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1.  Does clinical equipoise apply to cluster randomized trials in health research? 
Trials  2011;12:118.
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.
doi:10.1186/1745-6215-12-118
PMCID: PMC3113987  PMID: 21569349
2.  Variability in research ethics review of cluster randomized trials: a scenario-based survey in three countries 
Trials  2014;15:48.
Background
Cluster randomized trials (CRTs) present unique ethical challenges. In the absence of a uniform standard for their ethical design and conduct, problems such as variability in procedures and requirements by different research ethics committees will persist. We aimed to assess the need for ethics guidelines for CRTs among research ethics chairs internationally, investigate variability in procedures for research ethics review of CRTs within and among countries, and elicit research ethics chairs’ perspectives on specific ethical issues in CRTs, including the identification of research subjects. The proper identification of research subjects is a necessary requirement in the research ethics review process, to help ensure, on the one hand, that subjects are protected from harm and exploitation, and on the other, that reviews of CRTs are completed efficiently.
Methods
A web-based survey with closed- and open-ended questions was administered to research ethics chairs in Canada, the United States, and the United Kingdom. The survey presented three scenarios of CRTs involving cluster-level, professional-level, and individual-level interventions. For each scenario, a series of questions was posed with respect to the type of review required (full, expedited, or no review) and the identification of research subjects at cluster and individual levels.
Results
A total of 189 (35%) of 542 chairs responded. Overall, 144 (84%, 95% CI 79 to 90%) agreed or strongly agreed that there is a need for ethics guidelines for CRTs and 158 (92%, 95% CI 88 to 96%) agreed or strongly agreed that research ethics committees could be better informed about distinct ethical issues surrounding CRTs. There was considerable variability among research ethics chairs with respect to the type of review required, as well as the identification of research subjects. The cluster-cluster and professional-cluster scenarios produced the most disagreement.
Conclusions
Research ethics committees identified a clear need for ethics guidelines for CRTs and education about distinct ethical issues in CRTs. There is disagreement among committees, even within the same countries, with respect to key questions in the ethics review of CRTs. This disagreement reflects variability of opinion and practices pointing toward possible gaps in knowledge, and supports the need for explicit guidelines for the ethical conduct and review of CRTs.
doi:10.1186/1745-6215-15-48
PMCID: PMC3925119  PMID: 24495542
Cluster randomized trials; Informed consent; Research ethics guidelines; Research ethics review; Web-based survey
3.  Ethical issues posed by cluster randomized trials in health research 
Trials  2011;12:100.
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.
doi:10.1186/1745-6215-12-100
PMCID: PMC3107798  PMID: 21507237
4.  When is informed consent required in cluster randomized trials in health research? 
Trials  2011;12:202.
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 cluster trial is to be set on a firm ethical foundation. This paper addresses the second of the questions posed, namely, from whom, when, and how must informed consent be obtained in CRTs in health research? The ethical principle of respect for persons implies that researchers are generally obligated to obtain the informed consent of research subjects. Aspects of CRT design, including cluster randomization, cluster level interventions, and cluster size, present challenges to obtaining informed consent. Here we address five questions related to consent and CRTs: How can a study proceed if informed consent is not possible? Is consent to randomization always required? What information must be disclosed to potential subjects if their cluster has already been randomized? Is passive consent a valid substitute for informed consent? Do health professionals have a moral obligation to participate as subjects in CRTs designed to improve professional practice?
We set out a framework based on the moral foundations of informed consent and international regulatory provisions to address each of these questions. First, when informed consent is not possible, a study may proceed if a research ethics committee is satisfied that conditions for a waiver of consent are satisfied. Second, informed consent to randomization may not be required if it is not possible to approach subjects at the time of randomization. Third, when potential subjects are approached after cluster randomization, they must be provided with a detailed description of the interventions in the trial arm to which their cluster has been randomized; detailed information on interventions in other trial arms need not be provided. Fourth, while passive consent may serve a variety of practical ends, it is not a substitute for valid informed consent. Fifth, while health professionals may have a moral obligation to participate as subjects in research, this does not diminish the necessity of informed consent to study participation.
doi:10.1186/1745-6215-12-202
PMCID: PMC3184061  PMID: 21906277
5.  What is the role and authority of gatekeepers in cluster randomized trials in health research? 
Trials  2012;13:116.
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.
doi:10.1186/1745-6215-13-116
PMCID: PMC3443001  PMID: 22834691
6.  Electronic search strategies to identify reports of cluster randomized trials in MEDLINE: low precision will improve with adherence to reporting standards 
Background
Cluster randomized trials (CRTs) present unique methodological and ethical challenges. Researchers conducting systematic reviews of CRTs (e.g., addressing methodological or ethical issues) require efficient electronic search strategies (filters or hedges) to identify trials in electronic databases such as MEDLINE. According to the CONSORT statement extension to CRTs, the clustered design should be clearly identified in titles or abstracts; however, variability in terminology may make electronic identification challenging. Our objectives were to (a) evaluate sensitivity ("recall") and precision of a well-known electronic search strategy ("randomized controlled trial" as publication type) with respect to identifying CRTs, (b) evaluate the feasibility of new search strategies targeted specifically at CRTs, and (c) determine whether CRTs are appropriately identified in titles or abstracts of reports and whether there has been improvement over time.
Methods
We manually examined a wide range of health journals to identify a gold standard set of CRTs. Search strategies were evaluated against the gold standard set, as well as an independent set of CRTs included in previous systematic reviews.
Results
The existing strategy (randomized controlled trial.pt) is sensitive (93.8%) for identifying CRTs, but has relatively low precision (9%, number needed to read 11); the number needed to read can be halved to 5 (precision 18.4%) by combining with cluster design-related terms using the Boolean operator AND; combining with the Boolean operator OR maximizes sensitivity (99.4%) but would require 28.6 citations read to identify one CRT. Only about 50% of CRTs are clearly identified as cluster randomized in titles or abstracts; approximately 25% can be identified based on the reported units of randomization but are not amenable to electronic searching; the remaining 25% cannot be identified except through manual inspection of the full-text article. The proportion of trials clearly identified has increased from 28% between the years 2000-2003, to 60% between 2004-2007 (absolute increase 32%, 95% CI 17 to 47%).
Conclusions
CRTs should include the phrase "cluster randomized trial" in titles or abstracts; this will facilitate more accurate indexing of the publication type by reviewers at the National Library of Medicine, and efficient textword retrieval of the subset employing cluster randomization.
doi:10.1186/1471-2288-10-15
PMCID: PMC2833170  PMID: 20158899
7.  Researchers’ perceptions of ethical challenges in cluster randomized trials: a qualitative analysis 
Trials  2013;14:1.
Background
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.
Methods
Descriptive qualitative analysis of interviews conducted with a purposive sample of 20 experienced CRT researchers.
Results
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.
Conclusions
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.
doi:10.1186/1745-6215-14-1
PMCID: PMC3561139  PMID: 23286245
Cluster randomized trials; Research ethics; Informed consent; Clinical trials; Bioethics; Knowledge translation; Quality improvement; Implementation research
8.  Cost-effectiveness of cardiac resynchronisation therapy for patients with moderate-to-severe heart failure: a lifetime Markov model 
BMJ Open  2011;1(2):e000276.
Objective
To assess the cost-effectiveness of cardiac resynchronisation therapy (CRT) both with CRT-P (biventricular pacemaker only) and with CRT-D (biventricular pacemaker with defibrillator) in patients with New York Heart Association (NYHA) functional class III/IV from a Belgian healthcare-payer perspective.
Methods
A lifetime Markov model was designed to calculate the cost–utility of both interventions. In the reference case, the treatment effect was based on the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure trial. Costs were based on real-world data. Pharmacoeconomic guidelines were applied, including probabilistic modelling and sensitivity analyses.
Results
Compared with optimal medical treatment, on average 1.31 quality-adjusted life-years (QALY) are gained with CRT-P at an additional cost of €14 700, resulting in an incremental cost-effectiveness ratio (ICER) of about €11 200/QALY. As compared with CRT-P, CRT-D treatment adds on average an additional 0.55 QALYs at an extra cost of €30 900 resulting in an ICER of €57 000/QALY. This result was very sensitive to the incremental clinical benefit of the defibrillator function on top of CRT.
Conclusions
Based on efficiency arguments, CRT-P can be recommended for NYHA class III and IV patients if there is a willingness to pay more than €11 000/QALY. Even though CRT-D may offer a survival benefit over CRT-P, the incremental clinical benefit appears to be too marginal to warrant a threefold-higher device price for CRT-D. Further clinical research should focus on the added value of CRT-D over CRT-P.
Article summary
Article focus
To assess the cost-effectiveness of cardiac resynchronisation therapy (CRT) both with CRT-P (biventricular pacemaker only) and with CRT-D (biventricular pacemaker with defibrillator).
