Ethical considerations in malaria research proposal review: empirical evidence from 114 proposals submitted to an Ethics Committee in Thailand

The roles and responsibilities of an REC are to ensure protection of the safety, well-being and basic rights of potential participants and participants of a research study. The REC should review the protocol and associated documents and provide opinions on three different ethical considerations, i.e. science, ethics, and data quality [33]. The classical view of research ethics is governed by four ethical principles: respect for persons, beneficence, justice, and respect for communities [39, 40]. Ethical foundations to be considered and addressed include issues on research subjects, the informed consent process, study design concept, risk–benefit ratio, vulnerable group protection and research gatekeepers [10, 41]. In this study, the ethical issues raised in malaria research proposals fell within these common principles. Approximately half of the proposals required revision and clarification on the informed consent process and study participant protection; and, for those studies that required specimen collection, the process to obtain the specimen from the study participants. Approximately one-third required information about risk–benefit and study schedule-activities. Less than one-fifth required explanation of the research objectives and a few proposals required clarification or revision of research questions and supporting documents.

Although only approximately 12 % of the proposals in the present study needed elaboration or provision of more robust information about the research questions (study rationale and significance), debate remains whether the FTM-EC has gone beyond its designated roles. The highest percentage of ethical issues raised by the FTM-EC regarding the malaria research proposals in the study related to the specimen and data collection schedule and activities. At times, some investigators have also questioned whether the ethics committee should comment on research methodology. These scientific merit and research procedure issues remain controversial internationally. It has been reported that REC members are pressured to review a wide range of issues in research proposals, needing to provide opinions ranging from research design to patient privacy and budgeting matters [9, 33]. Some research investigators believe that these are beyond the scope of research protection [9]. Others have suggested that researchers should have already thought carefully about the nature of how the study results can be generated and how they are aligned with the aims of the research. Heterogeneity of bioethics ought to be welcomed, but those involved should engage meaningfully and explicitly with questions concerning normative justification and the methodological process and about the coherence of components of their study [42]. The OHRP also notes that REC members very often ask to what degree it is his/her responsibility to review the underlying science of the proposal [43]. It has long been argued that “if it is not good science, it is not ethical” and the US federal regulations do not clearly call for REC review of the scientific validity of the research design. However, if the underlying science is inadequate, then it follows that the study is unlikely to yield important knowledge [43]. To mitigate this controversial ethical consideration made by RECs, the ORHP guideline suggests that if the REC lacks expertise in the scientific matter of the particular proposal, the REC should recognise its limits. Although REC members are not required to be experts in scientific methodology or statistics, they should have certain basic knowledge about study design, and they should consult experts if they have concerns about the research rationale and methodology that seem to pose a significant problem [43]. At the FTM, besides some FTM-EC members who have been working in malaria research over decades, there is a pool of expertise in malaria research, ranging from molecular to field studies, and several of them have been consulted for advice for any unclear or controversial matter before issuing the letter to investigators or making a final decision on the submitted proposals.

The REC has a responsibility to consider the balance between the risks and benefits of the research proposal. International standards clearly state that the REC must safeguard the rights, safety and well-being of all study participants [10, 33, 44]. Based on the classic ethics principle of beneficence, researchers have an obligation not to harm needlessly and to promote the good of the study participants where possible. Regarding justice, researchers have an obligation to ensure that study procedures for the selection of research subjects are equitable [44]. It is also agreed that researchers neither exploit the vulnerable nor exclude unreasonably those who could be receive benefit from the study. This means that eligibility criteria listed in the proposal must be clearly justified [45]. Among all 114 malaria proposals submitted for FTM-EC review, about 28 % involved minority populations along the country borders, and 27 % involved other vulnerable groups (pregnant women, children, the elderly or unconscious patients). Thus, the finding that over one-third of proposals required clarification on the risk–benefit balance is not surprising.

As clearly stated in international standards on ethical review of research protocols [12, 23‐25, 46], the informed consent process is one of the main ethical considerations that must be observed by RECs. Indeed, it could be said that the informed consent process is a legal, ethical, and regulatory requirement for most research and healthcare transactions [20, 47]. The informed consent process is based on the classic ethical principle of respect for persons, such that researchers must ensure that potential study participants make their own decisions whether or not to take part [44]. It should also be noted that, by signing informed consent documents, the study participants have agreed to a controlled breach of their privacy/confidential information for a specific purpose mentioned in the study protocol, and for use over a specific period of time [14]. It is thus important that participants are clearly informed about the methods of handling and use of their personal data, the justification for requesting or obtaining their data from different sources, and the duration of data use and storage, while maintaining their right to withdraw their consent at any time [14]. All guidelines suggest that special attention should be paid to studies involving vulnerable participants who may be unable or have limited capacity to make a decision [10, 21, 48, 49]. In a study on ethical dilemmas in malaria drug and vaccine trials [1], it was stated that, in most cases, obtaining informed consent was problematic because the studies were usually conducted with patients or surrogates with limited educational attainment levels in developing countries, and thus were not able to fully understand the study protocol. Potential participants may not understand the science underlying the study and therefore be able to make proper informed decisions. The finding in that study suggests the need for a better consent processes. As suggested elsewhere in the literature, a consent process considered valid or truly informed should have the following characteristics: (1) provision of adequate information, (2) capacity to understand that information, (3) decision making voluntarily, (4) understanding of information provided, and (5) agreement to the proposed treatment or procedure [50]. It has also been suggested that the informed consent forms are usually too long and complex for a layperson to read and comprehend, but there are various methods to simplify such forms [51]. Researchers are obliged to ensure that they plan their informed consent process with care, even the complicated aspects of research, by having the information explained simply and comprehensibly to the potential study participants. In the present study, over half the malaria research proposals and all malaria drug trial proposals submitted to FTM-EC required revision of the informed consent process to meet such requirements.

