Cluster randomized trials (CRTs) pose ethical challenges for investigators and ethics committees. This study describes the views and experiences of CRT researchers with respect to: (1) ethical challenges in CRTs; (2) the ethics review process for CRTs; and (3) the need for comprehensive ethics guidelines for CRTs.
Descriptive qualitative analysis of interviews conducted with a purposive sample of 20 experienced CRT researchers.
Informants expressed concern over the potential for bias that may result from requirements to obtain informed consent from research participants in CRTs. Informants suggested that the need for informed consent ought to be related to the type of intervention under study in a CRT. Informants rarely expressed concern regarding risks to research participants in CRTs, other than risks to privacy. Important issues identified in the research ethics literature, including fair subject selection and other justice issues, were not mentioned by informants. The ethics review process has had positive and negative impacts on CRT conduct. Informants stated that variability in ethics review between jurisdictions, and increasingly stringent ethics review in recent years, have hampered their ability to conduct CRTs. Many informants said that comprehensive ethics guidelines for CRTs would be helpful to researchers and research ethics committees.
Informants identified key ethical challenges in the conduct of CRTs, specifically relating to identifying subjects, seeking informed consent, and the use of gatekeepers. These data have since been used to identify topics for in-depth ethical analysis and to guide the development of comprehensive ethics guidelines for CRTs.
Cluster randomized trials; Research ethics; Informed consent; Clinical trials; Bioethics; Knowledge translation; Quality improvement; Implementation research
Diabetes is an important contributor to the burden of disease in South Africa and prevalence rates as high as 33% have been recorded in Cape Town. Previous studies show that quality of care and health outcomes are poor. The development of an effective education programme should impact on self-care, lifestyle change and adherence to medication; and lead to better control of diabetes, fewer complications and better quality of life.
Trial design: Pragmatic cluster randomized controlled trial
Participants: Type 2 diabetic patients attending 45 public sector community health centres in Cape Town
Interventions: The intervention group will receive 4 sessions of group diabetes education delivered by a health promotion officer in a guiding style. The control group will receive usual care which consists of ad hoc advice during consultations and occasional educational talks in the waiting room.
Objective: To evaluate the effectiveness of the group diabetes education programme
Outcomes: Primary outcomes: diabetes self-care activities, 5% weight loss, 1% reduction in HbA1c. Secondary outcomes: self-efficacy, locus of control, mean blood pressure, mean weight loss, mean waist circumference, mean HbA1c, mean total cholesterol, quality of life
Randomisation: Computer generated random numbers
Blinding: Patients, health promoters and research assistants could not be blinded to the health centre’s allocation
Numbers randomized: Seventeen health centres (34 in total) will be randomly assigned to either control or intervention groups. A sample size of 1360 patients in 34 clusters of 40 patients will give a power of 80% to detect the primary outcomes with 5% precision. Altogether 720 patients were recruited in the intervention arm and 850 in the control arm giving a total of 1570.
The study will inform policy makers and managers of the district health system, particularly in low to middle income countries, if this programme can be implemented more widely.
Pan African Clinical Trial Registry PACTR201205000380384
Diabetes; Group education; Health education; Motivational interviewing; Mid-level health workers; South Africa; Primary care
Studies in General Internal Medicine [GIM] settings have shown that optimizing interprofessional communication is important, yet complex and challenging. While the physician is integral to interprofessional work in GIM there are often communication barriers in place that impact perceptions and experiences with the quality and quantity of their communication with other team members. This study aims to understand how team members’ perceptions and experiences with the communication styles and strategies of either hospitalist or consultant physicians in their units influence the quality and effectiveness of interprofessional relations and work.
A multiple case study methodology was used. Thirty-one semi-structured interviews were conducted with physicians, nurses and other health care providers [e.g. physiotherapist, social worker, etc.] working across 5 interprofessional GIM programs. Questions explored participants’ experiences with communication with all other health care providers in their units, probing for barriers and enablers to effective interprofessional work, as well as the use of communication tools or strategies. Observations in GIM wards were also conducted.
Three main themes emerged from the data:  availability for interprofessional communication,  relationship-building for effective communication, and  physician vs. team-based approaches. Findings suggest a significant contrast in participants’ experiences with the quantity and quality of interprofessional relationships and work when comparing the communication styles and strategies of hospitalist and consultant physicians. Hospitalist staffed GIM units were believed to have more frequent and higher caliber interprofessional communication and collaboration, resulting in more positive experiences among all health care providers in a given unit.
This study helps to improve our understanding of the collaborative environment in GIM, comparing the communication styles and strategies of hospitalist and consultant physicians, as well as the experiences of providers working with them. The implications of this research are globally important for understanding how to create opportunities for physicians and their colleagues to meaningfully and consistently participate in interprofessional communication which has been shown to improve patient, provider, and organizational outcomes.
