Abstract
Abstract
Introduction
Published clinical trials offer valuable insights into the clinical research landscape in Portuguese-speaking African countries (PSAC)—Angola, Cabo Verde, Guinea-Bissau, São Tomé and Príncipe and Mozambique. The objective of this comprehensive scoping review is to systematically map and analyse randomised clinical trials (RCTs) evaluating pharmacological interventions conducted in PSAC from 1995 to 2024, in order to identify research trends, targeted diseases, geographic distribution and evidence gaps to better understand the development and evolution of clinical trials in the region. This is the first comprehensive scoping review to examine the clinical trials landscape in PSAC.
Methods and analysis
This scoping review adheres to the Joanna Briggs Institute methodology for scoping reviews, which builds on the Arksey and O’Malley methodological framework (refined by Levac et al) and will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. A dual-search strategy will be used, consulting 4 electronic databases (MEDLINE, EMBASE, African Index Medicus, Cochrane Central Register of Clinical Trials) and 3 clinical trials registries platforms (Clinicaltrials.gov, International Clinical Trials Registry Platform, Pan African Clinical Trials Registry). Eligible studies will include RCTs conducted in at least one of the PSAC. Extracted data will include trial characteristics, targeted diseases, phases and designs, funding and ethical compliance. Risk of bias (RoB) will be assessed using the Cochrane RoB tool V.2.0 to evaluate the quality of the evidence included in the scoping review. Conclusions will be drawn upon the comparison between countries and their scope of clinical research, together with comparison with countries from other geographies, considering disease profiles.
Ethics and dissemination
Ethical approval is not required. Results will be disseminated through a peer-reviewed publication, conference presentation and in plain language in social media, both in Portuguese and in English.
PROSPERO registration number
This protocol is registered in the Open Science Framework https://osf.io/5nhc9.
Keywords: Clinical Trial, Research Design, Africa South of the Sahara, Systematic Review
STRENGTHS AND LIMITATIONS OF THIS STUDY.
This protocol provides a systematic and transparent study design for the first scoping review to map the development of clinical trials in Portuguese-speaking African countries (PSAC) over the last three decades.
This study fills a critical gap in the literature, as no previous reviews have been conducted on this topic, or explored the scope, quality and evolution of clinical trials in PSAC, a region where clinical research ecosystems remain underdeveloped and underreported.
This comprehensive scoping review includes a risk of bias (RoB) assessment for all randomised clinical trials (RCTs) included in the study, using the Cochrane RoB V.2.0 tool, offering a novel layer of critical appraisal not commonly implemented in scoping reviews.
This review focuses exclusively on RCTs evaluating pharmacological interventions, which enhances internal validity, although it may exclude valuable insights from non-randomised studies or non-pharmacological interventions.
Despite an inclusive search strategy, designed to minimise language and publication bias, some eligible studies may be missed if not indexed in the selected databases and registries.
