Introduction
Cluster randomized trials (CRTs) are an increasingly important method used in health research, including research conducted in low- and middle-income countries (LMICs). In CRTs, intact social units, or ‘clusters,’ are randomly allocated to intervention and control conditions, and outcomes are usually collected on individual cluster members [
1]. Clusters are diverse and include whole communities, neighborhoods, hospitals, clinics and schools. A random sample of CRTs published between 2000 and 2008 revealed that 15% were conducted in LMICs [
2] and a review of specific types of cluster trials reveal that a similar, if not greater, number of more recent cluster trials are conducted in LMICs [
3]. While there is a growing literature on the ethics of CRTs, [
4‐
7] few articles deal specifically with ethical issues arising in LMIC settings [
8‐
11]. In this article, we discuss ethical issues in two LMIC case studies, the PolyIran trial (Iran) and the PASTAL trial (Malawi).
Compared to individually randomized designs, CRTs are statistically inefficient and more prone to bias [
1,
12]. Consequently, the choice of a cluster randomized design must be justified [
13]. Public health, health services and health policy interventions are commonly administered at the level of the community, health system or hospital and, as a result, require a cluster randomized design. In other cases, education and training may be provided to health providers to promote evidence-based care. Evaluating these knowledge translation interventions requires a cluster design, as the patients cared for by each physician constitute a cluster. Individual level interventions, such as patient education, may justify the use of a cluster randomized design to prevent contamination—although only when the risk of contamination is high [
14]. Sometimes justifications of administrative efficiency or a reduction in costs are used.
CRTs also raise specific ethical challenges that differ from individually randomized designs and complicate the interpretation of standard research ethics guidelines [
4]. These ethical challenges include the following. First, CRTs involve groups rather than individuals. As the moral status of groups is often unclear, this complicates whether permission ought to be sought on behalf of the group, as group interests may conflict with individual interests. Second, in CRTs the units of randomization, intervention and outcome assessment may differ. This can complicate the identification of research participants. Third, clusters may be randomized before cluster members can be approached for informed consent for exposure to the intervention. This can further complicate the consent procedure as the role and permissions that gatekeepers are able to provide is often misunderstood. Fourth, the intervention may be delivered to the cluster as a whole, the individual, or both. As cluster level interventions may be difficult or impossible to avoid, this seems to render refusal of study participation meaningless. Nonetheless, informed consent for data collection in such cases may be required.
The Ottawa Statement on the ethical design and conduct of CRTs provides the first international ethics guidance for CRTs [
15]. The Ottawa Statement addresses seven broad ethical issues and sets out 15 recommendations for the design and conduct of CRTs (Table
1). It provides guidance on the justification of the use of a cluster randomized design, the need for research ethics committee review, the identification of research participants, obtaining informed consent, seeking gatekeeper permission, benefit–harm analyses, and protecting vulnerable participants. While the Ottawa Statement is intended to have international applicability, the authors acknowledge that “LMIC perspectives were underrepresented...[and] recommend that subsequent revisions include greater LMIC representation” [
15]. In what follows, we use the lens of the Ottawa Statement to analyze two CRTs conducted in LMIC settings in order to identify gaps or ethical issues requiring further analysis and guidance. The identified gaps and ethical issues will inform a forthcoming revision process for the Ottawa Statement. As such, we do not seek to provide solutions to these issues in this paper.