Interprofessional care; General internal medicine; Teamwork; Collaboration; Communication
Robust evidence of the effectiveness of task shifting of antiretroviral therapy (ART) from doctors to other health workers is scarce. We aimed to assess the effects on mortality, viral suppression, and other health outcomes and quality indicators of the Streamlining Tasks and Roles to Expand Treatment and Care for HIV (STRETCH) programme, which provides educational outreach training of nurses to initiate and represcribe ART, and to decentralise care.
We undertook a pragmatic, parallel, cluster-randomised trial in South Africa between Jan 28, 2008, and June 30, 2010. We randomly assigned 31 primary-care ART clinics to implement the STRETCH programme (intervention group) or to continue with standard care (control group). The ratio of randomisation depended on how many clinics were in each of nine strata. Two cohorts were enrolled: eligible patients in cohort 1 were adults (aged ≥16 years) with CD4 counts of 350 cells per μL or less who were not receiving ART; those in cohort 2 were adults who had already received ART for at least 6 months and were being treated at enrolment. The primary outcome in cohort 1 was time to death (superiority analysis). The primary outcome in cohort 2 was the proportion with undetectable viral loads (<400 copies per mL) 12 months after enrolment (equivalence analysis, prespecified difference <6%). Patients and clinicians could not be masked to group assignment. The interim analysis was blind, but data analysts were not masked after the database was locked for final analysis. Analyses were done by intention to treat. This trial is registered, number ISRCTN46836853.
5390 patients in cohort 1 and 3029 in cohort 2 were in the intervention group, and 3862 in cohort 1 and 3202 in cohort 2 were in the control group. Median follow-up was 16·3 months (IQR 12·2–18·0) in cohort 1 and 18·0 months (18·0–18·0) in cohort 2. In cohort 1, 997 (20%) of 4943 patients analysed in the intervention group and 747 (19%) of 3862 in the control group with known vital status at the end of the trial had died. Time to death did not differ (hazard ratio [HR] 0·94, 95% CI 0·76–1·15). In a preplanned subgroup analysis of patients with baseline CD4 counts of 201–350 cells per μL, mortality was slightly lower in the intervention group than in the control group (0·73, 0·54–1.00; p=0·052), but it did not differ between groups in patients with baseline CD4 of 200 cells per μL or less (0·94, 0·76–1·15; p=0·577). In cohort 2, viral load suppression 12 months after enrolment was equivalent in intervention (2156 [71%] of 3029 patients) and control groups (2230 [70%] of 3202; risk difference 1·1%, 95% CI −2·4 to 4·6).
Expansion of primary-care nurses' roles to include ART initiation and represcription can be done safely, and improve health outcomes and quality of care, but might not reduce time to ART or mortality.
UK Medical Research Council, Development Cooperation Ireland, and Canadian International Development Agency.
Reviews have repeatedly noted important methodological issues in the conduct and reporting of cluster randomized controlled trials (C-RCTs). These reviews usually focus on whether the intracluster correlation was explicitly considered in the design and analysis of the C-RCT. However, another important aspect requiring special attention in C-RCTs is the risk for imbalance of covariates at baseline. Imbalance of important covariates at baseline decreases statistical power and precision of the results. Imbalance also reduces face validity and credibility of the trial results. The risk of imbalance is elevated in C-RCTs compared to trials randomizing individuals because of the difficulties in recruiting clusters and the nested nature of correlated patient-level data. A variety of restricted randomization methods have been proposed as way to minimize risk of imbalance. However, there is little guidance regarding how to best restrict randomization for any given C-RCT. The advantages and limitations of different allocation techniques, including stratification, matching, minimization, and covariate-constrained randomization are reviewed as they pertain to C-RCTs to provide investigators with guidance for choosing the best allocation technique for their trial.
Cluster-randomized trials; Balanced allocation; Restricted randomization
This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the sixth of the questions posed, namely, what is the role and authority of gatekeepers in CRTs in health research? ‘Gatekeepers’ are individuals or bodies that represent the interests of cluster members, clusters, or organizations. The need for gatekeepers arose in response to the difficulties in obtaining informed consent because of cluster randomization, cluster-level interventions, and cluster size. In this paper, we call for a more restrictive understanding of the role and authority of gatekeepers.
Previous papers in this series have provided solutions to the challenges posed by informed consent in CRTs without the need to invoke gatekeepers. We considered that consent to randomization is not required when cluster members are approached for consent at the earliest opportunity and before any study interventions or data-collection procedures have started. Further, when cluster-level interventions or cluster size means that obtaining informed consent is not possible, a waiver of consent may be appropriate. In this paper, we suggest that the role of gatekeepers in protecting individual interests in CRTs should be limited. Generally, gatekeepers do not have the authority to provide proxy consent for cluster members. When a municipality or other community has a legitimate political authority that is empowered to make such decisions, cluster permission may be appropriate; however, gatekeepers may usefully protect cluster interests in other ways. Cluster consultation may ensure that the CRT addresses local health needs, and is conducted in accord with local values and customs. Gatekeepers may also play an important role in protecting the interests of organizations, such as hospitals, nursing homes, general practices, and schools. In these settings, permission to access the organization relies on resource implications and adherence to institutional policies.
