Clinical Question Of Interest Research Articles

Applying the Estimand Framework to Non‐Inferiority Trials

Most published applications of the estimand framework have focused on superiority trials. However, non-inferiority trials present specific challenges compared to superiority trials. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use notes in their addendum on estimands and sensitivity analysis in clinical trials that there may be special considerations to the implementation of estimands in clinical trials with a non-inferiority objective yet provides little guidance. This paper discusses considerations that trial teams should make when defining estimands for a clinical trial with a non-inferiority objective. We discuss how the pre-addendum way of establishing non-inferiority can be embraced by the estimand framework including a discussion of the role of the Per Protocol analysis set. We examine what clinical questions of interest can be formulated in the context of non-inferiority trials and outline why we do not think it is sensible to describe an estimand as 'conservative'. The impact of the estimand framework on key considerations in non-inferiority trials such as whether trials should have more than one primary estimand, the choice of non-inferiority margin, assay sensitivity, switching from non-inferiority to superiority and estimation are discussed. We conclude by providing a list of recommendations, and important considerations for defining estimands for trials with a non-inferiority objective.

Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.

Application of hypothetical strategies in acute pain.

Since the publication of ICH E9 (R1), "Addendum to statistical principles for clinical trials: on choosing appropriate estimands and defining sensitivity analyses in clinical trials," there has been a lot of debate about the hypothetical strategy for handling intercurrent events. Arguments against the hypothetical strategy are twofold: (1) the clinical question has limited clinical/regulatory interest; (2) the estimation may need strong statistical assumptions. In this article, we provide an example of a hypothetical strategy handling use of rescue medications in the acute pain setting. We argue that the treatment effect of a drug that is attributable to the treatment alone is the clinical question of interest and is important to regulators. The hypothetical strategy is important when developing non-opioid treatment as it estimates the treatment effect due to treatment during the pre-specified evaluation period whereas the treatment policy strategy does not. Two widely acceptable and non-controversial clinical inputs are required to construct a reasonable estimator. More importantly, this estimator does not rely on additional strong statistical assumptions and is considered reasonable for regulatory decision making. In this article, we point out examples where estimators for a hypothetical strategy can be constructed without any strong additional statistical assumptions besides acceptable clinical inputs. We also showcase a new way to obtain estimation based on disease specific clinical knowledge instead of strong statistical assumptions. In the example presented, we clearly demonstrate the advantages of the hypothetical strategy compared to alternative strategies including the treatment policy strategy and a composite variable strategy.

Adverse events in single-arm clinical trials with non-fatal time-to-event efficacy endpoint: from clinical questions to methods for statistical analysis

BackgroundIn any single-arm trial on novel treatments, assessment of toxicity plays an important role as occurrence of adverse events (AEs) is relevant for application in clinical practice. In the presence of a non-fatal time-to-event(s) efficacy endpoint, the analysis should be broadened to consider AEs occurrence in time. The AEs analysis could be tackled with two approaches, depending on the clinical question of interest. Approach 1 focuses on the occurrence of AE as first event. Treatment ability to protect from the efficacy endpoint event(s) has an impact on the chance of observing AEs due to competing risks action. Approach 2 considers how treatment affects the occurrence of AEs in the potential framework where the efficacy endpoint event(s) could not occur.MethodsIn the first part of the work we review the strategy of analysis for these two approaches. We identify theoretical quantities and estimators consistent with the following features: (a) estimators should address for the presence of right censoring; (b) theoretical quantities and estimators should be functions of time. In the second part of the work we propose the use of alternative methods (regression models, stratified Kaplan-Meier curves, inverse probability of censoring weighting) to relax the assumption of independence between the potential times to AE and to event(s) in the efficacy endpoint for addressing Approach 2.ResultsWe show through simulations that the proposed methods overcome the bias due to the dependence between the two potential times and related to the use of standard estimators.ConclusionsWe demonstrated through simulations that one can handle patients selection in the risk sets due to the competing event, and thus obtain conditional independence between the two potential times, adjusting for all the observed covariates that induce dependence.

Defining estimands for efficacy assessment in single arm phase 1b or phase 2 clinical trials in oncology early development.

