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1.  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
2.  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
3.  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
4.  Who is the research subject in cluster randomized trials in health research? 
Trials  2011;12:183.
This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the first of the questions posed, namely, who is the research subject in a CRT in health research? The identification of human research subjects is logically prior to the application of protections as set out in research ethics and regulation. Aspects of CRT design, including the fact that in a single study the units of randomization, experimentation, and observation may differ, complicate the identification of human research subjects. But the proper identification of human research subjects is important if they are to be protected from harm and exploitation, and if research ethics committees are to review CRTs efficiently.
We examine the research ethics literature and international regulations to identify the core features of human research subjects, and then unify these features under a single, comprehensive definition of human research subject. We define a human research subject as any person whose interests may be compromised as a result of interventions in a research study. Individuals are only human research subjects in CRTs if: (1) they are directly intervened upon by investigators; (2) they interact with investigators; (3) they are deliberately intervened upon via a manipulation of their environment that may compromise their interests; or (4) their identifiable private information is used to generate data. Individuals who are indirectly affected by CRT study interventions, including patients of healthcare providers participating in knowledge translation CRTs, are not human research subjects unless at least one of these conditions is met.
doi:10.1186/1745-6215-12-183
PMCID: PMC3162904  PMID: 21791064
5.  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
6.  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
7.  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
8.  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
9.  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
10.  Developing a new model for patient recruitment in mental health services: a cohort study using Electronic Health Records 
BMJ Open  2014;4(12):e005654.
Objectives
To develop a new model for patient recruitment that harnessed the full potential of Electronic Health Records (EHRs). Gaining access to potential participants’ health records to assess their eligibility for studies and allow an approach about participation (‘consent for contact’) is ethically, legally and technically challenging, given that medical data are usually restricted to the patient's clinical team. The research objective was to design a model for identification and recruitment to overcome some of these challenges as well as reduce the burdensome (and/or time consuming) gatekeeper role of clinicians in determining who is appropriate or not to participate in clinical research.
Setting
Large secondary mental health services context, UK.
Participants
2106 patients approached for ‘consent for contact’. All patients in different services within the mental health trust are gradually and systematically being approached by a member of the clinical care team using the ‘consent for contact’ model. There are no exclusion criteria.
Primary and secondary outcome measures
Provision of ‘consent for contact’.
Results
A new model (the South London and Maudsley NHS Trust Consent for Contact model (SLaM C4C)) for gaining patients’ consent to contact them about research possibilities, which is built around a de-identified EHR database. The model allows researchers to contact potential participants directly. Of 2106 patients approached by 25 October 2013, nearly 3 of every 4 gave consent for contact (1560 patients; 74.1%).
Conclusions
The SLaM C4C model offers an effective way of expediting recruitment into health research through using EHRs. It reduces the gatekeeper function of clinicians; gives patients greater autonomy in decisions to participate in research; and accelerates the development of a culture of active research participation. More research is needed to assess how many of those giving consent for contact subsequently consent to participate in particular research studies.
doi:10.1136/bmjopen-2014-005654
PMCID: PMC4256538  PMID: 25468503
MENTAL HEALTH; PSYCHIATRY
11.  Facilitating the Recruitment of Minority Ethnic People into Research: Qualitative Case Study of South Asians and Asthma 
PLoS Medicine  2009;6(10):e1000148.
Aziz Sheikh and colleagues report on a qualitative study in the US and the UK to investigate ways to bolster recruitment of South Asians into asthma studies, including making inclusion of diverse populations mandatory.
Background
There is international interest in enhancing recruitment of minority ethnic people into research, particularly in disease areas with substantial ethnic inequalities. A recent systematic review and meta-analysis found that UK South Asians are at three times increased risk of hospitalisation for asthma when compared to white Europeans. US asthma trials are far more likely to report enrolling minority ethnic people into studies than those conducted in Europe. We investigated approaches to bolster recruitment of South Asians into UK asthma studies through qualitative research with US and UK researchers, and UK community leaders.
Methods and Findings
Interviews were conducted with 36 researchers (19 UK and 17 US) from diverse disciplinary backgrounds and ten community leaders from a range of ethnic, religious, and linguistic backgrounds, followed by self-completion questionnaires. Interviews were digitally recorded, translated where necessary, and transcribed. The Framework approach was used for analysis. Barriers to ethnic minority participation revolved around five key themes: (i) researchers' own attitudes, which ranged from empathy to antipathy to (in a minority of cases) misgivings about the scientific importance of the question under study; (ii) stereotypes and prejudices about the difficulties in engaging with minority ethnic populations; (iii) the logistical challenges posed by language, cultural differences, and research costs set against the need to demonstrate value for money; (iv) the unique contexts of the two countries; and (v) poorly developed understanding amongst some minority ethnic leaders of what research entails and aims to achieve. US researchers were considerably more positive than their UK counterparts about the importance and logistics of including ethnic minorities, which appeared to a large extent to reflect the longer-term impact of the National Institutes of Health's requirement to include minority ethnic people.
