Barriers and facilitators to the conduct of critical care research in low and lower-middle income countries: A scoping review.

BACKGROUND: Improvements in health-related outcomes for critically ill adults in low and lower-middle income countries need systematic investments in research capacity and infrastructure. High-quality research has been shown to strengthen health systems; yet, research contributions from these regions remain negligible or absent. We undertook a scoping review to describe barriers and facilitators for the conduct of critical care research.
METHODS: We searched MEDLINE and EMBASE up to December 2021 using a strategy that combined keyword and controlled vocabulary terms. We included original studies that reported on barriers or facilitators to the conduct of critical care research in these settings. Two reviewers independently reviewed titles and abstracts, and where necessary, the full-text to select eligible studies. For each study, reviewers independently extracted data using a standardized data extraction form. Barriers and facilitators were classified along the lines of a previous review and based on additional themes that emerged. Study quality was assessed using appropriate tools.
RESULTS: We identified 2693 citations, evaluated 49 studies and identified 6 for inclusion. Of the included studies, four were qualitative, one was a cross-sectional survey and one was reported as an 'analysis'. The total number of participants ranged from 20-100 and included physicians, nurses, allied healthcare workers and researchers. Barriers identified included limited funding, poor institutional & national investment, inadequate access to mentors, absence of training in research methods, limited research support staff, and absence of statistical support. Our review identified potential solutions such as developing a mentorship network, streamlining of regulatory processes, implementing a centralized institutional research agenda, developing a core-outcome dataset and enhancing access to low-cost technology.
CONCLUSION: Our scoping review highlights important barriers to the conduct of critical care research in low and lower-middle income countries, identifies potential solutions, and informs researchers, policymakers and governments on the steps necessary for strengthening research systems.

Background

Over 75% of the global population resides in low or lower-middle income settings, as defined by the World Bank [1], and faces an enormous burden of communicable and non-communicable disease. Improvements in health-related outcomes in these regions requires systematic investments and focus on health-related infrastructure, public health capacity, training, general sanitation and hygiene, and poverty alleviation. In addition, and equally crucial, are investments in research capacity and infrastructure. While the health-related problems in these regions are often unique, locally led research solutions are either inadequate or non-existent [2]. Apart from describing epidemiology or developing diagnostic and prognostic tools or testing interventions, high quality research has been shown to strengthen health systems, especially in countries and settings where such systems are typically fragile [3]. And yet, across disciplines and specialities, the research contributions from low and lower-middle income settings are negligible or absent [4-6]. Specific to critical illness, the epidemiology in low and lower-middle income countries (LMICs) is distinct from high income countries (HIC) in several ways: diseases that bring patients into intensive care units (ICUs) (e.g. tropical infections, toxicology, snake and scorpion bites) [7-9], burden of antimicrobial resistance [10, 11], resources and expertise available for treatment, organization and provision of critical care as a service, quality of care provided, and outcomes from an episode of critical illness [12] In the absence of context-specific information, most ICUs in LMICs are forced to appraise and apply evidence generated from HIC settings. This situation creates gaps in evidence availability and in knowledge translation. The postulated reasons for this absence of context-relevant data include a heavy clinical burden, lack of research infrastructure and training in relevant skills, absence of funding, regulatory barriers and ambiguities, and the low priority accorded by governments and healthcare systems to research in these regions [13].

A previous systematic review published in 2018 focused on barriers for the conduct of clinical trials in developing countries [14]. However, as this review was focused on trials, rather than research using broader methodologies, and did not specifically focus on the critical care setting, we aimed to perform a review of the literature to describe the barriers and opportunities for the conduct of research in critical care settings of LMICs.

Methods

Search strategy and eligibility criteria for studies

With the help of a librarian, we searched Ovid versions of MEDLINE and EMBASE for all relevant publications from inception to December 2021. We used a strategy that combined multiple keyword terms and controlled vocabulary search terms covering ‘critical care’ and ‘barriers and facilitators’ and ‘research’. The detailed search strategy is provided in the S1 Appendix. Additionally, we screened the reference lists of all included articles. Based on the research teams’ language knowledge and the lack of resources to include a translator, the search was restricted to English-language publications.

We included original studies that reported on barriers or facilitators to the conduct of critical care research in LMICs. For this review, we included studies that used qualitative or quantitative approaches, or a mixture. We excluded editorials, commentaries, letters to editor and other non-peer reviewed work. For the purposes of this review, we included countries that have been classified as low or lower-middle income as per the World Bank country and lending groups classification [1]. Since the definition of critical care is variable, we included all studies where authors have identified the population as critically ill.

We used a modified PICO (Population, Intervention or Exposure, Comparator, Outcome) approach for study selection. Mapped to the Population-Concept-Context (PCC) framework designed by the Joanna Briggs Institute for Scoping Reviews, the corresponding PCC would be:

Population: critically ill patients of any age

Concept: barriers and facilitators to the conduct of critical care research

Context: Low and Lower-middle income countries

Study selection, data extraction and quality assessment

Two reviewers (BKTV and EG), both having critical care clinical and research experience in a LMIC setting, independently reviewed titles and abstracts, and where necessary, the full-text of identified articles to select eligible studies (as defined above). For each eligible study, the same two reviewers independently extracted data on barriers and facilitators. A standard data extraction form was designed, and pilot tested prior to extraction. For all studies, we extracted data on study country or region, design, population of interest and barriers and facilitators to research that are identified. Barriers and facilitators were classified broadly along the lines of the previous review [14] and based on additional themes that emerged. Disagreements, if any, were resolved in consultation with a third reviewer (NKJA).

Study quality was assessed using the tools developed by the CLARITY research group for all non-randomized designs [15], and criteria proposed by Kuper for qualitative studies [16]. Study quality was adjudicated independently by the same two reviewers and disagreements resolved as above.

