Research Ethics Committees (RECs) and epidemic response in low and middle income countries

The recent Ebola and Zika virus epidemics in some parts of Africa and Asia have showcased the porosity in disaster preparedness and response, not only in the affected countries, but on a global scale. For the Ebola epidemic, scientifically robust research was started late during the course of the epidemic, with waste of resources and lost research opportunities. Research Ethics Committees have a significant role to play with regards to epidemic response for the future. This paper presents key challenges and opportunities for ethics review during emergencies, specifically for low and middle income countries. There is no better moment to test the efficacy and safety of drugs or vaccines for infected, or at risk populations than during the disaster itself. The main mantras that form the back bone of research ethics review (Helsinki Declaration, the CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects, WHO and the ICH guidelines for Good Clinical Practice) are increasingly showing their limitations. Most protocols are generally from developed countries where the funding originates. Not only is the direct transposition to Low and Middle Income Country (LMIC) settings inappropriate on its own, also, using such guidelines in times of public health disasters might be time consuming, and might also lead to wastage of research opportunities, especially when sociocultural peculiarities, and anthropological research arms are completely excluded or avoided within the care and research packages. Governments should include RECs as key members during the elaboration, and daily functioning of their national public emergency response packages. Developing simple research ethics review guidelines, involvement of health care staff in ethics training, community mobilization, and incorporation of anthropological research during the medical response, research and communication phases, are imperatives in epidemic response.


Introduction
The recent Ebola and Zika virus epidemics in some parts of Africa and Asia have showcased the porosity in disaster preparedness and response, not only in the affected countries, but on a global scale [1,2]. The response of the international community, especially the World Health Organization, humanitarian organizations like Medecins Sans Frontiers (Doctors Without Borders (MSF) and other research partners has been described as late and exemplified by huge collaboration and coordination loopholes. For instance, it took the WHO over 8 months to declare the Ebola epidemic as a global public health concern [2], and well scientifically robust clinical trials came into the scene at the end of the crisis. Obtaining ethical approval from local ethics committees, as well as international collaborating partners for research protocols was a serious hindrance for timely initiation of the research process [2][3][4].
Inexperience and inadequate expertise for rapid and high quality review in emergencies, as well as weak collaboration and coordination gaps in cross-country /institutional research endeavors played significant roles for the late start of these studies [2,5,6].
Research during these disasters provides appreciation of the gravity of such disasters, maps disease spread and key drivers, guides response, permits monitoring and evaluation of interventions, and allows for a keener look at the natural evolution of disease and the rate of mortality and morbidity [2,3]. In conditions with unknown or unproven causes of diseases or available interventions, ethics review may be compelled to shift from the slow and traditional research ethics review process to a more rapid and properly guided approach; for instance, risk-benefit analysis, informed consent and vulnerability [1,3]. Transdisciplinary research teams, though difficult to constitute and coordinate, remain useful in properly handling public health emergency responses, from acute case identification and management, to research and proper anthropological appraisal of specificities of the affected regions. This does not only permit proper and appropriate recommended health practices, but could also go further to enhance trust existing between the response teams and the community. Carrying out research, alongside emergency and humanitarian response, is an ethical obligation during public health disasters [5,7]. Research Ethics Committees (RECs) in low and medium income countries need to be prepared, to properly review protocols in public health disasters in a timely manner, without losing protocol review quality.
There is no better moment to test the efficacy and safety of drugs or vaccines for infected or at-risk human beings than during the public health disaster itself [2]. In the case of the recent Ebola epidemic, over nine clinical trials were carried out when the epidemic had almost disappeared. It is regrettable that most scientifically rigorous clinical research efforts were initiated too late to yield useful data [1,2,4,6].
It is elusive and idle to contend that ethics review during disease can adhere to specific guidelines. The same disaster in different regions of the world mandate different considerations in the ethics review process (health system, human resource, sociocultural peculiarities). It is increasingly very common to accept deviations from standard review guidelines in disasters [8]. This, in no way, should put the ethical backbone of humanitarian, medical and research obligations of the respective intervening teams into the shadows [8]. The vulnerability of the affected countries and peoples is a reality during disasters, and deserves to be addressed with a lot of caution [9]. A poor assessment could lead to the exploitation of research participants, potential lack of trust or unnecessary exclusion of certain groups of persons that deserve to be researched upon, depending on the situation (e.g pregnant women as with the Zika virus epidemic and children). On the other hand, a poor demarcation of the concept of vulnerability can exclude specific groups from benefiting from research (pregnant women and children). For instance, mortality in Ebola was high as early as from the 2nd to 3rd day after contamination. This contrasts with the lengthy timeframes from submission of research protocols, to obtaining approval from RECs. In a review, reported by Rishu et al. [10], these could range from 42 to 188 days during the Zika and Ebola pandemics. We attempt to highlight a few areas to be considered in developing ethics review frameworks, as well as reviewing research protocols during emergencies in LMICs. How can LMICs be prepared to accelerate ethics review in public health emergencies while upholding high ethical standards, is the central question that we attempt to answer in this essay.

