Overcoming Logistical Barriers to Conducting Collaborative Clinical Research Between a High-Income Country and a Low- and Middle-Income Country

Abstract

PURPOSE

Building equitable research collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs) requires effective coordination among international ethical review committees, which is often logistically challenging. This case report presents the insights gained when acquiring ethical approval for a cervical cancer research program conducted jointly by the University of Pennsylvania and the University of Botswana.

METHODS

We conducted a descriptive case study of the Ipabalele project, a 6-year HIC-LMIC partnership involving three complex research protocols that required approvals by multiple distinct ethical bodies. We analyzed various challenges affecting review procedures, timelines, and staffing. We then documented strategies employed in Ipabalele and other global initiatives to strengthen ethical review processes and build research capacity in LMICs.

RESULTS

In Ipabalele, ethical approvals were initially delayed by 2 years because of fragmented review processes with variable timelines and conflicting recommendations. Innovations to the process included centralizing institutional review board oversight within Botswana, implementing joint virtual meetings among review bodies, enhancing digital infrastructure, and streamlining research staffing and communication.

CONCLUSION

By providing practical strategies, this study highlights how empowered local leadership, centralized review processes, joint review mechanisms, and intentional capacity building can overcome logistical barriers in multinational ethical review.

INTRODUCTION

Cervical cancer disease burden disproportionately affects low- and middle-income countries (LMICs).¹ Research conducted in LMICs should inform best practice recommendations for patients in those settings; however, most research is sponsored by entities in high-income countries (HICs).² Many barriers contribute to this disparity, including differences in processes, ethical perspectives, staffing, and infrastructure, among others.^3-5 There is a clear need for collaborative research capacity building among HICs and LMICs to mitigate these barriers and form sustainable partnerships. Here, we discuss the logistic challenges encountered and lessons learned while coordinating international ethics approval of Ipabalele, a research program between the University of Pennsylvania (UPenn) and the University of Botswana (UB) examining the natural history of cervical cancer.⁶

CONTEXT

• Key Objective

• How can multinational research partnerships between high-income and low- and middle-income countries optimize ethical review processes to promote equitable collaboration? This study uniquely examines the Ipabalele cervical cancer research program between the University of Pennsylvania and the University of Botswana, demonstrating practical innovations for navigating multinational institutional review board (IRB) systems.

• Knowledge Generated

• Ethical approvals were significantly delayed because of fragmented review structures and conflicting requirements. Centralizing IRB oversight within Botswana, establishing joint virtual review meetings, and improving administrative coordination markedly reduced delays and strengthened local IRB governance.

• Relevance

• These findings demonstrate how local leadership and joint review mechanisms can enhance the efficiency of low- and middle-income country research ethics systems. Applying such strategies can accelerate the initiation of clinically relevant studies, strengthen research capacity, and promote more equitable global oncology partnerships.

Typical Ethical Review Process

Reconciling the different requirements of international ethical review committees, commonly known as institutional review boards (IRBs), is a mandatory process in human subjects research. For a complex, multisite research protocol, the review process may extend beyond 6 months and require multiple iterations. IRBs at each institution must reapprove all study documents annually.

Challenges in Obtaining Ethical Approvals Across Countries

Projects conducted between HIC and LMIC institutions require full ethical review and approval by all parties involved. In settings with extensive research experience, one institution is typically designated as the primary IRB to lead these efforts, whereas secondary IRBs endorse these decisions with minimal or no modifications. In settings where centralization of IRB procedures is uncommon, reviews are conducted by multiple independent local IRBs. Each study document must be approved by all parties before use, and any amendment requested by one IRB must be resubmitted to all others for reapproval. Although appropriate and necessary in certain contexts, this decentralized process is administratively complex and often causes extended delays in program activities owing to varying procedures, timelines, staffing structures, and ethical and research priorities between IRBs.⁷

Case Study: The Ipabalele Project

Over the past 6 years, our research group has encountered many of these challenges and developed strategies to maintain an effective partnership between UPenn and UB. The Ipabalele consortium included three discrete protocols, each requiring its own approval. Each protocol had at least one informed consent form and multifaceted data collection tools involving basic, clinical, and behavioral sciences. As patients were eligible for enrollment on one or more protocols, we sought to synchronize recruitment for all three projects.