Table 1
Ottawa Statement on the ethical design and conduct of cluster randomized trials: summary of recommendations
1 | Justifying the cluster randomized design | Researchers should provide a clear rationale for the use of the cluster randomized design and adopt statistical methods appropriate for this design |
2 | REC review | Researchers must submit a CRT involving human research participants for approval by an REC before commencing |
3 | Identifying research participants | Researchers should clearly identify the research participants in CRTs. A research participant can be identified as an individual whose interests may be affected as a result of study interventions or data collection procedures; that is, an individual: |
1) who is the intended recipient of an experimental (or control) intervention; or |
2) who is the direct target of an experimental (or control) manipulation of his/her environment; or |
3) with whom an investigator interacts for the purpose of collecting data about that individual; or |
4) about whom an investigator obtains identifiable private information for the purpose of collecting data about that individual. |
Unless one or more of these criteria is met, an individual is not a research participant |
4 | Obtaining informed consent | Researchers must obtain informed consent from human research participants in a CRT, unless a waiver of consent is granted by an REC under specific circumstances |
5 | | When participants’ informed consent is required, but recruitment of participants is not possible before randomization of clusters, researchers must seek participants’ consent for trial enrollment as soon as possible after cluster randomization—that is, as soon as the potential participant has been identified, but before the participant has undergone any study interventions or data collection procedures |
6 | | An REC may approve a waiver or alteration of consent requirements when 1) the research is not feasible without a waiver or alteration of consent and 2) the study interventions and data collection procedures pose no more than minimal risk |
7 | | Researchers must obtain informed consent from professionals or other service providers who are research participants unless conditions for a waiver or alteration of consent are met |
8 | Gatekeepers | Gatekeepers should not provide proxy consent on behalf of individuals in their cluster |
9 | | When a CRT may substantially affect cluster or organizational interests, and a gatekeeper possesses the legitimate authority to make decisions on its behalf, the researcher should obtain the gatekeeper’s permission to enroll the cluster or organization in the trial. Such permission does not replace the need for the informed consent of research participants |
10 | | When CRT interventions may substantially affect cluster interests, researchers should seek to protect cluster interests through cluster consultation to inform study design, conduct and reporting. Where relevant, gatekeepers can often facilitate such a consultation |
11 | Assessing benefits and harms | The researcher must ensure that the study intervention is adequately justified. The benefits and harms of the study intervention must be consistent with competent practice in the field of study relevant to the CRT |
12 | | Researchers must adequately justify the choice of the control condition. When the control arm is usual practice or no treatment, individuals in the control arm must not be deprived of effective care or programs to which they would have access were there no trial |
13 | | Researchers must ensure that data collection procedures are adequately justified. The risks of data collection procedures must 1) be minimized consistent with sound design and 2) stand in reasonable relation to the knowledge to be gained |
14 | Protecting vulnerable participants | Clusters may contain some vulnerable participants. In these circumstances, researchers and RECs must consider whether additional protections are needed |
15 | | When individual informed consent is required, and there are individuals who may be less able to choose participation freely because of their position in a cluster or organizational hierarchy, RECs should pay special attention to recruitment, privacy and consent procedures for those participants |
Discussion
The Ottawa Statement on the ethical design and conduct of CRTs provides ethical guidance for CRTs but does not explicitly consider issues specific to the LMIC setting. Our ethical analysis of two case studies reveals gaps in the Ottawa Statement and shows that further work is required on ethical issues of CRTs in the LMIC setting. Here we briefly highlight four issues. First, obtaining informed consent remains a challenge in some LMIC settings. The ethical principle of respect for persons supports a general requirement that researchers acquire the informed consent of research participants. In some LMICs, however, low levels of literacy may impede the ability of researchers to seek and obtain informed consent in writing [
48]. In other settings, the fact that potential participants fail to distinguish research activities from clinical care or that they possess different health concepts poses a barrier to valid informed consent [
49].
In the PolyIran trial, high rates of illiteracy necessitated the use of verbal consent obtained and documented by local research staff. However, issues such as when is verbal consent acceptable and what practices ought to be in place to ensure accurate communication of study information and voluntary consent to study participation remain unanswered. In the PASTAL trial, pregnant women provided written informed consent to study participation, but their male partners did not. Criteria for a waiver of consent (socially valuable research, minimal risk, and infeasibility with consent) require considerable interpretation. How ought minimal risk be understood (e.g., is the possibility of partner violence consistent with minimal risk), and when is a study ‘infeasible’ if consent is required (e.g., lower recruitment, additional research staff required, cost); all these require due consideration if they are to be implemented reasonably and consistently.
