Showing papers in "Clinical Trials in 2018"
TL;DR: A novel calibrated Bayesian hierarchical model approach to evaluate the treatment effect in basket trials that is calibrated using simulation such that information is strongly borrowed across subgroups if their treatment effects are similar and barely borrowed if the treatment results are heterogeneous.
Abstract: Background:The basket trial evaluates the treatment effect of a targeted therapy in patients with the same genetic or molecular aberration, regardless of their cancer types. Bayesian hierarchical m...
82 citations
TL;DR: Interventions that leverage peer influence processes to facilitate PrEP uptake are promising strategies to improve sexual health engagement and overcome disparities in outcomes among this at-risk population.
Abstract: Background/aims:Advances in biomedical prevention strategies such as pre-exposure prophylaxis (PrEP) represent a new opportunity for reducing HIV incidence among young Black men who have sex with m...
78 citations
European Organisation for Research and Treatment of Cancer1, Mayo Clinic2, University of North Carolina at Chapel Hill3, University of Franche-Comté4, University of Birmingham5, Genentech6, University of Texas MD Anderson Cancer Center7, Otto-von-Guericke University Magdeburg8, University of British Columbia9, Medical University of Graz10, Boehringer Ingelheim11, University of Copenhagen12, University of Angers13, University of Sydney14, Food and Drug Administration15, University of Regensburg16, University of Arizona17, National Institutes of Health18, Fred Hutchinson Cancer Research Center19, Medicines and Healthcare Products Regulatory Agency20, Université libre de Bruxelles21, University of Coimbra22, European Centre for Disease Prevention and Control23, VU University Amsterdam24, Health Canada25, Leiden University26, University of Leeds27
TL;DR: The SISAQOL Consortium will focus on three key priorities in the coming year: developing a taxonomy of research objectives, identifying appropriate statistical methods to analyze patient-reported outcome data, and determining best practices to evaluate and deal with missing data.
Abstract: BackgroundThere is currently a lack of consensus on how health-related quality of life and other patient-reported outcome measures in cancer randomized clinical trials are analyzed and interpreted....
41 citations
TL;DR: Online advertisements effectively directed a relevant population to the authors' website, which resulted in new enrollees in the Survivorship Promotion In Reducing IGF-1 Trial at a cost comparable to traditional methods, however.
Abstract: Background/Aims:Despite widespread Internet adoption, online advertising remains an underutilized tool to recruit participants into clinical trials Whether online advertising is a cost-effective m
37 citations
TL;DR: An overview of the evidentiary standards required by the Food and Drug Administration’s expedited development and review programs is provided, the findings of the recent academic literature demonstrating some of the limitations of these programs are summarized, and potential opportunities to address these limitations are outlined.
Abstract: The US Food and Drug Administration has several regulatory programs and pathways to expedite the development and approval of therapeutic agents aimed at treating serious or life-debilitating conditions. A common feature of these programs is the regulatory flexibility, which allows for a customized approval approach that enables market authorization on the basis of less rigorous evidence, in exchange for requiring postmarket evidence generation. An increasing share of therapeutic agents approved by the Food and Drug Administration in recent years are associated with expedited programs. In this article, we provide an overview of the evidentiary standards required by the Food and Drug Administration's expedited development and review programs, summarize the findings of the recent academic literature demonstrating some of the limitations of these programs, and outline potential opportunities to address these limitations. Recent evidence suggests that therapeutic agents in the Food and Drug Administration's expedited programs are approved on the basis of fewer and smaller studies that may lack comparator groups and random allocation, and rather than focusing on clinical outcomes for study endpoints, rely instead on surrogate markers of disease. Once on the market, agents receiving expedited approvals are often quickly incorporated into clinical practice, and evidence generated in the postmarket period may not necessarily address the evidentiary limitations at the time of market entry. Furthermore, not all pathways require additional postmarket studies. Evidence suggests that drugs in expedited approval programs are associated with a greater likelihood that the Food and Drug Administration will take a safety action following market entry. There are several opportunities to improve the timeliness, information value, and validity of the pre- and postmarket studies of therapeutic agents receiving expedited approvals. When use of nonrandomized and uncontrolled studies cannot be avoided prior to market entry, randomized trials should be mandatory in the postmarket period, unless there are strong justifications for not carrying out such studies. In the premarket period, validity of the surrogate markers can be improved by more rigorously evaluating their correlation with patient-relevant clinical outcomes. Opportunities to reduce the duration, complexity, and cost of postmarket randomized trials should not compromise their validity and instead incorporate pragmatic "real-world" design elements. Despite recent enthusiasm for widely using real-world evidence, adaptive designs, and pragmatic trials in the regulatory setting, caution is warranted until large-scale empirical evaluations demonstrate their validity compared to more traditional trial designs.