Differences in Procedures

Both UPenn and UB have extensive research experience in their respective settings. However, their IRB procedures vastly differed in meeting schedules, areas of expertise, and approval criteria, especially for projects involving tissue specimens. Furthermore, certain recruitment sites in Botswana had never been used for research previously and lacked precedent on how to implement and approve protocols. These procedural differences caused substantial delays (approximately 2 years) in acquiring study initiation approvals, affecting research timelines, and funding disbursement.

To address these challenges and strengthen local IRB governance to supervise the new research sites, Botswana-based researchers and administrators created systems to integrate procedures more efficiently. This effort mandated close coordination between academic institutions, local and national government agencies, hospitals, health care facilities, and private entities in Botswana. These stakeholders agreed to defer the primary in-depth review to the UB IRB, one of the most recognized and experienced ethics bodies in the country. This centralization of IRB processes was innovative for Botswana and significantly streamlined review. UB research staff assumed full ownership of tracking procedural timelines, managing submissions to local offices, and responding to project-specific questions. The local leadership at UB strategically monitored the review process and connected with IRB chairs to ensure timely progress throughout each stage. The high level of coordination between the UPenn and UB IRBs would have been virtually impossible to achieve without the leadership from the local research team in Botswana.

Differences in Timelines and Queries

Discrepancies in the timeline and content of recommendations from the IRBs at UPenn, UB, and the Botswana Ministry of Health and Wellness made it difficult to secure all of the necessary ethical approvals. The UPenn IRB policy dictated that all approvals from Botswana-based ethical bodies were procured before their own review would begin. In practice, this approach proved untenable. Recommendations from each IRB varied widely, often mandating discordant changes to study documents. This resulted in a prolonged cycle of document submissions and resubmissions to all IRB committees before any research activity could commence.

A major innovation to the process was the full integration of the ethical and administrative review procedures through periodic, closed virtual meetings among the three IRBs. These meetings enabled them to collaborate directly, adjudicate any points of discord, and establish a unified set of queries and recommendations. From an operational standpoint, this streamlined a previously fragmented process. From an ethical standpoint, this approach ensured that all study documents and procedures were ethically sound and culturally appropriate. This fluid, bidirectional communication enhanced the understanding of values, priorities, and cultural matters affecting study implementation.

Personnel and Staffing

Having two research offices (one at UPenn, one at UB) working in tandem provided many benefits to study operations. Working under a Partnership model,⁸ the teams explicitly delineated roles among research investigators, coordinators, and assistants, which required a great deal of cross-cultural communication.

Concurrently, with capacity building in mind for both UPenn and UB research staff, the distribution of responsibilities remained relatively flexible. This allowed for longitudinal training and professional growth opportunities as investigators in Botswana developed more expertise, whereas research staff in the United States learned about conducting research internationally. To accommodate the needs of key research team members and openly address all decisions affecting local research activities, the teams at UPenn and UB modified their operating procedures and adopted exclusively remote communication across a large time difference. For example, we used shared folders on the cloud to exchange documents so that they could be edited by various members in different time zones without confusion.

Longitudinal Quality Control

Although initial ethical review board approvals are typically the most detailed, modifications and reapprovals for each study document continue throughout the project duration. For a complex study like Ipabalele with multiple investigators and protocols, this compounded to a large amount of internal organization and compliance monitoring to maintain smooth operations.

By identifying one research staff member at UPenn and UB to oversee study document version control, we managed to streamline these processes, confirm that all documents were current, and ensure no protocol would have to halt operations because of an ethical approval expiration. To facilitate capacity building, the research staff at each institution worked closely to incorporate training into administrative oversight.

The modifications to the IRB procedures in the Ipabalele project are summarized in Figure 1.

FIG 1.

(A) Before modifications to the IRB process in Ipabalele. Parallel, uncoordinated review processes by distinct ethical bodies resulted in discordant feedback and substantial delays in research activities. Ethical approval from Botswana-based regulatory bodies was required prior to review by the UPenn IRB, and any IRB recommendations or protocol revisions reinitiated the review process among each ethical body (curved arrows). This process was replicated for each of the three Ipabalele protocols and study documents. These approvals remain active for the duration of the study and were reviewed annually for reapproval by each reviewing body. (B) After modifications to the IRB process in Ipabalele. UB was designated as the primary reviewer for the Botswana-based regulatory bodies, strengthening local leadership. Closed, virtual meetings among the various IRBs expedited decision-making, unified feedback, and enhanced cultural understanding. IRB recommendations were reviewed in a streamlined, collaborative process. BMOHW, Botswana Ministry of Health and Wellness; IRB, Institutional Review Board; UB, University of Botswana; UPenn, University of Pennsylvania.

