RESUMEN

When evaluating principal surrogate biomarkers in vaccine trials, missingness in potential outcomes requires prediction using auxiliary variables and/or augmented study design with a close-out placebo vaccination (CPV) component. The estimated likelihood approach, which separates the estimation of biomarker distribution from the maximization of the estimated likelihood, has often been adopted. Here we develop a likelihood-based approach that jointly estimates the two parts and describe the methods for selecting auxiliary variables as risk predictors and/or biomarker predictors. Through numerical studies, we observe that in a standard trial design without a CPV component, the two methods achieve similar performance in estimation of the risk model and the marker model. However, for trials augmented with a CPV component, using the likelihood-based method achieves better estimation performance compared to the estimated likelihood method. Moreover, in the presence of a large number of covariates from which to select, the ML method achieves comparable or better performance compared to the EL method in both designs. While the CPV component has not yet been implemented in existing vaccine trials, our results have applications in the planning of future vaccine trials. We illustrate the method using data from a dengue vaccine trial.

RESUMEN

This article focuses on the evaluation of vaccine-induced immune responses as principal surrogate markers for predicting a given vaccine's effect on the clinical endpoint of interest. To address the problem of missing potential outcomes under the principal surrogate framework, we can utilize baseline predictors of the immune biomarker(s) or vaccinate uninfected placebo recipients at the end of the trial and measure their immune biomarkers. Examples of good baseline predictors are baseline immune responses when subjects enrolled in the trial have been previously exposed to the same antigen, as in our motivating application of the Zostavax Efficacy and Safety Trial (ZEST). However, laboratory assays of these baseline predictors are expensive and therefore their subsampling among participants is commonly performed. In this article, we develop a methodology for estimating principal surrogate values in the presence of baseline predictor subsampling. Under a multiphase sampling framework, we propose a semiparametric pseudo-score estimator based on conditional likelihood and also develop several alternative semiparametric pseudo-score or estimated likelihood estimators. We derive corresponding asymptotic theories and analytic variance formulas for these estimators. Through extensive numeric studies, we demonstrate good finite sample performance of these estimators and the efficiency advantage of the proposed pseudo-score estimator in various sampling schemes. We illustrate the application of our proposed estimators using data from an immune biomarker study nested within the ZEST trial.

Asunto(s)

Biomarcadores , Biometría/métodos , Estudios de Evaluación como Asunto , Vacunas/uso terapéutico , Protocolos de Ensayos Clínicos como Asunto , Humanos , Funciones de Verosimilitud , Métodos

RESUMEN

BACKGROUND: Electronic Medical Records (EMRs) are designed to automatically collect, store, and retrieve patients' information from healthcare providers within an organization. They assist clinicians in deciding the future course of treatment. The primary objective of this study is to investigate the practices of Electronic Health Record (EHR) project managers regarding the causes of EHR projects getting stalled or failing in Saudi Arabia. METHODS: Three focus groups were identified across three main cities of Saudi Arabia, namely Riyadh, Jeddah, and Dammam during the years 2013 and 2014. Each group consisted of 10-15 experienced EHR project managers. Qualitative analysis consisted of immersion and crystallization to develop a coding scheme that included both preconceived and emergent themes. RESULTS AND CONCLUSION: The findings of this study highlight the difficulties, which ensue between EHR and project management practice as well as the issues that can arise from the common use of these terms. It highlights how the aims of an EHR project and its management are transformed, and how the reputation of the project management is to achieve the exact and short-term objectives associated with the comprehensive aims of an EHR project.