Data analysis

We described the individual study settings, populations studied, design and key observations. In addition, we categorized by themes the barriers and facilitators identified across all the included studies.

Ethics, registration and reporting

Based on the study design, we did not seek ethics committee approval. The protocol was registered as a preprint on Open Science Forum (doi:10.17605/OSF.IO/9UQNS) prior to analysis [17]. The review is being reported as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) checklist (S4 Appendix) [18].

Deviations from protocol

While our original protocol specified inclusion of only original articles and articles restricted to critical care, we had to make exceptions to these prespecified rules in two instances. Our search yielded only 6 papers of relevance and we were keen to maximise information and learning. Hence, we shifted our strategy from a restrictive approach to including these studies in order to maximise insights on barriers and facilitators to the conduct of research in LMICs. We believe this approach is in alignment with the broad objectives and definitions of scoping reviews.

Results

Study flow

We identified 2693 citations from the search of electronic records (Ovid MEDLINE and EMBASE) and a review of the bibliography of the included studies and relevant review articles. We evaluated 49 studies in detail and identified 6 studies for inclusion (Fig 1). The two reviewers (BKTV and EG) achieved complete agreement on the included studies.

Fig 1

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only.

Study characteristics

We present the characteristics of the 6 included studies in Table 1. Of the included studies, 4 were qualitative [19-22], 1 was a cross-sectional survey [23] and the study by Aluisio and colleagues was described to be an ‘analysis’ [24]. All included studies were published as full articles. The study by Ahmed [21] included participants from Africa and Latin America; the study by Franzen [19] included participants from Ethiopia, Cameroon and Sri Lanka. The study by Johnson and colleagues [22] included participants from Colombia and Sawe’s study [20] included participants from Tanzania. The study by von Arnim [23] included participants from Southeast Asia, Latin America, Africa and Eastern Europe. The publication by Aluisio [24] was reported as an ‘analysis’ paper and the population of interest was broadly low and lower-middle income countries. The total number of participants ranged from 20–100 across the different studies and included physicians, nurses, allied healthcare workers and researchers.

Table 1

Characteristics of the included studies.

Author, Location/s	Year of publication	Subjects (n)	Type/ Methods	Focus of study	Additional details
Ahmed [21]Africa and Latin America	2020	Participants from Africa and Latin America (n = 21 in first year and 40 in second year)	Qualitative–focus group discussions	Barriers and strategies	Focus group discussions at the annual American Society of Tropical Medicine and Hygiene conference, led by researchers who had repatriated to home countries, with participants keen on taking a similar route.
Aluisio [24]Low and lower-middle income countries	2019	NA	Analysis	Challenges and opportunities	Analysis of the challenges and opportunities for clinical emergency care research in low and lower-middle income countries.
Franzen [19]Ethiopia, Cameroon and Sri Lanka	2017	Participants from Ethiopia, Cameroon and Sri Lanka (n = 57)	Qualitative–mixed methods (interviews, focus group discussions and process mapping)	Barriers and enablers	Qualitative evaluation of barriers and enablers to health research capacity from Ethiopia, Cameroon, and Sri Lanka.
Johnson [22]Colombia	2021	Participants from three centres in Colombia and the coordinating centre for the registry (n = 20)	Qualitative mixed methods (interviews and ethnography)	Barriers and enablers	Qualitative evaluation of stakeholders from 3 centres in Colombia focused on the challenges to implementing a neurotrauma registry
Sawe [20]Tanzania	2020	Participants from 5 centres in Tanzania (n = 49)	Qualitative—focus group discussions	Barriers and facilitators	Qualitative study examining barriers and facilitators to the collection of high-quality data for trauma patients with the intention of exploring opportunities and challenges for establishment of a trauma registry
Andre-von Arnim [23]Southeast Asia, Africa, Latin America and Eastern Europe	2017	Participants from Southeast Asia, Africa, Latin America and Eastern Europe (n = 47; predominantly from Latin America)	Quantitative -survey	Challenges and priorities	Survey of clinician scientists from LMICs regarding priorities and challenges for pediatric critical care research

LMIC, low-and lower middle income country.

Barriers and facilitators

Table 2 reports on the common barriers identified from the 6 studies and Table 3 provides details of the facilitators to research or the proposed solutions emerging from these studies. Barriers and facilitators were broadly classified under 7 themes–Finance, Human capacity/factors, Ethics, Governance and Regulatory, Research Environment, Operational, Competing demands and Others.

Table 2

Barriers for the conduct of critical care research in LMICs.