Conclusions
Most researchers and community leaders view the broadening of participation in research as important and are reasonably optimistic about the feasibility of recruiting South Asians into asthma studies provided that the barriers can be overcome. Suggested strategies for improving recruitment in the UK included a considerably improved support structure to provide academics with essential contextual information (e.g., languages of particular importance and contact with local gatekeepers), and the need to ensure that care is taken to engage with the minority ethnic communities in ways that are both culturally appropriate and sustainable; ensuring reciprocal benefits was seen as one key way of avoiding gatekeeper fatigue. Although voluntary measures to encourage researchers may have some impact, greater impact might be achieved if UK funding bodies followed the lead of the US National Institutes of Health requiring recruitment of ethnic minorities. Such a move is, however, likely in the short- to medium-term, to prove unpopular with many UK academics because of the added “hassle” factor in engaging with more diverse populations than many have hitherto been accustomed to.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In an ideal world, everyone would have the same access to health care and the same health outcomes (responses to health interventions). However, health inequalities—gaps in health care and in health between different parts of the population—exist in many countries. In particular, people belonging to ethnic minorities in the UK, the US, and elsewhere have poorer health outcomes for several conditions than people belonging to the ethnic majority (ethnicity is defined by social characteristics such as cultural tradition or national origin). For example, in the UK, people whose ancestors came from the Indian subcontinent (also known as South Asians and comprising in the main of people of Indian, Pakistani, and Bangladeshi origin) are three times as likely to be admitted to hospital for asthma as white Europeans. The reasons underpinning ethnic health inequalities are complex. Some inequalities may reflect intrinsic differences between groups of people—some ethnic minorities may inherit genes that alter their susceptibility to a specific disease. Other ethnic health inequalities may arise because of differences in socioeconomic status or because different cultural traditions affect the uptake of health care services.
Why Was This Study Done?
Minority ethnic groups are often under-represented in health research, which could limit the generalizability of research findings. That is, an asthma treatment that works well in a trial where all the participants are white Europeans might not be suitable for South Asians. Clinicians might nevertheless use the treatment in all their patients irrespective of their ethnicity and thus inadvertently increase ethnic health inequality. So, how can ethnic minorities be encouraged to enroll into research studies? In this qualitative study, the investigators try to answer this question by talking to US and UK asthma researchers and UK community leaders about how they feel about enrolling ethnic minorities into research studies. The investigators chose to compare the feelings of US and UK asthma researchers because minority ethnic people are more likely to enroll into US asthma studies than into UK studies, possibly because the US National Institute of Health's (NIH) Revitalization Act 1993 mandates that all NIH-funded clinical research must include people from ethnic minority groups; there is no similar mandatory policy in the UK.
What Did the Researchers Do and Find?
The investigators interviewed 16 UK and 17 US asthma researchers and three UK social researchers with experience of working with ethnic minorities. They also interviewed ten community leaders from diverse ethnic, religious and linguistic backgrounds. They then analyzed the interviews using the “Framework” approach, an analytical method in which qualitative data are classified and organized according to key themes and then interpreted. By comparing the data from the UK and US researchers, the investigators identified several barriers to ethnic minority participation in health research including: the attitudes of researchers towards the scientific importance of recruiting ethnic minority people into health research studies; prejudices about the difficulties of including ethnic minorities in health research; and the logistical challenges posed by language and cultural differences. In general, the US researchers were more positive than their UK counterparts about the importance and logistics of including ethnic minorities in health research. Finally, the investigators found that some community leaders had a poor understanding of what research entails and about its aims.
What Do These Findings Mean?
These findings reveal a large gap between US and UK researchers in terms of policy, attitudes, practices, and experiences in relation to including ethnic minorities in asthma research. However, they also suggest that most UK researchers and community leaders believe that it is both important and feasible to increase the participation of South Asians in asthma studies. Although some of these findings may have been affected by the study participants sometimes feeling obliged to give “politically correct” answers, these findings are likely to be generalizable to other diseases and to other parts of Europe. Given their findings, the researchers warn that a voluntary code of practice that encourages the recruitment of ethnic minority people into health research studies is unlikely to be successful. Instead, they suggest, the best way to increase the representation of ethnic minority people in health research in the UK might be to follow the US lead and introduce a policy that requires their inclusion in such research.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000148.
Families USA, a US nonprofit organization that campaigns for high-quality, affordable health care for all Americans, has information about many aspects of minority health in the US, including an interactive game about minority health issues
The US Agency for Healthcare Research and Quality has a section on minority health
The UK Department of Health provides information on health inequalities and a recent report on the experiences of patients in Black and minority ethnic groups
The UK Parliamentary Office of Science and Technology also has a short article on ethnicity and health
Information on the NIH Revitalization Act 1993 is available
NHS Evidences Ethnicity and Health has a variety of policy, clinical, and research resources on ethnicity and health
doi:10.1371/journal.pmed.1000148
PMCID: PMC2752116  PMID: 19823568
12.  Inadequate reporting of research ethics review and informed consent in cluster randomised trials: review of random sample of published trials 
Objectives To investigate the extent to which authors of cluster randomised trials adhered to two basic requirements of the World Medical Association’s Declaration of Helsinki and the International Committee of Medical Journal Editors’ uniform requirements for manuscripts (namely, reporting of research ethics review and informed consent), to determine whether the adequacy of reporting has improved over time, and to identify characteristics of cluster randomised trials associated with reporting of ethics practices.
Design Review of a random sample of published cluster randomised trials from an electronic search in Medline.
Setting Cluster randomised trials in health research published in English language journals from 2000 to 2008.
Study sample 300 cluster randomised trials published in 150 journals.