Introduction
Clinical trials, in particular randomised clinical trials (RCTs), are foundational for evidence-based medicine.1 Through minimising biases and confounding, RCTs offer robust evidence on the efficacy and safety of interventions.1 2 They advance medical knowledge and play a significant role in improving global health outcomes, particularly in regions with higher disease burden.3
Conducting RCTs is complex, requiring adherence to strict safety and ethical standards.4 Despite bearing the largest global disease burden, low- and middle-income countries (LMIC), particularly in Africa, still remain underrepresented in global clinical research—with <3% of the world’s clinical trials carried out on the continent.5,8 These regions benefit the most from clinical research and improvements in disease prevention and treatment.9
Developing LMICs requires locally initiated research, identifying needs and delivering culturally acceptable and cost-effective tailored solutions.10 The African environment has been labelled as ‘not conducive’ to clinical investigation, with many of the underlying challenges—insufficiently trained human resources and commercial viability—having yet to be formally explored.11 12 Trials are also influenced by early research phases being conducted elsewhere, often disconnected from local contexts.13 Despite these issues and challenges, Africa is becoming an emerging destination for clinical research.14 The creation of the African Medicines Agency and other regional efforts have leveraged opportunities to unlock clinical research potential on the continent, through strengthening systems and promoting harmonisation.15
Portuguese-speaking African countries (PSAC)—Angola, Cabo Verde, Guinea-Bissau, São Tomé and Príncipe and Mozambique—share cultural identity, linguistic and regulatory similarities that make them a particular cluster for examining clinical research development.16 17 These low- (Guinea-Bissau and Mozambique) and lower-middle (Angola, Cabo Verde and São Tomé and Príncipe) income countries represent a population of over 73 million people and cover an area exceeding 2 million square kilometres.18
PSAC face a dual burden of high infectious diseases prevalence (malaria, tuberculosis, HIV and neglected tropical diseases) and rising non-communicable diseases (cardiovascular diseases, cancer, diabetes and chronic respiratory diseases) that account for 32%–70% deaths. Slow progress in mitigating both categories contributes to increasing burden of disease.19 These shared challenges create opportunities for collaborative research initiatives, which remain sparse and fragmented.20
Structural and regulatory challenges have hindered RCTs implementation in the PSAC, the extent and quality of which remain unclear. Initiatives aimed at strengthening ethical review and clinical research regulatory capacity in PSAC have been rare (BERC-Luso, CT-Luso and LusoAfroBioEthics Projects) and began to address these gaps.21,23
To date, no scoping review has been conducted to map the scope, evolution, quality and characterisation of RCTs in PSAC in the last 30 years. This gap has been confirmed through a preliminary search of the body of literature in PROSPERO, Open Science Framework, Cochrane Database of Systematic Reviews, Medline (PubMed) and Joanna Briggs Institute (JBI) Evidence Synthesis on 22 March 2025. Authors have established that there are no current or underway scoping reviews (or systematic reviews) on this area.
Previous literature often excludes PSAC from broader analysis of LMICs or African RCTs.4 13 This comprehensive scoping review will systematically map and analyse RCTs evaluating pharmacological interventions conducted in PSAC from 1995 to 2024, identifying research trends, diseases targeted, geographic distribution and gaps to understand the development and evolution of clinical trials in the region. It will address the existing gap by using established methodology.24 It will also identify and quantify key variables—such as the number of clinical trials, diseases targeted, research output, evidence quality—and, where possible, compare findings with other African LMICs and Portuguese-speaking countries.
Methods and analysis
Protocol and registration
This protocol is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines and it is registered on the Open Science Framework https://osf.io/5nhc9.25 26 This scoping review will be conducted in accordance with the JBI methodology for scoping reviews, which builds on the Arksey and O’Malley methodological framework with refinements proposed by Levac et al, and will adhere to the indicated framework: (1) Identifying a research question, (2) Development of comprehensive search strategy, (3) Identification of relevant studies, (4) Selection of studies, (5) Charting data and (6) Collation, summary and report of results (table 1).27 28 No stakeholder consultation is planned for this scoping review.
Table 1. Application of Arksey and O’Malley methodological framework (refined by Levac et al).
| Arksey and O’Malley framework stage (rev. Levac et al) | Protocol application |
|---|---|
| Identifying a research question | “What are the characteristics and trends of clinical trials conducted in Portuguese-speaking African countries over the last three decades?” |
| Development of comprehensive search strategy | A dual-source strategy will search four bibliographic databases (MEDLINE, EMBASE, AIM, CENTRAL) and three clinical trial registries (ClinicalTrials.gov, ICTRP, PACTR), covering the period between 1995 and 2024, without language restriction |
| Identification of relevant studies | Records will be managed using Zotero for reference management and deduplication. Retrieved studies will be exported to Rayyan for blinded screening. Duplicate records will be identified and removed automatically and manually verified |
| Selection of studies | Inclusion and exclusion criteria are clearly defined based on study type, setting, design and participants. Two independent reviewers will screen studies using Rayyan, with conflicts resolved by consensus or third-party adjudication |
| Charting data | Data will be extracted into a piloted Excel-based form covering publication, trial design, target population, interventions, outcomes and ethics. Adjustments will be made if new relevant fields emerge |
| Collation, summary and report of results | Quantitative data will be summarised using descriptive statistics, and qualitative themes will be narratively synthesised. Risk of bias will be assessed using Cochrane RoB V.2.0 and presented visually (traffic light plots, bar charts). Comparative analyses between countries and disease profiles will be conducted. Results will inform research priorities and policy in PSAC |
AIM, African Index Medicus; CENTRAL, Cochrane Central Register of Clinical Trials; ICTRP, International Clinical Trials Registry Platform; PACTR, Pan African Clinical Trials Registry; PSAC, Portuguese-speaking African countries; RoB, Risk of Bias.