Theme	Sub-theme	References
Financial	Limited local funding for research and for projects in LMICs and limited national investment in research in generalForced to depend on international grant funding with low chances of successLimited funding for travel to International conferences which in turn reduces global peer support and networking	Ahmed [21], Aluisio [23], Franzen [19] and Andre-von Arnim [23]
Human capacity/factors	Lack of access to mentorsLack of awareness among researchers of local research prioritiesLimited research support staffLimited access to Statistical supportFewer trained researchers per capita in LMICs and low confidence among researchersAttitudes with respect to research related documentation among researchers	Ahmed [21], Andre-von Arnim [23], Franzen [19], Johnson [22] and Aluisio [24]
		Sawe [20]
Ethical, governance and regulatory issues	Issues related to Ethics Committee/Institutional review boardLess regulatory infrastructure with weak systems and limited guidance and oversightPaucity of training in ethical frameworks for personnelHigher prevalence of vulnerable patients which makes ethical issues more challengingBureaucratic organizations and centralized hierarchies in academic institutionsMultiple permissions and approvals needed for researchFinancial regulations inhibit purchasing of materials	Andre-von Arnim [23], Franzen [19], Johnson [22], Aluisio [24]
Research environment and infrastructure	Limited infrastructure and equipment in laboratories including access to materials and poor internet connectivityLack of or limited research job opportunitiesAccess to scientific material (journals, databases, etc.) is limitedLimited training opportunitiesLack of dedicated research timeLack of autonomy in research projectsDifficulty with publications, both in accessing published literature and in getting publishedAbsence of reliable medical recordsLimited teamwork, local networking and collaborative spiritInconsistent documentation and archiving systems	Ahmed [21], Aluisio [24], Andre-von Arnim [23], Franzen [19]
		Franzen [19]
		Franzen [19]
		Sawe [20]
Operational barriers	Difficulties with patient recruitmentTrial operations are complex and start-up stages are cumbersomeBurden of data collection when high seen as a barrier	Andre-von Arnim [23]
		Franzen [19]
		Johnson [22]
Competing demands	High clinical burdenComplexity and severity of diseases	Johnson [22], Andre-von Arnim [23], Aluisio [24]
Others	Lower access to technology and lower comfort levels with use of technologyPoor internet connectivity and information technology supportUnfeasible outcomes in studies of emergency and critical care, e.g. 90 day mortality	Johnson [22], Aluisio [24]

Table 3

Facilitators and proposed solutions for the conduct of critical care research in LMICs.

Theme	Facilitators/Solutions proposed	References
Finance	Greater national and institutional investmentPublic-private partnerships in LMICsCollaborative effort between local researchers to seek fundingPartnerships between HIC and LLMICs and joint applications for funding	Ahmed [21], Aluisio [24], Franzen [19], Sawe [20]
Human capacity/factors	Develop a local mentorship network that can actively promote junior colleagues and facilitate access to mentors from HICsFoster networking and knowledge sharing between local researchersStaying connected with local research priorities by engaging with national and regional professional organizationsMotivated and driven clinicians and researchers	Ahmed [21], Johnson [22], Franzen [19], Andre-von Arnim [23]
Ethical, Governance and Regulatory	Development of research ethics boards in LMICs which needs investment from local institutions and partnerships between institutions in these regionsTraining in research ethics and trial designGreater resources for Ethics Committees and legal backingGreater research-policy interaction and engagementStreamlined IRB review	Aluisio [24], Franzen [19], Andre-von Arnim [23]
Research Environment	Collaboration with HIC partners for sharing research resources (e.g. lab resources)To overcome the problem of limited job opportunities, researchers to consider framing proposals around local priorities and develop multi-disciplinary skillsetsOpportunities for career progression for researchers and other incentivesInstitutional support for accessing journals and databasesTraining researchers in methods starting from medical schoolDevelopment of a centralised institutional research agendaTraining in grant writing skills and work-based trainingInculcating a research culture at the institutional level and stakeholder engagementEvents to enable networking e.g. opportunity to participate at conferencesImproved medical recordsLocal support provided by hospital administration	Ahmed [21], Johnson [22], Aluisio [24], Franzen [19], Andre-von Arnim [23]
Operational	Facility commitment to standardizing care- which will promote research	Sawe [20]
Competing demands	Protected research time	Andre-von Arnim [23]
Others	Enhancing access to low-cost technology including mobile phones, tablet-devices for data collection and telemedicineThe presence of an easy-to-use online data collection tool and flexible data collection platformOutcomes for studies should be based on context and available resourcesA minimum core dataset to be developed in LMICs for specific disciplinesAddition of structure and process metrics in studies along with clinical and patient dataProviding rationale and context to stakeholders about the research being undertakenAbility of a project to serve future and long-term needs seen as a facilitator	Johnson [22], Aluisio [24]

Common barriers include the limited funding available for research and for conference travel in LMICs, the poor institutional and national investment in research, inadequate access to mentors, a lack of awareness of local research priorities, absence of training in research methods, limited research support staff, and absence of statistical support. Additional barriers related to ethical and governance systems including the need for multiple approvals, and the weak regulatory frameworks in place in these regions.

Quality of included studies

We were able to adjudicate on the quality of all studies with the exception of the publication by Aluisio et al. Given the different study designs and tools, we did not provide a global quality rating, but have made our assessments available as an appendix (S2 Appendix- Ahmed et al., Franzen et al. Johnson et al and Sawe et al. and S3 Appendix- von Arnim et al.). Broadly, studies were of moderate quality, in that each one partially satisfied quality requirements.

Discussion

Our scoping review sheds light on the key barriers and facilitators to the conduct of critical care research in low and lower-middle income countries. The absence of funding, the poor national and institutional investment in research, absence of mentors, the limited research support infrastructure, unreliable medical records, lack of research methods training, ethical and regulatory issues, and insufficient statistical support are key recurring themes. In addition, the high clinical burden, complex trial operations and the choice of outcomes in acute care research also emerge as barriers.

In a previous review, Alemayehu and colleagues examined the barriers for the conduct of clinical trials in developing countries and reviewed the published literature between the years 1995–2015 [14]. Their review broadly identified similar barriers related to funding, ethical and regulatory system obstacles, absence of research infrastructure, logistics and the competing demands on researchers. In addition to these, our study identified barriers related to the choice of outcomes in emergency/critical care research, the absence or the poor quality of medical records and documentation hindering research, and bureaucratic hurdles and the need for multiple permissions. In contrast to their review, our search was broader and extended from inception of databases to March 2021; we focused specifically on critical care research, but broadly on barriers and facilitators to all types of research (and study designs) and did not limit ourselves to clinical trials. Trials are, by definition, complex and large undertakings and perhaps understandably harder to design and execute in countries and regions with an absent or a nascent research infrastructure and culture.