Results 77 (26%, 95% confidence interval 21% to 31%) trials failed to report ethics review. The proportion reporting ethics review increased significantly over time (P<0.001). Trials with data collection interventions at the individual level were more likely to report ethics review than were trials that used routine data sources only (79% (n=151) v 55% (23); P=0.008). Trials that accounted for clustering in the design and analysis were more likely to report ethics review. The median impact factor of the journal of publication was higher for trials that reported ethics review (3.4 v 2.3; P<0.001). 93 (31%, 26% to 36%) trials failed to report consent. Reporting of consent increased significantly over time (P<0.001). Trials with interventions targeting participants at the individual level were more likely to report consent than were trials with interventions targeting the cluster level (87% (90) v 48% (41); P<0.001). Trials with data collection interventions at the individual level were more likely to report consent than were those that used routine data sources only (78% (146) v 29% (11); P<0.001).
Conclusions Reporting of research ethics protections in cluster randomised trials is inadequate. In addition to research ethics approval, authors should report whether informed consent was sought, from whom consent was sought, and what consent was for.
doi:10.1136/bmj.d2496
PMCID: PMC3092521  PMID: 21562003
13.  Ethical issues in implementation research: a discussion of the problems in achieving informed consent 
Background
Improved quality of care is a policy objective of health care systems around the world. Implementation research is the scientific study of methods to promote the systematic uptake of clinical research findings into routine clinical practice, and hence to reduce inappropriate care. It includes the study of influences on healthcare professionals' behaviour and methods to enable them to use research findings more effectively. Cluster randomized trials represent the optimal design for evaluating the effectiveness of implementation strategies. Various codes of medical ethics, such as the Nuremberg Code and the Declaration of Helsinki inform medical research, but their relevance to cluster randomised trials in implementation research is unclear. This paper discusses the applicability of various ethical codes to obtaining consent in cluster trials in implementation research.
Discussion
The appropriate application of biomedical codes to implementation research is not obvious. Discussion of the nature and practice of informed consent in implementation research cluster trials must consider the levels at which consent can be sought, and for what purpose it can be sought. The level at which an intervention is delivered can render the idea of patient level consent meaningless. Careful consideration of the ownership of information, and rights of access to and exploitation of data is required. For health care professionals and organizations, there is a balance between clinical freedom and responsibility to participate in research.
Summary
While ethical justification for clinical trials relies heavily on individual consent, for implementation research aspects of distributive justice, economics, and political philosophy underlie the debate. Societies may need to trade off decisions on the choice between individualized consent and valid implementation research. We suggest that social sciences codes could usefully inform the consideration of implementation research by members of Research Ethics Committees.
doi:10.1186/1748-5908-3-52
PMCID: PMC2639614  PMID: 19091100
14.  Does Type of Gatekeeping Model Affect Access to Outpatient Specialty Mental Health Services? 
Health Services Research  2007;42(1 Pt 1):104-123.
Objective
To measure how a change in gatekeeping model affects utilization of specialty mental health services.
Data Sources/Study Setting
Secondary data from health insurance claims for services during 1996–1999. The setting is a managed care organization that changed gatekeeping model in one of its divisions, from in-person evaluation to the use of a call-center.
Study Design
We evaluate the impact of the change in gatekeeping model by comparing utilization during the 2 years before and 2 years after the change, both in the affected division and in another division where gatekeeping model did not change. The design is thus a controlled quasi-experimental one. Subjects were not randomized. Key dependent variables are whether each individual had any specialty mental health visits in a year; the number of visits; and the proportion of users exceeding eight visits in a year. Key explanatory variables include demographic variables and indicators for patient diagnoses and their intervention status (time-period, study group).
Data Collection/Extraction Methods
Claims data were aggregated to create analytic files with one record per member per year, with variables reporting demographic characteristics and mental health service use.
Principal Findings
After controlling for secular trends at the other division, the division which changed gatekeeping model eventually experienced an increase in the proportion of enrollees receiving specialty mental health treatment, of 0.5 percentage point. Similarly, there was an increase of about 0.6 annual visits per user, concentrated at the low end of the distribution. These changes occurred only in the second year after the gatekeeping changes.
Conclusions
The results of this study suggest that the gatekeeping changes did lead to increases in utilization of mental health care, as hypothesized. At the same time, the magnitude of the increase in access and mean number of visits that we found was relatively modest. This suggests that while the change from face-to-face specialty gatekeeping to call-center intake does increase utilization, it is unlikely to overwhelm a system with new demand or create huge cost increases.
doi:10.1111/j.1475-6773.2006.00609.x
PMCID: PMC1955246  PMID: 17355584
Mental health; gatekeeping; utilization management
15.  Challenges for consent and community engagement in the conduct of cluster randomized trial among school children in low income settings: experiences from Kenya 
Trials  2013;14:142.
Background
There are a number of practical and ethical issues raised in school-based health research, particularly those related to obtaining consent from parents and assent from children. One approach to developing, strengthening, and supporting appropriate consent and assent processes is through community engagement. To date, much of the literature on community engagement in biomedical research has concentrated on community- or hospital-based research, with little documentation, if any, of community engagement in school-based health research. In this paper we discuss our experiences of consent, assent and community engagement in implementing a large school-based cluster randomized trial in rural Kenya.
Methods
Data collected as part of a qualitative study investigating the acceptability of the main trial, focus group discussions with field staff, observations of practice and authors’ experiences are used to: 1) highlight the challenges faced in obtaining assent/consent; and 2) strategies taken to try to both protect participant rights (including to refuse and to withdraw) and ensure the success of the trial.