Key messages
CRT-P can be recommended for reimbursement for New York Heart Association class III and IV patients if there is a willingness to pay more than €11 000/quality-adjusted life-year.
Current evidence is insufficient to show the superiority of CRT-D over CRT-P. With a threefold-higher device cost, CRT-D's cost-effectiveness is questionable.
Strengths and limitations
Hospital billing data of 342 Belgian CRT implantations were at our disposal for cost calculations.
The results of the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure trial were used to model the treatment effect. This happens to be the only trial that compared CRT-P as well as CRT-D versus optimal pharmacological treatment, allowing an indirect comparison to be made between CRT-P and CRT-D.
Following health economic theory, CRT-D is compared with CRT-P, not with optimal pharmacological treatment (ie, working on the cost-efficiency frontier).
A direct estimate of the added value of CRT-D versus CRT-P in patients with moderate to severe heart failure is lacking. This may be an interesting topic for further research in a randomised controlled trial, especially because of the threefold higher price for a CRT-D device versus CRT-P.
Generic utility instruments to measure quality of life are not always used in clinical trials. To support economic evaluations, it would be useful to include more systematically a generic utility instrument in the study protocol.
doi:10.1136/bmjopen-2011-000276
PMCID: PMC3211050  PMID: 22021894
9.  A systematic review of cognitive remediation therapy for anorexia nervosa – development, current state and implications for future research and clinical practice 
Objective
To systematically review studies of cognitive remediation therapy (CRT) for anorexia nervosa (AN), and to discuss findings with references to clinical practice and future research.
Method
The literature was reviewed using the PubMed, Web of Science and PsycINFO search terms “cognitive remediation therapy” AND “anorexia nervosa”. Papers published online between 2005 and 2013 were selected on the basis of three inclusion criteria: 1) studies of any design focusing on CRT for AN, 2) papers that were written in English or had an available published English translation, and 3) papers published in peer reviewed journals.
Results
A total of 45 papers were identified of which 21 were recognized as being relevant for the review. Relevant papers were divided into three different categories 1) single case reports, 2) case series and 3) randomised controlled trials (RCTs). Single case studies and case series yielded strong evidence of feasibility and acceptability of CRT for AN despite great variety in sample compositions. Four RCTs demonstrate that CRT has the potential of enhancing the effectiveness of current treatments, reduce attrition, increase cognitive set-shifting abilities and quality of life, as well as reduce eating disorder psychopathology.
Discussion
The number of CRT studies published is growing rapidly, in particular RCTs. Further research is needed to define the primary aim of delivering CRT to patients with eating disorders, and to establish how to best measure the effect of the intervention. Moreover, researchers and clinicians should focus on identifying and assessing specific versus non-specific CRT contributions, and explore long-term effects of the intervention. It is imperative that adolescent RCTs are conducted to evaluate how CRT may be effective as a treatment for this young patient group.
doi:10.1186/s40337-014-0026-y
PMCID: PMC4173002  PMID: 25254110
Cognitive remediation therapy; Anorexia nervosa; Review; Treatment; Neuropsychology; Eating disorders; Metacognition
10.  COST EFFECTIVENESS OF CARDIAC RESYNCHRONIZATION FOR THE PREVENTION OF HEART FAILURE 
Background
The Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial demonstrated that cardiac resynchronization therapy (CRT) when added to the implantable cardiac defibrillator (ICD) reduces risk of heart failure (HF) or death in minimally symptomatic patients with reduced cardiac ejection fraction and wide QRS complex.
Objectives
To evaluate 4-year cost-effectiveness of CRT-ICD compared to ICD alone using MADIT-CRT data.
Research Design
Patients enrolled in the trial were randomized to implantation of either ICD or CRT-ICD in a 2:3 ratio, with up to 4-year follow-up period. Cost-effectiveness analyses were conducted, and sensitivity analyses by age, gender and left bundle branch block (LBBB) conduction pattern were performed.
Subjects
1271 patients with ICD or CRT-ICD (U.S. centers only) who reported healthcare utilization and health-related quality of life data (HRQOL).
Measures
We used the EQ-5D (U.S. weights) to assess patient HRQOL and translated utilization data to costs using national Medicare reimbursement rates.
Results
Average 4-year healthcare expenditures in CRT-ICD patients were higher than costs of ICD patients ($62,600 vs. 57,050, p=0.015), mainly due to the device and implant-related costs. The incremental cost-effectiveness ratio of CRT-ICD compared to ICD was $58,330/quality-adjusted life years (QALY) saved. The cost effectiveness improved with longer time horizon and for the LBBB subgroup ($7,320/QALY), with no cost-effectiveness benefit being evident in the non-LBBB group.
Conclusions
In minimally symptomatic patients with low ejection fraction and LBBB, CRT-ICD is cost effective within 4-year horizon when compared to ICD-only
doi:10.1111/j.1540-8167.2012.02413.x
PMCID: PMC3711178  PMID: 22913474
implantable cardioverter-defibrillator (ICD); cardiac resynchronization therapy (CRT); cost-effectiveness; health-related quality-of-life (HRQOL); survival; MADIT-CRT
11.  CRTs – Cluster Randomized Trials or “Courting Real Troubles” 
This paper addresses the logistical challenges of implementing public health interventions in the setting of cluster randomized trials (CRTs), drawing on the experience of carrying out a CRT within a community-based health insurance (CBHI) scheme in rural India. Our CRT is seeking to improve the equity impact – i.e., reduce the differential in claims submission for hospitalization between poor and less poor – of this CBHI in rural areas. Five main challenges are identified and discussed: 1) assigning control clusters, 2) blinding, 3) implementing interventions simultaneously, 4) minimizing leakage, and 5) piggy-backing on a changing scheme. These challenges are not likely to be unique to low-income settings, although the fifth challenge is particularly likely when working with relatively small and resource-constrained programs. While compromises to methodological best-practice may reduce internal validity, they make the intervention more ‘real’, and potentially more applicable, to other programs and settings. Further, careful documentation of compromises allows them to be considered in the final analysis.
RÉSUMÉ
Cet article traite des difficultés logistiques rencontrées dans la mise en oeuvre d'interventions de santé publique dans le cadre d'essais contrôlés randomisés par grappes. Il tire les enseignements d'une expérience menée au sein d'un système d'assurance-santé communautaire dans une région rurale de l'Inde. Il s'agit d'une intervention randomisée par grappes qui a pour but d'améliorer l'équité du système, à savoir réduire l'écart entre les demandes de remboursement des frais d'hospitalisation soumises par les populations pauvres et moins pauvres. Cinq grandes difficultés sont présentées et discutées dans l'article : 1) la mise en place des groupes de contrôle, 2) la création des conditions d'un test en aveugle, 3) la simultanéité des interventions, 4) le risque de contamination entre les groupes et 5) l'implantation sur un dispositif connaissant des modifications. Ces problèmes ne sont pas propres au contexte des pays en développement, bien que le dernier soit plus courant dans le cas de petits programmes aux ressources limitées. Les concessions faites par rapport aux canons méthodologiques sont susceptibles de réduire la validité interne de l'étude, mais elles rendent l'intervention plus réaliste et potentiellement plus applicable à d'autres contextes. En outre, une documentation précise de ces compromis nous permet de les prendre en compte à la fin de l'analyse.
PMCID: PMC1791008  PMID: 16512334
Health insurance; India; nongovernmental organizations; randomized controlled trials
12.  Postoperative adjuvant chemoradiotherapy in D2-dissected gastric cancer: Is radiotherapy necessary after D2-dissection? 
World Journal of Gastroenterology : WJG  2014;20(36):12900-12907.
Studies from the Far East have demonstrated that D2-dissection is superior to D0/1-dissection. The effect of postoperative chemoradiotherapy (CRT) after D2-dissection has not been accepted due to the lack of D2-dissection in Western countries, as well as the potential harmful effect of radiotherapy. In the current NCCN guideline, adjuvant chemotherapy alone is recommended in D2-dissected patients. However, three recent prospective randomized controlled trials in South Korea and China (ARTIST, NCC and Multicenter IMRT Trials) demonstrated that adjuvant CRT can be safely administered to D2-dissected patients with notable benefits. To identify the role of radiotherapy (RT) in the D2-dissected postoperative setting, clinical research attempts should include (1) identification of high-risk patients for loco-regional recurrence who might benefit from CRT; (2) modification of RT target volume based on the findings that failure patterns should be different after D1- and D2-dissection; and (3) integration of new RT techniques to decrease treatment-related toxicity. The present paper is a review of recent studies addressing these fields. Well-designed prospective randomized studies are needed to clearly define the role of adjuvant CRT in D2-dissected gastric cancer, however, future clinical studies should also focus on answering these questions.
doi:10.3748/wjg.v20.i36.12900
PMCID: PMC4177472  PMID: 25278687
Gastric cancer; D2-dissection; Recurrence; Radiotherapy; Chemotherapy
13.  Factors associated with use of pre-operative chemoradiation therapy for rectal cancer in the Cancer Care Outcomes Research and Surveillance Consortium 
American journal of clinical oncology  2013;36(6):10.1097/COC.0b013e318261082b.
