Health Research Trials Research Articles

Adaptations to clinical trials in health research: a guide for clinical researchers.

Adaptations to clinical trials in health research: a guide for clinical researchers.

How can community engagement in health research be strengthened for infectious disease outbreaks in Sub-Saharan Africa? A scoping review of the literature

BackgroundCommunity engagement (CE) is a well-established practical and scholarly field, recognised as core to the science and ethics of health research, for which researchers and practitioners have increasingly asked questions about desired standards and evaluation. In infectious disease outbreak contexts, questions may be more complex. However, it is unclear what body of knowledge has been developed for CE specifically as it applies to emerging infectious diseases. This scoping review seeks to describe (1) How CE has been conceptualised and understood; and (2) What conclusions have research teams reached on the effectiveness of CE in these settings, including challenges and facilitators.MethodsWe used a scoping review framework by Arksey and O’Malley (Int J Soc Res Methodol 8:19–32, 2005) to structure our review. We conducted a brainstorming session and initial trial search to inform the protocol, search terms, and strategy. Three researchers discussed, developed and applied agreed screening tools and selection criteria to the final search results. Five researchers used the screening tools to screen abstracts and full text for inclusion by consensus. Additional publications were sought from references of retrieved publications and an expert call for literature. We analysed and reported emerging themes qualitatively.ResultsWe included 59 papers from a total of 722 articles derived from our trial and final literature searches, as well as a process of “citation chasing” and an expert call for grey literature. The core material related exclusively to health research trials during the 2014–2016 West Africa Ebola outbreak. We synthesized reports on components of effectiveness of CE to identify and propose three themes as essential elements of effective CE.ConclusionsWhile there is a large volume of literature documenting CE activities in infectious disease research settings generally, there are few accounts of effectiveness dimensions of CE. Our review proposes three themes to facilitate the effectiveness of CE initiatives as essential elements of CE activities in infectious diseases studies: (1) Communication towards building collaborative relationships; (2) Producing contextual knowledge; and (3) Learning lessons over time. As there were relatively few in-depth accounts of CE from our literature review, documentation and accounts of CE used in health research should be prioritised.

Randomized clinical trial: gold standard of experimental designs - importance, advantages, disadvantages and prejudices

BACKGROUND: Randomized controlled trial (RCT) is the gold standard of experimental design or clinical trial design. Only by RCT in research, the cause-and-effect relationship between a set of independent and dependent variables could be demonstrated. RCT has added advantages over other experimental designs due to the presence of the control group. The importance of control in health research trials and its advantages to be elaborated. Though various threats to internal validity in health research trials could be minimized by RCT, various biases in RCT and disadvantages add to its discredit. OBJECTIVE: The aim of the present narrative review is to brief the characteristics, advantages, disadvantages, and various biases in RCT. METHODS: This review does not follow the PRISMA statement, as it was a narrative review. Two databases, namely, Medline through PubMed and Scopus, were searched from inception to July 2020 for the information pertaining to RCTs and included in this narrative review. Only English language articles were searched with the keywords, “Randomized controlled trial,” “Randomized clinical trial,” “experimental design,” and “experimental study.” These keywords are linked together by the Boolean words, “AND,” “OR” and “NOT.” Conference proceedings and only abstracts were not considered for the review. RESULTS: RCTs were explained under characteristics, advantages, disadvantages, importance, and advantages of controls in research, the principle of equipoise, RCTs in the pediatric population, RCTs in the geriatric population, threats to internal validity and steps to minimize them and various biases in RCTs. CONCLUSION: The narrative presentation of RCTs under various important topics have been explained in this review.

An international, Delphi consensus study to identify priorities for methodological research in behavioral trials in health research

BackgroundNon-communicable chronic diseases are linked to behavioral risk factors (including smoking, poor diet and physical inactivity), so effective behavior change interventions are needed to improve population health. However, uptake and impact of these interventions is limited by methodological challenges. We aimed to identify and achieve consensus on priorities for methodological research in behavioral trials in health research among an international behavioral science community.MethodsAn international, Delphi consensus study was conducted. Fifteen core members of the International Behavioral Trials Network (IBTN) were invited to generate methodological items that they consider important. From these, the research team agreed a “long-list” of unique items. Two online surveys were administered to IBTN members (N = 306). Respondents rated the importance of items on a 9-point scale, and ranked their “top-five” priorities. In the second survey, respondents received feedback on others’ responses, before rerating items and re-selecting their top five.ResultsNine experts generated 144 items, which were condensed to a long-list of 33 items. The four most highly endorsed items, in both surveys 1 (n = 77) and 2 (n = 57), came from two thematic categories:“Intervention development” (“Specifying intervention components” and “Tailoring interventions to specific populations and contexts”) and “Implementation” (“How to disseminate behavioral trial research findings to increase implementation” and “Methods for ensuring that behavioral interventions are implementable into practice and policy”). “Development of novel research designs to test behavioral interventions” also emerged as a highly ranked research priority.ConclusionsFrom a wide array of identified methodological issues, intervention development, implementation and novel research designs are key themes to drive the future behavioral trials’ research agenda. Funding bodies should prioritize these issues in resource allocation.