36 citations
TL;DR: Although the asymmetric consent procedures for the experimental versus control arm subjects can initially raise ethical concerns, the Trials within Cohorts design is ethically superior to previous post-randomization consent designs and can have important advantages over traditional trial designs.
Abstract: Background:With increasing emphasis on pragmatic trials, new randomized clinical trial designs are being proposed to enhance the “real world” nature of the data generated. We describe one such design, appropriate for unmasked pragmatic clinical trials in which the control arm receives usual care, called “Trials within Cohorts” that is increasingly used in various countries because of its efficiency in recruitment, advantages in reducing subject burden, and ability to better mimic real-world consent processes.Methods:Descriptive, ethical, and US regulatory analysis of the Trials within Cohorts design.Results:Trials within Cohorts design involves, after recruitment into a cohort, randomization of eligible subjects, followed by an asymmetric treatment of the two arms: those selected for the experimental arm provide informed consent for the intervention trial, while the data from the control arm are used based on prior broad permission. Thus, unlike the traditional Zelen post-randomization consent design, the...
35 citations
TL;DR: Results from external pilot trials to estimate randomisation and attrition rates should be used with caution as comparison of the difference in the rates between pilots and their associated full trial demonstrates high variability.
Abstract: Background/aims:External pilot trials are recommended for testing the feasibility of main or confirmatory trials. However, there is little evidence that progress in external pilot trials actually p...
32 citations
TL;DR: Using a lower pressure than the hyperbaric oxygen group while breathing 21% oxygen best matches the inertness of the placebo, and although studies show that use of a lower Pressure does allow adequate blinding, this is associated with more practical issues than with the other strategies.
Abstract: BackgroundHyperbaric oxygen therapy, which consists of breathing 100% oxygen under a higher atmospheric pressure than normal, is utilized worldwide in the treatment of several diseases. With the gr...
31 citations
TL;DR: The Online resource for Recruitment Research in Clinical triAls project has identified the need for researchers to evaluate their recruitment strategies to improve the evidence base and broaden the narrow focus of existing research to help meet the complex challenges faced by those recruiting to clinical trials.
Abstract: BackgroundRecruiting the target number of participants within the pre-specified time frame agreed with funders remains a common challenge in the completion of a successful clinical trial and addres...
31 citations
TL;DR: Simulation results demonstrate that multi-state models and time-dependent Cox models evaluate treatment effects from different frameworks and can be used as a complementary tool to standard survival analyses to provide deeper insights to the effects of treatment in trial settings with complex disease process.
Abstract: Background/aims The goal of this article is to illustrate the utility of multi-state models in cancer clinical trials. Our specific aims are to describe multi-state models and how they differ from standard survival methods, to illustrate how multi-state models can facilitate deeper understanding of the treatment effect on multiple paths along the disease process that patients could experience in cancer clinical trials, to explain the differences between multi-state models and time-dependent Cox models, and to briefly describe available software to conduct such analyses. Methods Data from 717 newly diagnosed acute myeloid leukemia patients who enrolled in the CALGB 10603 trial were used as an illustrative example. The current probability-in-state was estimated using the Aalen-Johansen estimator. The restricted mean time in state was calculated as the area under the probability-in-state curves. Cox-type regression was used to evaluate the effect of midostaurin on the various clinical paths. Simulation was conducted using a newly constructed shiny application. All analyses were performed using the R software. Results Multi-state model analyses of CALGB 10603 suggested that the overall improvement in survival with midostaurin seen in the primary analysis possibly resulted from a higher complete remission rate in combination with a lower risk of relapse and of death after complete remission in patients treated with midostaurin. Simulation results, in a three-state illness-death without recovery model, demonstrate that multi-state models and time-dependent Cox models evaluate treatment effects from different frameworks. Conclusion Multi-state models allow detailed evaluation of treatment effects in complex clinical trial settings where patients can experience multiple paths between study enrollment and the final outcome. Multi-state models can be used as a complementary tool to standard survival analyses to provide deeper insights to the effects of treatment in trial settings with complex disease process.