Task-shifting is promoted widely as a mechanism for expanding antiretroviral treatment (ART) access. However, the evidence for nurse-initiated and managed ART (NIMART) in Africa is limited, and little is known about the key barriers and enablers to implementing NIMART programmes on a large scale. The STRETCH (Streamlining Tasks and Roles to Expand Treatment and Care for HIV) programme was a complex educational and organisational intervention implemented in the Free State Province of South Africa to enable nurses providing primary HIV/AIDS care to expand their roles and include aspects of care and treatment usually provided by physicians. STRETCH used a phased implementation approach and ART treatment guidelines tailored specifically to nurses. The effects of STRETCH on pre-ART mortality, ART provision, and the quality of HIV/ART care were evaluated through a randomised controlled trial. This study was conducted alongside the trial to develop a contextualised understanding of factors affecting the implementation of the programme.
This study was a qualitative process evaluation using in-depth interviews and focus group discussions with patients, health workers, health managers, and other key informants as well as observation in clinics. Research questions focused on perceptions of STRETCH, changes in health provider roles, attitudes and patient relationships, and impact of the implementation context on trial outcomes. Data were analysed collaboratively by the research team using thematic analysis.
NIMART appears to be highly acceptable among nurses, patients, and physicians. Managers and nurses expressed confidence in their ability to deliver ART successfully. This confidence developed slowly and unevenly, through a phased and well-supported approach that guided nurses through training, re-prescription, and initiation. The research also shows that NIMART changes the working and referral relationships between health staff, demands significant training and support, and faces workload and capacity constraints, and logistical and infrastructural challenges.
Large-scale NIMART appears to be feasible and acceptable in the primary level public sector health services in South Africa. Successful implementation requires a comprehensive approach with: an incremental and well supported approach to implementation; clinical guidelines tailored to nurses; and significant health services reorganisation to accommodate the knock-on effects of shifts in practice.
Antiretroviral treatment; NIMART; South Africa; Primary healthcare; Nurse training; Process evaluation; PALSA PLUS
Despite evidence-based recommendations supporting long-term use of cardiac medications in patients post ST-elevation myocardial infarction, adherence is known to decline over time. Discontinuation of cardiac medications in such patients is associated with increased mortality.
This is a pragmatic, cluster-randomized controlled trial with blinded outcome assessment and embedded qualitative process evaluation. Patients from one health region in Ontario, Canada who undergo a coronary angiogram during their admission for ST-elevation myocardial infarction and who survive their initial hospitalization will be included. Allocation of eligible patients to intervention or usual care will take place within one week after the angiogram using a computer-generated random sequence. To avoid treatment contamination, patients treated by the same family physician will be allocated to the same study arm. The intervention consists of recurrent, personalized, paper-based educational messages and reminders sent via post on behalf of the interventional cardiologist to the patient, family physician, and pharmacist urging long-term adherence to secondary prevention medications. The primary outcome is the proportion of patients who report in a phone interview taking all relevant classes of cardiac medications at twelve months. Secondary outcomes to be measured at three and twelve months include proportions of patients who report: actively taking each cardiac medication class of interest (item-by-item); stopping medications due to side effects; taking one or two or three medication classes concurrently; a perfect Morisky Medication Adherence Score for cardiac medication compliance; and having a discussion with their family physician about long-term adherence to cardiac medications. Self-reported measures of adherence will be validated using administrative data for prescriptions filled.
This intervention is designed to be easily generalizable. If effective, it could be implemented broadly. If it does not change medication utilization, the process evaluation will offer insights regarding how such an intervention could be optimized in future.
Randomized trial; Medication adherence; Reminders
Nearly 3 million people in resource-poor countries receive antiretrovirals for the treatment of HIV/AIDS, yet millions more require treatment. Key barriers to treatment scale up are shortages of trained health care workers, and challenges integrating HIV/AIDS care with primary care.
PALM PLUS (Practical Approach to Lung Health and HIV/AIDS in Malawi) is an intervention designed to simplify and integrate existing Malawian national guidelines into a single, simple, user-friendly guideline for mid-level health care workers. Training utilizes a peer-to-peer educational outreach approach. Research is being undertaken to evaluate this intervention to generate evidence that will guide future decision-making for consideration of roll out in Malawi. The research consists of a cluster randomized trial in 30 public health centres in Zomba District that measures the effect of the intervention on staff satisfaction and retention, quality of patient care, and costs through quantitative, qualitative and health economics methods.