Income Countries (LMICs) for the next Pandemic
Well prepared RECs for rapid protocol review remain ethical and scientific priorities, to better control and coordinate future public health disasters. Strengthening of Research Ethics Committees Page number not for citation purposes 3 competence in rapid ethics review is a key recommendation that requires immediate action before the next pandemic [4][5][6]. Clinical research during emergencies remains a key research opportunity not to be missed. Coordination, control and collaboration frameworks of the RECs need to be carefully reconsidered, more than ever before, since an epidemic somewhere remains a risk everywhere [1,[7][8]. The obstacles to conducting emergency research in LMICs include: obtaining timely research clearances, forging new collaborations, training research staff, negotiating material transfer agreements, sourcing and importing drugs and sophisticated equipments, and ensuring access to a reliable power [1][2][3]. It is a moral and ethical obligation for countries and the international scientific community to prepare RECs for rapid ethics review before the next pandemic. This is particularly concerning for  [1,2,4]. Not only is the appropriateness of direct transposition to LMIC settings inappropriate on its own [12], using such guidelines in times of public health disasters might also be time consuming and lead to waste of research opportunities, especially when sociocultural peculiarities and anthropological research arms are completely excluded or avoided within the research package [2,12]. Strengthening and building capacity of REC members in most LMICs remain an urgent imperative. Most of them receive little or no support from respective governments, have members not properly trained in research ethics, and operate on altruistic grounds [11]. This could predispose them to unconsciously underappreciate the ethical appropriateness of research protocols from elsewhere.
This becomes even more concerning in cases of emergencies.
Richardson et al. have advocated support of local RECs during emergencies to provide robust and rapid ethical review [8]. Without underrating the importance of such support, preparing country specific review guidelines for public health emergencies upfront would be more productive.
People experiencing a public health emergency, especially with high mortality and morbidity rates, and at times with unknown causes evidence-based treatment options are inherently vulnerable. Doing research in such a situation of uncertainty is a moral mandate for the scientific community. Imagine no research is done during epidemics, then, this will simply mean leaving the world at the expense of future pandemics, since the same inputs, are bound to produce the same outcomes, everything being equal. This however,  [18].
Secondly, high attrition rates from trials, and thirdly, return to traditional medical practices, which might be ineffective or even potentially dangerous. It must be remembered that many patients in LMIC do take concomitantly, western medicine and traditional medicine. Ethnographic inputs from Anthropologists and Sociologists are unavoidable and they justify the ethics review process in emergencies to be better appreciated, not as a one point event, but as an ongoing process. Ejeta et al. have highlighted the utmost importance of developing behavioral theories and models addressing preparedness needs specific to LMIC [14]. The

Adapting useful requirements for RECs during emergencies
A National Academy of Sciences, Engineering and Medicine expert committee (United States of America) have identified seven moral requirements to be respected during epidemics, which could be useful to RECs [5]: scientific and social value, respect for persons, community engagement, concern for participant welfare and interests, a favorable risk-benefit balance, justice in the distribution of risks and benefits and post-trial access.
It is a moral responsibility on the part of the research team to make affected communities to come to the realization that carrying out which competent REC has the competence to undertake such reviews. It is abominable and just unacceptable for public health disasters to be declared not by country public health officials, but by international bodies. Though cross-country collaboration remains an ideal, health systems strengthening to boost competence of national health systems to be capable of declaring, reacting to and managing these disasters, can only be better undertaken and coordinated by local actors. Clear rules for full and expedited review might be helpful for the organization of such reviews [1,4,6]. Adapting standardized or traditional ethics review guidelines during emergencies might be time consuming, inappropriate and could lead to sub-optimal quality of ethics review [12]. A simplified emergency response review framework for countries could be helpful. There is a risk of a mismatch in researcher and community perceptions of what makes research ethical, and this could disrupt trust and render efforts counterproductive with both sides tending to lose [12,18] Provision of documents in a simple language has been recommended elsewhere [20]. Pretesting of these documents could be helpful. This could be an opportunity, to, in a faster way, ascertain grey areas with the understanding of the meaning, causes, treatment and implications of these epidemics in specific areas.
The appropriateness of the research design is a key scientific and ethical consideration. Sound science is an ethical cornerstone [5].
With most of these studies generally very expensive to carry out (especially under disaster circumstances), it is further unethical to abuse the altruism of research participants for weak or poor quality research, where the findings would not be helpful.