31 citations
TL;DR: The authors describe key challenges facing the clinical trials community and propose solutions to these issues, including the role the Clinical Trials Transformation Initiative can play in addressing these issues.
Abstract: The authors describe key challenges facing the clinical trials community and propose solutions to these issues, including the role the Clinical Trials Transformation Initiative can play in addressing these issues. Specifically, the authors reflect on clinical trial globalization and the harmonization of frameworks and requirements across regions; the challenges associated with balancing the desire for external validity, pragmatic trials, and precision medicine; clinical trial transparency; and operational complexity and the expense of clinical trials. By addressing these challenges, future clinical trials will be more feasible, relevant, and credible, and support both the continuing altruistic contributions of patients and the collection of more meaningful data.
TL;DR: There has been a decline in the number of trials being funded by the National Institutes of Health over time, explained in part by a relatively constant budget, increases in trial costs, or other factors that cannot be quantified.
Abstract: BackgroundThe National Institutes of Health is one of the largest biomedical research agencies in the world. Clinical trials are an important component of National Institutes of Health research efforts. Given the recent updates in National Institutes of Health trial reporting requirements, more information regarding the current state of National Institutes of Health–funded clinical trials is warranted. The objective of this analysis was to describe characteristics and trends of clinical trials funded by the National Institutes of Health over time and by Institutes and Centers of the National Institutes of Health.MethodsInterventional studies funded by the National Institutes of Health and registered in ClinicalTrials.gov between 2005 and 2015 were included in the analysis. Trials were identified from the 27 March 2016 Clinical Trials Transformation Initiative Aggregate Analysis of ClinicalTrials.gov database. A descriptive analysis of trials by year and National Institutes of Health Institute/Center was p...
TL;DR: Many lessons have been learned about setting up and implementing a clinical trial during a devastating Ebola epidemic, and some of the experiences of the EBOVAC-Salone team were mirrored by those of other researchers operating in the region.
Abstract: Background/aims During the 2014-2016 West African Ebola epidemic, clinical trials were fast-tracked in order to identify prophylactic vaccines and experimental treatments that might be useful in preventing or treating Ebola. These trials included the ongoing EBOVAC-Salone study, which was established and implemented in Sierra Leone to assess the safety and immunogenicity of the Ad26.ZEBOV/MVA-BN-Filo prime-boost Ebola vaccine regimen. Methods This article describes the experiences of the EBOVAC-Salone research team in setting up and implementing the trial, and provides recommendations for research teams aiming to conduct clinical trials in future outbreak situations. Results Establishing a clinical trial during an outbreak brought some unique challenges, including those related to trial design and the regulatory environment, operational issues, and community engagement. The situation was further complicated by the weak infrastructure and limited experience of clinical trials in Sierra Leone. However, operating in an outbreak context also brought some benefits to the research team, including strong stakeholder support. The EBOVAC-Salone study recruited participants both during and after the outbreak, leading to additional challenges to trial implementation during the post-outbreak transition. Conclusion Many lessons have been learned about setting up and implementing a clinical trial during a devastating Ebola epidemic, and some of the experiences of the EBOVAC-Salone team were mirrored by those of other researchers operating in the region. Common to several of these research groups is a recommendation that research should be more closely incorporated into outbreak response planning, which could expedite the establishment of timely and appropriate research projects. We recommend that the lessons learned by researchers during the West African Ebola epidemic are built into programmes and strategies to improve the responses to future epidemics, wherever they occur.
