…
Various adaptive randomization procedures (adaptive designs) have been proposed to clinical trials. This paper discusses several broad families of procedures, such as the play-the-winner rule and Markov chain model, randomized play-the-winner rule and urn models, drop-the-loser rule, doubly biased coin adaptive design. Asymptotic theories are presented with several pivotal proofs. The effect of delayed responses, the power and variability comparison of these designs are also discussed.
Selective recruitment designs preferentially recruit individuals that are estimated to be statistically informative onto a clinical trial. Individuals that are expected to contribute less information have a lower probability of recruitment. Furthermore, in an information-adaptive design recruits are allocated to treatment arms in a manner that maximises information gain. The informativeness of an individual depends on their covariate (or biomarker) values and how information is defined is a critical element of information-adaptive designs. In this paper we define and evaluate four different me…
University of Virginia（弗吉尼亚大学）；University of Pennsylvania（宾夕法尼亚大学）；University of Cambridge（剑桥大学）；University of California, Los Angeles（加利福尼亚大学洛杉矶分校）
Phase I dose-finding trials are increasingly challenging as the relationship between efficacy and toxicity of new compounds (or combination of them) becomes more complex. Despite this, most commonly used methods in practice focus on identifying a Maximum Tolerated Dose (MTD) by learning only from toxicity events. We present a novel adaptive clinical trial methodology, called Safe Efficacy Exploration Dose Allocation (SEEDA), that aims at maximizing the cumulative efficacies while satisfying the toxicity safety constraint with high probability. We evaluate performance objectives that have opera…
A sufficient condition for the uniqueness of multinomial sequential unbiased estimators is provided generalizing a classical result for binomial samples. Unbiased estimators are applied to infer the parameters of multidimensional or multinomial Random Walks which are observed until they reach a boundary. An application to clinical trials is presented.
One of Pranab K. Sen's major research areas is sequential nonparametrics and semiparametrics and their applications to clinical trials, to which he has made many important contributions. Herein we review a number of these contributions and related developments. We also describe some recent work on nonparametric and semiparametric inference and the associated computational methods in time-sequential clinical trials with survival endpoints.
Randomization is a common technique used in clinical trials to eliminate potential bias and confounders in a patient population. Equal allocation to treatment groups is the standard due to its optimal efficiency in many cases. However, in certain scenarios, unequal allocation can improve efficiency. In superiority trials with more than two groups, the optimal randomization is not always a balanced randomization. In non-inferiority trials, additive margin with equal variance is the only instance with balanced randomization. Optimal randomization for non-inferiority trials can be far from 1:1 an…
A major impediment to successful drug development is the complexity, cost, and scale of clinical trials. The detailed internal structure of clinical trial data can make conventional optimization difficult to achieve. Recent advances in machine learning, specifically graph-structured data analysis, have the potential to enable significant progress in improving the clinical trial design. TrialGraph seeks to apply these methodologies to produce a proof-of-concept framework for developing models which can aid drug development and benefit patients. In this work, we first introduce a curated clinica…