The addendum of the ICH E9 guideline on the statistical principles for clinical trials introduced the estimand framework. The framework is designed to strengthen the dialog between different stakeholders, to introduce greater clarity in the clinical trial objectives and to provide alignment between the estimand and statistical analysis. Estimand framework related publications thus far have mainly focused on randomized clinical trials. The intention of the Early Development Estimand Nexus (EDEN), a task force of the cross-industry Oncology Estimand Working Group (www.oncoestimand.org), is to apply it to single arms Phase 1b or Phase 2 trials designed to detect a treatment-related efficacy signal, typically measured by objective response rate. Key recommendations regarding the estimand attributes include that in a single arm early clinical trial, the treatment attribute should start when the first dose is received by the participant. Focusing on the estimation of an absolute effect, the population-level summary measure should reflect only the property used for the estimation. Another major component introduced in the ICH E9 addendum is the definition of intercurrent events and the associated possible ways to handle them. Different strategies reflect different clinical questions of interest that can be answered based on the journeys an individual subject can take during a trial. We provide detailed strategy recommendations for intercurrent events typically seen in early-stage oncology. We highlight where implicit assumptions should be made transparent as whenever follow-up is suspended, a while-on-treatment strategy is implied.

Estimands for atopic dermatitis clinical trials: Expert opinion on the importance of intercurrent events.

Despite the emergence of novel targeted treatments for atopic dermatitis (AD), there is a lack of guidelines on standardizing analysis of clinical trial data. To define and estimate meaningful treatment comparisons, several factors, including intercurrent events, must be taken into account. Intercurrent events are defined as events occurring after treatment initiation that affect either the interpretation or existence of the measurements associated with clinical questions of interest. Due to the relapsing, unpredictable nature of AD, intercurrent events frequently occur in AD trials, such as use of rescue therapy for intense itch and sleep deprivation. Despite the impact of intercurrent events in AD, they are often handled in an inconsistent manner across trials, which limits results interpretation. The estimand framework is increasingly used to estimate treatment effects while accounting for intercurrent events. This review explores how guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) on the use of estimands can be applied to support AD clinical trial design and analysis. We propose that estimands are used in AD trials and defined early during trial design. The use of estimands can provide clinicians with interventional trial results that are more reflective of clinical practice, help facilitate comparisons across clinical trials, and are more informative to enable improved treatment selection for patients.

Estimands and their Estimators for Clinical Trials Impacted by the COVID-19 Pandemic: A Report from the NISS Ingram Olkin Forum Series on Unplanned Clinical Trial Disruptions

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 on estimands and sensitivity analyses provides a rigorous basis to discuss potential pandemic-related trial disruptions and to embed these disruptions in the context of study objectives and design elements. We introduce several hypothetical estimand strategies and review various causal inference and missing data methods, as well as a statistical method that combines unbiased and possibly biased estimators for estimation. To illustrate, we describe the features of a stylized trial, and how it may have been impacted by the pandemic. This stylized trial will then be revisited by discussing the changes to the estimand and the estimator to account for pandemic disruptions. Finally, we outline considerations for designing future trials in the context of unforeseen disruptions.

Time to deterioration of symptoms or function using patient-reported outcomes in cancer trials

Time-to-event endpoints for patient-reported outcomes, such as time to deterioration of symptoms or function, are frequently used in cancer clinical trials. Although time-to-deterioration endpoints might seem familiar to cancer researchers for being similar to survival or disease-progression endpoints, there are unique considerations associated with their use. The complexity of time-to-deterioration endpoints should be weighed against the information that they add to the tumour, survival, and safety data used to inform the risks and benefits of an investigational drug. Here we use the estimand framework to show how analytical decisions answer different clinical questions of interest, some of which might be uninformative. Challenges including the consideration of intercurrent events, the difficulty in maintaining adequate completion rates, and considerable patient and trial burden from long-term, serial, patient-reported outcome measurements render time to deterioration a problematic approach for widespread use. For trials in which a comparative benefit in symptoms or function is an objective, an analysis at pre-specified relevant timepoints could be a better approach.

Systematic reviews in hematopoietic cell transplantation and cellular therapy: considerations and guidance from the American Society for Transplantation and Cellular Therapy, European Society for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research late effects and quality of life working committee.