TL;DR: High parental interest in pediatric neuromuscular trials was found that was tempered by concerns about the potential for randomization to a placebo arm, perhaps reflecting waning parental interest with a greater understanding of limitations in trial access, increased sophistication in their understanding of trial design, and appreciation of potential burden.
Abstract: Background/aims:Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of chil...
TL;DR: TEMPER assessed the ability of targeted monitoring, as used in three ongoing phase III randomised multi-site oncology trials, to distinguish sites at which higher and lower rates of protocol and/or Good Clinical Practice violations would be found during site visits and suggested triggered monitoring approaches were not sufficiently discriminatory.
Abstract: Background/aimsIn multi-site clinical trials, where trial data and conduct are scrutinised centrally with pre-specified triggers for visits to sites, targeted monitoring may be an efficient way to ...
TL;DR: Data Monitoring Committee Contract Agreements, Indemnification Agreements and Charters should be developed in a manner to protect data Monitoring Committee members and their independence, in order to enhance the Data Monitoring Committee’s ability to effectively address their mission.
Abstract: Maintaining confidentiality of emerging data and ensuring the independence of Data Monitoring Committees are best practices of considerable importance to the ability of these committees to achieve their mission of safeguarding the interests of study participants and enhancing the integrity and credibility of clinical trials. Even with the wide recognition of these principles, there are circumstances where confidentiality issues remain challenging, controversial or inconsistently addressed. First, consider settings where a clinical trial's interim data could provide the evidence regulatory authorities require for decisions about marketing approval, yet where such a trial would be continued post-approval to provide more definitive evidence about principal safety and/or efficacy outcomes. In such settings, data informative about the longer term objectives of the trial should remain confidential until pre-specified criteria for trial completion have been met. Second, for those other than Data Monitoring Committee members, access to safety and efficacy outcomes during trial conduct, even when presented as data pooled across treatment arms, should be on a limited "need to know" basis relating to the ability to carry out ethical or scientific responsibilities in the conduct of the trial. Third, Data Monitoring Committee members should have access to unblinded efficacy and safety data throughout the trial to enable timely and informed judgments about risks and benefits. Fourth, it should be recognized that a mediator potentially could be useful in rare settings where the Data Monitoring Committee would have serious ethical or scientific concerns about the sponsor's dissemination or lack of dissemination of information. Data Monitoring Committee Contract Agreements, Indemnification Agreements and Charters should be developed in a manner to protect Data Monitoring Committee members and their independence, in order to enhance the Data Monitoring Committee's ability to effectively address their mission.
TL;DR: Trialists planning mediation analyses should measure baseline values of putative mediators as well as of continuous clinical outcomes to avoid potential biases due to confounding processes involving baseline measures of intermediate or clinical outcomes.
Abstract: Background:Random allocation avoids confounding bias when estimating the average treatment effect. For continuous outcomes measured at post-treatment as well as prior to randomisation (baseline), analyses based on (A) post-treatment outcome alone, (B) change scores over the treatment phase or (C) conditioning on baseline values (analysis of covariance) provide unbiased estimators of the average treatment effect. The decision to include baseline values of the clinical outcome in the analysis is based on precision arguments, with analysis of covariance known to be most precise. Investigators increasingly carry out explanatory analyses to decompose total treatment effects into components that are mediated by an intermediate continuous outcome and a non-mediated part. Traditional mediation analysis might be performed based on (A) post-treatment values of the intermediate and clinical outcomes alone, (B) respective change scores or (C) conditioning on baseline measures of both intermediate and clinical outcome...
TL;DR: Methods and consensus recommendations for selecting specific Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items to include in early-phase and late-phase oncology clinical trials are presented.