When examining different research designs, it was found that proposals on laboratory-based (usually using archived specimens) and epidemiological studies had fewer ethical issues raised by the FTM-EC than clinical research and drug trials. However, “privacy and confidentiality” showed an opposite, albeit non-statistically significant, trend. This concurs with one of the main ethical considerations in all international guidelines, that possible invasions of privacy of individuals and breaches of confidentiality may arise in biomedical and behavioural/social research [22, 24, 25, 27, 46]. As suggested in the guideline on ethics of research related to healthcare in developing countries, one of the RECs’ primary tasks is to review the ethical acceptability of research proposals with special attention to the provisions for protecting the security and confidentiality of data about patients [7]. From a data protection and privacy issues point of view, all study participants must be informed about not only what they have to do in the research, if they decide to participate, but also what and how the research plans to use the data that they provide [46]. There were reports of potential improper use or misuse of the collected data; even in case studies showing that what seems to be unlinked information can sometimes be taken for use out of context and lead to a personal data breach [46]. This could be because study procedures in clinical and drug trial proposals tended to be stated clearly by the study investigators in protecting participants’ personal information, whereas proposals of laboratory (predominantly using stored specimens) and epidemiology studies (predominantly using medical records and CRFs in healthcare settings) were generally not as clear. As suggested in the literature about ethical and legal issues of research using human specimens and clinical data, materials should be provided to the investigator with the minimal clinical information needed for the study and specimens should not be individually identifiable where applicable [15, 16, 20].

The malaria proposals that required additional review by other RECs, whether international or local, appeared to raise more ethical issues regarding study design and methodology, study participants, informed consent processes and study facility and supporting documents. This might be because such proposals are likely to be developed by non-local investigators and thus there might be certain local sensitive issues that were overseen by the proposal developers. As suggested in the literature regarding ethical principles in conducting clinical research in developing countries, investigators should consider the principle of collaboration by developing partnerships with local researchers, policy makers and the community [2]. It is recommended that the study should respect the community’s values, culture, traditions, and social practices. Even regarding scientific validity, the research team should ensure that the scientific design and methodology has recognized social value for the primary beneficiaries of the research, and is feasible within the social, political, and cultural context, or provides sustainable improvements in the local healthcare and physical infrastructure [2].

Ethical issues that should be considered, as part of field studies of malaria in developing countries, were also discussed in terms of practical problems that arise in the course of research. These include differing circumstances in developing countries, such as standards of care, incentives and reimbursement, insurance and indemnity [28]. The local REC should ensure that local context is adequately addressed and convey their knowledge of local factors that affect human subject protection [52]. The issues raised by the FTM-EC for these international studies confirm the notion that local ethical review should consider the vulnerability of study participants, particularly in remote border areas with no or poor access to healthcare services, alongside cultural beliefs and attitudes, literacy and language [25, 28]. As has also been suggested by others, the REC should provide public assurance of such protection by ensuring that investigator(s) are suitable to conduct the study, facilities are adequate, and that the methods and materials and informed consent process are appropriate [33].

Malaria research studies conducted along the Thai borders generally involved minority populations in endemic areas. These populations are considered vulnerable, with poor/limited educational attainment and cross-border/migrant status. Therefore, it is not surprising to observe that all ethical issues (except study rationale) were raised for such proposals by FTM-EC. The principle of fair selection of study population is important to minimize risks while enhancing other critical principles of collaborative partnership and social value when the research study is taking place in local communities [2]. Balancing risk–benefit considerations, informed consent processes and having respect for recruited participants and study communities, especially among vulnerable populations, remain the major concerns of all RECs [2, 25].

There were more ethical considerations in almost all aspects for drug trials and clinical studies compared with proposals for epidemiological studies. Clinical research studies usually directly involve human subjects, either with preventive, therapeutic, or non-therapeutic procedures. In general, the study procedures in such study designs put human subjects at higher risks, thus there are more ethical concerns. The primary ethical considerations of clinical studies are competent medical treatment and care, alongside an acceptable risk–benefit balance [40, 41, 44]. However, many laboratory research studies use stored specimens, with less invasive procedures, and epidemiology studies usually employ data collection through medical records, CRFs or questionnaires. Ethical issues for the latter, therefore, mainly concern confidentiality and privacy of the study participants [25]. However, it was found that studies that collect new specimens received more comments on ethical issues. There remains debate among RECs about solutions for issues around sample export, storage, and reuse [15, 16, 34]. However, it is recommended that in order to ensure adequate protection of human research subjects participating in scientific research, RECs bear the responsibility of guaranteeing that participants are provided with sufficient detail to be able to provide informed consent as well as to understand the reality of genetic research as it is practiced [53].