Results and outcomes
In the first phase of qualitative inquiry respondents from intervention sites demonstrated in-depth knowledge of PALM PLUS compared to those from control sites. Participants in intervention sites felt that the PALM PLUS tool empowered them to provide better health services to patients. Interim staff retention data shows that there were, on average, 3 to 4 staff departing from the control and intervention sites per month. Additional qualitative, quantitative and economic analyses are planned.
Dignitas International and the Knowledge Translation Unit at the University of Cape Town Lung Institute have led the adaptation and development of the PALM PLUS intervention, using experience gained through the implementation of the South African precursor, PALSA PLUS. The Malawian partners, REACH Trust and the Research Unit at the Ministry of Health, have led the qualitative and economic evaluations. Dignitas and Ministry of Health have facilitated interaction with implementers and policy-makers.
Challenges and successes
This initiative is an example of South-South knowledge translation between South Africa and Malawi, mediated by a Canadian academic-NGO hybrid. Our success in developing and rolling out PALM PLUS in Malawi suggests that it is possible to adapt and implement this intervention for use in other resource-limited settings.
Task shifting and the integration of human immunodeficiency virus (HIV) care into primary care services have been identified as possible strategies for improving access to antiretroviral treatment (ART). This paper describes the development and content of an intervention involving these two strategies, as part of the Streamlining Tasks and Roles to Expand Treatment and Care for HIV (STRETCH) pragmatic randomised controlled trial.
Methods: Developing the intervention
The intervention was developed following discussions with senior management, clinicians, and clinic staff. These discussions revealed that the establishment of separate antiretroviral treatment services for HIV had resulted in problems in accessing care due to the large number of patients at ART clinics. The intervention developed therefore combined the shifting from doctors to nurses of prescriptions of antiretrovirals (ARVs) for uncomplicated patients and the stepwise integration of HIV care into primary care services.
Results: Components of the intervention
The intervention consisted of regulatory changes, training, and guidelines to support nurse ART prescription, local management teams, an implementation toolkit, and a flexible, phased introduction. Nurse supervisors were equipped to train intervention clinic nurses in ART prescription using outreach education and an integrated primary care guideline. Management teams were set up and a STRETCH coordinator was appointed to oversee the implementation process.
Three important processes were used in developing and implementing this intervention: active participation of clinic staff and local and provincial management, educational outreach to train nurses in intervention sites, and an external facilitator to support all stages of the intervention rollout.
The STRETCH trial is registered with Current Control Trials ISRCTN46836853.
Only about one-third of eligible HIV/AIDS patients receive anti-retroviral treatment (ART). Decentralizing treatment is crucial to wider and more equitable access, but key obstacles are a shortage of trained healthcare workers (HCW) and challenges integrating HIV/AIDS care with other primary care. This report describes the development of a guideline and training program (PALM PLUS) designed to integrate HIV/AIDS care with other primary care in Malawi. PALM PLUS was adapted from PALSA PLUS, developed in South Africa, and targets middle-cadre HCWs (clinical officers, nurses, and medical assistants). We adapted it to align with Malawi's national treatment protocols, more varied healthcare workforce, and weaker health system infrastructure.
The international research team included the developers of the PALSA PLUS program, key Malawi-based team members and personnel from national and district level Ministry of Health (MoH), professional associations, and an international non-governmental organization. The PALSA PLUS guideline was extensively revised based on Malawi national disease-specific guidelines. Advice and input was sought from local clinical experts, including middle-cadre personnel, as well as Malawi MoH personnel and representatives of Malawian professional associations.
An integrated guideline adapted to Malawian protocols for adults with respiratory conditions, HIV/AIDS, tuberculosis, and other primary care conditions was developed. The training program was adapted to Malawi's health system and district-level supervision structure. PALM PLUS is currently being piloted in a cluster-randomized trial in health centers in Malawi (ISRCTN47805230).
The PALM PLUS guideline and training intervention targets primary care middle-cadre HCWs with the objective of improving HCW satisfaction and retention, and the quality of patient care. Successful adaptations are feasible, even across health systems as different as those of South Africa and Malawi.
This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the first of the questions posed, namely, who is the research subject in a CRT in health research? The identification of human research subjects is logically prior to the application of protections as set out in research ethics and regulation. Aspects of CRT design, including the fact that in a single study the units of randomization, experimentation, and observation may differ, complicate the identification of human research subjects. But the proper identification of human research subjects is important if they are to be protected from harm and exploitation, and if research ethics committees are to review CRTs efficiently.
We examine the research ethics literature and international regulations to identify the core features of human research subjects, and then unify these features under a single, comprehensive definition of human research subject. We define a human research subject as any person whose interests may be compromised as a result of interventions in a research study. Individuals are only human research subjects in CRTs if: (1) they are directly intervened upon by investigators; (2) they interact with investigators; (3) they are deliberately intervened upon via a manipulation of their environment that may compromise their interests; or (4) their identifiable private information is used to generate data. Individuals who are indirectly affected by CRT study interventions, including patients of healthcare providers participating in knowledge translation CRTs, are not human research subjects unless at least one of these conditions is met.