Abstract: As new cancer treatment regimens demonstrate increased potential to improve patients' survival, more focus is directed toward the quality of that extension of life and to obtaining additional information from patients regarding their experience with treatment. The utility of capturing patient-reported treatment-related symptoms to complement traditional clinician-rated symptomatic adverse event reporting is well-documented. The National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events is an item library aimed at capturing patient-reported symptoms to inform the patient perspective on a treatment's tolerability. The U.S. Food and Drug Administration has recommended using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events in clinical trials. A practical guideline is needed to inform a priori selection of specific Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items for use in any given industry-sponsored oncology clinical trial. Standardizing this selection process will foster systematic and consistent data collection as part of drug development and enhance our knowledge on how to use patient-relevant information as part of a treatment's risk/benefit assessment. This article presents methods and consensus recommendations for selecting specific Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items to include in early-phase and late-phase oncology clinical trials.
TL;DR: The evolution of patient engagement is described including the origins of the patient engagement movement; barriers to successful engagement and remaining challenges to full and valuable collaboration between patient groups and trial sponsors; and Clinical Trials Transformation Initiative’s role in influencing the field through organizational practices, formal project work and resulting recommendations, and external advocacy efforts.
Abstract: Patient engagement is an increasingly important aspect of successful clinical trials. Over the past decade, as patient group involvement in clinical trials has continued to increase and diversify, the Clinical Trials Transformation Initiative has not only recognized the crucial role patients play in improving the clinical trial enterprise but also made a deep commitment to help grow and shape the emerging field of patient engagement. This article describes the evolution of patient engagement including the origins of the patient engagement movement; barriers to successful engagement and remaining challenges to full and valuable collaboration between patient groups and trial sponsors; and Clinical Trials Transformation Initiative's role in influencing the field through organizational practices, formal project work and resulting recommendations, and external advocacy efforts.
TL;DR: The SPeED study (Sport/Exercise Therapy and Psychotherapy—evaluating treatment Effects in Depressive patients) is a randomized controlled trial to investigate underlying physiological, neurobiological, and psychological mechanisms of the augmentation of cognitive behavioral therapy with endurance exercise.
Abstract: Background/Aims:Even though cognitive behavioral therapy has become a relatively effective treatment for major depressive disorder and cognitive behavioral therapy–related changes of dysfunctional neural activations were shown in recent studies, remission rates still remain at an insufficient level. Therefore, the implementation of effective augmentation strategies is needed. In recent meta-analyses, exercise therapy (especially endurance exercise) was reported to be an effective intervention in major depressive disorder. Despite these findings, underlying mechanisms of the antidepressant effect of exercise especially in combination with cognitive behavioral therapy have rarely been studied to date and an investigation of its neural underpinnings is lacking. A better understanding of the psychological and neural mechanisms of exercise and cognitive behavioral therapy would be important for developing optimal treatment strategies in depression. The SPeED study (Sport/Exercise Therapy and Psychotherapy—eval...
TL;DR: While central IRB review was associated with a shorter time from IRB submission to IRB approval compared to localIRB review, the total time from protocol receipt toIRB approval varied markedly across sites.
Abstract: Background/aims:Central institutional review board (IRB) review will be required for National Institutes of Health–funded multisite human subjects research as of January 2018, with similar requirements extending to most US multisite human research in 2020. Nonetheless, little is known regarding the relative efficiency of central versus local IRB review for multicenter studies. We compared the amount of time required for central versus local IRB review and approval for sites in one ongoing multicenter randomized trial.Methods:The REGAIN Trial (Regional versus General Anesthesia for Promoting Independence after Hip Fracture; clinicaltrials.gov number: NCT02507505) is an ongoing randomized trial comparing standard-care spinal anesthesia to standard-care general anesthesia for patients undergoing hip fracture surgery. After approval of the protocol by the sponsor IRB, each participating US site opted either to submit the protocol for local IRB review or to designate the sponsor IRB as the IRB of record (i.e. ...
TL;DR: A pragmatic, observational comparative effectiveness study that takes advantage of diversity in the management of a rare disease, comparing non-biologic and biologic consensus treatment plans for new-onset systemic juvenile idiopathic arthritis within the 60-center Childhood Arthritis and Rheumatology Research Alliance Registry (CARRA).
Abstract: Background:Systemic juvenile idiopathic arthritis is a rare febrile arthritis of childhood characterized by a potentially severe course, including prolonged glucocorticoid exposure, growth failure,...
