Addressing guideline and policy changes during pragmatic clinical trials.
ABSTRACT: While conducting a set of large-scale multi-site pragmatic clinical trials involving high-impact public health issues such as end-stage renal disease, opioid use, and colorectal cancer, there were substantial changes to both policies and guidelines relevant to the trials. These external changes gave rise to unexpected challenges for the trials, including decisions regarding how to respond to new clinical practice guidelines, increased difficulty in implementing trial interventions, achieving separation between treatment groups, and differential responses across sites. In this article, we describe these challenges and the approaches used to address them. When deliberating appropriate action in the face of external changes during a pragmatic clinical trial, we recommend considering the well-being of the participants, clinical equipoise, and the strength and quality of the evidence associated with the change; involving those charged with data and safety monitoring; and where possible, planning for potential external changes as the trial is being designed. Any solution must balance the primary obligation to protect the well-being of participants with the secondary obligation to protect the integrity of the trial in order to gain meaningful answers to important public health questions.
Project description:BACKGROUND: Controlled clinical trials of health care interventions are either explanatory or pragmatic. Explanatory trials test whether an intervention is efficacious; that is, whether it can have a beneficial effect in an ideal situation. Pragmatic trials measure effectiveness; they measure the degree of beneficial effect in real clinical practice. In pragmatic trials, a balance between external validity (generalizability of the results) and internal validity (reliability or accuracy of the results) needs to be achieved. The explanatory trial seeks to maximize the internal validity by assuring rigorous control of all variables other than the intervention. The pragmatic trial seeks to maximize external validity to ensure that the results can be generalized. However the danger of pragmatic trials is that internal validity may be overly compromised in the effort to ensure generalizability. We are conducting two pragmatic randomized controlled trials on interventions in the management of hypertension in primary care. We describe the design of the trials and the steps taken to deal with the competing demands of external and internal validity. DISCUSSION: External validity is maximized by having few exclusion criteria and by allowing flexibility in the interpretation of the intervention and in management decisions. Internal validity is maximized by decreasing contamination bias through cluster randomization, and decreasing observer and assessment bias, in these non-blinded trials, through baseline data collection prior to randomization, automating the outcomes assessment with 24 hour ambulatory blood pressure monitors, and blinding the data analysis. SUMMARY: Clinical trials conducted in community practices present investigators with difficult methodological choices related to maintaining a balance between internal validity (reliability of the results) and external validity (generalizability). The attempt to achieve methodological purity can result in clinically meaningless results, while attempting to achieve full generalizability can result in invalid and unreliable results. Achieving a creative tension between the two is crucial.
Project description:Numerous explanatory randomized trials support the efficacy of chronic disease interventions, including smoking cessation treatments. However, there is often inadequate adoption of these interventions for various reasons, one being the limitation of generalizability of the explanatory studies in real-world settings. Randomized controlled trials can be rated as more explanatory versus pragmatic along 10 dimensions. Pragmatic randomized clinical trials generate more realistic estimates of effectiveness with greater relevance to clinical practice and for health resource allocation decisions. However, there is no clear method to scale each dimension during the trial design phase to ensure that the design matches the intended purpose of the study.We designed a pragmatic, randomized, controlled study to maximize external validity by addressing several barriers to smoking cessation therapy in ambulatory care. We analyzed our design and methods using the recently published 'Pragmatic-Explanatory Continuum Indicatory Summary (PRECIS)' tool, a qualitative method to assess trial design across 10 domains. We added a 20-point numerical rating scale and a modified Delphi process to improve consensus in rating these domains.After two rounds of review, there was consensus on all 10 domains of study design. No single domain was scored as either fully pragmatic or fully explanatory; but overall, the study scored high on pragmatism.This addition to the PRECIS tool may assist other trial designers working with interdisciplinary co-investigators to rate their study design while building consensus.