Clinical practice guidelines have the potential to facilitate the implementation of evidence into practice, support clinical decision making, specify beneficial therapeutic approaches, and influence public policy. However, these potential benefits have not been consistently achieved. The limited impact of guidelines can be attributed to organisational constraints, the complexity of the guidelines, and the lack of usability testing or end-user involvement in their development. Implementability has been referred to as the perceived characteristics of guidelines that predict the relative ease of their implementation at the clinical level, but this concept is as yet poorly defined. The objective of our study is to identify guideline attributes that affect uptake in practice by considering evidence from four disciplines (medicine, psychology, management, human factors engineering) to determine the relationship between the perceived characteristics of recommendations and their uptake and to develop a framework of implementability.
A realist-review approach to knowledge synthesis will be used to understand attributes of guidelines (e.g., its text and content) and how changing these elements might impact clinical practice and clinical decision making. It also allows for the exploration of 'what works for whom, in what circumstances, and in what respects'. The realist review will be structured according to Pawson's five practical steps in realist reviews: (1) clarifying the scope of the review, (2) determining the search strategy, (3) ensuring proper article selection and study quality assessment, (4) extracting and organising data, and (5) synthesising the evidence and drawing conclusions. Data will be synthesised according to a two-stage analysis: (1) we will extract and define all relevant guideline attributes from the different disciplines, then create a shortlist of unique attributes and investigate their relationships with uptake, and (2) we will compare and contrast the attributes and guideline uptake within each and between the four disciplines to create a robust framework of implementability.
Creating guidelines that are designed to maximise uptake may be a potentially effective and inexpensive way of increasing their impact. However, this is best achieved by a comprehensive framework to inform the design of guidelines drawing on a range of disciplines that study behaviour change. This study will use a customised realist-review approach to synthesising the literature to better understand and operationalise a complex and under-theorised concept.
This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, Weijer and colleagues set out six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation. This paper addresses the third of the questions posed, namely, does clinical equipoise apply to CRTs in health research? The ethical principle of beneficence is the moral obligation not to harm needlessly and, when possible, to promote the welfare of research subjects. Two related ethical problems have been discussed in the CRT literature. First, are control groups that receive only usual care unduly disadvantaged? Second, when accumulating data suggests the superiority of one intervention in a trial, is there an ethical obligation to act?
In individually randomized trials involving patients, similar questions are addressed by the concept of clinical equipoise, that is, the ethical requirement that, at the start of a trial, there be a state of honest, professional disagreement in the community of expert practitioners as to the preferred treatment. Since CRTs may not involve physician-researchers and patient-subjects, the applicability of clinical equipoise to CRTs is uncertain. Here we argue that clinical equipoise may be usefully grounded in a trust relationship between the state and research subjects, and, as a result, clinical equipoise is applicable to CRTs. Clinical equipoise is used to argue that control groups receiving only usual care are not disadvantaged so long as the evidence supporting the experimental and control interventions is such that experts would disagree as to which is preferred. Further, while data accumulating during the course of a CRT may favor one intervention over another, clinical equipoise supports continuing the trial until the results are likely to be broadly convincing, often coinciding with the planned completion of the trial. Finally, clinical equipoise provides research ethics committees with formal and procedural guidelines that form an important part of the assessment of the benefits and harms of CRTs in health research.
Objective To investigate whether PALSA PLUS, an on-site educational outreach programme of non-didactic, case based, iterative clinical education of staff, led by a trainer, can increase access to and comprehensiveness of care for patients with HIV/AIDS.
Design Cluster randomised trial.
Setting Public primary care clinics offering HIV/AIDS care, antiretroviral treatment (ART), tuberculosis care, and ambulatory primary care in Free State province, South Africa.
Participants Fifteen clinics all implementing decentralisation and task shifting were randomised. The clinics cared for 400 000 general primary care patients and 10 136 patients in an HIV/AIDS/ART programme. There were 150 nurses.
Intervention On-site outreach education in eight clinics; no such education in seven (control).
Main outcome measures Provision of co-trimoxazole prophylaxis among patients referred to the HIV/AIDS/ART programme, and detection of cases of tuberculosis among those in the programme. Proportion of patients in the programme enrolled through general primary care consultations.