Purpose
Pre-operative (pre-op) chemoradiation therapy (CRT) improves local control and reduces toxicity more than post-operative (post-op) CRT for the treatment of stages II/III rectal cancer, but studies suggest many patients still receive post-op CRT. We examined patient beliefs, and clinical and provider characteristics associated with receipt of recommended therapy.
Methods
We identified stage II/III rectal cancer patients who had primary site resection and CRT among subjects in the Cancer Care Outcomes Research and Surveillance Consortium, a population- and health system-based prospective cohort of newly diagnosed colorectal cancer patients from 2003 to 2005. Patient surveys and abstracted medical records were used to construct variables and determine sequence of CRT and surgery. Logistic regression was used to model the association between predictors and receipt of pre-op CRT.
Results
Of the 201 patients, 66% received pre-op and 34% received post-op CRT. Those visiting a medical oncologist and/or radiation oncologist prior to a surgeon had a 96% (95% CI, 92% to 100%) predicted probability of receiving pre-op CRT, compared to 48% (95% CI, 41% to 55%) for those visiting a surgeon first. Among those visiting a surgeon first, documentation of recommended staging procedures was associated with receiving pre-op CRT.
Conclusion
Sequence of provider visits and documentation of recommended staging procedures were important predictors of receiving pre-op CRT. Initial multidisciplinary evaluation led to better adherence to CRT guidelines. Further evaluation of provider characteristics, referral patterns and related health system processes should be undertaken to inform targeted interventions to reduce variation from recommended care.
doi:10.1097/COC.0b013e318261082b
PMCID: PMC3556239  PMID: 22992624
14.  The Role of Community Health Workers (CHWs) in Health Promotion Research: Ethical Challenges and Practical Solutions 
Health promotion practice  2009;12(1):86-93.
This article aims to describe the role of community health workers (CHWs) in health promotion research and address the challenges and ethical concerns associated with this research approach. A series of six focus groups are conducted with project managers and investigators (n = 5 to 11 per session) who have worked with CHWs in health promotion research. These focus groups are part of a larger study funded by the National Institutes of Health titled “Training in Research Ethics and Standards” (Project TRES). Participants are asked to describe their training needs for CHWs with respect to human subject protections as well as to identify associated challenges regarding research practice (i.e., recruitment, random assignment, protocol implementation, etc.). Findings reveal a number of challenges that investigators and project managers encounter when working with CHWs on research projects involving the community. These include characteristics inherent to CHWs such as education level and personal beliefs about their own community and its needs, institutional regulations regarding research practice, and problems inherent to research studies such as training materials and protocols that cannot account for the complexity of conducting research in community settings. Investigators should carefully consider the role that CHWs have in their communities before creating research programs that depend on the CHWs’ existing social networks and their propensity to be natural helpers. These strengths could lead to compromises in research requirements for random assignment, control groups, and fully informed consent.
doi:10.1177/1524839908330809
PMCID: PMC3748275  PMID: 19346410
lay health workers; ethical research practice; research integrity; promotores
15.  Predicting Nursing Home Adherence to a Clinical Trial Intervention: Lessons for the Conduct of Cluster Randomized Trials 
Background/Objectives
Lack of adherence to a clinical trial intervention threatens the ability of a study to yield meaningful results. Since developing methods to predict intervention adherence in cluster randomized trials (CRT) will facilitate the successful conduct of studies in the nursing home (NH) setting, we sought to describe factors predictive of NH adherence to a clinical trial intervention.
Research Design, Subjects, Measures
Post-hoc analysis of a CRT evaluating a structured communication intervention to improve nurse-physician telephone communication in 26 NHs. Adherence was defined as active participation for at least 3 months of the 12 month trial. A priori, we measured NH characteristics hypothesized to affect trial outcomes (profit-status, bedsize, nursing staff time, NH quality, and leadership turnover). We examined the association between intervention adherence, NH characteristics and pre-intervention questionnaire response rate.
Results
Of 13 intervention homes, 7 were adherent to the intervention. Three factors differentiated adherent from non-adherent NHs: director of nursing turnover (non-adherent NHs [50%] vs adherent NHs [0%], p<0.03); Centers for Medicare and Medicaid Services' (CMS) nurse staffing rating (range 1-5) (non-adherent NHs [mean 3.7, standard deviation (SD) 0.5] vs adherent NHs [mean 4.3, SD 0.5)], p<0.05); and questionnaire response rate (non-adherent NH [15.6%, SD 10.0] vs adherent NH [34.2%, SD 12.1], p=0.02). Profit status, bedsize, and number of NH deficiencies on state surveys were not significantly associated with intervention adherence.
Conclusion
CMS nurse staffing rating, leadership turnover, and questionnaire response rate are associated with adherence to a CRT intervention. Pre-trial evaluation of NH staffing rating by CMS and of response to a questionnaire can help investigators improve trial efficiency by screening for NHs likely to be adherent to a CRT intervention.
doi:10.1111/j.1532-5415.2011.03697.x
PMCID: PMC4164958  PMID: 22091689
cluster randomized trials; methodology; adherence; run-in period; intervention trials
16.  Internet-Based Device-Assisted Remote Monitoring of Cardiovascular Implantable Electronic Devices 
Executive Summary
Objective
The objective of this Medical Advisory Secretariat (MAS) report was to conduct a systematic review of the available published evidence on the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted remote monitoring systems (RMSs) for therapeutic cardiac implantable electronic devices (CIEDs) such as pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. The MAS evidence-based review was performed to support public financing decisions.
Clinical Need: Condition and Target Population
Sudden cardiac death (SCD) is a major cause of fatalities in developed countries. In the United States almost half a million people die of SCD annually, resulting in more deaths than stroke, lung cancer, breast cancer, and AIDS combined. In Canada each year more than 40,000 people die from a cardiovascular related cause; approximately half of these deaths are attributable to SCD.
Most cases of SCD occur in the general population typically in those without a known history of heart disease. Most SCDs are caused by cardiac arrhythmia, an abnormal heart rhythm caused by malfunctions of the heart’s electrical system. Up to half of patients with significant heart failure (HF) also have advanced conduction abnormalities.
Cardiac arrhythmias are managed by a variety of drugs, ablative procedures, and therapeutic CIEDs. The range of CIEDs includes pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. Bradycardia is the main indication for PMs and individuals at high risk for SCD are often treated by ICDs.
Heart failure (HF) is also a significant health problem and is the most frequent cause of hospitalization in those over 65 years of age. Patients with moderate to severe HF may also have cardiac arrhythmias, although the cause may be related more to heart pump or haemodynamic failure. The presence of HF, however, increases the risk of SCD five-fold, regardless of aetiology. Patients with HF who remain highly symptomatic despite optimal drug therapy are sometimes also treated with CRT devices.
With an increasing prevalence of age-related conditions such as chronic HF and the expanding indications for ICD therapy, the rate of ICD placement has been dramatically increasing. The appropriate indications for ICD placement, as well as the rate of ICD placement, are increasingly an issue. In the United States, after the introduction of expanded coverage of ICDs, a national ICD registry was created in 2005 to track these devices. A recent survey based on this national ICD registry reported that 22.5% (25,145) of patients had received a non-evidence based ICD and that these patients experienced significantly higher in-hospital mortality and post-procedural complications.
In addition to the increased ICD device placement and the upfront device costs, there is the need for lifelong follow-up or surveillance, placing a significant burden on patients and device clinics. In 2007, over 1.6 million CIEDs were implanted in Europe and the United States, which translates to over 5.5 million patient encounters per year if the recommended follow-up practices are considered. A safe and effective RMS could potentially improve the efficiency of long-term follow-up of patients and their CIEDs.
Technology
In addition to being therapeutic devices, CIEDs have extensive diagnostic abilities. All CIEDs can be interrogated and reprogrammed during an in-clinic visit using an inductive programming wand. Remote monitoring would allow patients to transmit information recorded in their devices from the comfort of their own homes. Currently most ICD devices also have the potential to be remotely monitored. Remote monitoring (RM) can be used to check system integrity, to alert on arrhythmic episodes, and to potentially replace in-clinic follow-ups and manage disease remotely. They do not currently have the capability of being reprogrammed remotely, although this feature is being tested in pilot settings.