Systematic reviews apply rigorous methodologies to address a pre-specified, clearly formulated clinical research question. The conclusion that results is often cited to more robustly inform decision-making by clinicians, third-party payers and managed care organizations about the clinical question of interest. While systematic reviews provide a rigorous standard, they may be unfeasible when the task is to create general disease-focused guidelines comprised of multiple clinical practice questions versus a single major clinical practice question. Collaborating transplantation and cellular therapy societal committees also recognize that the quantity and or quality of reference sources may be insufficient for a meaningful systematic review. As the conduct of systematic reviews has evolved over time in terms of grading systems, reporting requirements and use of technology, here we provide current guidance in methodologies, resources for reviewers, and approaches to overcome challenges in conducting systematic reviews in transplantation and cellular therapy.

Estimand framework: Delineating what to be estimated with clinical questions of interest in clinical trials

ICH (International Council for Harmonization) E9 R1 (2019) proposes a framework to define estimands in clinical trials. Although the concept of estimand was proposed previously when US Food and Drug Administration (FDA) issued the panel report on handling missing data in clinical trials, many details including attributes and different strategies have not been developed until the recent ICH E9 (R1) addendum. A clearly defined estimand should include considerations of five attributes including patient population, treatment regimen of interest, endpoint/variables, handling of intercurrent events (IEs), and summary measures for assessing treatment effect. To evaluate the underlying treatment effects of a new investigational drug or biologic product, it is desirable to consider estimands that are aligned with the objectives of the study and that are meaningful to the stakeholders such as physicians or patients, health authority administration, and payers, etc.. In this paper, the concepts, attributes and strategies of the estimand framework will be reviewed and illustrated with clinical trial examples. Some common estimands and their associated scientific questions are discussed within a causal inference framework for longitudinal clinical trials.

Clinical Trial Drug Safety Assessment With Interactive Visual Analytics

In this article, we provide guidance on how statisticians can use interactive visual analytics to assist medical personnel through the entire clinical safety review process. For the general assessment of safety data (e.g., adverse events, laboratory measurements), we recommend a review flow with the first step using a display that leverages statistical methods to identify events with stronger evidence of a treatment difference. In combination with clinical knowledge, reviewers can identify events that need further scrutiny. Next, clinical reviewers will be provided with displays that show additional details on these events or patient level information to aid their decision making. For safety topics of interest (e.g., suicidal ideation and behavior), we propose a tailored approach to each topic both at the summary level as well as the patient level. Displays will show only information relevant to the specific topic and for the clinical questions of interest. We also discuss some challenges to fully implement and leverage interactive displays and tools. We encourage broad use of interactive visual analytics in the analysis and display of clinical data. Study sponsor: Eli Lilly and Company.

Future of evidence ecosystem series: 2. current opportunities and need for better tools and methods

To become user driven and more useful for decision-making, the current evidence synthesis ecosystem requires significant changes (Paper 1. Future of evidence ecosystem series). Reviewers have access to new sources of data (clinical trial registries, protocols, and clinical study reports from regulatory agencies or pharmaceutical companies) for more information on randomized control trials. With all these newly available data, the management of multiple and scattered trial reports is even more challenging. New types of data are also becoming available: individual patient data and routinely collected data. With the increasing number of diverse sources to be searched and the amount of data to be extracted, the process needs to be rethought. New approaches and tools, such as automation technologies and crowdsourcing, should help accelerate the process. The implementation of these new approaches and methods requires a substantial rethinking and redesign of the current evidence synthesis ecosystem. The concept of a “living” evidence synthesis enterprise, with living systematic review and living network meta-analysis, has recently emerged. Such an evidence synthesis ecosystem implies conceptualizing evidence synthesis as a continuous process built around a clinical question of interest and no longer as a small team independently answering a specific clinical question at a single point in time.

¿Existe un estudio ideal para el seguimiento posoperatorio de los paciente llevados a pieloplastia por laparoscopia?

Stenosis of the pyeloureteral junction is a disorder that occurs from gestation, but can appear at any stage of life. Nowadays, one of the courses of treatment is laparoscopic pyeloplasty as it has less postoperative complications, with a reduction in the risk of future interventions. A systematic review of the literature was conducted in order to establish the best follow-up in order to study and evaluate postoperative outcomes, as well as to measure the frequency of pyeloureteral re-stenosis in adult patients undergoing laparoscopic pyeloplasty.The clinical question of interest was set. A systematic search of articles in 4 databases was conducted based on inclusion and exclusion criteria. Duplicated bibliography was excluded and the articles were analysed and selected based on the number of patients in each study, country, year of publication, post-operative follow-up method, follow-up time, and procedure success rate.The diuretic renogram was the study of choice for postoperative follow-up. This was followed by the renogram with MAG 3, and renal ultrasound. The mean postoperative follow-up time was 25.88 months. The mean success rate was 92.92%, including imaging success, gamma success, or success in resolution of symptoms.The chosen studies for the follow-up of patients that undergo laparoscopic pyeloplasty are gamma-ray studies, due to their effectiveness in evaluating functional or obstructive kidney involvement. There is no agreement on the parameters that are ideal for follow-up studies, the definition of success rate, or expected ideal time.