Results Patients referred to the HIV/AIDS programme through general primary care at intervention clinics were more likely than those at control clinics to receive co-trimoxazole prophylaxis (41%, (2253/5523) v 32% (1340/4210); odds ratio 1.95, 95% confidence interval 1.11 to 3.40), and tuberculosis was more likely to be diagnosed among patients with HIV/AIDS/ART (7% (417/5793) v 6% (245/4343); 1.25, 1.01 to 1.55). Enrolment in the HIV/AIDS and ART programme through HIV testing in general primary care was not significantly increased (53% v 50%; 1.19, 0.51 to 2.77). Secondary outcomes were similar, except for weight gain, which was higher in the intervention group (2.3 kg v 1.9 kg, P<0.001).
Conclusion Though outreach education is an effective and feasible strategy for improving comprehensiveness of care and wellbeing of patients with HIV/AIDS, there is no evidence that it increases access to the ART programme. It is now being widely implemented in South Africa.
Trial registration Current Controlled Trials ISRCTN 24820584.
The cluster randomized trial (CRT) is used increasingly in knowledge translation research, quality improvement research, community based intervention studies, public health research, and research in developing countries. However, cluster trials raise difficult ethical issues that challenge researchers, research ethics committees, regulators, and sponsors as they seek to fulfill responsibly their respective roles. Our project will provide a systematic analysis of the ethics of cluster trials. Here we have outlined a series of six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation:
1. Who is a research subject?
2. From whom, how, and when must informed consent be obtained?
3. Does clinical equipoise apply to CRTs?
4. How do we determine if the benefits outweigh the risks of CRTs?
5. How ought vulnerable groups be protected in CRTs?
6. Who are gatekeepers and what are their responsibilities?
Subsequent papers in this series will address each of these areas, clarifying the ethical issues at stake and, where possible, arguing for a preferred solution. Our hope is that these papers will serve as the basis for the creation of international ethical guidelines for the design and conduct of cluster randomized trials.
Advances in resuscitation science have dramatically improved survival rates following cardiac arrest. However, about 60% of adults that regain spontaneous circulation die before leaving the hospital. Recently it has been shown that inducing hypothermia in cardiac arrest survivors immediately following their arrival in hospital can dramatically improve both overall survival and neurological outcomes. Despite the strong evidence for its efficacy and the apparent simplicity of this intervention, recent surveys show that therapeutic hypothermia is delivered inconsistently, incompletely, and often with delay.
Methods and design
This study will evaluate a multi-faceted knowledge translation strategy designed to increase the utilization rate of induced hypothermia in survivors of cardiac arrest across a network of 37 hospitals in Southwestern Ontario, Canada. The study is designed as a stepped wedge randomized trial lasting two years. Individual hospitals will be randomly assigned to four different wedges that will receive the active knowledge translation strategy according to a sequential rollout over a number of time periods. By the end of the study, all hospitals will have received the intervention. The primary aim is to measure the effectiveness of a multifaceted knowledge translation plan involving education, reminders, and audit-feedback for improving the use of induced hypothermia in survivors of cardiac arrest presenting to the emergency department. The primary outcome is the proportion of eligible OHCA patients that are cooled to a body temperature of 32 to 34°C within six hours of arrival in the hospital. Secondary outcomes will include process of care measures and clinical outcomes.
Inducing hypothermia in cardiac arrest survivors immediately following their arrival to hospital has been shown to dramatically improve both overall survival and neurological outcomes. However, this lifesaving treatment is frequently not applied in practice. If this trial is positive, our results will have broad implications by showing that a knowledge translation strategy shared across a collaborative network of hospitals can increase the number of patients that receive this lifesaving intervention in a timely manner.
ClinicalTrials.gov Trial Identifier: NCT00683683
Audit and feedback to physicians is commonly used alone or as part of multifaceted interventions. While it can play an important role in quality improvement, the optimal design of audit and feedback is unknown. This study explores how feedback can be improved to increase acceptability and usability in primary care. The trial seeks to determine whether a theory-informed worksheet appended to feedback reports can help family physicians improve quality of care for their patients with diabetes and/or ischemic heart disease.
Two-arm cluster trial was conducted with participating primary care practices allocated using minimization to simple feedback or enhanced feedback group. The simple feedback group receives performance feedback reports every six months for two years regarding the proportion of their patients with diabetes and/or ischemic heart disease who are meeting quality targets. The enhanced feedback group receives these same reports as well as a theory-informed worksheet designed to facilitate goal setting and action plan development in response to the feedback reports. Participants are family physicians from across Ontario who use electronic medical records; data for rostered patients are used to produce the feedback reports and for analysis.
The primary disease outcomes are the blood pressure (BP), and low-density lipoprotein cholesterol (LDL) levels. The primary process measure is a composite score indicating the number of recommended activities (e.g., tests and prescriptions) conducted by the family physicians for their patients with diabetes and/or ischemic heart disease within the appropriate timeframe. Secondary outcomes are the proportion of patients whose results meet targets for glucose, LDL, and BP as well as the percent of patients receiving relevant prescriptions. A qualitative process evaluation using semi-structured interviews will explore perceived barriers to behaviour change in response to feedback reports and preferences with regard to feedback design.