Every RMS is specifically designed by a manufacturer for their cardiac implant devices. For Internet-based device-assisted RMSs, this customization includes details such as web application, multiplatform sensors, custom algorithms, programming information, and types and methods of alerting patients and/or physicians. The addition of peripherals for monitoring weight and pressure or communicating with patients through the onsite communicators also varies by manufacturer. Internet-based device-assisted RMSs for CIEDs are intended to function as a surveillance system rather than an emergency system.
Health care providers therefore need to learn each application, and as more than one application may be used at one site, multiple applications may need to be reviewed for alarms. All RMSs deliver system integrity alerting; however, some systems seem to be better geared to fast arrhythmic alerting, whereas other systems appear to be more intended for remote follow-up or supplemental remote disease management. The different RMSs may therefore have different impacts on workflow organization because of their varying frequency of interrogation and methods of alerts. The integration of these proprietary RM web-based registry systems with hospital-based electronic health record systems has so far not been commonly implemented.
Currently there are 2 general types of RMSs: those that transmit device diagnostic information automatically and without patient assistance to secure Internet-based registry systems, and those that require patient assistance to transmit information. Both systems employ the use of preprogrammed alerts that are either transmitted automatically or at regular scheduled intervals to patients and/or physicians.
The current web applications, programming, and registry systems differ greatly between the manufacturers of transmitting cardiac devices. In Canada there are currently 4 manufacturers—Medtronic Inc., Biotronik, Boston Scientific Corp., and St Jude Medical Inc.—which have regulatory approval for remote transmitting CIEDs. Remote monitoring systems are proprietary to the manufacturer of the implant device. An RMS for one device will not work with another device, and the RMS may not work with all versions of the manufacturer’s devices.
All Internet-based device-assisted RMSs have common components. The implanted device is equipped with a micro-antenna that communicates with a small external device (at bedside or wearable) commonly known as the transmitter. Transmitters are able to interrogate programmed parameters and diagnostic data stored in the patients’ implant device. The information transfer to the communicator can occur at preset time intervals with the participation of the patient (waving a wand over the device) or it can be sent automatically (wirelessly) without their participation. The encrypted data are then uploaded to an Internet-based database on a secure central server. The data processing facilities at the central database, depending on the clinical urgency, can trigger an alert for the physician(s) that can be sent via email, fax, text message, or phone. The details are also posted on the secure website for viewing by the physician (or their delegate) at their convenience.
Research Questions
The research directions and specific research questions for this evidence review were as follows:
To identify the Internet-based device-assisted RMSs available for follow-up of patients with therapeutic CIEDs such as PMs, ICDs, and CRT devices.
To identify the potential risks, operational issues, or organizational issues related to Internet-based device-assisted RM for CIEDs.
To evaluate the safety, acceptability, and effectiveness of Internet-based device-assisted RMSs for CIEDs such as PMs, ICDs, and CRT devices.
To evaluate the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted RMSs for CIEDs compared to usual outpatient in-office monitoring strategies.
To evaluate the resource implications or budget impact of RMSs for CIEDs in Ontario, Canada.
Research Methods
Literature Search
The review included a systematic review of published scientific literature and consultations with experts and manufacturers of all 4 approved RMSs for CIEDs in Canada. Information on CIED cardiac implant clinics was also obtained from Provincial Programs, a division within the Ministry of Health and Long-Term Care with a mandate for cardiac implant specialty care. Various administrative databases and registries were used to outline the current clinical follow-up burden of CIEDs in Ontario. The provincial population-based ICD database developed and maintained by the Institute for Clinical Evaluative Sciences (ICES) was used to review the current follow-up practices with Ontario patients implanted with ICD devices.
Search Strategy
A literature search was performed on September 21, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from 1950 to September 2010. Search alerts were generated and reviewed for additional relevant literature until December 31, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
published between 1950 and September 2010;
English language full-reports and human studies;
original reports including clinical evaluations of Internet-based device-assisted RMSs for CIEDs in clinical settings;
reports including standardized measurements on outcome events such as technical success, safety, effectiveness, cost, measures of health care utilization, morbidity, mortality, quality of life or patient satisfaction;
randomized controlled trials (RCTs), systematic reviews and meta-analyses, cohort and controlled clinical studies.
Exclusion Criteria
non-systematic reviews, letters, comments and editorials;
reports not involving standardized outcome events;
clinical reports not involving Internet-based device assisted RM systems for CIEDs in clinical settings;
reports involving studies testing or validating algorithms without RM;
studies with small samples (<10 subjects).
Outcomes of Interest
The outcomes of interest included: technical outcomes, emergency department visits, complications, major adverse events, symptoms, hospital admissions, clinic visits (scheduled and/or unscheduled), survival, morbidity (disease progression, stroke, etc.), patient satisfaction, and quality of life.
Summary of Findings
The MAS evidence review was performed to review available evidence on Internet-based device-assisted RMSs for CIEDs published until September 2010. The search identified 6 systematic reviews, 7 randomized controlled trials, and 19 reports for 16 cohort studies—3 of these being registry-based and 4 being multi-centered. The evidence is summarized in the 3 sections that follow.
1. Effectiveness of Remote Monitoring Systems of CIEDs for Cardiac Arrhythmia and Device Functioning
In total, 15 reports on 13 cohort studies involving investigations with 4 different RMSs for CIEDs in cardiology implant clinic groups were identified in the review. The 4 RMSs were: Care Link Network® (Medtronic Inc,, Minneapolis, MN, USA); Home Monitoring® (Biotronic, Berlin, Germany); House Call 11® (St Jude Medical Inc., St Pauls, MN, USA); and a manufacturer-independent RMS. Eight of these reports were with the Home Monitoring® RMS (12,949 patients), 3 were with the Care Link® RMS (167 patients), 1 was with the House Call 11® RMS (124 patients), and 1 was with a manufacturer-independent RMS (44 patients). All of the studies, except for 2 in the United States, (1 with Home Monitoring® and 1 with House Call 11®), were performed in European countries.
The RMSs in the studies were evaluated with different cardiac implant device populations: ICDs only (6 studies), ICD and CRT devices (3 studies), PM and ICD and CRT devices (4 studies), and PMs only (2 studies). The patient populations were predominately male (range, 52%–87%) in all studies, with mean ages ranging from 58 to 76 years. One study population was unique in that RMSs were evaluated for ICDs implanted solely for primary prevention in young patients (mean age, 44 years) with Brugada syndrome, which carries an inherited increased genetic risk for sudden heart attack in young adults.
Most of the cohort studies reported on the feasibility of RMSs in clinical settings with limited follow-up. In the short follow-up periods of the studies, the majority of the events were related to detection of medical events rather than system configuration or device abnormalities. The results of the studies are summarized below:
The interrogation of devices on the web platform, both for continuous and scheduled transmissions, was significantly quicker with remote follow-up, both for nurses and physicians.
In a case-control study focusing on a Brugada population–based registry with patients followed-up remotely, there were significantly fewer outpatient visits and greater detection of inappropriate shocks. One death occurred in the control group not followed remotely and post-mortem analysis indicated early signs of lead failure prior to the event.
Two studies examined the role of RMSs in following ICD leads under regulatory advisory in a European clinical setting and noted:
– Fewer inappropriate shocks were administered in the RM group.
– Urgent in-office interrogations and surgical revisions were performed within 12 days of remote alerts.
– No signs of lead fracture were detected at in-office follow-up; all were detected at remote follow-up.
Only 1 study reported evaluating quality of life in patients followed up remotely at 3 and 6 months; no values were reported.
Patient satisfaction was evaluated in 5 cohort studies, all in short term follow-up: 1 for the Home Monitoring® RMS, 3 for the Care Link® RMS, and 1 for the House Call 11® RMS.
– Patients reported receiving a sense of security from the transmitter, a good relationship with nurses and physicians, positive implications for their health, and satisfaction with RM and organization of services.
– Although patients reported that the system was easy to implement and required less than 10 minutes to transmit information, a variable proportion of patients (range, 9% 39%) reported that they needed the assistance of a caregiver for their transmission.
– The majority of patients would recommend RM to other ICD patients.
– Patients with hearing or other physical or mental conditions hindering the use of the system were excluded from studies, but the frequency of this was not reported.
Physician satisfaction was evaluated in 3 studies, all with the Care Link® RMS:
– Physicians reported an ease of use and high satisfaction with a generally short-term use of the RMS.
– Physicians reported being able to address the problems in unscheduled patient transmissions or physician initiated transmissions remotely, and were able to handle the majority of the troubleshooting calls remotely.
– Both nurses and physicians reported a high level of satisfaction with the web registry system.