Concepts, Methods, and Practical Considerations of Meta-Analysis in Drug Development

ABSTRACTMeta-analysis is the statistical methodology to combine study results from different clinical trials to address questions of clinical interest. It is done as a systematic review of the relevant clinical trials. Meta-analysis is usually conducted in three steps: data/study selection, statistical analysis, and interpretation. We discuss the practical issues in these three steps and introduce how a proper meta-analysis is conducted. A case study of meta-analysis of fatal adverse events in cancer patients treated with aflibercept is introduced and its limitations are discussed.

Microenvironment-Mediated Modeling of Tumor Response to Vascular-Targeting Drugs.

The tumor-associated microvasculature is one of the key elements of the microenvironment that helps shape, and is shaped by, tumor progression. Given the important role of the vasculature in tumor progression, and the fact that tumor and normal vasculature are physiologically and molecularly distinct, much effort has gone into the development of vascular-targeting drugs that in theory should target tumors without significant risk to normal tissue. In this chapter, a multiscale hybrid mathematical model of tumor-vascular interactions is presented to provide a theoretical basis for assessing tumor response to vascular-targeting drugs. Model performance is calibrated to quantitative clinical data on tumor response to angiogenesis inhibitors (AIs), preclinical data on response to a cytotoxic chemotherapy, and qualitative preclinical data on response to vascular disrupting agents (VDAs). The calibrated model is then used to explore two questions of clinical interest. First, the hypothesis that AIs and VDAs are complementary treatments, rather than redundant, is explored. The model predicts a minimal increase in antitumor activity as a result of adding a VDA to an AI treatment regimen, and in fact at times the combination can exert less antitumor activity than stand-alone AI treatment. Second, the question of identifying an optimal dosing strategy for treating with an AI and a cytotoxic agent is addressed. Using a stochastic optimization scheme, an intermittent schedule for both chemotherapy and AI administration is identified that can eradicate the simulated tumors. We propose that this schedule may have increased clinical antitumor activity compared to currently used treatment protocols.

1835 – Antipsychotics for schizophrenia: too little progress after 50 years?

Introduction ll antipsychotics act via dopaminergic receptor antagonism. This pharmacology is shared by all first (FGA) & second (SGA) generation antipsychotics. We reviewed the efficacy & safety of all antipsychotics in clinical use for BMJ Clinical Evidence (Barry et al 2012). Methods & questions Our paper summarises key results from this systematic review based on comprehensive literature search of the Medline, Embase, Cochrane Library, and other databases including safety information from the FDA and MHRA in UK. The main clinical questions of interest were: What is the efficacy of drug treatments for positive, negative, or cognitive symptoms of schizophrenia? How effective are treatments for people with schizophrenia resistant to standard antipsychotic drugs? Results We found 51 systematic reviews, RCTs, or observational studies that met our inclusion/quality criteria and performed GRADE analysis to assess quality of evidence. Key results are presented for efficacy & safety for: amisulpiride, chlorpromazine, clozapine, depot haloperidol, haloperidol, olanzapine, pimozide, quetiapine, risperidone, sulpiride, ziprasidone, zotepine, aripiprazole, sertindole, paliperidone, flupentixol, depot flupentixol, zuclopenthixol, depot zuclopenthixol, and clozapine. Discussion The evidence for some ‘standard’ treatments is surprisingly weak. Up to 1/3 -1/2 of patients fail to respond to currently available antipsychotics, and all antipsychotics cause side effects in most people. This downbeat conclusion is not surprising, given clinical experience and the common mechanism of action of all antipsychotics. More efficacious antipsychotic medication will only be developed from understanding the biological pathogenesis of schizophrenia.Barry S, Gaughin T, and Hunter R. Schizophrenia. BMJ Clinical Evidence 13 July 2012. http://clinicalevidence.bmj.com/x/systematic-review/1007/overview.html .

The screening mammography paradox: better when found, perhaps better not to find

The screening mammography paradox: better when found, perhaps better not to find