We conducted preliminary searches to mature the search strategy. Final searches, screening of information, data extraction and charting are projected to be conducted in June 2025, and the scoping review will be finalised by June 2026.
We address our objectives through a comprehensive protocol targeting RCTs in any of the PSAC, from 1995 to 2024, to assess the general development level of each country, identify research trends, geographical distribution, diseases targeted and identify gaps in the literature. The starting date was chosen based on the implementation of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice in 1995.
Review question
The PRISMA-ScR checklist will be used as guidance, and the guiding research question to perform the literature search is “What are the characteristics and trends of clinical trials conducted in PSAC over the last three decades?”.
Eligibility criteria
Types of studies: this scoping review will include RCTs involving pharmacological interventions. These are considered the gold standard for evaluating intervention efficacy, offering the highest level of internal validity through minimisation of bias. Given the objective of this review is to assess the development and quality of clinical research in PSAC, focusing solely on RCTs ensures consistency in trial design and allows for meaningful comparisons across time, geography and disease areas. Including only RCTs also enables the application of a RoB assessment tool, which is not feasible across diverse non-randomised designs. Non-randomised, quasi-randomised or pseudo-RCTs, quasi-experimental studies (without controls), case reports, case-series, before and after studies, interrupted time-series studies, analytical observational studies (including prospective and retrospective cohort studies, case-control studies, case-only designs), ecological and cross-sectional studies will be excluded. Qualitative studies will be excluded. Trials enrolling non-local populations (such as tourists), trials in non-PSAC and trials not in humans will also be excluded.
Articles will be selected for inclusion in the study if they are a primary research paper reporting original clinical research done in at least one of the PSAC. The review will include all types of design of RCT, including active control, placebo control, multiple arm, cluster randomisation, adaptive design and platform trials. Multinational trials will be included if at least one patient had been recruited in at least one of the PSAC. In these cases, only the data relevant to PSAC participation will be extracted and analysed, when available. If the study-level data are not disaggregated by country, the RCT will still be included. However, its limitations in country-specific provenance will be noted during data synthesis and interpretation. A multinational trial will be counted once in the overall total of trials, and each PSAC country involved will be credited with one trial in the country-specific tally, whenever possible. A participant’s concept and context framework is detailed in table 2.
Table 2. Participants, concept and context framework.
| Participants (P) | Concept (C) | Context (C) | |
|---|---|---|---|
| Inclusion | Studies will include human participants of any age, enrolled in RCTs, conducted in at least one PSAC | Primary research papers reporting RCTs (any design or phase) evaluating pharmacological interventions, comparing active or inactive comparators (eg, no treatment, placebo, standard care) | RCTs conducted in any of the 5 Portuguese-speaking African countries: Angola, Cabo Verde, Guinea-Bissau, São Tomé and Príncipe and Mozambique, with no language restriction and within the timeframe 1995–2024 |
| Exclusion | Non-human participants | Surgical interventions, non-randomised, quasi-randomised, pseudo-randomised clinical trials, medical devices or other non-pharmacological interventions | Clinical trials outside the PSAC territories, before 1995 or after 2024 |
PSAC, Portuguese-speaking African countries; RCTs, randomised clinical trials.
Inclusion criteria:
RCTs performed in at least one of the PSACs.
Published as a primary research paper between 1 January 1995 and 31 December 2024.