2. Effectiveness of Remote Monitoring Systems in Heart Failure Patients for Cardiac Arrhythmia and Heart Failure Episodes
Remote follow-up of HF patients implanted with ICD or CRT devices, generally managed in specialized HF clinics, was evaluated in 3 cohort studies: 1 involved the Home Monitoring® RMS and 2 involved the Care Link® RMS. In these RMSs, in addition to the standard diagnostic features, the cardiac devices continuously assess other variables such as patient activity, mean heart rate, and heart rate variability. Intra-thoracic impedance, a proxy measure for lung fluid overload, was also measured in the Care Link® studies. The overall diagnostic performance of these measures cannot be evaluated, as the information was not reported for patients who did not experience intra-thoracic impedance threshold crossings or did not undergo interventions. The trial results involved descriptive information on transmissions and alerts in patients experiencing high morbidity and hospitalization in the short study periods.
3. Comparative Effectiveness of Remote Monitoring Systems for CIEDs
Seven RCTs were identified evaluating RMSs for CIEDs: 2 were for PMs (1276 patients) and 5 were for ICD/CRT devices (3733 patients). Studies performed in the clinical setting in the United States involved both the Care Link® RMS and the Home Monitoring® RMS, whereas all studies performed in European countries involved only the Home Monitoring® RMS.
3A. Randomized Controlled Trials of Remote Monitoring Systems for Pacemakers
Two trials, both multicenter RCTs, were conducted in different countries with different RMSs and study objectives. The PREFER trial was a large trial (897 patients) performed in the United States examining the ability of Care Link®, an Internet-based remote PM interrogation system, to detect clinically actionable events (CAEs) sooner than the current in-office follow-up supplemented with transtelephonic monitoring transmissions, a limited form of remote device interrogation. The trial results are summarized below:
In the 375-day mean follow-up, 382 patients were identified with at least 1 CAE—111 patients in the control arm and 271 in the remote arm.
The event rate detected per patient for every type of CAE, except for loss of atrial capture, was higher in the remote arm than the control arm.
The median time to first detection of CAEs (4.9 vs. 6.3 months) was significantly shorter in the RMS group compared to the control group (P < 0.0001).
Additionally, only 2% (3/190) of the CAEs in the control arm were detected during a transtelephonic monitoring transmission (the rest were detected at in-office follow-ups), whereas 66% (446/676) of the CAEs were detected during remote interrogation.
The second study, the OEDIPE trial, was a smaller trial (379 patients) performed in France evaluating the ability of the Home Monitoring® RMS to shorten PM post-operative hospitalization while preserving the safety of conventional management of longer hospital stays.
Implementation and operationalization of the RMS was reported to be successful in 91% (346/379) of the patients and represented 8144 transmissions.
In the RM group 6.5% of patients failed to send messages (10 due to improper use of the transmitter, 2 with unmanageable stress). Of the 172 patients transmitting, 108 patients sent a total of 167 warnings during the trial, with a greater proportion of warnings being attributed to medical rather than technical causes.
Forty percent had no warning message transmission and among these, 6 patients experienced a major adverse event and 1 patient experienced a non-major adverse event. Of the 6 patients having a major adverse event, 5 contacted their physician.
The mean medical reaction time was faster in the RM group (6.5 ± 7.6 days vs. 11.4 ± 11.6 days).
The mean duration of hospitalization was significantly shorter (P < 0.001) for the RM group than the control group (3.2 ± 3.2 days vs. 4.8 ± 3.7 days).
Quality of life estimates by the SF-36 questionnaire were similar for the 2 groups at 1-month follow-up.
3B. Randomized Controlled Trials Evaluating Remote Monitoring Systems for ICD or CRT Devices
The 5 studies evaluating the impact of RMSs with ICD/CRT devices were conducted in the United States and in European countries and involved 2 RMSs—Care Link® and Home Monitoring ®. The objectives of the trials varied and 3 of the trials were smaller pilot investigations.
The first of the smaller studies (151 patients) evaluated patient satisfaction, achievement of patient outcomes, and the cost-effectiveness of the Care Link® RMS compared to quarterly in-office device interrogations with 1-year follow-up.
Individual outcomes such as hospitalizations, emergency department visits, and unscheduled clinic visits were not significantly different between the study groups.
Except for a significantly higher detection of atrial fibrillation in the RM group, data on ICD detection and therapy were similar in the study groups.
Health-related quality of life evaluated by the EuroQoL at 6-month or 12-month follow-up was not different between study groups.
Patients were more satisfied with their ICD care in the clinic follow-up group than in the remote follow-up group at 6-month follow-up, but were equally satisfied at 12- month follow-up.
The second small pilot trial (20 patients) examined the impact of RM follow-up with the House Call 11® system on work schedules and cost savings in patients randomized to 2 study arms varying in the degree of remote follow-up.
The total time including device interrogation, transmission time, data analysis, and physician time required was significantly shorter for the RM follow-up group.
The in-clinic waiting time was eliminated for patients in the RM follow-up group.
The physician talk time was significantly reduced in the RM follow-up group (P < 0.05).
The time for the actual device interrogation did not differ in the study groups.
The third small trial (115 patients) examined the impact of RM with the Home Monitoring® system compared to scheduled trimonthly in-clinic visits on the number of unplanned visits, total costs, health-related quality of life (SF-36), and overall mortality.
There was a 63.2% reduction in in-office visits in the RM group.
Hospitalizations or overall mortality (values not stated) were not significantly different between the study groups.
Patient-induced visits were higher in the RM group than the in-clinic follow-up group.
The TRUST Trial
The TRUST trial was a large multicenter RCT conducted at 102 centers in the United States involving the Home Monitoring® RMS for ICD devices for 1450 patients. The primary objectives of the trial were to determine if remote follow-up could be safely substituted for in-office clinic follow-up (3 in-office visits replaced) and still enable earlier physician detection of clinically actionable events.
Adherence to the protocol follow-up schedule was significantly higher in the RM group than the in-office follow-up group (93.5% vs. 88.7%, P < 0.001).
Actionability of trimonthly scheduled checks was low (6.6%) in both study groups. Overall, actionable causes were reprogramming (76.2%), medication changes (24.8%), and lead/system revisions (4%), and these were not different between the 2 study groups.
The overall mean number of in-clinic and hospital visits was significantly lower in the RM group than the in-office follow-up group (2.1 per patient-year vs. 3.8 per patient-year, P < 0.001), representing a 45% visit reduction at 12 months.
The median time from onset of first arrhythmia to physician evaluation was significantly shorter (P < 0.001) in the RM group than in the in-office follow-up group for all arrhythmias (1 day vs. 35.5 days).
The median time to detect clinically asymptomatic arrhythmia events—atrial fibrillation (AF), ventricular fibrillation (VF), ventricular tachycardia (VT), and supra-ventricular tachycardia (SVT)—was also significantly shorter (P < 0.001) in the RM group compared to the in-office follow-up group (1 day vs. 41.5 days) and was significantly quicker for each of the clinical arrhythmia events—AF (5.5 days vs. 40 days), VT (1 day vs. 28 days), VF (1 day vs. 36 days), and SVT (2 days vs. 39 days).
System-related problems occurred infrequently in both groups—in 1.5% of patients (14/908) in the RM group and in 0.7% of patients (3/432) in the in-office follow-up group.
The overall adverse event rate over 12 months was not significantly different between the 2 groups and individual adverse events were also not significantly different between the RM group and the in-office follow-up group: death (3.4% vs. 4.9%), stroke (0.3% vs. 1.2%), and surgical intervention (6.6% vs. 4.9%), respectively.
The 12-month cumulative survival was 96.4% (95% confidence interval [CI], 95.5%–97.6%) in the RM group and 94.2% (95% confidence interval [CI], 91.8%–96.6%) in the in-office follow-up group, and was not significantly different between the 2 groups (P = 0.174).
The CONNECT Trial
The CONNECT trial, another major multicenter RCT, involved the Care Link® RMS for ICD/CRT devices in a15-month follow-up study of 1,997 patients at 133 sites in the United States. The primary objective of the trial was to determine whether automatically transmitted physician alerts decreased the time from the occurrence of clinically relevant events to medical decisions. The trial results are summarized below:
Of the 575 clinical alerts sent in the study, 246 did not trigger an automatic physician alert. Transmission failures were related to technical issues such as the alert not being programmed or not being reset, and/or a variety of patient factors such as not being at home and the monitor not being plugged in or set up.
The overall mean time from the clinically relevant event to the clinical decision was significantly shorter (P < 0.001) by 17.4 days in the remote follow-up group (4.6 days for 172 patients) than the in-office follow-up group (22 days for 145 patients).
– The median time to a clinical decision was shorter in the remote follow-up group than in the in-office follow-up group for an AT/AF burden greater than or equal to 12 hours (3 days vs. 24 days) and a fast VF rate greater than or equal to 120 beats per minute (4 days vs. 23 days).
Although infrequent, similar low numbers of events involving low battery and VF detection/therapy turned off were noted in both groups. More alerts, however, were noted for out-of-range lead impedance in the RM group (18 vs. 6 patients), and the time to detect these critical events was significantly shorter in the RM group (same day vs. 17 days).
