Power Considerations in Designing and Interpreting Adaptive Clinical Trials.

Adaptive clinical trials allow researchers to make preplanned modifications based on accumulating data from an ongoing trial while preserving the trial's integrity and validity. These modifications may include early termination in cases of successes or lack of efficacy, refining the sample size, altering treatments or doses, or focusing recruitment efforts on individuals most likely to benefit. In this issue of NEJM Evidence, Geisler et al.1 report results from the Apixaban for Treatment of Embolic Stroke of Undetermined Source (ATTICUS) trial, a multicenter randomized trial of apixaban compared with aspirin in patients with cardioembolism risk factors.

Optimizing clinical nutrition research: the role of adaptive and pragmatic trials.

Evidence-based nutritional recommendations address the health impact of suboptimal nutritional status. Efficacy randomized controlled trials (RCTs) have traditionally been the preferred method for determining the effects of nutritional interventions on health outcomes. Nevertheless, obtaining a holistic understanding of intervention efficacy and effectiveness in real-world settings is stymied by inherent constraints of efficacy RCTs. These limitations are further compounded by the complexity of nutritional interventions and the intricacies of the clinical context. Herein, we explore the advantages and limitations of alternative study designs (e.g., adaptive and pragmatic trials), which can be incorporated into RCTs to optimize the efficacy or effectiveness of interventions in clinical nutrition research. Efficacy RCTs often lack external validity due to their fixed design and restrictive eligibility criteria, leading to efficacy-effectiveness and evidence-practice gaps. Adaptive trials improve the evaluation of nutritional intervention efficacy through planned study modifications, such as recalculating sample sizes or discontinuing a study arm. Pragmatic trials are embedded within clinical practice or conducted in settings that resemble standard of care, enabling a more comprehensive assessment of intervention effectiveness. Pragmatic trials often rely on patient-oriented primary outcomes, acquire outcome data from electronic health records, and employ broader eligibility criteria. Consequently, adaptive and pragmatic trials facilitate the prompt implementation of evidence-based nutritional recommendations into clinical practice. Recognizing the limitations of efficacy RCTs and the potential advantages of alternative trial designs is essential for bridging efficacy-effectiveness and evidence-practice gaps. Ultimately, this awareness will lead to a greater number of patients benefiting from evidence-based nutritional recommendations.

Considerations for identifying the "right" subgroup in adaptive enrichment trials.

Adaptive Enrichment Trials aim to make efficient use of data in a pivotal trial of a new targeted therapy to both (a) more precisely identify who benefits from that therapy and (b) improve the likelihood of successfully concluding that the drug is effective, while controlling the probability of false positives. There are a number of frameworks for conducting such a trial and decisions that must be made regarding how to identify that target subgroup. Among those decisions, one must choose how aggressively to restrict enrollment criteria based on the accumulating evidence in the trial. In this article, we empirically evaluate the impact of aggressive versus conservative enrollment restrictions on the power of the trial to detect an effect of treatment. We identify that, in some cases, a more aggressive strategy can substantially improve power. This additionally raises an important question regarding label indication: To what degree do we need a formal test of the hypothesis of no treatment effect in the exact population implied by the label indication? We discuss this question and evaluate how our answer for adaptive enrichment trials may relate to the answer implied by current practice for broad eligibility trials.

Adaptive Clinical Trials in Pediatric Critical Care: A Systematic Review.