Intention-to-treat approach will be used to analyze the trial. Analysis will be performed on patient-level variables using generalized estimating equation models to adjust for covariates and account for the clustered nature of the data. The trial is powered to show small, but clinically important differences of 7 mmHG in systolic BP and 0.32 mmol/L in LDL.
In low-income countries, only about a third of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) patients eligible for anti-retroviral treatment currently receive it. Providing decentralized treatment close to where patients live is crucial to a faster scale up, however, a key obstacle is limited health system capacity due to a shortage of trained health-care workers and challenges of integrating HIV/AIDS care with other primary care services (e.g. tuberculosis, malaria, respiratory conditions). This study will test an adapted primary care health care worker training and guideline intervention, Practical Approach to Lung Health and HIV/AIDS Malawi (PALM PLUS), on staff retention and satisfaction, and quality of patient care.
A cluster-randomized trial design is being used to compare usual care with a standardized clinical guideline and training intervention, PALM PLUS. The intervention targets middle-cadre health care workers (nurses, clinical officers, medical assistants) in 30 rural primary care health centres in a single district in Malawi. PALM PLUS is an integrated, symptom-based and user-friendly guideline consistent with Malawian national treatment protocols. Training is standardized and based on an educational outreach approach. Trainers will be front-line peer healthcare workers trained to provide outreach training and support to their fellow front-line healthcare workers during focused (1-2 hours), intermittent, interactive sessions on-site in health centers. Primary outcomes are health care worker retention and satisfaction. Secondary outcomes are clinical outcomes measured at the health centre level for HIV/AIDS, tuberculosis, prevention-of-mother-to-child-transmission of HIV and other primary care conditions. Effect sizes and 95% confidence intervals for outcomes will be presented. Assessment of outcomes will occur at 1 year post- implementation.
The PALM PLUS trial aims to address a key problem: strengthening middle-cadre health care workers to support the broader scale up of HIV/AIDS services and their integration into primary care. The trial will test whether the PALM PLUS intervention improves staff satisfaction and retention, as well as the quality of patient care, when compared to usual practice.
Current controlled Trials: ISRCTN47805230
The gap between the level of care recommended by evidence-based clinical practice guidelines and the actual care delivered to patients in practice has been well established. The Canadian Diabetes Association (CDA) created an implementation strategy to improve the implementation of its 2008 guidelines. This study will evaluate the impact of the strategy to improve cardiovascular disease (CVD) screening, prevention and treatment for people with diabetes.
A pragmatic cluster-randomized trial will be conducted to evaluate the CDA's CVD Toolkit. All family physicians in Ontario, Canada were randomly allocated to receive the Toolkit, which includes several printed educational materials targeting CVD screening, prevention and treatment, either in spring 2009 (intervention arm) or in spring 2010 (control arm). Randomization occurred at the level of the practice. Forty family physicians from each arm will be recruited to participate, and the medical records for 20 of their diabetic patients at high risk for CVD will be retrospectively reviewed. Outcome measures will be assessed for each patient between July 2009 and March 2010. The primary outcome will be that the patient is receiving a statin. Secondary outcomes will include 1) the receipt of an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, 2) various intermediate measures (A1c, blood pressure, LDL-cholesterol, total-/HDL-cholesterol ratio, body mass index and waist circumference), and 3) clinical inertia (the failure to change therapy in response to an abnormal A1c, blood pressure or cholesterol reading). The analysis will be carried out using multilevel hierarchical logistic regression models to account for the clustered nature of the data. The group assignment will be a physician-level variable. In addition, a process evaluation study with six focus groups of family physicians will assess the acceptability of the CDA's Toolkit and will explore factors contributing to any change or lack of change in behaviour, from the perspectives of family physicians.
Printed educational materials for physicians have been shown to exert small-to-moderate changes in patient care. The CDA's CVD Toolkit is an example of a practice guideline implementation strategy that can be disseminated to a wide audience relatively inexpensively, and so demonstrating its effectiveness at improving diabetes care could have important consequences for guideline developers, policy makers and clinicians.
The trial is registered with http://www.clinicaltrials.gov, ID # NCT01026688
Many measurement scales for interprofessional collaboration are developed for one health professional group, typically nurses. Evaluating interprofessional collaborative relationships can benefit from employing a measurement scale suitable for multiple health provider groups, including physicians and other health professionals. To this end, the paper begins development of a new interprofessional collaboration measurement scale designed for use with nurses, physicians, and other professionals practicing in contemporary acute care settings. The paper investigates validity and reliability of data from nurses evaluating interprofessional collaboration of physicians and shows initial results for other rater/target combinations.