Second, the choice of an ethically appropriate control arm remains contentious in LMIC settings. The ethical principle of beneficence requires that the potential benefits and risks of participation stand in reasonable relation. This means, in part, that the study intervention and control need to be consistent with equipoise. The short-course zidovudine trial to prevent maternal–fetal transmission of HIV in sub-Saharan Africa raised prominently the issue of appropriate level of care for control groups in trials conducted in LMICs [
50]. Should those in the control arm receive augmented care, care as defined by national (or even international) standards, or locally available care [
51]?
The PolyIran trial employed both an augmented care arm with nonpharmacological prevention for cardiovascular disease and a nonrandomized comparator cohort who received no study interventions. The PASTAL trial employed a usual care arm but discovered at a planned interim analysis that local care was producing very poor results in terms of follow-up testing of male partners (13% compared to an expected 25%). The issue of locally available care versus care mandated by national or international standards is an especially pressing issue in CRTs of implementation interventions. In order to obtain evidence that an intervention will improve care at the local level, locally available care is needed as the comparator group.
Third, post-trial access is an important issue for CRTs in LMIC settings. The ethical principle of justice requires that the burdens and benefits of study participation ought to be distributed equitably. Post-trial access to study interventions that are proven effective is particularly important in LMIC settings [
52]. The Ottawa Statement says that research ethics committees “should consider whether and when the control clusters will receive the study intervention if the study intervention is shown to be effective” [
15]. More recent guidance from the Council for International Organizations of Medical Sciences requires researchers and sponsors to “make every effort, in cooperation with government and other relevant stakeholders, to make available as soon as possible any intervention or product developed, and knowledge generated, for the population or community in which the research is carried out” [
23].
However, further guidance is required. The PolyIran trial raises the issue of how broadly post-trial access should be conceived—to trial participants only or all those who contributed data to the analysis? The PASTAL trial highlights the difficulty of ensuring access to effective interventions after the trial.
Fourth, there is a pressing need for ethics education and capacity building regarding CRTs in LMIC settings. The need for capacity building and education in research ethics in LMICs has been recognized for some years. Millum and colleagues observe that:
Global health research will not thrive without a knowledgeable global discussion of the ethics of the research to shape its course. Given the expected further increases in the health research hosted by LMICs, more capacity will have to be built in order to ensure that human subjects protections are maintained even at present levels… Neglected disease trials in disease-endemic countries pose particularly difficult ethical challenges [
53].
Innovative or unfamiliar trial designs also pose ethical challenges for researchers and research ethics committees in LMICs. CRTs are increasingly used in LMICs and they raise issues that complicate the interpretation of standard ethics guidelines.
While the Ottawa Statement on the ethical design and conduct of CRTs provides useful guidance, [
15] the research ethics committees reviewing the PolyIran and PASTAL trials did not refer to the document. In our experience, the Ottawa Statement is not widely known or used within LMICs. Thus, education on ethics issues in CRTs and available guidance is a priority for health research in LMICs. Web-based educational materials on the ethics of CRTs with LMIC examples would provide a widely accessible resource. Regional workshops for researchers and research ethics committees would provide the opportunity for deeper discussion of issues and learning. Finally, training fellowships would allow researchers and ethics committee members the opportunity to develop specific projects with internationally recognized experts.
Conclusion
Our ethical analysis of the PolyIran and PASTAL trials reveals gaps in the Ottawa Statement and shows that further work is required on ethical issues of CRTs in the LMIC setting.
First, standards for verbal consent and waivers of consent require methods for operationalization if they are to be employed consistently. Second, the appropriate choice of a control arm remains contentious, and the acceptability of locally available care as the comparator in implementation CRTs, especially when such care falls below national standards, should be assessed. Third, as it is often not possible to guarantee post-trial access to study interventions, clarity on stakeholder obligations is needed. Fourth, there is a pressing need for ethics education and capacity building on CRTs. These identified gaps and ethical issues will inform a forthcoming revision process for the Ottawa Statement.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.