OBJECTIVES: This systematic review investigates the use of adaptive designs in randomized controlled trials (RCTs) in pediatric critical care. DATA SOURCES: PICU RCTs, published between 1986 and 2020, stored in the www.PICUtrials.net database and MEDLINE, EMBASE, CENTRAL, and LILACS databases were searched (March 9, 2022) to identify RCTs published in 2021. PICU RCTs using adaptive designs were identified through an automated full-text screening algorithm. STUDY SELECTION: All RCTs involving children (< 18 yr old) cared for in a PICU were included. There were no restrictions to disease cohort, intervention, or outcome. Interim monitoring by a Data and Safety Monitoring Board that was not prespecified to change the trial design or implementation of the study was not considered adaptive. DATA EXTRACTION: We extracted the type of adaptive design, the justification for the design, and the stopping rule used. Characteristics of the trial were also extracted, and the results summarized through narrative synthesis. Risk of bias was assessed using the Cochrane Risk of Bias Tool 2. DATA SYNTHESIS: Sixteen of 528 PICU RCTs (3%) used adaptive designs with two types of adaptations used; group sequential design and sample size reestimation. Of the 11 trials that used a group sequential adaptive design, seven stopped early due to futility and one stopped early due to efficacy. Of the seven trials that performed a sample size reestimation, the estimated sample size decreased in three trials and increased in one trial. CONCLUSIONS: Little evidence of the use of adaptive designs was found, with only 3% of PICU RCTs incorporating an adaptive design and only two types of adaptations used. Identifying the barriers to adoption of more complex adaptive trial designs is needed.

Borrowing Concurrent Information from Non-Concurrent Control to Enhance Statistical Efficiency in Platform Trials.

A platform trial is a trial involving an innovative adaptive design with a single master protocol to efficiently evaluate multiple interventions. It offers flexible features such as dropping interventions for futility and adding new interventions to be evaluated during the course of a trial. Although there is a consensus that platform trials can identify beneficial interventions with fewer patients, less time, and a higher probability of success than traditional trials, there remains debate on certain issues, one of which is whether (and how) the non-concurrent control (NCC) (i.e., patients in the control group recruited prior to the new interventions) can be combined with the current control (CC) in the analysis, especially if there is a change of standard of care during the trial. METHODS: In this paper, considering time-to-event endpoints under the proportional hazard model assumption, we introduce a new concept of NCC concurrent observation time (NCC COT), and propose to borrow NCC COT through left truncation. This assumes that the NCC COT and CC are comparable. If the protocol does not prohibit NCC patients to change the standard of care while on study, NCC COT and CC likely will share the same standard of care. A simulated example is provided to demonstrate the approach. RESULTS: Using exponential distributions, the simulated example assumes that NCC COT and CC have the same hazard, and the treatment group has a lower hazard. The estimated HR comparing treatment to the pooled control group is 0.744 (95% CI 0.575, 0.962), whereas the comparison to the CC group alone is 0.755 (95% CI 0.566, 1.008), with corresponding p-values of 0.024 versus 0.057, respectively. This suggests that borrowing NCC COT can improve statistical efficiency when the exchangeability assumption holds. CONCLUSION: This article proposes an innovative approach of borrowing NCC COT to enhance statistical inference in platform trials under appropriate scenarios.

Adaptive clinical trials and master protocols.

Methodologies for randomized, double-blind, placebo-controlled clinical trials continue to develop in concert with evolving scientific and translational knowledge. Adaptive trial designs, in which data generated during the study are used to modify subsequent study activity (i.e., sample sizes, entry criteria, or outcomes), can optimize flexibility and expedite the safety and efficacy assessments for interventions of interest. This chapter will summarize general designs, advantages, and pitfalls associated with adaptive clinical trials and compare their features with those of conventional trial designs. It will also review novel ways for which seamless designs and master protocols may improve trial efficiency while offering interpretable data.

Protocol for a cohort study to evaluate the effectiveness and cost-effectiveness of general population screening for cardiovascular disease: the Viborg Screening Programme (VISP).