All clinical trial phases, all designs.
No language restriction.
Exclusion criteria:
Research conducted outside any of the PSAC.
Non-randomised, quasi-randomised, pseudo-RCTs.
Clinical trials using surgical interventions, medical devices or other non-pharmacological interventions.
Non-clinical studies.
Theoretical research and qualitative studies.
Editorials, commentaries, expert opinion and letters to the editor.
Other reviews such as systematic reviews, scoping reviews, umbrella reviews, rapid reviews, overviews and meta-analyses.
Scoping reviews follow an iterative process, which allows for research objectives to be further refined, adapting questions as literature revision becomes more familiar to researchers.29
Non-pharmacological interventions (eg, surgical, behavioural, device-based or public-health interventions) are excluded to ensure methodological consistency, as pharmacological intervention RCTs follow comparable regulatory pathways, trial designs and classification systems (such as the WHO Anatomic Therapeutic Classification (ATC)), whereas including heterogeneous intervention types would introduce substantial variability that would limit meaningful synthesis across PSAC.
Types of information sources
Search strategy: the search strategy aims at finding published articles only, through a dual-search strategy in both electronic bibliographic databases and clinical trials registries. No language restrictions will be imposed.
The research team will search for studies published during or after January 1995 and indexed until December 2024, covering a 30-year period. Databases used for the research will be MEDLINE (via PubMed), EMBASE (via Scopus), African Index Medicus and The Cochrane Central Register of Clinical Trials (via the Cochrane Register of Studies).
The search strategy will use the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE sensitivity-maximising version (2008 revision), together with a regional filter developed (PSAC search string) and a date-sensitive prompt.30 31 Online supplemental annex 1 details the proposed MEDLINE search strategy, which will be adapted for other databases.
In addition, the following clinical trials registries will be hand-searched to include eventual publications that were not identified in the database search: US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and the Pan African Clinical Trials Registry.
Selection of sources of evidence
Study selection: the search results will be imported into the reference list management tool Zotero. Any duplicates will be identified and removed using Zotero. The reference list will be exported to the Rayyan platform, a web-based tool for managing scoping reviews.32
The first stage of this scoping review will involve the screening of titles, abstracts and eligibility of studies by two reviewers. Studies will be independently assessed by two reviewers and reported using the PRISMA flow diagram.26
Two review authors will receive training and conduct pilot testing of the screening process using a random sample of 100 references from the search results. The same two authors will independently screen the titles and abstracts of the search results and code them as ‘retrieve’ (eligible or potentially eligible/unclear) or ‘do not retrieve’. The full texts of all potentially eligible studies will be retrieved and assessed for inclusion by the same reviewers, with reasons for exclusion documented and reported in the scoping review. Discrepancies will be resolved through discussion or, if necessary, through consultation with a third reviewer. We will identify and remove duplicate records and collate multiple reports of the same study to ensure that each study, rather than each publication, is counted once. When multiple publications exist for a single study, we will extract data from the most complete and up-to-date source (eg, final results will be prioritised over interim findings). Clinical Trials Registry entries will be hand-selected and reviewed and, where appropriate, studies will be included for data extraction and reported in the PRISMA flow diagram to ensure comprehensive coverage of relevant evidence. Authors will not perform hand searching of references due to resource constraints and the utilisation of a robust dual search strategy methodology.
Data charting process
Two authors will extract data from the full texts of papers in the designed form accordingly. This form has been piloted with at least 10 examples and adapted to increase efficiency and consistency of data extraction and will be refined if needed during the early stage of full-text retrieval. The extracted data will include specific details on population, concept, context and key findings linked with the review question. Additional fields of data that may occur during this process will be added according to research relevance. The data extracted will include all details specific to the scoping review topic and fulfilment of the requirements for the narrative synthesis of outcomes. The research team will also contact corresponding authors for key information when data are ambiguous or missing from the published study. Data extraction will be independently cross-checked. The extraction form is available as online supplemental annex 2.
Any disagreements that arise between the reviewers will be resolved through discussion. In cases where the disagreement cannot be resolved, the viewpoints of a third reviewer will be used.