Project description:To characterize Practice-Based Opportunities for Weight Reduction (POWER) trials along the pragmatic-explanatory continuum.The POWER trials consist of three individual studies that target obesity treatment in primary care settings.Using the PRagmatic Explanatory Continuum Indicator Summary (PRECIS) criteria, nine reviewers independently scored each trial.Average and median ratings, inter-rater reliability, and relationships to additional ratings of the extent to which study designs were explanatory (i.e., efficacy) versus pragmatic (i.e., practical) and related to external validity were determined.One trial was consistently rated as being significantly more pragmatic than the others (R(2) =0.43, p< .001), although all three were in the moderate range on the PRECIS scales. Ratings varied across PRECIS dimensions, being most pragmatic on comparison condition and primary outcome. Raters, although undergoing training and using identical definitions, scored their own study as more pragmatic than the other studies/interventions.These results highlight the need for more comprehensive reporting on PRECIS and related criteria for research translation. The PRECIS criteria provide a richer understanding of the POWER studies. It is not clear whether the original criteria are sufficient to provide a comprehensive profile.
Project description:BACKGROUND:Clinical trials pose potential risks in both communications and management due to the various stakeholders involved when performing clinical trials. The academic medical center has a responsibility and obligation to conduct and manage clinical trials while maintaining a sufficiently high level of quality, therefore it is necessary to build an information technology system to support standardized clinical trial processes and comply with relevant regulations. OBJECTIVE:The objective of the study was to address the challenges identified while performing clinical trials at an academic medical center, Asan Medical Center (AMC) in Korea, by developing and utilizing a clinical trial management system (CTMS) that complies with standardized processes from multiple departments or units, controlled vocabularies, security, and privacy regulations. METHODS:This study describes the methods, considerations, and recommendations for the development and utilization of the CTMS as a consolidated research database in an academic medical center. A task force was formed to define and standardize the clinical trial performance process at the site level. On the basis of the agreed standardized process, the CTMS was designed and developed as an all-in-one system complying with privacy and security regulations. RESULTS:In this study, the processes and standard mapped vocabularies of a clinical trial were established at the academic medical center. On the basis of these processes and vocabularies, a CTMS was built which interfaces with the existing trial systems such as the electronic institutional review board health information system, enterprise resource planning, and the barcode system. To protect patient data, the CTMS implements data governance and access rules, and excludes 21 personal health identifiers according to the Health Insurance Portability and Accountability Act (HIPAA) privacy rule and Korean privacy laws. Since December 2014, the CTMS has been successfully implemented and used by 881 internal and external users for managing 11,645 studies and 146,943 subjects. CONCLUSIONS:The CTMS was introduced in the Asan Medical Center to manage the large amounts of data involved with clinical trial operations. Inter- and intraunit control of data and resources can be easily conducted through the CTMS system. To our knowledge, this is the first CTMS developed in-house at an academic medical center side which can enhance the efficiency of clinical trial management in compliance with privacy and security laws.
Project description:BACKGROUND:All clinical trial investigators have ethical and regulatory obligations to monitor participant safety and trial integrity. Specific procedures for meeting these obligations, however, may differ substantially between pragmatic trials and traditional explanatory clinical trials. METHODS/RESULTS:Appropriate monitoring of clinical trials typically includes assessing rate of recruitment or enrollment; monitoring safe and effective delivery of study treatments; assuring that study staff act to minimize risks; monitoring quality and timeliness of study data; and considering interim analyses for early detection of benefit, harm, or futility. Each of these responsibilities applies to pragmatic clinical trials. Just as design of pragmatic trials typically involves specific and necessary departures from methods of explanatory clinical trials, appropriate monitoring of pragmatic trials typically requires specific departures from monitoring procedures used in explanatory clinical trials. We discuss how specific aspects of pragmatic trial design and operations influence selection of monitoring procedures and illustrate those choices using examples from three ongoing pragmatic trials conducted by the Mental Health Research Network. CONCLUSIONS:Pragmatic trial investigators should not routinely adopt monitoring procedures used in explanatory clinical trials. Instead, investigators should consider core principles of trial monitoring and design monitoring procedures appropriate for each pragmatic trial.
Project description:Pragmatic clinical trials of mental health services are increasingly being developed to establish comparative effectiveness, influence sustainable implementation, and address real world policy decisions. However, use of time and resource intensive qualitative methods in pragmatic trials may be inconsistent with the aims of efficiency and cost minimization. This paper introduces a qualitative method known as Rapid Assessment Procedure-Informed Clinical Ethnography (RAPICE) that combines the techniques of Rapid Assessment Procedures with clinical ethnography. A case study is presented to illustrate how RAPICE can be used to efficiently understand pragmatic trial implementation processes and associated real world policy implications.