Asunto(s)

Registros Electrónicos de Salud , Registros Electrónicos de Salud/organización & administración , Registros Electrónicos de Salud/normas , Registros Electrónicos de Salud/estadística & datos numéricos , Humanos , Arabia Saudita

RESUMEN

BACKGROUND: The ending of a clinical trial may be challenging, particularly if staff are required to withdraw the investigated treatment(s); however, this aspect of trial work is surprisingly under-researched. To address this gap, we explored the experiences of staff involved in closing out a trial that entailed withdrawal of treatment (insulin pumps) from some patients. METHODS: Interviews were conducted with n = 22 staff, recruited from seven trial sites. Data were analysed thematically. RESULTS: Staff described a myriad of ethical and emotional challenges at closeout, many of which had been unforeseen when the trial began. A key challenge for staff was that, while patients gave their agreement to participate on the understanding that pump treatment could be withdrawn, they often found themselves benefitting from this regimen in ways they could not have foreseen. Hence, as the trial progressed, patients became increasingly anxious about withdrawal of treatment. This situation forced staff to consider whether the consent patients had given at the outset remained valid; it also presented them with a dilemma at closeout because many of those who had wanted to remain on a pump did not meet the clinical criteria required for post-trial funding. When deciding whether to withdraw treatment, staff not only had to take funding pressures and patient distress into account, but they also found themselves caught between an ethic of Hippocratic individualism and one of utilitarianism. These conflicting pressures and ethical considerations resulted in staff decision-making varying across the sites, an issue that some described as a further source of ethical unease. Staff concluded that, had there been more advanced planning and discussion, and greater accountability to an ethics committee, some of the challenges they had confronted at closeout could have been lessened or even prevented. CONCLUSIONS: The same kinds of ethical issues that may vex staff at the beginning of a trial (e.g. patients having unrealistic expectations of trial participation; staff experiencing conflicts between research and clinical roles) may re-present themselves at the end. To safeguard the wellbeing of staff and patients, greater planning, coordination and ethical oversight should go into the closeout of trials involving withdrawal of treatment(s). TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ISRCTN61215213 . Registered on 11 May 2011.

Asunto(s)

Actitud del Personal de Salud , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Conocimientos, Actitudes y Práctica en Salud , Hipoglucemiantes/administración & dosificación , Sistemas de Infusión de Insulina , Insulina/administración & dosificación , Investigadores/psicología , Privación de Tratamiento , Toma de Decisiones Clínicas , Conflicto de Intereses , Ahorro de Costo , Análisis Costo-Beneficio , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/economía , Diabetes Mellitus Tipo 1/psicología , Costos de los Medicamentos , Emociones , Disparidades en Atención de Salud , Humanos , Hipoglucemiantes/economía , Insulina/economía , Sistemas de Infusión de Insulina/economía , Entrevistas como Asunto , Pautas de la Práctica en Medicina , Investigación Cualitativa , Investigadores/ética , Reino Unido , Privación de Tratamiento/economía , Privación de Tratamiento/ética

RESUMEN

BACKGROUND: The HALT Polycystic Kidney Disease Trials Network consisted of two randomized, double blind, placebo-controlled trials among patients with autosomal dominant polycystic kidney disease. The trials involved 5-8years of participant follow-up with interventions in blood pressure and antihypertensive therapy. We provide a framework for designing and implementing closeout near the end of a trial while ensuring patient safety and maintaining scientific rigor and study morale. METHODS: We discuss issues and resolutions for determining the last visit, tapering medications, and unblinding of participants to study allocation and results. We also discuss closure of clinical sites and Data Coordinating Center responsibilities to ensure timely release of study results and meeting the requirements of regulatory and funding authorities. RESULTS: Just over 90% of full participants had a 6-month study visit prior to their last visit preparing them for trial closeout. Nearly all patients wanted notification of study results (99%) and treatment allocation (99%). All participants were safely tapered off study and open label blood pressure medications. Within 6months, the trials were closed, primary papers published, and 805 letters distributed to participants with results and allocation. DCC obligations for data repository and clinicaltrials.gov reporting were completed within 12months of the last study visit. CONCLUSIONS: Closeout of our trials involved years of planning and significant human and financial resources. We provide questions for investigators to consider when planning closeout of their trials with focus on (1) patient safety, (2) dissemination of study results and (3) compliance with regulatory and funding responsibilities.