In 2004, the World Health Organization, in its “World Report On Knowledge for Better Health”, emphasized on the need for research as a fundamental component of solutions aimed at improving health in all countries [25]. Despite this, most clinical research continues to be funded, designed, and conducted only in HIC settings. For instance, in an analysis by Thiers and colleagues of country-specific data on trial participation, 66% of all trial sites were from 5 countries in North America, Western Europe and Oceania [26]. While the paper highlighted several encouraging trends suggesting improvement in trial participation from non-HIC settings, gaps remain large.

A 2017 report from the Academy of Medical Sciences, U.K. on “Strengthening clinical research capacity in low-and middle-income countries” [27] identified similar gaps and barriers as highlighted by our review. In addition, the report identified opportunities for strengthening clinical research, including suggestions for formalising career pathways, promoting clinical research early in the professional training of clinicians, and in connecting young scientists with the various stakeholders involved in clinical research in their respective countries and regions.

Implications for practice and research

Our scoping review throws light on some of the persistent challenges to the strengthening of research systems in LMICs. It identifies deep-rooted issues that have plagued healthcare systems in resource-constrained settings. Yet, the review also calls attention to potential solutions and opportunities, several of which are immediately feasible and implementable. Some of these relate to greater collaboration between HIC and LMIC researchers, including joint funding applications, development of a strong mentorship network within LMICs as well as between LMIC and HIC researchers, and the sharing of resources (equipment, technology etc.) between these regions [28, 29]. Additional solutions include training clinicians in research methods as well as in grant-writing and manuscript writing [30, 31], improving the quality of medical documentation and record keeping, and enhancing access to low-cost ubiquitous technology such as mobile phones and tablet-devices for easier data collection and entry. Other solutions specific to critical care research include the development of core dataset for specific disciplines and choosing outcomes that are both relevant, context-specific and feasible [32, 33].

Encouragingly, several newer models are addressing some of the above challenges- the development of critical care registries in Asia and Africa focused on evaluating case-mix and outcomes from critical illness with harmonized data collection tools [34, 35], the embedding of the Randomized Embedded Multifactorial Adaptive Platform Trial for Community Acquired Pneumonia (REMAP-CAP) within these registries [36], the recently published international collaborative trial comparing two doses of corticosteroids in severe COVID-19 with nearly 40% of trial participants enrolled from India [37] the World Health Organization led pragmatic SOLIDARITY trial [38] are some important examples.

Strengths and limitations

Our review has several important strengths. We used robust scoping review methods: two researchers searched the databases and extracted data independently; the data abstraction form was piloted; and we did not limit our search to a narrow time period or to a specific research design. We extracted key concepts from the included studies and categorized them into practical themes. Our results inform researchers, policy makers and governments in LMICs on the steps necessary for strengthening research systems in their respective countries.

Our review also has several key limitations. We restricted our search to the two databases MEDLINE and EMBASE as we only found 6 studies that could be included from these two large and popular databases with robust indexing methods. In discussion between the authors, it was strongly felt that the additional effort needed to search other databases would be disproportionate to the likely success in finding additional literature. The ‘effort to yield’ ratio was thought to be low and hence we made the decision to stop with the two largest databases. Included studies were of ‘moderate’ quality and we were unable to provide a global rating for each study. While several of the identified themes overlap with previously identified concepts, our review highlights additional barriers and facilitators, several of which are readily addressable.

Conclusion

Our scoping review highlights important and persistent barriers to the conduct of critical care research in LMICs, identifies potential solutions, and informs researchers, policy-makers and governments on the steps necessary for strengthening research systems. While there have been recent encouraging examples that address some of these challenges, broader, multifaceted and systematic strategies with short and longer term goals are essential from Ministries of Health, Public health agencies and other key stakeholders to addressing the deep-rooted problems that have plagued research in LMICs.

Search strategy.

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Study quality assessment (for references [20–23]).

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Study quality assessment (for reference [24]).

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PRISMA scoping review checklist.

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15 Dec 2021

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Please consider using the Mixed Method Appraisal Tool (MMAT) for quality assessment or other appropriate tools as advised by the peer reviewer.

A scoping review highlights gaps to be addressed. To help readers better, please include a paragraph on implications for practice and research based on the scoping exercise.

Do refer to the following guidance on scoping reviews:

1. Peters MDJ, Marnie C, Tricco AC, Pollock D, Munn Z, Alexander L, McInerney P, Godfrey CM, Khalil H. Updated methodological guidance for the conduct of scoping reviews. JBI Evid Synth. 2020 Oct;18(10):2119-2126. doi: 10.11124/JBIES-20-00167

2. Peters MD, Godfrey CM, Khalil H, McInerney P, Parker D, Soares CB. Guidance for conducting systematic scoping reviews. Int J Evid Based Healthc. 2015 Sep;13(3):141-6. doi: 10.1097/XEB.0000000000000050

3.  https://jbi-global-wiki.refined.site/space/MANUAL/3283910770/Chapter+11%3A+Scoping+reviews

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Reviewer #1: This is a well executed and written scoping review. The authors have reported their findings in accordance with the PRISMA-ScR checklist. Extending the inclusion criteria to other languages such as French, Spanish and Portuguese may have provided more studies for consideration. However, this may not be a feasible undertaking for the authors.

Reviewer #2: Summary of the research

The authors have summarized the gaps in the health care systems based in low and lower middle-income countries. One of the main concerns is that there is lack of resources that go into research and infrastructure to support the health care systems. They have also noted that high quality research contributes to quality health care system yet this lacks in low and lower middle-income countries where their health systems are wanting. Their focus is on critical illness where contextual issues matter in that evidence generated from high income settings might not be applicable to these settings. Moreover, the authors have highlighted that there is paucity of data regarding critical care research. Therefore, the authors have set out to conduct a scoping review with an aim to describe the barriers and facilitators for the conduct of critical care research in low and lower middle-income countries.