Total in-office clinic visits were reduced by 38% from 6.27 visits per patient-year in the in-office follow-up group to 3.29 visits per patient-year in the remote follow-up group.
Health care utilization visits (N = 6,227) that included cardiovascular-related hospitalization, emergency department visits, and unscheduled clinic visits were not significantly higher in the remote follow-up group.
The overall mean length of hospitalization was significantly shorter (P = 0.002) for those in the remote follow-up group (3.3 days vs. 4.0 days) and was shorter both for patients with ICD (3.0 days vs. 3.6 days) and CRT (3.8 days vs. 4.7 days) implants.
The mortality rate between the study arms was not significantly different between the follow-up groups for the ICDs (P = 0.31) or the CRT devices with defribillator (P = 0.46).
Conclusions
There is limited clinical trial information on the effectiveness of RMSs for PMs. However, for RMSs for ICD devices, multiple cohort studies and 2 large multicenter RCTs demonstrated feasibility and significant reductions in in-office clinic follow-ups with RMSs in the first year post implantation. The detection rates of clinically significant events (and asymptomatic events) were higher, and the time to a clinical decision for these events was significantly shorter, in the remote follow-up groups than in the in-office follow-up groups. The earlier detection of clinical events in the remote follow-up groups, however, was not associated with lower morbidity or mortality rates in the 1-year follow-up. The substitution of almost all the first year in-office clinic follow-ups with RM was also not associated with an increased health care utilization such as emergency department visits or hospitalizations.
The follow-up in the trials was generally short-term, up to 1 year, and was a more limited assessment of potential longer term device/lead integrity complications or issues. None of the studies compared the different RMSs, particularly the different RMSs involving patient-scheduled transmissions or automatic transmissions. Patients’ acceptance of and satisfaction with RM were reported to be high, but the impact of RM on patients’ health-related quality of life, particularly the psychological aspects, was not evaluated thoroughly. Patients who are not technologically competent, having hearing or other physical/mental impairments, were identified as potentially disadvantaged with remote surveillance. Cohort studies consistently identified subgroups of patients who preferred in-office follow-up. The evaluation of costs and workflow impact to the health care system were evaluated in European or American clinical settings, and only in a limited way.
Internet-based device-assisted RMSs involve a new approach to monitoring patients, their disease progression, and their CIEDs. Remote monitoring also has the potential to improve the current postmarket surveillance systems of evolving CIEDs and their ongoing hardware and software modifications. At this point, however, there is insufficient information to evaluate the overall impact to the health care system, although the time saving and convenience to patients and physicians associated with a substitution of in-office follow-up by RM is more certain. The broader issues surrounding infrastructure, impacts on existing clinical care systems, and regulatory concerns need to be considered for the implementation of Internet-based RMSs in jurisdictions involving different clinical practices.
PMCID: PMC3377571  PMID: 23074419
17.  Strengths and weaknesses of guideline approaches to safeguard voluntary informed consent of patients within a dependent relationship 
BMC Medicine  2014;12:52.
Background
It is thought that a dependent relationship between patients and physicians who enroll their own patients in research compromises voluntary informed consent. Therefore, several ethical guidelines for human subject research provide approaches to mitigate these compromises. Currently, these approaches have not been critically evaluated. In this article, we analyze the approaches of ethical guidelines to manage the influence of a dependent relationship between patients and physicians on voluntary informed consent and discuss the strengths and weaknesses of these approaches.
Methods
We performed a review of international ethical guidance documents on human subject research, listed in the Oxford Textbook of Clinical Research Ethics and found through cross referencing. We also searched Global Ethics Observatory (GEObs) and the World Health Organization (WHO) website. Guidelines from all years were eligible for inclusion. The date last searched was December 2013.
Discussion
We identified two basic guideline approaches: 1. a process approach, which focuses on the person who obtains informed consent, that is, an independent individual, such as a research nurse or counselor; and 2. a content approach, emphasizing the voluntary nature of participation. Both approaches are valuable, either because the influence of the physician may diminish or because it empowers patients to make voluntary decisions. However, the approaches also face challenges. First, research nurses are not always independent. Second, physician-investigators will be informed about decisions of their patients. Third, involvement of a counselor is sometimes unfeasible. Fourth, the right to withdraw may be difficult to act upon in a dependent relationship.
Conclusions
Current guideline approaches to protect voluntary informed consent within a dependent relationship are suboptimal. To prevent compromises to voluntary informed consent, consent should not only be obtained by an independent individual, but this person should also emphasize the voluntary nature of participation. At the same time, dependency as such does not imply undue influence. Sometimes the physician may be best qualified to provide information, for example, for a very specialized study. Still, the research nurse should obtain informed consent. In addition, patients should be able to consult a counselor, who attends the informed consent discussions and is concerned with their interests. Finally, both physicians and research nurses should disclose research interests.
doi:10.1186/1741-7015-12-52
PMCID: PMC3998040  PMID: 24655604
Dependent relationships; Voluntary informed consent; Ethical guidelines; Clinical research; Research ethics; Double roles; Research nurses; Undue influence
18.  Ethical and policy issues in cluster randomized trials: rationale and design of a mixed methods research study 
Trials  2009;10:61.
Background
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.
Methods
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.
doi:10.1186/1745-6215-10-61
PMCID: PMC2725043  PMID: 19638233
19.  Participant Informed Consent in Cluster Randomized Trials: Review 
PLoS ONE  2012;7(7):e40436.
Background
The Nuremberg code defines the general ethical framework of medical research with participant consent as its cornerstone. In cluster randomized trials (CRT), obtaining participant informed consent raises logistic and methodologic concerns. First, with randomization of large clusters such as geographical areas, obtaining individual informed consent may be impossible. Second, participants in randomized clusters cannot avoid certain interventions, which implies that participant informed consent refers only to data collection, not administration of an intervention. Third, complete participant information may be a source of selection bias, which then raises methodological concerns. We assessed whether participant informed consent was required in such trials, which type of consent was required, and whether the trial was at risk of selection bias because of the very nature of participant information.
Methods and Findings
We systematically reviewed all reports of CRT published in MEDLINE in 2008 and surveyed corresponding authors regarding the nature of the informed consent and the process of participant inclusion. We identified 173 reports and obtained an answer from 113 authors (65.3%). In total, 23.7% of the reports lacked information on ethics committee approval or participant consent, 53.1% of authors declared that participant consent was for data collection only and 58.5% that the group allocation was not specified for participants. The process of recruitment (chronology of participant recruitment with regard to cluster randomization) was rarely reported, and we estimated that only 56.6% of the trials were free of potential selection bias.
Conclusions
For CRTs, the reporting of ethics committee approval and participant informed consent is less than optimal. Reports should describe whether participants consented for administration of an intervention and/or data collection. Finally, the process of participant recruitment should be fully described (namely, whether participants were informed of the allocation group before being recruited) for a better appraisal of the risk of selection bias.
doi:10.1371/journal.pone.0040436
PMCID: PMC3391275  PMID: 22792319
20.  The Ethical Odyssey in Testing HIV Treatment as Prevention 
Background
Obtaining the definitive data necessary to determine the safety and efficacy of using antiretroviral treatment (ART) to reduce the sexual transmission of HIV in heterosexual couples encountered an array of ethical challenges that threatened to compromise HPTN 052, the multinational clinical trial addressing this issue that has profound public health implications.
Purpose
To describe and analyze the major ethical challenges faced in HPTN 052.
Methods
The ethical issues and modifications of HPTN 052 in response to these issues were catalogued by the principal investigator, the lead coordinator, and the ethicist working on the trial. The major ethical issues that were unique to the trial were then described and analyzed, referring as appropriate to published literature and emerging guidance and policies. Ethical challenges that must be addressed in many clinical trials, such as those related to obtaining informed consent and making provisions for ancillary care, are not described.
Results
When HPTN 052 was being designed, ethical questions emerged related to the relevance of the research question itself given data from observational research and a range of beliefs about the appropriate means of preventing and treating HIV-infection and AIDS. Further, ethical challenges were faced regarding site selection since there was a scientific need to conduct the research in settings where HIV incidence was high, but alternatives to study participation should be available. As in most HIV prevention research, ethical questions surrounded the determination of the appropriate prevention package for all of those enrolled. During the course of the trial, guidance documents and policies emerged that were of direct relevance to the research questions, calling for a balancing of concerns for the research subjects and trial integrity. When the study results were made public, there was a need to ensure access to the treatment shown to be effective that in some cases differed from the guidelines used at the sites where the research was being conducted. In addition, questions were raised about whether there was an obligation to notify subjects about “unlinked’ transmissions of HIV, that is, infections acquired outside of the designated sexual partners enrolled in the study.