Results
Early meetings with national, district and local level stakeholders were important in establishing their co-operation and support for the project. Despite this support, both practical and ethical challenges were encountered during consenting and assenting procedures. Our strategy for addressing these challenges focused on improving communication and understanding of the trial, and maintaining dialogue with all the relevant stakeholders throughout the study period.
Conclusions
A range of stakeholders within and beyond schools play a key role in school based health trials. Community entry and information dissemination strategies need careful planning from the outset, and with on-going consultation and feedback mechanisms established in order to identify and address concerns as they arise. We believe our experiences, and the ethical and practical issues and dilemmas encountered, will be of interest for others planning to conduct school-based research in Africa.
Trial registration
National Institute of Health NCT00878007
doi:10.1186/1745-6215-14-142
PMCID: PMC3661351  PMID: 23680181
Malaria; Cluster-randomized trial; Consent; Community engagement; School-based research; Kenya
16.  Automated Detection of Infectious Disease Outbreaks in Hospitals: A Retrospective Cohort Study 
PLoS Medicine  2010;7(2):e1000238.
Susan Huang and colleagues describe an automated statistical software, WHONET-SaTScan, its application in a hospital, and the potential it has to identify hospital infection clusters that had escaped routine detection.
Background
Detection of outbreaks of hospital-acquired infections is often based on simple rules, such as the occurrence of three new cases of a single pathogen in two weeks on the same ward. These rules typically focus on only a few pathogens, and they do not account for the pathogens' underlying prevalence, the normal random variation in rates, and clusters that may occur beyond a single ward, such as those associated with specialty services. Ideally, outbreak detection programs should evaluate many pathogens, using a wide array of data sources.
Methods and Findings
We applied a space-time permutation scan statistic to microbiology data from patients admitted to a 750-bed academic medical center in 2002–2006, using WHONET-SaTScan laboratory information software from the World Health Organization (WHO) Collaborating Centre for Surveillance of Antimicrobial Resistance. We evaluated patients' first isolates for each potential pathogenic species. In order to evaluate hospital-associated infections, only pathogens first isolated >2 d after admission were included. Clusters were sought daily across the entire hospital, as well as in hospital wards, specialty services, and using similar antimicrobial susceptibility profiles. We assessed clusters that had a likelihood of occurring by chance less than once per year. For methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE), WHONET-SaTScan–generated clusters were compared to those previously identified by the Infection Control program, which were based on a rule-based criterion of three occurrences in two weeks in the same ward. Two hospital epidemiologists independently classified each cluster's importance. From 2002 to 2006, WHONET-SaTScan found 59 clusters involving 2–27 patients (median 4). Clusters were identified by antimicrobial resistance profile (41%), wards (29%), service (13%), and hospital-wide assessments (17%). WHONET-SaTScan rapidly detected the two previously known gram-negative pathogen clusters. Compared to rule-based thresholds, WHONET-SaTScan considered only one of 73 previously designated MRSA clusters and 0 of 87 VRE clusters as episodes statistically unlikely to have occurred by chance. WHONET-SaTScan identified six MRSA and four VRE clusters that were previously unknown. Epidemiologists considered more than 95% of the 59 detected clusters to merit consideration, with 27% warranting active investigation or intervention.
Conclusions
Automated statistical software identified hospital clusters that had escaped routine detection. It also classified many previously identified clusters as events likely to occur because of normal random fluctuations. This automated method has the potential to provide valuable real-time guidance both by identifying otherwise unrecognized outbreaks and by preventing the unnecessary implementation of resource-intensive infection control measures that interfere with regular patient care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Admission to a hospital is often a life-saving necessity—individuals injured in a road accident, for example, may need immediate medical and surgical attention if they are to survive. Unfortunately, many patients acquire infections, some of which are life-threatening, during their stay in a hospital. The World Health Organization has estimated that, globally, 8.7% of hospital patients develop hospital-acquired infections (infections that are identified more than two days after admission to hospital). In the US alone, 2 million people develop a hospital-acquired infection every year, often an infection of a surgical wound, or a urinary tract or lung infection. Infections are common among hospital patients because increasing age or underlying illnesses can reduce immunity to infection and because many medical and surgical procedures bypass the body's natural protective barriers. In addition, poor infection control practices can facilitate the transmission of bacteria—including meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE)—and other infectious agents (pathogens) between patients.
Why Was This Study Done?
Sometimes, the number of cases of hospital-acquired infections increases unexpectedly or a new infection emerges. Such clusters account for relatively few health care–associated infections, but, because they may arise from the transmission of a pathogen within a hospital, they need to be rapidly identified and measures implemented (for example, isolation of affected patients) to stop transmission if an outbreak is confirmed. Currently, the detection of clusters of hospital-acquired infections is based on simple rules, such as the occurrence of three new cases of a single pathogen in two weeks on the same ward. This rule-based approach relies on the human eye to detect infection clusters within microbiology data (information collected on the pathogens isolated from patients), it focuses on a few pathogens, and it does not consider the random variation in infection rates or the possibility that clusters might be associated with shared facilities rather than with individual wards. In this study, the researchers test whether an automated statistical system can detect outbreaks of hospital-acquired infections quickly and accurately.
What Did the Researchers Do and Find?