Inadequacy of ethical conduct and reporting of stepped wedge cluster randomized trials: Results from a systematic review.

Background/aims The use of the stepped wedge cluster randomized design is rapidly increasing. This design is commonly used to evaluate health policy and service delivery interventions. Stepped wedge cluster randomized trials have unique characteristics that complicate their ethical interpretation. The 2012 Ottawa Statement provides comprehensive guidance on the ethical design and conduct of cluster randomized trials, and the 2010 CONSORT extension for cluster randomized trials provides guidelines for reporting. Our aims were to assess the adequacy of the ethical conduct and reporting of stepped wedge trials to date, focusing on research ethics review and informed consent. Methods We conducted a systematic review of stepped wedge cluster randomized trials in health research published up to 2014 in English language journals. We extracted details of study intervention and data collection procedures, as well as reporting of research ethics review and informed consent. Two reviewers independently extracted data from each trial; discrepancies were resolved through discussion. We identified the presence of any research participants at the cluster level and the individual level. We assessed ethical conduct by tabulating reporting of research ethics review and informed consent against the presence of research participants. Results Of 32 identified stepped wedge trials, only 24 (75%) reported review by a research ethics committee, and only 16 (50%) reported informed consent from any research participants-yet, all trials included research participants at some level. In the subgroup of 20 trials with research participants at cluster level, only 4 (20%) reported informed consent from such participants; in 26 trials with individual-level research participants, only 15 (58%) reported their informed consent. Interventions (regardless of whether targeting cluster- or individual-level participants) were delivered at the group level in more than two-thirds of trials; nine trials (28%) had no identifiable data collected from any research participants. Overall, only three trials (9%) indicated that a waiver of consent had been granted by a research ethics committee. When considering the combined requirement of research ethics review and informed consent (or a waiver), only one in three studies were compliant. Conclusion The ethical conduct and reporting of key ethical protections in stepped wedge trials, namely, research ethics review and informed consent, are inadequate. We recommend that stepped wedge trials be classified as research and reviewed and approved by a research ethics committee. We also recommend that researchers appropriately identify research participants (which may include health professionals), seek informed consent or appeal to an ethics committee for a waiver of consent, and include explicit details of research ethics approval and informed consent in the trial report.

Maximising the value of combining qualitative research and randomised controlled trials in health research: the QUAlitative Research in Trials (QUART) study--a mixed methods study.

Researchers sometimes undertake qualitative research with randomised controlled trials (RCTs) of health interventions. To systematically explore how qualitative research is being used with trials and identify ways of maximising its value to the trial aim of providing evidence of effectiveness of health interventions. A sequential mixed methods study with four components. (1) Database search of peer-reviewed journals between January 2008 and September 2010 for articles reporting the qualitative research undertaken with specific trials, (2) systematic search of database of registered trials to identify studies combining qualitative research and trials, (3) survey of 200 lead investigators of trials with no apparent qualitative research and (4) semistructured telephone interviews with 18 researchers purposively sampled from the first three methods. Qualitative research was undertaken with at least 12% of trials. A large number of articles reporting qualitative research undertaken with trials (n=296) were published between 2008 and 2010. A total of 28% (82/296) of articles reported qualitative research undertaken at the pre-trial stage and around one-quarter concerned drugs or devices. The articles focused on 22 aspects of the trial within five broad categories. Some focused on more than one aspect of the trial, totalling 356 examples. The qualitative research focused on the intervention being trialled (71%, 254/356), the design and conduct of the trial (15%, 54/356), the outcomes of the trial (1%, 5/356), the measures used in the trial (3%, 10/356), and the health condition in the trial (9%, 33/356). The potential value of the qualitative research to the trial endeavour included improving the external validity of trials and facilitating interpretation of trial findings. This value could be maximised by using qualitative research more at the pre-trial stage and reporting findings with explicit attention to the implications for the trial endeavour. During interviews, three models of study were identified: qualitative research as peripheral to the trial, qualitative research as an 'add-on' to the trial and a study with qualitative research and trial as essential components, with the third model offering more opportunity to maximise the value of the qualitative research. Interviewees valued the use of qualitative research with trials and identified team structures and wider structural issues which gave more value to the trial than the qualitative research as barriers to maximising the value of the qualitative research. A large number of articles were published between 2008 and 2010, addressing a wide range of aspects of trials. There were examples of this research affecting the trial by facilitating interpretation of trial findings, developing and refining interventions for testing in the trial and changing the measures used in the trial. However, researchers were not necessarily maximising the value of qualitative research undertaken with trials to the endeavour of generating evidence of effectiveness of health interventions. Researchers can maximise value by promoting its use at the pre-trial stage to ensure that the intervention and trial conduct is optimised at the main trial stage, being explicit about the conclusions for the trial endeavour in peer-reviewed journal articles reporting the qualitative research and valuing the contribution of the qualitative research as much as the trial. Future recommendations for researchers include: plan the qualitative research, design and implement studies not trials, use qualitative research at the feasibility and pilot stage of trials, be explicit in publications about the impact of the qualitative research on the trial and implications for the trial endeavour, undertake in-depth qualitative research, allow qualitative research to take a challenging role and develop a learning environment around the use of qualitative research and trials. This project was funded by the Medical Research Council (MRC) as part of the MRC-National Institute for Health Research Methodology Research programme.