INTRODUCTION: The prevalence of cardiovascular disease (CVD) is increasing. Furthermore, asymptomatic individuals may not receive timely preventive initiatives to minimise the risk of further CVD events. Paradoxically, 80% of CVD events are preventable by early detection, followed by prophylactic initiatives. Consequently, we introduced the population-based Viborg Screening Programme (VISP) for subclinical and manifest CVD, focusing on commonly occurring, mainly asymptomatic conditions, followed by prophylactic initiatives.The aim of the VISP was to evaluate the health benefits, harms and cost-effectiveness of the VISP from a healthcare sector perspective. Furthermore, we explored the participants' perspectives. METHODS AND ANALYSIS: From August 2014 and currently ongoing, approximately 1100 men and women from the Viborg municipality, Denmark, are annually invited to screening for abdominal aortic aneurysm, peripheral arterial disease, carotid plaque, hypertension, diabetes mellitus and cardiac arrhythmia on their 67th birthday. A population from the surrounding municipalities without access to the VISP acts as a control. The VISP invitees and the controls are followed on the individual level by nationwide registries. The primary outcome is all-cause mortality, while costs, hospitalisations and deaths from CVD are the secondary endpoints.Interim evaluations of effectiveness and cost-effectiveness are planned every 5 years using propensity score matching followed by a Cox proportional hazards regression analysis by the 'intention-to-treat' principle. Furthermore, censoring-adjusted incremental costs, life-years and quality-adjusted life-years are estimated. Finally, the participants' perspectives are explored by semistructured face-to-face interviews, with participant selection representing participants with both negative and positive screening results. ETHICS AND DISSEMINATION: The VISP is not an interventional trial. Therefore, approval from a regional scientific ethical committee is not needed. Data collection from national registries was approved by the Regional Data Protection Agency (record no. 1-16-02-232-15). We ensure patient and public involvement in evaluating the acceptability of VISP by adopting an interviewing approach in the study. TRIAL REGISTRATION NUMBER: NCT03395509.

Ensuring the Scientific Value and Feasibility of Clinical Trials: A Qualitative Interview Study.

BACKGROUND: Ethical and scientific principles require that clinical trials address an important question and have the resources needed to complete the study. However, there are no clear standards for review that would ensure that these principles are upheld. METHODS: We conducted semi-structured interviews with a convenience sample of nineteen experts in clinical trial design, conduct, and/or oversight to elucidate current practice and identify areas of need with respect to ensuring the scientific value and feasibility of clinical trials prior to initiation and while ongoing. We used a priori and grounded theory to analyze the data and constant comparative method to induce higher order themes. RESULTS: Interviewees perceived determination of scientific value as the responsibility of the investigator and, secondarily, other parties who review or oversee research. Interviewees reported that ongoing trials are rarely reevaluated due to emerging evidence from external sources, evaluation is complex, and there would be value in the development of standards for monitoring and evaluating evidence systematically. Investigators, IRBs, and/or data monitoring committees (DMCs) could undertake these responsibilities. Feasibility assessments are performed but are typically inadequate; potential solutions are unclear. CONCLUSIONS: There are three domains where current approaches are suboptimal and in which further guidance is needed. First, who has the responsibility for conducting scientific review, whether it be the investigator, IRB, and/or DMC is often unclear. Second, the standards for scientific review (e.g., appropriate search terms, data sources, and analytic plan) should be defined. Third, guidance is needed on the evaluation of ongoing studies in light of potentially new and evolving evidence, with particular reference to evidence from outside the trial itself.

Inference in response-adaptive clinical trials when the enrolled population varies over time.

A common assumption of data analysis in clinical trials is that the patient population, as well as treatment effects, do not vary during the course of the study. However, when trials enroll patients over several years, this hypothesis may be violated. Ignoring variations of the outcome distributions over time, under the control and experimental treatments, can lead to biased treatment effect estimates and poor control of false positive results. We propose and compare two procedures that account for possible variations of the outcome distributions over time, to correct treatment effect estimates, and to control type-I error rates. The first procedure models trends of patient outcomes with splines. The second leverages conditional inference principles, which have been introduced to analyze randomized trials when patient prognostic profiles are unbalanced across arms. These two procedures are applicable in response-adaptive clinical trials. We illustrate the consequences of trends in the outcome distributions in response-adaptive designs and in platform trials, and investigate the proposed methods in the analysis of a glioblastoma study.

Mobile App Interventions to Improve Medication Adherence Among Type 2 Diabetes Mellitus Patients: A Systematic Review of Clinical Trials.