METHODS

Overview of IRB and Ethics Review Challenges

The Ipabalele case study reflects broader patterns of the challenges encountered within the ethical review process, particularly when navigating multinational research partnerships. Ethical and regulatory obstacles—compounded by logistical hurdles, limited trained personnel, and inadequate research infrastructure—may hinder the initiation and progression of research activities and further limit opportunities to strengthen local research governance in LMICs.⁵ These issues are particularly emphasized in multisite studies, where each institution directs its own ethical review process in a fragmented, often redundant manner, leading to contradictory recommendations and administrative inefficiencies that delay research timelines.^9-11 Informed consent procedures present an additional layer of difficulty. Standardization of consent documents is critical to streamline ethics review and ensure participant safety; however, researchers must also respect diverse literacy levels, languages, and cultural norms across countries to ensure participant understanding and autonomy.¹² Furthermore, translating study documents, including consent forms, can place additional burdens on already limited administrative capacity in settings where IRBs may lack adequate resources or staff. For example, the ConCerv trial, a prospective, single-arm multicenter study evaluating the feasibility of conservative surgery in patients with early-stage cervical cancer, was conducted across nine countries, including the United States, Colombia, Peru, Brazil, Argentina, Mexico, Thailand, Australia, and Italy.¹³ Protocol and informed consent amendments required language translation and approval from each participating institution, resulting in repeated delays and pauses that prolonged the study period to almost 9 years. Researchers in LMICs have also reported that approval delays can be so extensive that funding may expire before the research begins.¹⁴ These logistical, infrastructural, and procedural barriers within the ethical review process may disincentivize equitable research partnerships between HICs and LMICs.

RESULTS

Global Solutions to Improve Ethical Reviews

Many of the ethical review challenges described above are not unique to Botswana, nor are they unique to oncologic research studies. These issues, as well as proposed solutions, have been described in various fields. Global initiatives across various fields have emerged to strengthen ethical review processes in LMICs and facilitate equitable research partnerships (Table 1).

TABLE 1.

Examples of Global Initiatives to Enhance Ethical Review Processes and Strengthen HIC-LMIC Research Partnerships

Initiative	Region	Key Lesson for HIC-LMIC Partnership
AVAREF	Africa	Joint reviews among ethical committees from multiple countries increase efficiency, enhance transparency, and expedite research approvals
EDCTP	Europe, Sub-Saharan Africa	Enhanced information technology infrastructure, including virtual platforms, can harmonize ethical reviews and facilitate the exchange of ideas
NIH Fogarty International Center	Various	Investing in research bioethics training in LMICs fosters local research governance and improves the efficiency and quality of research ethics reviews
PAHO, CEP/CONEP	Latin America and the Caribbean	Health systems strengthening through regulations and policies implemented at the state or national level can promote a robust framework for research ethics reviews

Abbreviations: AVAREF, African Vaccine Regulatory Forum; CEP/CONEP, Comitê de Ética em Pesquisas/Comissão Nacional de Ética em Pesquisa; EDCTP, European and Developing Countries Clinical Trials Partnership; HIC, high-income country; LMICs, low- and middle-income countries; NIH, National Institutes of Health; PAHO, Pan American Health Organization.

Joint Ethics Review Models

The African Vaccine Regulatory Forum (AVAREF) was established by the WHO in 2006 and offers a model for centralization and collaboration among ethical review bodies.^15,16 Authorities from multiple African countries conduct joint reviews of multisite protocols, which helps to standardize regulatory and ethics reviews, increase efficiency, optimize review timelines, and facilitate the exchange of ideas among peer institutions. Although traditional models may take multiple years for approval, this process concludes within 60 days, which has expedited approval for clinical trials investigating vaccines and medicines for Ebola virus, meningitis, malaria, and other diseases.

Digital Infrastructure

The European and Developing Countries Clinical Trials Partnership (EDCTP) led by the European Union strengthens ethical review and regulatory framework structures in sub-Saharan Africa through bioethics training and improved information technology infrastructure to facilitate the exchange of ideas.¹⁷ Projects such as BUCARERZ: Building Capacity for Research Ethics and Regulation in Zambia¹⁸ and STReK: Strengthening Research Ethics and Review and Oversight in Kenya¹⁹ exemplify efforts to improve the efficiency of ethical reviews through electronic submission platforms, virtual meetings, and cloud-based databases.