TL;DR: The margins for the hazard ratio may seem large but translate to relatively small differences in restricted mean survival time, which should be considered more widely in the design and analysis of non-inferiority trials with time-to-event outcomes.
Abstract: Background/aimsNon-inferiority trials with time-to-event outcomes are becoming increasingly common. Designing non-inferiority trials is challenging, in particular, they require very large sample si...
Journal Article•
TL;DR: Higher expression of CCNE1 was associated with relative resistance to palbociclib, although all biomarker groups derived benefit from treatment, which supports CDK2 as the key bypass kinase of CDK4/6 inhibition, and potential to targetCDK2 to subvert resistance.
Abstract: BACKGROUND: The CDK4/6 inhibitor palbociclib in combination with fulvestrant (F) improved progression-free survival (PFS) vs F alone in previously-treated MBC. Prior pre-clinical research, and the NeoPalAna window study, identified high CCNE1 expression as a potential palbociclib resistance marker. We conducted large panel gene expression analysis of baseline tumor tissue to identify biomarkers (BMs) that predicted the relative benefit of palbociclib. METHODS: The PALOMA3 trial randomized 521 patients (pts) with endocrine-pretreated MBC to receive palbociclib + F or placebo (PBO) + F. All pts, except bone only or early relapse, provided FFPE tissue taken from recurrent disease. EdgeSeq Oncology BM Panel (HTG Molecular Diagnostics) was used for mRNA profiling, assessing 2534 cancer related genes. Primary objective was to evaluate the association of cell cycle pathway with palbociclib + F vs F alone treatment effect by using gene expression as a continuous variable or dichotomization by median level with Cox regression analysis. RESULTS: 302 pts had tumor tissue analyzed (194/347 [56%] palbociclib + F; 108/174 [62%] PBO+F). The BM and overall populations had similar treatment effect. Benefit from palbociclib was greater in patients with low tumor CCNE1 expression (median PFS: palbociclib + F 14.1 mo vs PBO+F 4.8 mo, HR 0.32) than high tumor CCNE1 expression (palbociclib + F 7.6 mo vs PBO+F 4.0 mo; HR 0.85) (interaction p=0.0024). Similar results were observed with CCNE1 as a continuous variable (interaction p=0.0008). Expression levels of CDK4, CDK6, cyclin D1 and RB1 did not associate with benefit from palbociclib, and both luminal A and B tumors derived benefit from palbociclib. In exploratory analysis, high E2F-regulon expression predicted for relative resistance to palbociclib. CONCLUSION: Higher expression of CCNE1 was associated with relative resistance to palbociclib, although all biomarker groups derived benefit from treatment. This data supports CDK2 as the key bypass kinase of CDK4/6 inhibition, and potential to target CDK2 to subvert resistance. Sponsor: Pfizer Citation Format: Nicholas C. Turner, Yuan Liu, Zhou Zhu, Sherene Loi, Marco Colleoni, Sibylle Loibl, Angela DeMichele, Nadia Harbeck, Fabrice Andre, Zhe Zhang, Carla Giorgetti, Cynthia Huang Bartlett, Massimo Cristofanilli. Cyclin E1 (CCNE1) expression associates with benefit from palbociclib in metastatic breast cancer (MBC) in the PALOMA3 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT039.
TL;DR: It is concluded that waivers of consent should be rare and that institutional review boards and researchers must explicitly address study acceptability in the community at large and the target population of their proposed research.
Abstract: Waivers of informed consent for research participation are permitted in the United States under the Common Rule, the Health Insurance Portability and Accountability Act regulations, and the US Food and Drug Administration's Exception from Informed Consent rule for emergency research. We assess the novel question regarding what legal right researchers have to carry out research procedures on or about another person, be it experimental medical intervention, psychological or social manipulation, or invasion of privacy, without the permission of their subjects. Our analysis frames waivers of consent as a species of presumed consent, and we address the underlying empirical question of whether it is reasonable to believe that subjects from whom no consent is sought would in fact agree, if asked. A scoping review of what is known about participation and refusal rates in United States-based research suggests that a large minority, on average, do not agree to take part in research. Refusal rates vary widely. This suggests that, while researchers may assert the social utility of their studies are high enough to justify waivers, there is reason to suspect that many who would be enrolled under a waiver of consent would not want to be enrolled. We conclude that waivers should be rare and that institutional review boards and researchers must explicitly address study acceptability in the community at large and the target population of their proposed research.