BACKGROUND: Medication adherence in type 2 diabetes mellitus (T2DM) patients is often suboptimal resulting in complications. There has been a growing interest in using mobile apps for improving medication adherence. OBJECTIVE: The objective of this work was to systematically review the clinical trials that have used mobile app-based interventions in T2DM patients for improving medication adherence. METHODOLOGY: A systematic search was performed to identify published clinical trials between January 2008 and December 2020 in databases-PubMed, Cochrane Library, and Google Scholar. All studies were assessed for risk of bias using quality rating tool from the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Seven clinical studies having 649 participants were studied. The median sample size was 58 (range = 41-247) and the median age of participants was 53.2 (range = 48-69.4) years. All studies showed improvements in adherence; however, only three studies reported statically significant improvements in adherence measures. Selected studies were deemed as unclear in their risk of bias and the most common source of risk of bias among the studies was the absence of objective outcome assessment. CONCLUSIONS: Mobile apps appear to be effective interventions to help improve medication adherence in T2DM patients compared with conventional care strategies. The features of the App to improvise medical adherence cannot be defined based on the meta-analysis because of heterogeneity of study designs and less number of sample size. Systematically planned studies would set up applicability of mobile apps in the clinical management of T2DM.

Platform trials.

For the past few years, platform trials have experienced a significant increase, recently amplified by the COVID-19 pandemic. The implementation of a platform trial is particularly useful in certain pathologies, particularly when there is a significant number of drug candidates to be assessed, a rapid evolution of the standard of care or in situations of urgent need for evaluation, during which the pooling of protocols and infrastructure optimizes the number of patients to be enrolled, the costs, and the deadlines for carrying out the investigation. However, the specificity of platform trials raises methodological, ethical, and regulatory issues, which have been the subject of the round table and which are presented in this article. The round table was also an opportunity to discuss the complexity of sponsorship and data management related to the multiplicity of partners, funding, and governance of these trials, and the level of acceptability of their findings by the competent authorities.

Diet or additional supplement to increase potassium intake: protocol for an adaptive clinical trial.

BACKGROUND: High blood pressure is the leading cause of cardiovascular disease worldwide. The prevalence of high blood pressure is steadily rising as the population grows amongst older adults with the ageing population. Therapeutical treatments are widely available to decrease blood pressures, in addition to many lifestyle options, such as dietary changes and exercise. There is a marked preference amongst patients, as reiterated by Hypertension Canada, for more research into non-therapeutic methods for controlling blood pressure or to reduce the burden of taking many pills to control high blood pressure. Indeed, effective options do exist, especially with diet, specifically decreasing sodium and increasing potassium intake. Current public health outreach primarily focusses on sodium intake, even though potassium intake remains low in the Western world. Excellent data exist in published research that increasing potassium intake, either via dietary modification or supplements, reduces blood pressure and reduces risk of cardiovascular outcomes such as stroke. However, the advice most often provided by medical professionals is to 'eat more fruits and vegetables' which has little impact on patient outcomes. METHODS: We propose to do a clinical trial in two stages with an adaptive trial design. In the first stage, participants with high blood pressure and proven low potassium intake (measured on the basis of a 24-h urine collection) will get individually tailored dietary advice, reinforced by weekly supportive phone/email support. At 4 weeks, if there has not been a measured increase in potassium intake, participants will be prescribed an additional potassium supplement. Testing will be conducted again at 8 weeks, to confirm the efficacy of the potassium supplement. Final measurements will be planned at 52 weeks to observe and measure the persistence of the effect of diet or additional supplement. Concurrent measurements of sodium intake, blood pressure, participant satisfaction, and safety measures will also be done. DISCUSSION: The results of the study will help determine the most effective method of increasing potassium intake, thus reducing blood pressure and need for blood pressure-lowering medicines, and at the same time potentially increasing participant satisfaction. The current guidelines recommend changes in diet, not a potassium supplement, to increase potassium intake; hence, the two-stage design will only add supplements if the most rigorous dietary advice does not work. TRIAL REGISTRATION: This study has been registered on ClinicalTrials.gov NCT03809884 . Registered on January 18, 2019.