The researchers combined two software packages used to track diseases in populations to create the WHONET-SaTScan cluster detection tool. They then compared the clusters of hospital-acquired infection identified by the new tool in microbiology data from a 750-bed US academic medical center with those generated by the hospital's infection control program, which was largely based on the simple rule described above. WHONET-SaTScan found 59 clusters of infection that occurred between 2002 and 2006, about three-quarters of which were identified by characteristics other than a ward-based location. Nearly half the cluster alerts were generated on the basis of shared antibiotic susceptibility patterns. Although WHONET-SaTScan identified all the clusters previously identified by the hospital's infection control program, it classified most of these clusters as likely to be the result of normal random variations in infection rates rather than the result of “true” outbreaks. By contrast, the hospital's infection control department only identified three of the 59 statistically significant clusters identified by WHONET-SaTScan. Furthermore, the new tool identified six previously unknown MRSA outbreaks and four previously unknown VRE outbreaks. Finally, two hospital epidemiologists (scientists who study diseases in populations) classified 95% of the clusters detected by WHONET-SaTScan as worthy of consideration by the hospital infection control team and a quarter of the clusters as warranting active investigation or intervention.
What Do These Findings Mean?
These findings suggest that automated statistical software should be able to detect clusters of hospital-acquired infections that would escape detection using routine rule-based systems. Importantly, they also suggest that an automated system would be able to discount a large number of supposed outbreaks identified by rule-based systems. These findings need to be confirmed in other settings and in prospective studies in which the outcomes of clusters detected with WHONET-SaTScan are carefully analyzed. For now, however, these findings suggest that automated statistical tools could provide hospital infection control experts with valuable real-time guidance by identifying outbreaks that would be missed by routine detection methods and by preventing the implementation of intensive and costly infection control measures in situations where they are unnecessary.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000238.
The World Health Organization's Prevention of Hospital-Acquired Infections, A Practical Guide contains detailed information on all aspects of hospital-acquired infections
MedlinePlus provides links to information on infection control in hospitals (in English and Spanish)
The US Centers for Disease Control and Prevention also provides information on infectious diseases in health care settings (in English and Spanish)
The WHONET/Baclink software and the SatScan software, the two components of WHONET-SaTScan are both available on the internet (the WHONET-SaTScan cluster detection tool is freely available as part of the version of WHONET/BacLink released June 2009)
doi:10.1371/journal.pmed.1000238
PMCID: PMC2826381  PMID: 20186274
17.  A Multilevel Analysis of Gatekeeper Characteristics and Consistent Condom Use Among Establishment-Based Female Sex Workers in Guangxi, China 
Sexually transmitted diseases  2010;37(11):700-705.
Background
Multilevel analytical techniques are being applied in condom use research to ensure the validity of investigation on environmental/structural influences and clustered data from venue-based sampling. The literature contains reports of consistent associations between perceived gatekeeper support and condom use among entertainments establishment-based female sex workers (FSWs) in Guangxi, China. However, the clustering inherent in the data (FSWs being clustered within establishment) has not been accounted in most of the analyses. We used multilevel analyses to examine perceived features of gatekeepers and individual correlates of consistent condom use among FSWs and to validate the findings in the existing literature.
Methods
We analyzed cross-sectional data from 318 FSWs from 29 entertainment establishments in Guangxi, China in 2004, with a minimum of 5 FSWs per establishment. The Hierarchical Linear Models program with Laplace estimation was used to estimate the parameters in models containing random effects and binary outcomes.
Results
About 11.6% of women reported consistent condom use with clients. The intraclass correlation coefficient indicated 18.5% of the variance in condom use could be attributed to their similarity between FSWs within the same establishments. Women’s perceived gatekeeper support and education remained positively associated with condom use (P < 0.05), after controlling for other individual characteristics and clustering.
Conclusions
After adjusting for data clustering, perceived gatekeeper support remains associated with consistent condom use with clients among FSWs in China. The results imply that combined interventions to intervene both gatekeepers and individual FSW may effectively promote consistent condom use.
doi:10.1097/OLQ.0b013e3181e1a2b2
PMCID: PMC2948072  PMID: 20539262
18.  Successful recruitment to trials: a phased approach to opening gates and building bridges 
Background
The pragmatic randomised controlled trial is widely regarded as the gold standard method for evaluating the effectiveness of health care interventions. Successful conduct of trials and generalisation of findings depends upon efficient recruitment of representative samples, which often requires the collaboration of 'gatekeepers' who mediate access to potential participants. Effective negotiation of gatekeeping is thus vital to process and outcomes of trials and the quality of evidence. Whilst relevant literature contains discussion of the problems of recruitment and gatekeeping, little is known about how recruitment can be optimised and factors leading to successful recruitment.
Discussion
As practised researchers with first-hand experience of gatekeeping, we were aware that some researchers recruit more effectively than others and curious about the ingredients of success. With the goal of developing practical guidance, we conducted a series of workshops with 19 expert researchers to investigate and map successful recruitment. Workshops were digitally recorded and transcribed. Analysis of discussion supported modelling of effective recruitment as a process involving three phases, each comprising two key tasks. Successful negotiation of set-up, alliance, and exchange require judicious deployment of interpersonal skills in an appropriately assertive manner. Researcher flexibility and credibility are vital for success, such that a foundation for rapprochement between the worlds of research and practice is established.