Data items
Data will be collected as follows:
Research information (first author, country of first author, publication title, year of publication).
Trial information (geographic trial location (country), aims/purpose, disease targeted, research design, trial phase, trial duration, unit of randomisation (individual or cluster), population, funding source(s), trial registration, country of ethical approval, promotors, sponsors, reference to ethical standards).
Participants (number of trial participants, participants’ country of recruitment, number of participants from PSAC, gender).
Intervention and comparison (number of groups, blinding procedure, type of intervention, dose, comparators, treatment withdrawal (number of loss to follow-up), compassionate use).
Outcome measures (primary efficacy outcome, statistical significance of primary outcome, direction of effect, proportion of participants with at least one adverse event (ADR), proportion of participants with serious ADRs, proportion of deaths, ADR reporting methodology).
A third author will review the collected data. Cases of disagreement between the authors will be resolved based on the opinions of another author.
Data management and storage: all data related to study selection and screening will be managed using the Rayyan Platform, which supports blinded screening, tagging, resolution of conflicts and audit trail to ensure transparent reviewer decisions and enables collaboration. Extracted data will be stored securely on encrypted, password-protected cloud storage, with regular back-ups maintained. Access to the working datasets will be restricted to the lead researcher and co-authors. Data extraction will be managed in a structured Microsoft Excel-based spreadsheet template and backed up periodically to ensure consistency. To ensure reproducibility, all decisions related to screening, inclusion and data extraction will be documented, and a de-identified version of the final dataset may be made available on reasonable request, in accordance with data sharing policies and ethical approvals. All records and audit trails will be preserved for at least 5 years following publication.
Methodological quality assessment: authors recognise that it is not common to assess RoB in scoping reviews; however, as we will only include RCTs, the review is eligible for a critical appraisal of individual sources of evidence.24 33 Two reviewers will assess independently the RoB for RCTs included in order to evaluate the quality of the evidence in the scoping review. Any disagreement will be resolved through discussion and consensus among the review authors. If no agreement should be reached, a third reviewer will be consulted to reach a consensus.
We will use the Cochrane RoB tool V.2.0 due to the exclusive study focus on RCTs, as it is the most comprehensive and widely accepted method for assessing the RoB in RCTs and being considered as a gold standard.34 This tool evaluates the RoB in RCTs based on five domains: randomisation, deviations from intended interventions, missing outcome data, measurement of the outcome and selection of the reported result.25 Undertaking this quality assessment will allow for further understanding of the overall quality of the RCTs and present the methodological rigour and reliability of the literature.
RoB assessments will be presented both narratively and visually. Summary figures and tables will be generated to illustrate the overall and domain-specific RoB across included studies, using traffic light plots and weighted bar charts following Cochrane RoB V.2.0 guidance. This will enhance the transparency and the interpretability of the critical appraisal. While RoB is included in this review, the main focus of this study remains mapping RCTs. RoB V.2.0 will be used solely to describe general trial quality and not for excluding studies.
Synthesis of results
The number of sources of evidence screened, those assessed for eligibility and included in the review will be detailed using a flow diagram (PRISMA-ScR flow diagram). Reasons for exclusion at each stage will be provided. For each included study, key characteristics and extracted variables relevant to the review objectives will be presented, providing citations.
The outcomes and further information collected will be synthesised using both quantitative and qualitative methods. Quantitative data will be summarised descriptively using frequencies and percentages for categorical variables, and medians with IQRs for continuous variables. Qualitative data will be synthesised through a narrative format, including content and thematic analysis. Where sufficient data are available, stratified analyses will be explored, such as by trial period or by type of principal investigator, to examine potential differences in trial characteristics and focus areas.
Key variables of interest: data will be collected and reported on the following areas:
Publications: number of publications between 1995–2024, geographic origin of first author, publication year.