Strengths and limitations of the study

The manuscript has been written clearly. The authors have used standardized and clear methodology. The authors went ahead and conducted quality assessment of the included studies. The authors have also acknowledged their limitations in their methods.

The authors are addressing a key area in health by conducting a scoping review though, they only conducted the search in two databases without providing a justification for their choice, this limits the literature available to provide the required evidence. The eligibility criteria were not very explicit for example type of original studies to be included and the specific study designs. Furthermore, the authors used PRISMA 2009 guidelines to guide their PRISMA flow diagram yet there is an updated PRISMA 2020 guidelines (Page et al,2021).

Examples and Evidence

Major issues

Line 126 to line 132, describes the eligibility criteria for the studies. The authors might want to look at the five included studies again (Table 1) and verify if they meet the eligibility criteria.

1. Andre-von Arnim et al focuses on critical care research in children

2. Sawe et al addresses the barriers and facilitators in implementing the trauma registries

3. Franzen et al addresses the challenges and enablers in conducting clinical trials but the focus is not on critically ill patients

4. Ahmed et al focuses on broader issues of researchers and not the ones involved in care of critically ill patients

5. Alusio et al appears to be a literature review on clinical emergency care research

The authors could come up with a clear eligibility criterion guided by the Population-Concept-Context (PCC) framework designed by the Joanna Briggs Institute for scoping reviews. This will guide them in developing a focused question and in study selection.

Minor issues

1. In line 115, “……. perform an updated review of literature”, this may not be appropriate given the two different methodologies and focus, that the former evidence synthesis Alemayehu et al, was a systematic review on a different focus on clinical trials while for the authors’ synthesis, it is a scoping review with a focus on critically ill patients.

2. In line 49, ‘….to understand barriers and facilitators ….’ while in line 115, ‘….to describe the barriers and opportunities….’. The authors have used different words to state their objective. From the findings of the scoping review ‘….to describe.’ would be more appropriate and scientifically measurable as compared to understand.

3. In line 120, ‘…Ovid versions of MEDLINE and EMBASE.’ The authors searched only two databases. Can the authors provide the justification for using only the two and not any other databases? Given the topic they are addressing, they might have benefited in conducting searches in more than two databases.

Additionally, they can also provide the rationale for restricting the publications to English language only.

4. In line 1,2,101,127,135,191,197,201,246,248,261,265,274 there is use of the abbreviations LMICs and LLMICs. The authors’ focus is on low and lower middle-income countries as indicated in the title. The authors should use the right abbreviation and be consistent throughout the manuscript to prevent confusion to the readers

5. In line 144, the authors indicated they used Cochrane Risk of Bias 2.0 tool to assess quality in the randomized controlled trials (RCTs) yet in the included studies RCTs, were not part of the studies.

6. In line 152, the authors have reported ‘We also provide a descriptive summary of the quality of the included studies.’ However, there is no reference to where the description can be found such as a table, supplementary material etc.

7. In line 182, Table 1: the authors can include year of publication in column one in addition to author and location. For column 2, I would suggest the authors to use the title ‘participants’ so that to eliminate repetition of the word in all the rows. Column 3, ‘type/methods’ title is not clear you need to state … ‘type of…or methods of….’ Or you can use the term ‘study design’ for the title of column 3.

8. In line 197 and 201, table 2 and 3, the authors have reported on the barriers and facilitators for the conduct of critical care research. The authors had indicated they will use themes in data synthesis; however, they have listed the themes from line 188 to line 195 but no further description of the themes.

9. In figure 1, PRISMA flow diagram, the authors have used PRISMA 2009, they should use the updated PRISMA 2020 guidelines (Page et al ,2021) to guide their flow diagram. The authors could add some footnotes to clarify wrong population for instance, is it people who are not critically ill, or participants are from high income settings etc.

Also, wrong study design needs to be clarified since the authors had indicated in line 126-127, that they will include original studies that had used qualitative or quantitative or mixed methods design.

The included studies in last box, it is indicated ‘studies included in qualitative synthesis’, yet this is a scoping review (had both quantitative and qualitative). The authors can revise to read ‘studies included in the synthesis.’

10. In line 272-275, the conclusion is the same as the one in the abstract. In the main manuscript, the conclusion can be revised with focus on the summarized findings in relation to the objective of the review and in addition, the authors can highlight the gap in their findings and recommend the type of research to address it.

11. In S2 appendix, please indicate the tool used for quality assessments in the titles.

12. In S3 appendix, please indicate the study that was assessed using the tool mentioned

13. In line 352, Aluisio AR paper appears to be a literature review on the topic. The authors might want to look at their eligibility criteria which they had stated they will include original studies; therefore, this study might not be included. Nonetheless, the authors might want to look at the references and see if they could identify a study that answers their questions

14. The authors can report on any deviations from the protocol published in the open science framework.

15. Since it is more than six months from their last search (March 2021), the authors could consider doing an updated search.

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11 Feb 2022

We would like to begin by thanking the Editorial team and the Reviewers for the in-depth comments and feedback. We appreciate their insights and feel it has helped improve our manuscript. We respond below (reviewer comments are italicized).

Additional Editor Comments:

Please consider using the Mixed Method Appraisal Tool (MMAT) for quality assessment or other appropriate tools as advised by the peer reviewer.

Response: Thank you for pointing us to this resource. For the papers identified by us that were eligible for quality assessment ( one of them a quantitative survey and the other four that used qualitative methods), we have used well validated tools (the tools developed by the CLARITY research group for all non-randomized designs, and criteria proposed by Kuper for qualitative studies). We are happy to use the MMAT if the editorial team strongly feels this is essential.

A scoping review highlights gaps to be addressed. To help readers better, please include a paragraph on implications for practice and research based on the scoping exercise.