Our model provides a framework to support design and implementation of recruitment activities and will enable trouble shooting and support recruitment, supervision and training of effective researchers. This, in turn will support delivery of trials on time and on budget, maximising return on investment in the production of evidence.
Summary
Pragmatic trials are central to development of evidence based health care but often failure to recruit the necessary sample in a timely manner means many fail or require costly extensions. Gatekeeping is implicated in this. Drawing on the knowledge of 19 expert researchers, we argue that successful researchers are resourceful and personable, judiciously deploying interpersonal skills and expertise to engage with gatekeepers and establish a shared objective. We propose that understanding recruitment as a phased process can enhance design and conduct of trials, supporting completion on time, on budget.
doi:10.1186/1471-2288-11-73
PMCID: PMC3114795  PMID: 21595906
19.  Making birthing safe for Pakistan women: a cluster randomized trial 
Background
Two out of three neonatal deaths occur in just 10 countries and Pakistan stands third among them. Maternal mortality is also high with most deaths occurring during labor, birth, and first few hours after birth. Enhanced access and utilization of skilled delivery and emergency obstetric care is the demonstrated strategy in reducing maternal and neonatal mortality. This trial aims to compare reduction in neonate mortality and utilization of available safe birthing and Emergency Obstetric and Neonatal Care services among pregnant mothers receiving ‘structured birth planning’, and/or ‘transport facilitation’ compared to routine care.
Methods
A pragmatic cluster randomized trial, with qualitative and economic studies, will be conducted in Jhang, Chiniot and Khanewal districts of Punjab, Pakistan, from February 2011 to May 2013. At least 29,295 pregnancies will be registered in the three arms, seven clusters per arm; 1) structured birth planning and travel facilitation, 2) structured birth planning, and 3) control arm. Trial will be conducted through the Lady Health Worker program. Main outcomes are difference in neonatal mortality and service utilization; maternal mortality being the secondary outcome. Cluster level analysis will be done according to intention-to-treat.
Discussion
A nationwide network of about 100,000 lady health workers is already involved in antenatal and postnatal care of pregnant women. They also act as “gatekeepers” for the child birthing services. This gate keeping role mainly includes counseling and referral for skill birth attendance and travel arrangements for emergency obstetric care (if required). The review of current arrangements and practices show that the care delivery process needs enhancement to include adequate information provision as well as informed “decision” making and planned “action” by the pregnant women. The proposed three-year research is to develop, through national technical working group process, and then test a set of arrangements for achieving the enhanced utilization of safe birthing services.
Trial registration
Current Controlled Trials ISRCTN86264432
doi:10.1186/1471-2393-12-67
PMCID: PMC3449181  PMID: 22793877
20.  The disclosure of incidental genomic findings: an “ethically important moment” in pediatric research and practice 
Journal of Community Genetics  2013;4(4):435-444.
Although there are numerous position papers on the issues and challenges surrounding disclosure of incidental genomic findings involving children, there is very little research. To fill this gap, the purpose of this study was to explore the perspectives of multiple professional (N = 103) and public (N = 63) stakeholders using both interviews and focus groups. Using qualitative analysis, we identified one overarching theme, “It's hard for us; it's hard for them,” and three subthemes/questions: “What to disclose?,” “Who gets the information?,” and “What happens later?” Perspectives differed between professional (Institutional Review Board chairs, clinicians, and researchers) and public stakeholders. While professionals focused on the complexities of what to disclose, the lay public stated that parents should have all information laid out for them. Professionals pondered multiple parent and child situations, while the public identified parents as informational gatekeepers who know their children best. Professionals described the potential requirement for follow-up over time as a logistical “nightmare,” while the public believed that parents have the responsibility for managing their children's health information over time. However, the parent role as gatekeeper was seen as time limited and in need of professional support and backup. Our findings present a case for needed dialogue around what we propose as an “ethically important moment,” with the goal of protecting and respecting the viewpoints of all stakeholders when policies regarding children are developed.
doi:10.1007/s12687-013-0145-1
PMCID: PMC3773311  PMID: 23572417
Incidental findings; Genomics; Children; Gatekeepers
21.  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
22.  Tailoring Consent to Context: Designing an Appropriate Consent Process for a Biomedical Study in a Low Income Setting 
Background
Currently there is increasing recognition of the need for research in developing countries where disease burden is high. Understanding the role of local factors is important for undertaking ethical research in developing countries. We explored factors relating to information and communication during the process of informed consent, and the approach that should be followed for gaining consent. The study was conducted prior to a family-based genetic study among people with podoconiosis (non-filarial elephantiasis) in southern Ethiopia.
Methodology/Principal Findings
We adapted a method of rapid assessment validated in The Gambia. The methodology was entirely qualitative, involving focus-group discussions and in-depth interviews. Discussions were conducted with podoconiosis patients and non-patients in the community, fieldworkers, researchers, staff of the local non-governmental organisation (NGO) working on prevention and treatment of podoconiosis, and community leaders. We found that the extent of use of everyday language, the degree to which expectations of potential participants were addressed, and the techniques of presentation of information had considerable impact on comprehension of information provided about research. Approaching podoconiosis patients via locally trusted individuals and preceding individual consent with community sensitization were considered the optimal means of communication. Prevailing poverty among podoconiosis patients, the absence of alternative treatment facilities, and participants' trust in the local NGO were identified as potential barriers for obtaining genuine informed consent.
Conclusions
Researchers should evaluate the effectiveness of consent processes in providing appropriate information in a comprehensible manner and in supporting voluntary decision-making on a study-by-study basis.