Cyclin-dependent kinase (CDK) inhibitors in solid tumors: a review of clinical trials

Cyclin-dependent kinases (CDKs) play a key regulating role in the cell cycle, which is almost universally altered in cancer, leading to sustained proliferation. Early pan-CDK inhibitors showed poor results in clinical trials for solid malignancies, as the lack of selectivity produced significant toxicity. The production of more selective inhibitors led to significant developments in cancer therapy, as CDK4/6 inhibitors in combination with endocrine therapy changed the landscape of the treatment of hormone-receptor positive (HR +) metastatic breast cancer. Recently, Trilaciclib demonstrated benefits regarding hematological toxicity compared to placebo when administered in combination with chemotherapy in small cell lung cancer. Newer agents, such as SY-5609, a selective CDK7 inhibitor, have also shown promising results in early clinical trials. In this paper, we review the data from clinical trials of CDK inhibitors in solid tumors, either as a monotherapy or in combination with other agents, with an emphasis on novel agents and potential new indications for this drug class.

SEOR SBRT-SG stereotactic body radiation therapy consensus guidelines for non-spine bone metastasis

The use of stereotactic body radiation therapy (SBRT) to treat non-spine bone metastases (NSBM) is becoming increasingly common in clinical practice. The clinical advantages of SBRT include good pain control and high local control rates, although only limited data are available. The Spanish Society of Radiation Oncology (SEOR) SBRT group recently convened a task force of experts in the field to address key questions related to SBRT for NSBM, including treatment indications, planning, techniques, and dose fractionation. The task force reviewed the available literature to develop evidence-based recommendations for the safe application of NSBM SBRT and to standardize and optimize SBRT processes. The present document provides a comprehensive analysis of the available data, including ongoing clinical trials and controversies, providing clinically applicable recommendations.

Enfermedad hemolítica perinatal en recién nacido por aloinmunización anti-E / Foetal Haemolytic Disease in a new-born with Anti-E alloimmunization

AntecedentesLa aloinmunización anti-E es una etiología rara de enfermedad hemolítica perinatal (EHP). Su incidencia es muy baja, y menos del 3% es grave. Dado que la titulación de anticuerpos no se correlaciona con la gravedad, resulta interesante notificar casos que requieren tratamiento en el periodo postnatal.ObjetivoReportar el caso de un recién nacido tratado con fototerapia y exanguinotransfusión por EHP por aloinmunizacion anti-E.CasoMujer 42 años, escrutinio de anticuerpos irregulares positivo con aloanticuerpos anti-E.ConclusionesSe requiere un manejo activo tanto en el periodo prenatal como neonatal de la aloinmunización anti-E. Aunque no se haya documentado anemia en el periodo fetal, el recién nacido sigue siendo de alto riesgo para la presentación de clínica compatible con enfermedad hemolítica en el periodo postnatal.

BackgroundAnti-E alloimmunization is a rare aetiology of haemolytic disease of the foetus and new-born (HDFN). The incidence is low, with less than 3% with severity criteria. Antibody titre does not correlate with severity, so cases that require treatment should be notified.ObjectiveTo report the case of a new-born who required phototherapy as treatment of HDFN secondary to anti-E alloimmunization.Case42-year-old woman, positive irregular antibody screening, with anti-E alloantibodies.ConclusionsActive management is required in both the prenatal and the neonatal period. Although anaemia has not been documented in the foetal period, the new-born is still at high risk for the presentation of symptoms compatible with haemolytic disease in the postnatal period.

Advantages of multi-arm non-randomised sequentially allocated cohort designs for Phase II oncology trials.