Describing qualitative research undertaken with randomised controlled trials in grant proposals: a documentary analysis

BackgroundThere is growing recognition of the value of conducting qualitative research with trials in health research. It is timely to reflect on how this qualitative research is presented in grant proposals to identify lessons for researchers and research commissioners. As part of a larger study focusing on how to maximise the value of undertaking qualitative research with trials, we undertook a documentary analysis of proposals of funded studies.MethodsUsing the metaRegister of Controlled Trials (mRCT) database we identified trials funded in the United Kingdom, ongoing between 2001 and 2010, and reporting the use of qualitative research. We requested copies of proposals from lead researchers. We extracted data from the proposals using closed and open questions, analysed using descriptive statistics and content analysis respectively.Results2% (89/3812) of trials in the mRCT database described the use of qualitative research undertaken with the trial. From these 89 trials, we received copies of 36 full proposals, of which 32 met our inclusion criteria. 25% used less than a single paragraph to describe the qualitative research. The aims of the qualitative research described in these proposals focused mainly on the intervention or trial conduct. Just over half (56%) of the proposals included an explicit rationale for conducting the qualitative research with the trial, the most frequent being to optimise implementation into clinical practice or to interpret trial findings. Key information about methods, expertise and resources was missing in a large minority of proposals, in particular sample size, type of analysis, and non-personnel resources. 28% specifically stated that qualitative researchers would conduct the qualitative research.ConclusionsOur review of proposals of successfully funded studies identified good practice but also identified limited space given to describing the qualitative research, with an associated lack of attention to the rationale for doing the qualitative research and important methodological details. Acknowledging the space restrictions faced by researchers writing grant proposals, we suggest a starting point for providing practical guidance to help researchers write proposals and research commissioners assess proposals of qualitative research with trials.

Concept, characteristics and implications of cluster randomization

The concept of cluster randomization The vast majority of randomized controlled trials in health research are structured around the individual patient: the patient is recruited and allocated independently to either intervention or control arm, administered the allocated intervention and observed prospectively. This design is optimal in the sense that the number of independent allocation units is the same as the number of observations to be analyzed. On the other hand, the defining feature of a cluster randomized trial is that natural groups (‘clusters’) of individuals are allocated as a unit and, thus, the number of independent units allocated is smaller than the number of observations. Cluster randomized trials are not new; there are now four texts addressing their design and ana lysis, including references [1–3]. Researchers considering this design should bear in mind that cluster randomized trials are more difficult to design and analyze correctly, are more susceptible to biases [4,5] and raise distinct ethical challenges that may require more thought and time at the protocol development and research ethics application stages [6,7]. The decision to adopt cluster rather than individual randomization should therefore not be made lightly.

Integrating public health research trials into health systems in Africa: individual or cluster randomisation?

Integrating public health research trials into health systems in Africa: individual or cluster randomisation?

What is the role and authority of gatekeepers in cluster randomized trials in health research?

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.

When is informed consent required in cluster randomized trials in health research?

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.

Who is the research subject in cluster randomized trials in health research?

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.

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...

Ethical issues posed by cluster randomized trials in health research

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.