Limitations
The ethical issues described are limited to those discerned by the authors and not those of other stakeholders who may have identified additional issues or had a different perspective in analyzing them.
Conclusions
Understanding the ethical challenges faced in HPTN 052 promises to inform the design and conduct of future complex, long-term clinical trials aimed at addressing critical scientific and public health questions, where data and practice patterns emerge over the course of the trial.
doi:10.1177/1740774512443594
PMCID: PMC3486723  PMID: 22692805
21.  Bureaucracy stifles medical research in Britain: a tale of three trials 
Background
Recent developments aiming to standardise and streamline processes of gaining the necessary approvals to carry out research in the National Health Service (NHS) in the United Kingdom (UK), have resulted in lengthy and costly delays. The national UK governmental Department of Health’s Research Governance Framework (RGF) for Health and Social Care requires that appropriate checks be conducted before research involving human participants, their organs, tissues or data can commence in the NHS. As a result, medical research has been subjected to increased regulation and governance, with the requirement for approvals from numerous regulatory and monitoring bodies. In addition, the processes and outcomes of the attribution of costs in NHS research have caused additional difficulties for researchers. The purpose of this paper is to illustrate, through three trial case studies, the difficulties encountered during the set-up and recruitment phases of these trials, related to gaining the necessary ethical and governance approvals and applying for NHS costs to undertake and deliver the research.
Methods
Empirical evidence about delays and difficulties related to regulation and governance of medical research was gathered during the period 2009–2010 from three UK randomised controlled trials with sites in England, Wales and Scotland (1. SAFER 2- an emergency care based trial of a protocol for paramedics to refer patients directly to community based falls services; 2. COnStRUCT- a trial of two drugs for acute ulcerative colitis; and 3. Family Links - a trial of a public health intervention, a 10 week community based parenting programme). Findings and recommendations were reported in response to a call for evidence from The Academy of Medical Sciences regarding difficulties encountered in conducting medical research arising from R&D governance and regulation, to inform national policy.
Results
Difficulties and delays in navigating and gaining the appropriate approvals and NHS costs required to undertake the research were encountered in all three trials, at various points in the bureaucratic processes of ethical and research and information governance approvals. Conduct of each of the three trials was delayed by at least 12 months, with costs increasing by 30 – 40%.
Conclusions
Whilst the three trials encountered a variety of challenges, there were common issues. The processes for gaining approvals were overly complex and differed between sites and UK countries; guidance about processes was unclear; and information regarding how to define and claim NHS costs for undertaking the research was inconsistent. The competitive advantage of a publicly funded, open access health system for undertaking health services research and clinical trials within the UK has been outweighed in recent years by stifling bureaucratic structures and processes for governance of research. The recommendations of the Academy of Medical Sciences are welcomed, and the effects of their implementation are awaited with interest.
Trial Registration numbers
SAFER 2: ISRCTN 60481756; COnStRUCT: ISRCTN22663589; Family Links: ISRCTN 13929732
doi:10.1186/1471-2288-12-122
PMCID: PMC3537588  PMID: 22898336
22.  Contrast-induced acute kidney injury in patients undergoing cardiac resynchronization therapy—incidence and prognostic importance. Sub-analysis of data from randomized TRUST CRT trial 
Introduction
Because data on contrast-induced acute kidney injury (CI-AKI) in patients undergoing cardiac resynchronization therapy (CRT-D) are scarce, we aimed to assess the incidence, natural course and prognostic importance of this syndrome in CRT recipients.
Methods
Study population consisted of 100 consecutive patients enrolled into the Triple Site Versus Standard Cardiac Resynchronization (TRUST CRT) trial, who were treated with CRT-D. Two patients were excluded up to 3 months after randomization and not analysed further. CI-AKI was defined as a rise in serum creatinine of at least 26.5 μmol/L (0.3 mg/dL) within 48 h after contrast exposure, or at least 50 % increase from the baseline value during index hospital stay with CRT-D implantation according to KDIGO Clinical Practice Guideline for Acute Kidney Injury.
Results
Among 98 subjects of TRUST CRT trial, 10 patients (10.2 %) developed CI-AKI after CRT-D implantation. In patients with glomerular filtration rate (GFR) <60 mL/min/1.73 m2 on admission, the incidence of CI-AKI was almost twofold (15.4 %) higher than in subjects with GFR ≥60 (8.3 %). CRT-D recipients with CI-AKI had significantly higher mortality rate (50.0 %) compared to those without CI-AKI (17.0 %) during 30 months of follow-up (logrank p = 0.012). Multivariate Cox regression analysis showed CI-AKI as significant and independent risk factor for death in CRT-D recipients (hazard ratio 5.71; 95 % CI 5.16–6.26; p = 0.001).
Conclusions
Contrast-induced acute kidney injury is a serious and frequent procedural complication of CRT-D implantation with a significant negative influence on long-term survival. The results suggest that clinical evaluation regarding renal function should be considered in CRT-D recipients, both before and after device implantation.
doi:10.1007/s10840-014-9887-x
PMCID: PMC4062808  PMID: 24626998
Cardiac resynchronization therapy; Chronic kidney disease; Contrast-induced acute kidney injury; Heart failure; Renal function
23.  United States Private-Sector Physicians and Pharmaceutical Contract Research: A Qualitative Study 
PLoS Medicine  2012;9(7):e1001271.
Jill Fisher and Corey Kalbaugh describe their findings from a qualitative research study evaluating the motivations of private-sector physicians conducting contract research for the pharmaceutical industry.
Background
There have been dramatic increases over the past 20 years in the number of nonacademic, private-sector physicians who serve as principal investigators on US clinical trials sponsored by the pharmaceutical industry. However, there has been little research on the implications of these investigators' role in clinical investigation. Our objective was to study private-sector clinics involved in US pharmaceutical clinical trials to understand the contract research arrangements supporting drug development, and specifically how private-sector physicians engaged in contract research describe their professional identities.
Methods and Findings
We conducted a qualitative study in 2003–2004 combining observation at 25 private-sector research organizations in the southwestern United States and 63 semi-structured interviews with physicians, research staff, and research participants at those clinics. We used grounded theory to analyze and interpret our data. The 11 private-sector physicians who participated in our study reported becoming principal investigators on industry clinical trials primarily because contract research provides an additional revenue stream. The physicians reported that they saw themselves as trial practitioners and as businesspeople rather than as scientists or researchers.
Conclusions
Our findings suggest that in addition to having financial motivation to participate in contract research, these US private-sector physicians have a professional identity aligned with an industry-based approach to research ethics. The generalizability of these findings and whether they have changed in the intervening years should be addressed in future studies.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Before a new drug can be used routinely by physicians, it must be investigated in clinical trials—studies that test the drug's safety and effectiveness in people. In the past, clinical trials were usually undertaken in academic medical centers (institutes where physicians provide clinical care, do research, and teach), but increasingly, clinical trials are being conducted in the private sector as part of a growing contract research system. In the US, for example, most clinical trials completed in the 1980s took place in academic medical centers, but nowadays, more than 70% of trials are conducted by nonacademic (community) physicians working under contract to pharmaceutical companies. The number of private-sector nonacademic physicians serving as principal investigators (PIs) for US clinical trials (the PI takes direct responsibility for completion of the trial) increased from 4,000 in 1990 to 20,250 in 2010, and research contracts for clinical trials are now worth more than USṩ11 billion annually.
Why Was This Study Done?
To date, there has been little research on the implications of this change in the conduct of clinical trials. Academic PIs are often involved in both laboratory and clinical research and are therefore likely to identify closely with the science of trials. By contrast, nonacademic PIs may see clinical trials more as a business opportunity—pharmaceutical contract research is profitable to US physicians because they get paid for every step of the trial process. As a result, pharmaceutical companies may now have more control over clinical trial data and more opportunities to suppress negative data through selective publication of study results than previously. In this qualitative study, the researchers explore the outsourcing of clinical trials to private-sector research clinics through observations of, and in-depth interviews with, physicians and other research staff involved in the US clinical trials industry. A qualitative study collects non-quantitative data such as how physicians feel about doing contract research and about their responsibilities to their patients.
What Did the Researchers Do and Find?
Between October 2003 and September 2004, the researchers observed the interactions between PIs, trial coordinators (individuals who undertake many of the trial activities such as blood collection), and trial participants at 25 US research organizations in the southwestern US and interviewed 63 informants (including 12 PIs) about the trials they were involved in and their reasons for becoming involved. The researchers found that private-sector physicians became PIs on industry-sponsored clinical trials primarily because contract research was financially lucrative. The physicians perceived their roles in terms of business rather than science and claimed that they offered something to the pharmaceutical industry that academics do not—the ability to carry out a diverse range of trials quickly and effectively, regardless of their medical specialty. Finally, the physicians saw their primary ethical responsibility as providing accurate data to the companies that hired them and did not explicitly refer to their ethical responsibility to trial participants. One possible reason for this shift in ethical concerns is the belief among private-sector physicians that pharmaceutical companies must be making scientifically and ethically sound decisions when designing trials because of the amount of money they invest in them.