Trial characteristics: geographic distribution, diseases targeted, trial purpose (eg, prevention, treatment, diagnosis, detection/screening), trial phases, study design (including number of arms), duration, randomisation unit (individual or cluster), population size, funding and financing (foundations, private, public); trial registration status, ethical approval (country responsible for ethical revision and oversight), characteristics of sponsors and promotors (country and affiliation), adherence to ethical standards and guidelines.
Target population: overall number of trial participants and number of participants from PSAC, gender distribution.
Type of intervention: use of blinding, type of intervention (including WHO ATC), comparators, treatment withdrawal and loss to follow-up, post-trial compassionate use.
Efficacy outcome: primary efficacy outcome, statistical significance of primary outcome, direction of effect.
Safety outcomes: proportion of ADRs, proportion of serious ADRs, mortality, ADRs reporting methodology (pharmacovigilance system).
Critical appraisal: RoB across included RCTs using the Cochrane RoB V.2.0 tool.
The RoB evaluation will be summarised both narratively and visually, supported by tables and figures (traffic light plots and bar charts), illustrating methodological quality in RCTs. The synthesis will be assisted with tables, summary data in graphs, and individual data for each study in tables. The synthesis aims to identify the main characteristics of RCTs conducted in PSAC. Conclusions will be drawn on the comparison between countries and their scope of clinical research, together with comparison with countries from other geographies, considering disease profiles. This study is planned to take place between 1 June 2025 and 30 June 2026.
Discussion
This scoping review will present the most comprehensive assessment of RCTs in PSAC over the last 30 years. By analysing trial characteristics, targeted diseases and funding models, it will provide key insights into how clinical research aligns—or fails to align—with countries’ health priorities in underrepresented settings. Findings will be compared with similar reviews conducted for other regions to contextualise results. Periodic reviews of clinical trials in these countries can help identify gaps, match research with clinical needs and serve as a mechanism to realign resources, thus mapping the development of research in countries with low resources.35
The strengths of this study lie in the application of a reproducible and transparent methodology in the scoping review, along with a comprehensive search strategy. Through an inclusive and rigorous approach—integrating searches from both electronic bibliographic databases and clinical trials registries—we will minimise publication bias and enhance the findings’ robustness, thus aligning with established best practices in evidence review.36 37
The protocol’s adherence to PRISMA-ScR, the use of the Cochrane RoB V.2.0 tool, and protocol registration and publishing will increase methodological transparency and reproducibility, reducing potential biases, namely selective outcome reporting.25 This will also help set a standard for future reviews in similar settings.
The review will point out gaps in clinical trials infrastructure, regulatory oversight and research focus in these countries. Findings will inform stakeholders, including policymakers, researchers, academics and practitioners, by highlighting gaps, prioritising research areas and supporting evidence-based decisions on clinical trials in PSAC.
While this scoping review addresses only RCTs—providing a robust snapshot of high-quality research—it might exclude potentially valuable evidence derived from including non-randomised studies, particularly in interventions or populations where RCTs might be impractical or unethical to be conducted. This, however, supports the long-term aim of reinforcing ethical, scientifically rigorous clinical research in resource-limited countries.
Finally, this work will serve as a strategic tool to strengthen regional collaboration, support evidence-informed policymaking and elevate the visibility and contribution of PSAC in the global clinical research landscape, to the significant benefit of patients and communities, both in scientific equity and health outcomes. By synthesising three decades of clinical trials conducted in PSAC, this first scoping review will inform future improvements in clinical research and guide policy developments and practice.
Patient and public involvement
It was not appropriate or possible to involve patients or the public in the design, conduct, reporting or dissemination plans of our research.
Ethics and dissemination
Formal ethical approval is not required for this scoping review, as primary data will not be collected. This work will summarise studies that have already undergone peer review in keeping with journal policies. This scoping review will assess and provide evidence on the quantity and quality of clinical trials in PSAC. The results will be disseminated through a peer-reviewed publication, conference presentation and in plain language in social media to spread the knowledge with the society and the public interested in the topic. Dissemination will be undertaken in both Portuguese and English, thereby strengthening community outreach and increasing engagement with international audiences.
Supplementary material
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2025-105490).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
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