Response: We have now added a paragraph in the Discussion section on implications(below).

“Our scoping review throws light on some of the persistent challenges to the strengthening of research systems in LMICs. It identifies deep-rooted issues that have plagued healthcare systems in resource-constrained settings. Yet, the review also calls attention to potential solutions and opportunities, several of which are immediately feasible and implementable. Some of these relate to greater collaboration between HIC and LMIC researchers, including joint funding applications, development of a strong mentorship network within LMICs as well as between LMIC and HIC researchers, and the sharing of resources (equipment, technology etc.) between these regions. Additional solutions include training clinicians in research methods as well as in grant-writing and manuscript writing, improving the quality of medical documentation and record keeping, and enhancing access to low-cost ubiquitous technology such as mobile phones and tablet-devices for easier data collection and entry. Other solutions specific to critical care research include the development of core dataset for specific disciplines and choosing outcomes that are both relevant, context-specific and feasible.

Encouragingly, several newer models are addressing some of the above challenges- the development of critical care registries in Asia and Africa focused on evaluating case-mix and outcomes from critical illness with harmonized data collection tools [29,30], the embedding of the Randomized Embedded Multifactorial Adaptive Platform Trial for Community Acquired Pneumonia (REMAP-CAP) within these registries [31], the recently published international collaborative trial comparing two doses of corticosteroids in severe COVID-19 with nearly 40% of trial participants enrolled from India [32] the World Health Organization led pragmatic SOLIDARITY trial [33] are some important examples. “

Do refer to the following guidance on scoping reviews:

1. Peters MDJ, Marnie C, Tricco AC, Pollock D, Munn Z, Alexander L, McInerney P, Godfrey CM, Khalil H. Updated methodological guidance for the conduct of scoping reviews. JBI Evid Synth. 2020 Oct;18(10):2119-2126. doi: 10.11124/JBIES-20-00167

2. Peters MD, Godfrey CM, Khalil H, McInerney P, Parker D, Soares CB. Guidance for conducting systematic scoping reviews. Int J Evid Based Healthc. 2015 Sep;13(3):141-6. doi: 10.1097/XEB.0000000000000050

3. https://jbi-global-wiki.refined.site/space/MANUAL/3283910770/Chapter+11%3A+Scoping+reviews

Response: Thank you for sharing these excellent resources. In referring to these papers, we note that we have followed the guidance provided in them as well in the original 2005 paper by Arksey and O’Malley paper (https://www.tandfonline.com/doi/abs/10.1080/1364557032000119616).

Specifically, we are well aligned with some of the important points of the updated methodological guidance for the conduct of scoping reviews referred by you (doi: 10.11124/JBIES-20-00167). For instance:

1. Definition of scoping review as provided in the paper: “exploratory projects that systematically map the literature available on a topic, identifying key concepts, theories, source of evidence and gaps in the literature”- we believe our work fits well with this definition. We have now addressed the specific lacunae you have highlighted on the need to add a section on implications for practice and research.

2. Need for a prespecified protocol: “authors conducting a scoping review should consider publishing, registering or making their protocols available via platforms such as Figshare, Open Science Framework..”. Our protocol was registered on Open Science Framework prior to data extraction/analysis.

3. Need for scoping review to be broad-based, exploratory and focused on maximising the output on knowledge gaps: Keeping this in mind, we shifted our strategy from a restrictive approach to including studies to maximising insights on barriers and facilitators to the conduct of research (e.g. inclusion of Alusio et al).

We have also broadly adhered to the recommendations and guidance provided in these papers and have also provided the specific PRISMA Scoping review checklist.

Reviewer #1:

This is a well-executed and written scoping review. The authors have reported their findings in accordance with the PRISMA-ScR checklist. Extending the inclusion criteria to other languages such as French, Spanish and Portuguese may have provided more studies for consideration. However, this may not be a feasible undertaking for the authors.

Response: Thank you so much for this positive feedback. Yes, inclusion of other languages was not feasible for us, given that we don’t have expertise in any of these languages and our lack of access to resources for translation of such work for review.

Reviewer #2:

Summary of the research

The authors have summarized the gaps in the health care systems based in low and lower middle-income countries. One of the main concerns is that there is lack of resources that go into research and infrastructure to support the health care systems. They have also noted that high quality research contributes to quality health care system yet this lacks in low and lower middle-income countries where their health systems are wanting. Their focus is on critical illness where contextual issues matter in that evidence generated from high income settings might not be applicable to these settings. Moreover, the authors have highlighted that there is paucity of data regarding critical care research. Therefore, the authors have set out to conduct a scoping review with an aim to describe the barriers and facilitators for the conduct of critical care research in low and lower middle-income countries.

Strengths and limitations of the study

The manuscript has been written clearly. The authors have used standardized and clear methodology. The authors went ahead and conducted quality assessment of the included studies. The authors have also acknowledged their limitations in their methods.

The authors are addressing a key area in health by conducting a scoping review though, they only conducted the search in two databases without providing a justification for their choice, this limits the literature available to provide the required evidence. The eligibility criteria were not very explicit for example type of original studies to be included and the specific study designs. Furthermore, the authors used PRISMA 2009 guidelines to guide their PRISMA flow diagram yet there is an updated PRISMA 2020 guidelines (Page et al,2021).

Response: We thank the reviewer for this detailed feedback.

1. Use of two databases only: We restricted our search to the two databases MEDLINE and EMBASE as we only found 6 studies that could be included from these two large and popular databases with robust indexing methods. In discussion between the researchers, it was strongly felt that the additional effort needed to search other databases would be disproportionate to the likely success in finding additional literature. The ‘effort to yield’ ratio was thought to be low and hence we made the decision to stop with the two largest databases. We acknowledge this to be a limitation and have added this as an additional point under limitations.

