Issues specific to resource-limited settings
Introduction
Clinical trials are necessary for the development of new therapeutic agents and for optimizing the use of many medical practices in general. It is not surprising that few clinical trials sponsored by pharmaceutical companies and developed nations take place in low-middle income countries. These countries require large scale clinical trials including representative patient populations and addressing clinical questions relevant to their practice. It may also be that international trial efficiency can be improved owing to the reduced cost of research and the high burden of treatment naïve disease. However, those conducting clinical trials in resource poor settings (RPSs) are faced with wide range of challenges. While each country or region is distinct, examples of challenges include inadequate infrastructure, poverty, cultural differences and differing ethical issues, cumbersome administrative procedures, difficulties in obtaining informed consent and limited or absent regulatory and governing bodies.
To prevent developing countries participating in international trials from exploitation and ensure safety of participants, all multinational trials must pass through ethical reviews by the ethical committees or IRBs of both sponsor and host countries. IRB reviews in the host countries are meant to assess the risks and benefits of the trial to its population, ensure the trial addresses its health priorities, and identify the drawbacks in the IRB review of the sponsors. However, in many resource poor settings, they are either non-existence or lack human resources or standard operating procedures to conduct ethical reviews. Some of them lack personnel with skills in research ethics and thus, may find complex research protocols difficult to review.
Delay in ethical review process is another barrier to conducting clinical trials in resource limited settings. In some countries, the ethical review board and regulatory systems are complex and unduly strict. Trial protocols have to pass through multiple ethical review committees/ regulatory bodies within the same country and approval has to be at the various levels in a sequential manner, causing unnecessary delay and sometimes non approval. Oftentimes, these committees have different ethical review standards and come up with conflicting findings without a clear definition of an authority hierarchy. Lengthy ethical and regulatory review time delays grant implementation such that the research grant might have expired before recruitment starts.
See links below for useful resources and further information.
Obtaining informed consent for clinical trials in resource limited settings can be challenging because of the low level of literacy, and sociocultural and language barriers. Unlike in developed world, an individual approach to obtaining consent may not be appropriate in many cultures in developing countries because of their communal way of life. Individuals regard themselves as a member of a family, religious group or a community rather than independent individuals. Thus, they seek opinions from one another and sometimes may need to obtain consent from the head of the family, mother in laws, head of various religious groups or their community leaders about their decision to participate in a research. In some communities, researchers will need to take permission from community elders or leaders before they can access members of such communities. In situations where participants give consent to be a part of a trial despite the objection by their leaders or head of families, investigators should identify and take steps to reduce the psychosocial risks associated with such decisions.
Low literacy level and multiple languages in resource poor settings are major barriers to obtaining informed consent. Research questionnaires and informed consent forms have to be translated to the various languages and translations need to be tested and verified for accuracy. The use of innovative means of communications such as hand fliers, street theaters, group meetings, and jingles in local languages can precede discussions with potential trial participants
It also important for investigators to adopt a consent process that is culturally acceptable in that community. Sometimes participants may hesitate to append their signature or thumbprint on the consent form, thinking this can be used against them in the future. In such instances investigators may (with approval from local IRB) fall back on verbal consent, perhaps in the presence a witness who is independent of the study or with an audio recording of the consent.
Administrative systems in resource poor settings are frequently unused to or unsupportive of clinical trials. Complex and unpredictable bureaucracy may hinder progress. A local administrative officer dedicated to handling administrative issues related to the trial can be an invaluable asset in this setting.
Compliance with Good Clinical Practice and maintenance of participant safety requires monitoring of Adverse Events (AE) and Severe adverse events (SAE). Oftentimes, SAE are assessed by linking the trial intervention (drug used) with hospitalization and survival outcomes. In resource-limited settings, this may be quite challenging. This is because factors like level of education, communication, socio-economic and cultural factors influences the health seeking behavior of its members. In Africa for example, people may seek different types of care simultaneously when they are sick (including traditional medicine, self-medication, religious homes and western medicine). Thus, it will be difficult to compare AE/SAE data obtained on the same drug at the same dose but in different settings with different health care system and culture.
Similar issues may hinder accessibility to information from participants. Poorer people may move out of their area to seek support from family members living elsewhere or to seek help from another healthcare facility and are lost to follow up. Losses to follow up may also be as a result of morbidity or demise of participants and for cultural reasons participants’ caregiver may not be readily available to divulge such information. For example, after a woman loses her spouse, there may be a period of mourning during which the woman will be indoors and may not be allowed to talk to strangers about the circumstances surrounding the death of her husband. Educational-cultural differences between clinical trial staff and participants may create a barrier to understanding the context of talking about causes of disease and death.
Careful planning, community engagement and detailed discussions with local healthcare workers may help to ensure that these issues are identified. If identified during the planning stage then strategies to circumvent them or to factor them into the expected study power and analysis can be developed.
Finally, destabilizing events such as disasters, crises, or wars pose enormous practical and ethical challenges to researchers and may call for urgent efforts to protect study participants. A discussion of the various issues that arise in such scenarios is presented here.
- Council for International Organizations of Medical Sciences (CIOMS): International ethical guidelines for health-related research involving humans
- Ndebele P, et al. Regulatory challenges associated with conducting multicountry clinical trials in resource-limited settings. J Acquir Immune Defic Syndr. 2014;65 Suppl 1:S29-31.
- IEA online textbooks [includes Field Trials of Health Interventions, a free download pdf textbook including chapters on Ethical Considerations, Trial Governance, and Community Engagement; produced by London School of Hygiene and Tropical Medicine]
- Research in Low-Resource Countries [Nuffield Council on Bioethics]
- ClinRegs [very useful site aggregating links to IRB and regulatory information around the world, maintained by US NIH]
- Implementation Research Toolkit [although aimed at implementation research rather than randomized trials, this toolkit contains much useful information about research in low-resource countries; produced by WHO Special Programme for Research and Training in Tropical Diseases]
- Clinical Trials in Resource-Limited Settings [series of informative podcasts from the University of Oxford Global Health Clinical Trials Programme]
- Global Health Trials [developed by a collaboration between many research organisations that work in the field of global health aiming to facilitate contact between those working on trials in resource limited settings. It is open access and free. Contains many useful resources]
- Global Health Training Centre
- Dal-Ré, R., Ndebele, P., Higgs, E., Sewankambo, N., & Wendler, D. (2014). Protections for clinical trials in low and middle income countries need strengthening not weakening. Bmj, 349.
- The Ethical Implications of Clinical Trials in Low- and Middle-Income Countries