Abstract 977: A Strategy to Increase African American Awareness of Health Research

Abstract Evidence shows that there is a shortage of participation in health research trials and blood donations from African American communities. African Americans may be willing to enter into health research studies; however, African Americans are an underrepresented group in health research studies. Although most clinical trial participants are middle-class Caucasian males, due to genetic differences, having a gene pool that is representative of a range of affected individuals will be instrumental in widening our knowledge of various diseases. For instance, there are racial differences in some cancers such as breast, ovarian and prostate cancers. Thus, African American participation will aid in experimental design of health studies in order to target better evaluation, prevention, and treatment of these cancers and other diseases. The purpose of this study is to increase the education and awareness of the Black community because of the need for African American participation in health research studies and blood donations. The three components of this study are to survey, educate, and call to action (SEA). The first component includes administering anonymous surveys to aid in the understanding of current perceptions of health research within the Coppin State University (CSU) community. The second component consists of educational seminars that focus on presenting the history of Blacks and their positive and negative experiences with health research. The third component is a call to action such as having the opportunity to donate blood. The methods and procedures for this study include surveying the CSU community over several questions that focus on a participant's interest in participating in a study, knowledge of health research studies in the past such as the Tuskegee Syphilis Study, and ideas on what can be done to increase awareness of health research studies in the CSU community. The study population of 500 students, faculty members, and staff members was able to access surveys via an online website or by completing a form at an on campus location and submitting the form to a sealed box. Preliminary survey results of 59 participants show that 62.7% are interested in donating blood and/or participating in a health research study. In addition, 40.7% were aware of the Tuskegee Syphilis Study. Several participants suggested increasing media avenues such as pamphlets, workshops, and informational commercials in order to better educate the community. In conclusion, the SEA program has made an impact on the CSU community in that several members that have attended the seminars have a better knowledge of previous health research studies and are in a position to make better decisions about donating blood and entering into health research studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 977.

Effect of imbalance and intracluster correlation coefficient in cluster randomization trials with binary outcomes when the available number of clusters is fixed in advance

In some cluster randomization trials, the number of clusters cannot exceed a specified maximum value due to cost constraints or other practical reasons. Donner and Klar [Donner A, and Klar N. Design and analysis of cluster randomization trials in health research. Oxford University Press 2000] provided the sample size formula for the number of subjects required per cluster when the number of clusters cannot exceed a specified maximum value. The sample size formula of Donner and Klar assumes that the number of subjects is the same in each cluster. In practical situations, the number of subjects may be different among clusters. We conducted simulation studies to investigate the effect of the cluster size variability ( κ) and the intracluster correlation coefficient ( ρ) on the power of the study in which the number of available clusters is fixed in advance. For the balanced case ( κ = 1.0), i.e., equal cluster size among clusters, the sample size formula yielded empirical powers close to the nominal level even when the number of available clusters per group ( k ⁎) is as small as 10. The sample size formula yielded empirical powers close to the nominal level when the number of available clusters per group ( k ⁎) is at least 20 and the imbalance parameter ( κ) is at least 0.8. Empirical powers were close to the nominal level when ( ρ ≤ 0.02, κ ≥ 0.8, and k ⁎ = 10) or ( ρ ≤ 0.02, κ = 0.8, and k ⁎ = 20).

Maximising response to postal questionnaires – A systematic review of randomised trials in health research

BackgroundPostal self-completion questionnaires offer one of the least expensive modes of collecting patient based outcomes in health care research. The purpose of this review is to assess the efficacy of methods of increasing response to postal questionnaires in health care studies on patient populations.MethodsThe following databases were searched: Medline, Embase, CENTRAL, CDSR, PsycINFO, NRR and ZETOC. Reference lists of relevant reviews and relevant journals were hand searched. Inclusion criteria were randomised trials of strategies to improve questionnaire response in health care research on patient populations. Response rate was defined as the percentage of questionnaires returned after all follow-up efforts. Study quality was assessed by two independent reviewers. The Mantel-Haenszel method was used to calculate the pooled odds ratios.ResultsThirteen studies reporting fifteen trials were included. Implementation of reminder letters and telephone contact had the most significant effect on response rates (odds ratio 3.7, 95% confidence interval 2.30 to 5.97 p = <0.00001). Shorter questionnaires also improved response rates to a lesser degree (odds ratio 1.4, 95% confidence interval 1.19 to 1.54). No evidence was found that incentives, re-ordering of questions or including an information brochure with the questionnaire confer any additional advantage.ConclusionImplementing repeat mailing strategies and/or telephone reminders may improve response to postal questionnaires in health care research. Making the questionnaire shorter may also improve response rates. There is a lack of evidence to suggest that incentives are useful. In the context of health care research all strategies to improve response to postal questionnaires require further evaluation.

Design and Analysis of Cluster Randomization Trials in Health Research.

Design and Analysis of Cluster Randomization Trials in Health Research.