What Do These Findings Mean?
These findings suggest that private-sector physicians participate as PIs in pharmaceutical clinical trials primarily for financial reasons and see themselves as trial practitioners and businesspeople rather than as scientists. The accuracy of these findings is likely to be limited by the small number of PIs interviewed and by the time that has elapsed since the researchers collected their qualitative data. Moreover, these findings may not be generalizable to other regions of the US or to other countries. Nevertheless, they have potentially troubling implications for drug development. By hiring private-sector physicians who see themselves as involved more with the business than the science of contract research, pharmaceutical companies may be able to exert more control over the conduct of clinical trials and the publication of trial results than previously. Compared to the traditional investigatorinitiated system of clinical research, this new system of contract research means that clinical trials now lack the independence that is at the heart of best science practices, a development that casts doubt on the robustness of the knowledge being produced about the safety and effectiveness of new drugs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001271.
The ClinicalTrials.gov website is a searchable register of federally and privately supported clinical trials in the US; it provides information about all aspects of clinical trials
The US National Institutes of Health provides information about clinical trials, including personal stories about clinical trials from patients and researchers
The UK National Health Service Choices website has information for patients about clinical trials and medical research, including personal stories about participating in clinical trials
The UK Medical Research Council Clinical Trials Unit also provides information for patients about clinical trials and links to information on clinical trials provided by other organizations
MedlinePlus has links to further resources on clinical trials (in English and Spanish)
doi:10.1371/journal.pmed.1001271
PMCID: PMC3404112  PMID: 22911055
24.  Selection in Reported Epidemiological Risks: An Empirical Assessment 
PLoS Medicine  2007;4(3):e79.
Background
Epidemiological studies may be subject to selective reporting, but empirical evidence thereof is limited. We empirically evaluated the extent of selection of significant results and large effect sizes in a large sample of recent articles.
Methods and Findings
We evaluated 389 articles of epidemiological studies that reported, in their respective abstracts, at least one relative risk for a continuous risk factor in contrasts based on median, tertile, quartile, or quintile categorizations. We examined the proportion and correlates of reporting statistically significant and nonsignificant results in the abstract and whether the magnitude of the relative risks presented (coined to be consistently ≥1.00) differs depending on the type of contrast used for the risk factor. In 342 articles (87.9%), ≥1 statistically significant relative risk was reported in the abstract, while only 169 articles (43.4%) reported ≥1 statistically nonsignificant relative risk in the abstract. Reporting of statistically significant results was more common with structured abstracts, and was less common in US-based studies and in cancer outcomes. Among 50 randomly selected articles in which the full text was examined, a median of nine (interquartile range 5–16) statistically significant and six (interquartile range 3–16) statistically nonsignificant relative risks were presented (p = 0.25). Paradoxically, the smallest presented relative risks were based on the contrasts of extreme quintiles; on average, the relative risk magnitude was 1.41-, 1.42-, and 1.36-fold larger in contrasts of extreme quartiles, extreme tertiles, and above-versus-below median values, respectively (p < 0.001).
Conclusions
Published epidemiological investigations almost universally highlight significant associations between risk factors and outcomes. For continuous risk factors, investigators selectively present contrasts between more extreme groups, when relative risks are inherently lower.
An evaluation of published articles reporting epidemiological studies found that they almost universally highlight significant associations between risk factors and outcomes.
Editors' Summary
Background.
Medical and scientific researchers use statistical tests to try to work out whether their observations—for example, seeing a difference in some characteristic between two groups of people—might have occurred as a result of chance alone. Statistical tests cannot determine this for sure, rather they can only give a probability that the observations would have arisen by chance. When researchers have many different hypotheses, and carry out many statistical tests on the same set of data, they run the risk of concluding that there are real differences where in fact there are none. At the same time, it has long been known that scientific and medical researchers tend to pick out the findings on which to report in their papers. Findings that are more interesting, impressive, or statistically significant are more likely to be published. This is termed “publication bias” or “selective reporting bias.” Therefore, some people are concerned that the published scientific literature might contain many false-positive findings, i.e., findings that are not true but are simply the result of chance variation in the data. This would have a serious impact on the accuracy of the published scientific literature and would tend to overestimate the strength and direction of relationships being studied.
Why Was This Study Done?
Selective reporting bias has already been studied in detail in the area of randomized trials (studies where participants are randomly allocated to receive an intervention, e.g., a new drug, versus an alternative intervention or “comparator,” in order to understand the benefits or safety of the new intervention). These studies have shown that very many of the findings of trials are never published, and that statistically significant findings are more likely to be included in published papers than nonsignificant findings. However, much medical research is carried out that does not use randomized trial methods, either because that method is not useful to answer the question at hand or is unethical. Epidemiological research is often concerned with looking at links between risk factors and the development of disease, and this type of research would generally use observation rather than experiment to uncover connections. The researchers here were concerned that selective reporting bias might be just as much of a problem in epidemiological research as in randomized trials research, and wanted to study this specifically.
What Did the Researchers Do and Find?
In this investigation, searches were carried out of PubMed, a database of biomedical research studies, to extract epidemiological studies that were published between January 2004 and October 2005. The researchers wanted to specifically look at studies reporting the effect of continuous risk factors and their effect on health or disease outcomes (a continuous risk factor is something like age or glucose concentration in the blood, is a number, and can have any value on a sliding scale). Three hundred and eighty-nine original research studies were found, and the researchers pulled out from the abstracts and full text of these papers the relative risks that were reported along with the results of statistical tests for them. (Relative risk is the chance of getting an outcome, say disease, in one group as compared to another group.) The researchers found that nearly 90% of these studies had one or more statistically significant risks reported in the abstract, but only 43% reported one or more risks that were not statistically significant. When looking at all of the findings reported anywhere in the full text for 50 of these studies, the researchers saw that papers overall reported more statistically significant risks than nonsignificant risks. Finally, it seemed that in the set of papers studied here, the way in which statistical analyses were done produced a bias towards more extreme findings: for datasets showing small relative risks, papers were more likely to report a comparison between extreme subsets of the data so as to report larger relative risks.
What Do These Findings Mean?
These findings suggest that there is a tendency among epidemiology researchers to highlight statistically significant findings and to avoid highlighting nonsignificant findings in their research papers. This behavior may be a problem, because many of these significant findings could in future turn out to be “false positives.” At present, registers exist for researchers to describe ongoing clinical trials, and to set out the outcomes that they plan to analyze for those trials. These registers will go some way towards addressing some of the problems described here, but only for clinical trials research. Registers do not yet exist for epidemiological studies, and therefore it is important that researchers and readers are aware of and cautious about the problem of selective reporting in epidemiological research.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040079.
Wikipedia entry on publication bias (note: Wikipedia is an internet encyclopedia that anyone can edit)
The International Committee of Medical Journal Editors gives guidelines for submitting manuscripts to its member journals, and includes comments about registration of ongoing studies and the obligation to publish negative studies
ClinicalTrials.gov and the ISRCTN register are two registries of ongoing clinical trials
doi:10.1371/journal.pmed.0040079
PMCID: PMC1808481  PMID: 17341129
25.  Hidden Data for Research Ethicists: An Introduction to the Concept and A Series of Papers 
This special section of the Journal of Empirical Research on Human Research Ethics (JERHRE) is based upon the assumption that much of the best empirical data relevant to research ethics is hidden from the view of Research Ethics Committee (REC) members and others who are interested in research ethics. There are at least three different senses in which ethics-relevant empirical research may be hidden: (1) it may be published in a journal that ethics committee members would not regularly read, (2) it may not use key words that would guide one to its ethics-relevant content, or (3) it may be sequestered in part of a research article that is about something else. This special section of JERHRE reviews all of these types of “hidden ethics” articles on the following issues: What is the relative frequency of hidden ethics articles in journals that focus on vulnerable populations? What does the non-ethics literature in clinical research and experimental economic decision theory teach us about ways of improving subjects’ comprehension of risk information? How satisfied are parents and children with their experience with pediatric psychotrophic medication trials? And, how can retention rates be improved in longitudinal studies of difficult regimens such as drug rehabilitation? There is a major amount of ethics-relevant literature that is hidden. Without better ways of communicating the existence of this literature through use of key words, or recasting of the information to highlight its relevance to research ethics in journals that ethics committee members read, the benefits of evidence-based ethical problem solving will be lost.
doi:10.1525/jer.2008.3.3.3
PMCID: PMC2679509  PMID: 19385765
research ethics; review article; institutional review boards; human experimentation; vulnerable populations

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