Project description:Abstract: In the conduct of clinical trials for pharmaceutical research, access to investigational medicines following clinical trials is often necessary for the continued health and well-being of the trial participants; it is an ethical obligation under some circumstances, as outlined in the Declaration of Helsinki 2013 Article 34. This obligation becomes particularly important in lower-income countries, where access to medical care may be limited. Although there is agreement among global research and bioethics communities that continued access should be provided with prospectively defined parameters and procedures, the process is complex, as many responsible parties and complicated logistics are involved. Roche Pharmaceuticals developed and publicly posted the company’s policy regarding continued access to investigational medicines in 2013. This article provides insights on the policy, including the parameters that determine when continued access is and is not considered to be appropriate, along with an example from an active clinical development program. It also describes how multiple stakeholders, including those in academia, industry, government, and patient advocacy, have worked together to assess approaches to continued access. Continued access plans should be transparent and agreed to by research participants, investigators, and governments prior to the study and reassessed based on clinical trial evidence of safety and efficacy and availability of adequate treatments, along with relevant international laws and customs. Conducting responsible continued access programs requires close partnerships with investigators, health authorities, and third-party research partners.
Project description:Randomized controlled trials in CKD lag in number behind those of other chronic diseases, despite the high morbidity and mortality experienced by patients with kidney disease and the exorbitant costs of their health care. Observational studies of CKD frequently yield seemingly paradoxic associations of traditional risk factors with outcomes, making it difficult to extrapolate the results of trials conducted in people with normal kidney function to patients with CKD. However, many completed trials in CKD have been limited by intermediate outcomes of unclear clinical significance or narrow eligibility criteria that limit external validity, and implementation of proven therapies remains a challenge. It is therefore imperative that the nephrology community capitalize on recent interest in novel approaches to trial design, such as pragmatic clinical trials. These trials are meant to promote research within real world settings to yield clinically relevant results with greater applicability than those of traditional trials, while maintaining many advantages, such as controlling for potential sources of bias. We provide a description of pragmatic clinical trials and a discussion of advantages, disadvantages, and practical challenges inherent to this study design, in the context of specific scientific questions relevant to patients with CKD.
Project description:The coronavirus disease 2019 pandemic has disrupted the lives of whole communities and nations. The multinational multicenter National Institute of Neurological Disorders and Stroke Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial stroke prevention trial rapidly experienced the effects of the pandemic and had to temporarily suspend new enrollments and shift patient follow-up activities from in-person clinic visits to telephone contacts. There is an ethical obligation to the patients to protect their health while taking every feasible step to ensure that the goals of the trial are successfully met. Here, we describe the effects of the pandemic on the trial and steps that are being taken to mitigate the effects of the pandemic so that trial objectives can be met.
Project description:Pragmatic trials comparing standard-of-care interventions may improve the quality of care for future patients, but raise ethical questions about limitations on decisional autonomy. We sought to understand how patients and physicians view and respond to these questions in the contexts of pragmatic trials and of usual clinical care.We conducted scenario-based, semi-structured interviews with 32 patients with end-stage renal disease (ESRD) receiving maintenance hemodialysis in outpatient dialysis units and with 24 nephrologists. Each participant was presented with two hypothetical scenarios in which a protocolized approach to hemodialysis treatment time was adopted for the entire dialysis unit as part of a clinical trial or a new clinical practice.A modified grounded theory analysis revealed three major themes: 1) the value of research, 2) the effect of protocolized care on patient and physician autonomy, and 3) information exchange between patients and physicians, including the mechanism of consent. Most patients and physicians were willing to relinquish decisional autonomy and were more willing to relinquish autonomy for research purposes than in clinical care. Patients' concerns towards clinical trials were tempered by their desires for certainty for a positive outcome and for physician validation. Patients tended to believe that being informed about research was more important than the actual mechanism of consent, and most were content with being able to opt out from participating.This qualitative study suggests the general acceptability of a pragmatic clinical trial comparing standard-of-care interventions that limits decisional autonomy for nephrologists and patients receiving hemodialysis. Future studies are needed to determine whether similar findings would emerge among other patients and providers considering other standard-of-care trials.