TL;DR: A scoping review on the ethical considerations of biomedical clinical research with uninsured and low-income participants in high-income countries reveals significant gaps in both data and thoughtful analysis on how to ethically involve uninsured research participants.
Abstract: Background/aims Sparse literature exists on the challenges and ethical considerations of including people with limited access to healthcare, such as the uninsured and low-income, in clinical research in high-income countries. However, many ethical issues should be considered with respect to working with uninsured and low-income participants in clinical research, including enrollment and retention, ancillary care, and post-trial responsibilities. Attention to the uninsured and low-income is particularly salient in the United States due to the high rates of uninsurance and underinsurance. Thus, we conducted a scoping review on the ethical considerations of biomedical clinical research with uninsured and low-income participants in high-income countries in order to describe what is known and to pinpoint areas of needed research on this issue. Methods MEDLINE/PubMed, Embase, and Scopus databases were searched using terms that described main concepts of interest (e.g., uninsured, underinsured, access to healthcare, poverty, ethics, compensation, clinical research). Articles were included if they met four inclusion criteria: (1) English, (2) high-income countries context, (3) about research participants who are uninsured or low-income, which limits their access to healthcare, and in biomedical clinical research that either had a prospect of direct medical benefit or was offered to them on the basis of their ill health, and (4) recognizes and/or addresses challenges or ethical considerations of uninsured or low-income participants in biomedical clinical research. Results The searches generated a total of 974 results. Ultimately, 23 papers were included in the scoping review. Of 23 articles, the majority (n = 19) discussed enrollment and retention of uninsured or low-income participants. Several barriers to enrolling uninsured and low-income groups were identified, including limited access to primary or preventive care; lack of access to institutions conducting trials or physicians with enough time or knowledge about trials; overall lack of trust in the government, research, or medical system; and logistical issues. Considerably fewer articles discussed treatment of these participants during the course of research (n = 5) or post-trial responsibilities owed to them (n = 4). Thus, we propose a research agenda that builds upon the existing literature by addressing three broad questions: (1) What is the current status of uninsured research participants in biomedical clinical research in high-income countries? (2) How should uninsured research participants be treated during and after clinical research? (3) How, if at all, should additional protections for uninsured research participants affect their enrollment? Conclusions This review reveals significant gaps in both data and thoughtful analysis on how to ethically involve uninsured research participants. To address these gaps, we propose a research agenda to gather needed data and theoretical analysis that addresses three broad research questions.
TL;DR: A systematic review of the literature revealed 46 unique categories of factors associated with missing patient-reported outcome data, organized into 5 main component groups and 46 categories, each with one or more sub-categories or examples.
Abstract: Background/aims:Missing patient-reported outcome data can lead to biased results, to loss of power to detect between-treatment differences, and to research waste. Awareness of factors may help researchers reduce missing patient-reported outcome data through study design and trial processes. The aim was to construct a Classification Framework of factors associated with missing patient-reported outcome data in the context of comparative studies. The first step in this process was informed by a systematic review.Methods:Two databases (MEDLINE and CINAHL) were searched from inception to March 2015 for English articles. Inclusion criteria were (a) relevant to patient-reported outcomes, (b) discussed missing data or compliance in prospective medical studies, and (c) examined predictors or causes of missing data, including reasons identified in actual trial datasets and reported on cover sheets. Two reviewers independently screened titles and abstracts. Discrepancies were discussed with the research team prior t...
TL;DR: Recruitment, randomisation and treatment errors are common in individually randomised, phase III, randomised controlled trials published in leading medical journals, but reporting practices are inadequate and reporting standards are needed.