Items from a published scale originally designed for nurses were adapted to a round robin proxy report format appropriate for multiple health provider groups. Registered nurses, physicians, and allied health professionals practicing in inpatient wards/services of 15 community and academic hospitals in Toronto, Canada completed the adapted scale. Exploratory and confirmatory factor analysis of responses to the adapted scale examined dimensionality, construct and concurrent validity, and reliability of nurses' response data. Correlations between the adapted scale, the nurse-physician relations subscale of the Nursing Work Index, and the Attitudes Toward Health Care Teams Scale were calculated. Differences of mean scores on the Nursing Work Index and the interprofessional collaboration scale were compared between hospitals.
Exploratory factor analysis revealed 3 factors in the adapted interprofessional collaboration scale - labeled Communication, Accommodation, and Isolation - which were subsequently corroborated by confirmatory factor analysis. Nurses' scale responses about physician collaboration had convergent, discriminant, and concurrent validity, and acceptable reliability.
The new scale is suitable for use with nurses assessing physicians. The scale may yield valid and reliable data from physicians and others, but measurement equivalence and other properties of the scale should be investigated before it is used with multiple health professional groups.
Cluster randomized trials are an increasingly important methodological tool in health research. In cluster randomized trials, intact social units or groups of individuals, such as medical practices, schools, or entire communities – rather than individual themselves – are randomly allocated to intervention or control conditions, while outcomes are then observed on individual cluster members. The substantial methodological differences between cluster randomized trials and conventional randomized trials pose serious challenges to the current conceptual framework for research ethics. The ethical implications of randomizing groups rather than individuals are not addressed in current research ethics guidelines, nor have they even been thoroughly explored. The main objectives of this research are to: (1) identify ethical issues arising in cluster trials and learn how they are currently being addressed; (2) understand how ethics reviews of cluster trials are carried out in different countries (Canada, the USA and the UK); (3) elicit the views and experiences of trial participants and cluster representatives; (4) develop well-grounded guidelines for the ethical conduct and review of cluster trials by conducting an extensive ethical analysis and organizing a consensus process; (5) disseminate the guidelines to researchers, research ethics boards (REBs), journal editors, and research funders.
We will use a mixed-methods (qualitative and quantitative) approach incorporating both empirical and conceptual work. Empirical work will include a systematic review of a random sample of published trials, a survey and in-depth interviews with trialists, a survey of REBs, and in-depth interviews and focus group discussions with trial participants and gatekeepers. The empirical work will inform the concurrent ethical analysis which will lead to a guidance document laying out principles, policy options, and rationale for proposed guidelines. An Expert Panel of researchers, ethicists, health lawyers, consumer advocates, REB members, and representatives from low-middle income countries will be appointed. A consensus conference will be convened and draft guidelines will be generated by the Panel; an e-consultation phase will then be launched to invite comments from the broader community of researchers, policy-makers, and the public before a final set of guidelines is generated by the Panel and widely disseminated by the research team.
Rigorous evaluation of an intervention requires that its allocation be unbiased with respect to confounders; this is especially difficult in complex, system-wide healthcare interventions. We developed a short survey instrument to identify factors for a minimization algorithm for the allocation of a hospital-level intervention to reduce emergency department (ED) waiting times in Ontario, Canada.
Potential confounders influencing the intervention's success were identified by literature review, and grouped by healthcare setting specific change stages. An international multi-disciplinary (clinical, administrative, decision maker, management) panel evaluated these factors in a two-stage modified-delphi and nominal group process based on four domains: change readiness, evidence base, face validity, and clarity of definition.
An original set of 33 factors were identified from the literature. The panel reduced the list to 12 in the first round survey. In the second survey, experts scored each factor according to the four domains; summary scores and consensus discussion resulted in the final selection and measurement of four hospital-level factors to be used in the minimization algorithm: improved patient flow as a hospital's leadership priority; physicians' receptiveness to organizational change; efficiency of bed management; and physician incentives supporting the change goal.
We developed a simple tool designed to gather data from senior hospital administrators on factors likely to affect the success of a hospital patient flow improvement intervention. A minimization algorithm will ensure balanced allocation of the intervention with respect to these factors in study hospitals.
Randomised controlled trials are the best research design for decisions about the effect of different interventions but randomisation does not, of itself, promote the applicability of a trial's results to situations other than the precise one in which the trial was done. While methodologists and trialists have rightly paid great attention to internal validity, much less has been given to applicability.
This narrative review is aimed at those planning to conduct trials, and those aiming to use the information in them. It is intended to help the former group make their trials more widely useful and to help the latter group make more informed decisions about the wider use of existing trials. We review the differences between the design of most randomised trials (which have an explanatory attitude) and the design of trials more able to inform decision making (which have a pragmatic attitude) and discuss approaches used to assert applicability of trial results.
If we want evidence from trials to be used in clinical practice and policy, trialists should make every effort to make their trial widely applicable, which means that more trials should be pragmatic in attitude.