2. PRISMA: Sorry for missing the updated version. This is now rectified and the PRISMA 2020 flow diagram has been incorporated.

Examples and Evidence

Major issues

Line 126 to line 132, describes the eligibility criteria for the studies. The authors might want to look at the five included studies again (Table 1) and verify if they meet the eligibility criteria.

Responses: For the section below, we have included the reviewer text as is and immediately followed it up with a response/justification.

1. Andre-von Arnim et al focuses on critical care research in children: We did not propose to restrict to adult patients- hence, this study was included.

2. Sawe et al addresses the barriers and facilitators in implementing the trauma registries: Admissions related to trauma form a major part of intensive care unit admissions globally. It was our view that this would very much be within the purview of the review.

3. Franzen et al addresses the challenges and enablers in conducting clinical trials but the focus is not on critically ill patients: Yes, we discussed between the 2 reviewers (BKTV and EG) and also with the third reviewer (NJKA)- as the study did not specifically exclude critically ill patients, we proceeded to include. Our search produced limited literature and we were conscious that we don’t exclude any of the relevant published literature in order to ensure that the review maximised the learning opportunities. This approach is consistent with the broad nature of scoping reviews.

We have now added a section under ‘methods’ on ‘deviations from protocol’.

4. Ahmed et al focuses on broader issues of researchers and not the ones involved in care of critically ill patients: Once again, this paper was included after extensive discussions between the reviewers as it was felt that the paper contributed important information to the challenges of conducting research in LMICs. This paper identifies the challenges faced by a unique cohort of research health professionals with a desire to return to LMICs. This provided an opportunity to examine these responses and recognize these challenges. Hence, we considered this paper valuable to our aims.

5. Alusio et al appears to be a literature review on clinical emergency care research: This paper generated the most debate within our group- however, we finally did include for similar reasons as above- that the paper provided important insights. This paper is a systematic analysis of the focussed barriers to research in emergency care in LMICs, where emergency and critical care are closely linked.

The authors could come up with a clear eligibility criterion guided by the Population-Concept-Context (PCC) framework designed by the Joanna Briggs Institute for scoping reviews. This will guide them in developing a focused question and in study selection.

Response: Thank you for directing us to this resource. While we did not explicitly use the PCC approach, our study selection was based on a modification of the PICO approach. The corresponding PCC would be:

Population: critically ill patients of any age- we specified in our methods that since the definition of critical care is variable, we included all studies where authors have defined the population as critically ill. The exception to this is the study by Franzen and we have explained above we chose to include this study.

Concept: barriers and facilitators to the conduct of critical care research

Context: Lower-middle income countries

And the components of this PCC are specified in the section on ‘search strategy and eligibility criteria’ under ‘methods’.

Despite our prespecified approach (protocol was published apriori) and focused question, the scarcity of literature around the topic of interest meant that we had to make decisions on inclusion on a case-case basis for some of the studies.

Minor issues

1. In line 115, “……. perform an updated review of literature”, this may not be appropriate given the two different methodologies and focus, that the former evidence synthesis Alemayehu et al, was a systematic review on a different focus on clinical trials while for the authors’ synthesis, it is a scoping review with a focus on critically ill patients.

Response: Thank you- we have modified this statement.

2. In line 49, ‘….to understand barriers and facilitators ….’ while in line 115, ‘….to describe the barriers and opportunities….’. The authors have used different words to state their objective. From the findings of the scoping review ‘….to describe.’ would be more appropriate and scientifically measurable as compared to understand.

Response: Thank you- agree, we have made the change.

3. In line 120, ‘…Ovid versions of MEDLINE and EMBASE.’ The authors searched only two databases. Can the authors provide the justification for using only the two and not any other databases? Given the topic they are addressing, they might have benefited in conducting searches in more than two databases.

Response: We restricted our search to the two databases MEDLINE and EMBASE as we only found 6 studies that could be included from these two large and popular databases with robust indexing methods. In discussion between the researchers, it was strongly felt that the additional effort needed to search several other databases would be disproportionate to the likely success in finding additional literature. The ‘effort to yield’ ratio was thought to be low and hence we made the decision to stop with the two largest databases. We acknowledge this to be a limitation and have added this as an additional point under limitations.

Additionally, they can also provide the rationale for restricting the publications to English language only.

Response: Our own limited familiarity with other languages and the lack of resources to search and translate from other languages. We have now added a line under ‘ Search Strategy and eligibility criteria for studies’ to reflect this.

4. In line 1,2,101,127,135,191,197,201,246,248,261,265,274 there is use of the abbreviations LMICs and LLMICs. The authors’ focus is on low and lower middle-income countries as indicated in the title. The authors should use the right abbreviation and be consistent throughout the manuscript to prevent confusion to the readers

Response: Thank you- agreed and apologise for the varying abbreviations. We have changed this to LMICs through the document for consistency.

5. In line 144, the authors indicated they used Cochrane Risk of Bias 2.0 tool to assess quality in the randomized controlled trials (RCTs) yet in the included studies RCTs, were not part of the studies.

Response: The intention was to use the ROB 2.0 tool in the event of identifying RCTs. This was prespecified in the methods. Eventually, we did not find any RCTs.

6. In line 152, the authors have reported ‘We also provide a descriptive summary of the quality of the included studies.’ However, there is no reference to where the description can be found such as a table, supplementary material etc.

Response: Apologies for poorly framing the sentence – what we meant is that we have appraised the quality of the included studies. However, this is already mentioned in the previous paragraph under the section ‘study selection, data extraction and quality assessment’. Hence, we have now deleted this sentence as it does not add anything further.