BACKGROUND: Efficient trial designs are required to prioritise promising drugs within Phase II trials. Adaptive designs are examples of such designs, but their efficiency is reduced if there is a delay in assessing patient responses to treatment. METHODS: Motivated by the WIRE trial in renal cell carcinoma (NCT03741426), we compare three trial approaches to testing multiple treatment arms: (1) single-arm trials in sequence with interim analyses; (2) a parallel multi-arm multi-stage trial and (3) the design used in WIRE, which we call the Multi-Arm Sequential Trial with Efficient Recruitment (MASTER) design. The MASTER design recruits patients to one arm at a time, pausing recruitment to an arm when it has recruited the required number for an interim analysis. We conduct a simulation study to compare how long the three different trial designs take to evaluate a number of new treatment arms. RESULTS: The parallel multi-arm multi-stage and the MASTER design are much more efficient than separate trials. The MASTER design provides extra efficiency when there is endpoint delay, or recruitment is very quick. CONCLUSIONS: We recommend the MASTER design as an efficient way of testing multiple promising cancer treatments in non-comparative Phase II trials.

Opportunity for efficiency in clinical development: An overview of adaptive clinical trial designs and innovative machine learning tools, with examples from the cardiovascular field.

Modern data analysis tools and statistical modeling techniques are increasingly used in clinical research to improve diagnosis, estimate disease progression and predict treatment outcomes. What seems less emphasized is the importance of the study design, which can have a serious impact on the study cost, time and statistical efficiency. This paper provides an overview of different types of adaptive designs in clinical trials and their applications to cardiovascular trials. We highlight recent proliferation of work on adaptive designs over the past two decades, including some recent regulatory guidelines on complex trial designs and master protocols. We also describe the increasing role of machine learning and use of metaheuristics to construct increasingly complex adaptive designs or to identify interesting features for improved predictions and classifications.

Ethics of emerging infectious disease outbreak responses: Using Ebola virus disease as a case study of limited resource allocation.

Emerging infectious diseases such as Ebola Virus Disease (EVD), Nipah Virus Encephalitis and Lassa fever pose significant epidemic threats. Responses to emerging infectious disease outbreaks frequently occur in resource-constrained regions and under high pressure to quickly contain the outbreak prior to potential spread. As seen in the 2020 EVD outbreaks in the Democratic Republic of Congo and the current COVID-19 pandemic, there is a continued need to evaluate and address the ethical challenges that arise in the high stakes environment of an emerging infectious disease outbreak response. The research presented here provides analysis of the ethical challenges with regard to allocation of limited resources, particularly experimental therapeutics, using the 2013-2016 EVD outbreak in West Africa as a case study. In-depth semi-structured interviews were conducted with senior healthcare personnel (n = 16) from international humanitarian aid organizations intimately engaged in the 2013-2016 EVD outbreak response in West Africa. Interviews were recorded in private setting, transcribed, and iteratively coded using grounded theory methodology. A majority of respondents indicated a clear propensity to adopt an ethical framework of guiding principles for international responses to emerging infectious disease outbreaks. Respondents agreed that prioritization of frontline workers' access to experimental therapeutics was warranted based on a principle of reciprocity. There was widespread acceptance of adaptive trial designs and greater trial transparency in providing access to experimental therapeutics. Many respondents also emphasized the importance of community engagement in limited resource allocation scheme design and culturally appropriate informed consent procedures. The study results inform a potential ethical framework of guiding principles based on the interview participants' insights to be adopted by international response organizations and their healthcare workers in the face of allocating limited resources such as experimental therapeutics in future emerging infectious disease outbreaks to ease the moral burden of individual healthcare providers.

The Bayesian Design of Adaptive Clinical Trials.

This paper presents a brief overview of the recent literature on adaptive design of clinical trials from a Bayesian perspective for statistically not so sophisticated readers. Adaptive designs are attracting a keen interest in several disciplines, from a theoretical viewpoint and also-potentially-from a practical one, and Bayesian adaptive designs, in particular, have raised high expectations in clinical trials. The main conceptual tools are highlighted here, with a mention of several trial designs proposed in the literature that use these methods, including some of the registered Bayesian adaptive trials to this date. This review aims at complementing the existing ones on this topic, pointing at further interesting reading material.