Author Summary
Informed consent to biomedical research in developing countries is a highly topical issue. When consent forms and processes are simply borrowed from developed countries, obtaining genuine informed consent becomes extremely challenging. This paper examines how a quick and relatively simple intervention (Rapid Assessment) can influence the design and implementation of informed consent processes in the context of biomedical research involving poor, socially stigmatized and illiterate communities in a developing country. The paper goes on to discuss the effect of social, cultural, and economic factors identified by the intervention in a particular context and demonstrates how knowledge of these influences helped to develop a socially relevant and practical consent process prior to conducting a programme of community-based genetic research. The paper concludes that this intervention is an effective and economical means by which to ensure the efficacy and ethical integrity of consent processes when recruiting participants to new research sites, even within countries with which researchers are already acquainted.
doi:10.1371/journal.pntd.0000482
PMCID: PMC2705797  PMID: 19621067
23.  Use of deferred consent for severely ill children in a multi-centre phase III trial 
Trials  2011;12:90.
Background
Voluntary participation of a subject in research respects a subject's rights, strengthens its ethical conduct, and is formalized by the informed consent process. Clinical trials of life-saving interventions for medical emergencies often necessitate enrolment of patients where prior written individual informed consent is impossible. Although there are regulations and guidelines on protecting subjects in emergency research, these have been criticised for being limited and unnecessarily restrictive. Across Europe and the United States stringent regulations have resulted in a substantial decline of clinical trials involving emergency interventions.
Methods
We are conducting a trial of fluid resuscitation in children with hypovolaemic shock in six hospitals across three malaria-endemic African countries. The design is pragmatic as children are enrolled on clinical criteria alone and is being conducted in hospitals with facilities typical of many district hospitals across Africa. The trial aims to inform strategy for managing children with febrile illness and features of shock. In order to develop appropriate consent processes for the trial, we conducted a narrative review of current international recommendations for emergency consent.
Results
Practical or specific guidance was generally sparse or confusing with few examples in the literature to direct our informed consent process. For a sub-group of children who were critically sick or where parents themselves were otherwise too distressed to consider prior written consent, we opted for a modified form of deferred consent. This included verbal assent from guardians at the point of enrolment, with full written consent obtained after stabilising the child. For children who died prior to full written consent, ethical permission was received to waiver full consent.
Conclusions
In light of the controversy around guidance and regulations in this area we report how and why we have used a modified system of deferred consent in an emergency intervention trial in children. Although approved by all relevant ethics committees and operational in 3 countries in Africa, formal research is now necessary to explore the perceptions and experiences of parents, health workers, researchers and ethics committees of the modified method of deferred consent.
doi:10.1186/1745-6215-12-90
PMCID: PMC3077324  PMID: 21453454
24.  e-Consent: The Design and Implementation of Consumer Consent Mechanisms in an Electronic Environment 
The effective coordination of health care relies on communication of confidential information about consumers between different health and community care services. However, consumers must be able to give or withhold “e-Consent” to those who wish to access their electronic health information. There are several possible forms for e-Consent. In the general consent model, a patient provides blanket consent for access to his or her information by an organization for all future information requests. Conversely, general denial explicitly denies consent for information to be used in future circumstances, and in each new episode of care, a new consent would be needed to obtain information. In the general consent with specific denial model, a patient attaches specific exclusion conditions to his or her general approval to future accesses. In contrast, in the general denial with explicit consent model, a patient issues a blanket block on all future accesses but allows the inclusion of future use under specified conditions. There also are several alternative functions for an e-Consent system. Consent could be captured as a matter of legal record. E-Consent systems could be more active by prompting clinicians to indicate that they have noted consent conditions before they access a record. Finally, the record of patient consent could be fully active and used as a gatekeeper in a distributed information environment. There probably will need to be some form of data object that is associated with patient information. This e-Consent object (or e-Co) will contain the specific conditions under which the data to which it is attached can be retrieved. Given the complexity of clinical work and the substantial variation we can expect in an individual's desire to make his or her personal medical details available, it is unlikely a “one size fits all” approach to e-Consent will work. Consequently, with a well-chosen consent design, it should be possible to balance the specific need for privacy of some of the population against the desire by others to err on the side of clinical safety, and clinicians desire to minimize the burden that an electronic consent mechanism would impose.
doi:10.1197/jamia.M1480
PMCID: PMC353020  PMID: 14662803
25.  Community Mobilization in Mumbai Slums to Improve Perinatal Care and Outcomes: A Cluster Randomized Controlled Trial 
PLoS Medicine  2012;9(7):e1001257.
David Osrin and colleagues report findings from a cluster-randomized trial conducted in Mumbai slums; the trial aimed to evaluate whether facilitator-supported women's groups could improve perinatal outcomes.
Introduction
Improving maternal and newborn health in low-income settings requires both health service and community action. Previous community initiatives have been predominantly rural, but India is urbanizing. While working to improve health service quality, we tested an intervention in which urban slum-dweller women's groups worked to improve local perinatal health.