7. In line 182, Table 1: the authors can include year of publication in column one in addition to author and location. For column 2, I would suggest the authors to use the title ‘participants’ so that to eliminate repetition of the word in all the rows. Column 3, ‘type/methods’ title is not clear you need to state … ‘type of…or methods of….’ Or you can use the term ‘study design’ for the title of column 3.

Response: Thank you- all of these changes are now incorporated.

8. In line 197 and 201, table 2 and 3, the authors have reported on the barriers and facilitators for the conduct of critical care research. The authors had indicated they will use themes in data synthesis; however, they have listed the themes from line 188 to line 195 but no further description of the themes.

Response: Thank you- we used 7 themes – finance, human capacity, ethics, governance and regulatory, research environment, operational, competing demands and others. The themes are listed in the tables (Table 2 and 3) on barriers and facilitators. We did not provide any additional text as we feel they are self-explanatory.

9. In figure 1, PRISMA flow diagram, the authors have used PRISMA 2009, they should use the updated PRISMA 2020 guidelines (Page et al ,2021) to guide their flow diagram. The authors could add some footnotes to clarify wrong population for instance, is it people who are not critically ill, or participants are from high income settings etc.

Also, wrong study design needs to be clarified since the authors had indicated in line 126-127, that they will include original studies that had used qualitative or quantitative or mixed methods design.

Response: Thank you- these are now done and the PRISMA 2020 version of the flow diagram has been incorporated.

The included studies in last box, it is indicated ‘studies included in qualitative synthesis’, yet this is a scoping review (had both quantitative and qualitative). The authors can revise to read ‘studies included in the synthesis.’

Response: Thank you- this is done.

10. In line 272-275, the conclusion is the same as the one in the abstract. In the main manuscript, the conclusion can be revised with focus on the summarized findings in relation to the objective of the review and in addition, the authors can highlight the gap in their findings and recommend the type of research to address it.

Response: We have now updated the conclusion in the manuscript.

Below the edited conclusion:

“Our scoping review highlights important and persistent barriers to the conduct of critical care research in LMICs, identifies potential solutions, and informs researchers, policy-makers and governments on the steps necessary for strengthening research systems. While there have been recent encouraging examples that address some of these challenges, broader, multifaceted and systematic strategies with short and longer term goals are essential from Ministries of Health, public health agencies and other key stakeholders to addressing the deep-rooted problems that have plagued research in LMICs. “

11. In S2 appendix, please indicate the tool used for quality assessments in the titles.

Response: Done and also referenced in the main manuscript.

12. In S3 appendix, please indicate the study that was assessed using the tool mentioned

Response: Done and also referenced in the main manuscript.

13. In line 352, Aluisio AR paper appears to be a literature review on the topic. The authors might want to look at their eligibility criteria which they had stated they will include original studies; therefore, this study might not be included. Nonetheless, the authors might want to look at the references and see if they could identify a study that answers their questions

Response: Thank you- this paper generated the most debate within our group- however, we finally did include for similar reasons as above- that the paper provided important insights.

We have checked the bibliography of all the included papers.

14. The authors can report on any deviations from the protocol published in the open science framework.

Response: We have added a section under ‘methods’.

15. Since it is more than six months from their last search (March 2021), the authors could consider doing an updated search.

Response: This is now done and one additional study Johnson et al. was identified. The manuscript has been updated accordingly.

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Response: These are done.

2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

Response: Done

3. Thank you for stating the following in the Funding Section of your manuscript:

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The funder had no role in the design, conduct, analysis of this scoping review or in the decision to submit for publication”

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Response: This is done now

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Response: The PRISMA checklist specific for Scoping reviews is part of the supplementary appendix.

Submitted filename: Response to Editorial and Reviewer comments 2nd Feb 2022.docx

Click here for additional data file.

21 Mar 2022

28 Mar 2022

Response to Reviewer Comments

We thank the Editor and Reviewers for the thoughtful feedback and are grateful for their assistance in improving the manuscript. We respond below- all editorial and reviewer comments are italicized with responses below each comment.

Additional Editor Comments:

Please provide some references for the implications of practice section especially from line 272-278. There are already a number of published studies and systematic reviews on the solutions proposed by the author team.

Response: This is now done- we have added references 29-34 which support the statements in the ‘implications for practice’ section

Reviewer 2 Comments:

Summary:

The authors have responded comprehensively to the comments and incorporated the changes in the manuscript.

Response: Thank you.

Minor issues

1. In line 134, the context can be modified to read ‘Low and Lower-middle income countries’.

Response: this is now done.

2. In line 147 to 148, ‘Study quality was assessed using Cochrane Risk of Bias 2.0 tool…….’

I suggest this sentence should not be included since there was no RCTs in the included studies but relevant to be included in the protocol.

Response: This sentence has now been deleted.

3. In line 149 to line 150, please check the font size

Response: thank you- corrected.

4. In line 196, Please include year of publication in table 1. It helps the reader to interpret the findings appropriately based on the time the research was conducted. It also saves the reader the time and energy taken to go through the list of references to check the year of publication.

Response: Thank you- agree and added.

5. Figure 1 is not clear; the words are faint therefore the reader may strain to make sense of it.

Response: We have now revised this figure for better clarity.

Submitted filename: Response to Reviewer Comments 28 march 2022.docx

Click here for additional data file.

29 Mar 2022

Barriers and facilitators to the conduct of critical care research in Low and Lower-middle income countries: A scoping review

PONE-D-21-24699R2

Dear Bharath Vijayaraghavan,

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Additional Editor Comments:

Table 1 will need to be reformatted or resized to fit to the page.

31 Mar 2022

PONE-D-21-24699R2

Barriers and facilitators to the conduct of critical care research in Low and Lower-middle income countries: A scoping review

Dear Dr. Tirupakuzhi Vijayaraghavan:

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