Research Ethics Training Initiatives and Capacity Building

Several institutions have invested in ethics programs to augment the number and expertise of research personnel in LMICs. One notable example includes the National Institutes of Health (NIH) Fogarty International Center, which has sponsored almost 20 international bioethics programs in LMICs worldwide, including the development of the Center for Bioethics and Research in Nigeria and similar programs across Asia.²⁰ Many trainees from these programs serve on local IRBs, bolstering ethical review capacity within their home countries.²¹

National Policies to strengthen Research Standards

The Comitê de Ética em Pesquisas/Comissão Nacional de Ética em Pesquisa in Brazil is a two-tiered system that distributes ethical oversight among local and national review boards to ensure cultural relevance, local oversight, and adherence to global research standards.²² Similarly, the Pan American Health Organization has developed a systematic national health research ethics framework in more than ten Latin American and Caribbean countries to address gaps in clinical trial registration and ethical oversight.^23,24

DISCUSSION

The Ipabelele project offers valuable insights for investigators navigating ethical approvals and operational challenges in LMIC-HIC research partnerships. Taken together with lessons from global initiatives such as AVAREF, EDCTP, and NIH Fogarty, several recommendations can be gleaned from this case study to strengthen ethical review systems and build research capacity in LMICs.

1. Centralize IRB oversight within the LMIC. Academic institutions should work with local institutions, government entities, and partner organizations to centralize IRB processes within the host LMIC. This coordination also minimizes discordant feedback across multiple institutions. Furthermore, shared governance structures ensure that local health priorities and norms are valued alongside research standards.

2. Develop joint review mechanisms. To reconcile conflicting recommendations from HIC and LMIC ethical bodies, the respective IRBs should hold joint virtual meetings early in the review process. This strategy streamlines approval timelines, fosters mutual understanding, and limits the potential for ethical imperialism. ²⁵

3. Enhance administrative and monitoring capacity. Ethical review processes extend beyond the initial IRB review. Multisite global health studies require ongoing meticulous oversight to maintain research integrity and patient safety. To ensure efficient operations, designated personnel at both HIC and LMIC institutions should track protocol amendments, consent modifications, and adverse outcomes. Furthermore, digital platforms should also be used to manage submissions and improve communication among research stakeholders.

4. Strengthen local capacity for ethical oversight. Long-term investments in ethics training can yield lasting benefits for the global research landscape. LMIC researchers should be empowered to lead ethical reviews and oversee research implementation, promoting local autonomy and sustainability. Identifying a local liaison can further optimize coordination between partner institutions and reinforce local leadership.

5. Promote equitable partnerships and shared leadership. HIC and LMIC institutions must continue to create equitable partnerships with shared leadership, mentorship, and authorship opportunities. Rather than impose the ethical standards of the HIC on the LMIC, both parties should seek bidirectional learning and respect ethical considerations grounded in cultural norms.

In conclusion, the ethical review process is a critical step for conducting human subjects research, yet it often presents substantial barriers for researchers involved in LMIC-HIC partnerships. The Ipabalele study exemplifies how empowered local leadership and strong institutional collaboration can streamline ethical approvals and build local research capacity. As researchers face various challenges within the ethical review process, proposed solutions, such as centralized procedures, joint review mechanisms, enhanced training, and increased administrative support, can reduce delays and alleviate the burden of obtaining approvals. Efforts must also prioritize the development of local research governance structures that promote autonomy and sustainability. Strengthening ethics infrastructure in this way will facilitate global research partnerships that are more efficient, equitable, and mutually prosperous.

AUTHOR CONTRIBUTIONS

Conception and design: Surbhi Grover, Allison Chambers, Chinenye Azoba, Nthabiseng Phaladze, Motseiwa Mokalake, Bramwell Koyabe, John B Jemmott III, Erle Robertson, Doreen Ramogola-Masire

Financial support: Erle Robertson

Administrative support: Surbhi Grover, Allison Chambers, Chinenye Azoba, Motseiwa Mokalake, Erle Robertson

Provision of study materials or patients: Surbhi Grover, Bramwell Koyabe, Erle Robertson, Nicola Zetola

Collection and assembly of data: Surbhi Grover, Allison Chambers, Motseiwa Mokalake, Bramwell Koyabe, Erle Robertson, Nicola Zetola

Data analysis and interpretation: Surbhi Grover, Allison Chambers, Rohini K. Bhatia, Motseiwa Mokalake, Bramwell Koyabe, Erle Robertson, Doreen Ramogola-Masire

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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