Methods and Findings
A cluster randomized controlled trial in 24 intervention and 24 control settlements covered a population of 283,000. In each intervention cluster, a facilitator supported women's groups through an action learning cycle in which they discussed perinatal experiences, improved their knowledge, and took local action. We monitored births, stillbirths, and neonatal deaths, and interviewed mothers at 6 weeks postpartum. The primary outcomes described perinatal care, maternal morbidity, and extended perinatal mortality. The analysis included 18,197 births over 3 years from 2006 to 2009. We found no differences between trial arms in uptake of antenatal care, reported work, rest, and diet in later pregnancy, institutional delivery, early and exclusive breastfeeding, or care-seeking. The stillbirth rate was non-significantly lower in the intervention arm (odds ratio 0.86, 95% CI 0.60–1.22), and the neonatal mortality rate higher (1.48, 1.06–2.08). The extended perinatal mortality rate did not differ between arms (1.19, 0.90–1.57). We have no evidence that these differences could be explained by the intervention.
Conclusions
Facilitating urban community groups was feasible, and there was evidence of behaviour change, but we did not see population-level effects on health care or mortality. In cities with multiple sources of health care, but inequitable access to services, community mobilization should be integrated with attempts to deliver services for the poorest and most vulnerable, and with initiatives to improve quality of care in both public and private sectors.
Trial registration
Current Controlled Trials ISRCTN96256793
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Substantial progress is being made to reduce global child mortality (deaths of children before the age of 5 years) and maternal mortality (deaths among women because of complications of pregnancy and childbirth)—two of the Millennium Development Goals agreed by world leaders in 2000 to end extreme poverty. Even so, worldwide, in 2010, 7.6 million children died before their fifth birthday and there were nearly 360,000 maternal deaths. Almost all child and maternal deaths occur in developing countries—a fifth of under-five deaths and more than a quarter of neonatal deaths (deaths during the first month of life, which account for two-fifths of all child deaths) occur in India alone. Moreover, most child and maternal deaths are caused by avoidable conditions. Specifically, the major causes of neonatal death—complications of preterm delivery, breathing problems during or after delivery, and infections of the blood (sepsis) and lungs (pneumonia)—and of maternal deaths—hemorrhage (abnormal bleeding), sepsis, unsafe abortion, obstructed labor, and hypertensive diseases of pregnancy—could all be largely prevented by improved access to reproductive health services and skilled health care workers.
Why Was This Study Done?
Experts believe that improvements to maternal and newborn health in low-income settings require both health service strengthening and community action. That is, the demand for better services, driven by improved knowledge about maternal and newborn health (perinatal issues), has to be increased in parallel with the supply of those services. To date, community mobilization around perinatal issues has largely been undertaken in rural settings but populations in developing countries are becoming increasingly urban. In India, for example, 30% of the population now lives in cities. In this cluster randomized controlled trial (a study in which groups of people are randomly assigned to receive alternative interventions and the outcomes in the differently treated “clusters” are compared), City Initiative for Newborn Health (CINH) researchers investigate the effect of an intervention designed to help women's groups in the slums of Mumbai work towards improving local perinatal health. The CINH aims to improve maternal and newborn health in slum communities by improving public health care provision and by working with community members to improve maternal and newborn care practices and care-seeking behaviors.
What Did the Researchers Do and Find?
The researchers enrolled 48 Mumbai slum communities of at least 1,000 households into their trial. In each of the 24 intervention clusters, a facilitator supported local women's groups through a 36-meeting learning cycle during which group members discussed their perinatal experiences, improved their knowledge, and took action. To measure the effect of the intervention, the researchers monitored births, stillbirths, and neonatal deaths in all the clusters and interviewed mothers 6 weeks after delivery. During the 3-year trial, there were 18,197 births in the participating settlements. The women in the intervention clusters were enthusiastic about acquiring new knowledge and made substantial efforts to reach out to other women but were less successful in undertaking collective action such as negotiations with civic authorities for more amenities. There were no differences between the intervention and control communities in the uptake of antenatal care, reported work, rest, and diet in late pregnancy, institutional delivery, or in breast feeding and care-seeking behavior. Finally, the combined rate of stillbirths and neonatal deaths (the extended perinatal mortality rate) was the same in both arms of the trial, as was maternal mortality.
What Do These Findings Mean?
These findings indicate that it is possible to facilitate the discussion of perinatal health care by urban women's groups in the challenging conditions that exist in the slums of Mumbai. However, they fail to show any measureable effect of community mobilization through the facilitation of women's groups on perinatal health at the population level. The researchers acknowledge that more intensive community activities that target the poorest, most vulnerable slum dwellers might produce measurable effects on perinatal mortality, and they conclude that, in cities with multiple sources of health care and inequitable access to services, it remains important to integrate community mobilization with attempts to deliver services to the poorest and most vulnerable, and with initiatives to improve the quality of health care in both the public and private sector.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001257.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on the reduction of child mortality (Millennium Development Goal 4); its Childinfo website provides information about all the Millennium Development Goals and detailed statistics about on child survival and health, newborn care, and maternal health (some information in several languages)
The World Health Organization also has information about Millennium Development Goal 4 and Millennium Development Goal 5, the reduction of maternal mortality, provides information on newborn infants, and provides estimates of child mortality rates (some information in several languages)
Further information about the Millennium Development Goals is available
Information on the City Initiative for Newborn Health and its partners and a detailed description of its trial of community mobilization in Mumbai slums to improve care during pregnancy, delivery, postnatally and for the newborn are available
Further information about the Society for Nutrition, Education and Health Action (SNEHA) is available
doi:10.1371/journal.pmed.1001257
PMCID: PMC3389036  PMID: 22802737

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