Abstract: Background/aims In clinical trials, it is not unusual for errors to occur during the process of recruiting, randomising and providing treatment to participants. For example, an ineligible participant may inadvertently be randomised, a participant may be randomised in the incorrect stratum, a participant may be randomised multiple times when only a single randomisation is permitted or the incorrect treatment may inadvertently be issued to a participant at randomisation. Such errors have the potential to introduce bias into treatment effect estimates and affect the validity of the trial, yet there is little motivation for researchers to report these errors and it is unclear how often they occur. The aim of this study is to assess the prevalence of recruitment, randomisation and treatment errors and review current approaches for reporting these errors in trials published in leading medical journals. Methods We conducted a systematic review of individually randomised, phase III, randomised controlled trials published in New England Journal of Medicine, Lancet, Journal of the American Medical Association, Annals of Internal Medicine and British Medical Journal from January to March 2015. The number and type of recruitment, randomisation and treatment errors that were reported and how they were handled were recorded. The corresponding authors were contacted for a random sample of trials included in the review and asked to provide details on unreported errors that occurred during their trial. Results We identified 241 potentially eligible articles, of which 82 met the inclusion criteria and were included in the review. These trials involved a median of 24 centres and 650 participants, and 87% involved two treatment arms. Recruitment, randomisation or treatment errors were reported in 32 in 82 trials (39%) that had a median of eight errors. The most commonly reported error was ineligible participants inadvertently being randomised. No mention of recruitment, randomisation or treatment errors was found in the remaining 50 of 82 trials (61%). Based on responses from 9 of the 15 corresponding authors who were contacted regarding recruitment, randomisation and treatment errors, between 1% and 100% of the errors that occurred in their trials were reported in the trial publications. Conclusion Recruitment, randomisation and treatment errors are common in individually randomised, phase III trials published in leading medical journals, but reporting practices are inadequate and reporting standards are needed. We recommend researchers report all such errors that occurred during the trial and describe how they were handled in trial publications to improve transparency in reporting of clinical trials.
TL;DR: The unblinded statisticians responsible for preparing closed data monitoring committee reports should be familiar with the statistical methods, the trial protocol, and the data collection plan and be capable of customizing the report to the current stage of the trial.
Abstract: Background:Data monitoring committees for randomized clinical trials have the responsibility of safeguarding interests of trial participants. To do so, the data monitoring committee must receive reports on safety and efficacy to assess risk/benefit and on trial conduct to ensure that the study can achieve its goals. This article outlines the key components of reports to the data monitoring committee and the important role of the unblinded statistician in preparing those reports.Methods:Most data monitoring committee meetings include open and closed sessions. For each session, there is a report of interim results. The open session is attended by the sponsor and lead investigators, including the statistician(s) responsible for the trial design. These investigators are blinded to the interim treatment comparisons. The closed session is attended by the data monitoring committee members and by the statistician(s) who prepared the closed report. These individuals are unblinded to interim treatment comparisons a...
TL;DR: A “just-in-time” consent is proposed in which consent discussions take place in two stages: an initial consent to research from all participants and a later specific consent to randomized treatment only from those assigned to the experimental intervention.
Abstract: Informed consent for randomized trials often causes significant and persistent anxiety, distress and confusion to patients. Where an experimental treatment is compared to a standard care control, much of this burden is potentially avoidable in the control group. We propose a "just-in-time" consent in which consent discussions take place in two stages: an initial consent to research from all participants and a later specific consent to randomized treatment only from those assigned to the experimental intervention. All patients are first approached and informed about research procedures, such as questionnaires or tests. They are also informed that they might be randomly selected to receive an experimental treatment and that, if selected, they can learn more about the treatment and decide whether or not to accept it at that time. After randomization, control patients undergo standard clinical consent whereas patients randomized to the experimental procedure undergo a second consent discussion. Analysis would be by intent-to-treat, which protects the trial from selection bias, although not from poor acceptance of experimental treatment. The advantages of just-in-time consent stem from the fact that only patients randomized to the experimental treatment are subject to a discussion of that intervention. We hypothesize that this will reduce much of the patient's burden associated with the consent process, such as decisional anxiety, confusion and information overload. We recommend well-controlled studies to compare just-in-time and traditional consent, with endpoints to include characteristics of participants, distress and anxiety and participants' understanding of research procedures.