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Building Networks for Global Clinical Research

The Basics

Shearer, David W. MD, MPH*; Volberding, Paul A. MD; Schemitsch, Emil H. MD, FRCSC‡,§; Cook, Gillian E. MHSc‡,‖; Slobogean, Gerard P. MD, MPH; Morshed, Saam MD, PhD*

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Journal of Orthopaedic Trauma: December 2015 - Volume 29 - Issue - p S15-S18
doi: 10.1097/BOT.0000000000000466



There is increasing recognition of the potential benefit of international collaboration in orthopaedic surgery to address important clinical questions and health policy issues in both high and low-resource contexts. In this article, we aim to describe the historical context of the emerging role of orthopaedic surgery in global health and emphasize key principles important in establishing successful international partnerships.


In the past, global health research was based on a very US-centric perspective and was therefore aimed largely at monitoring and protecting the country from imported diseases. However, there has been growing recognition of the benefits of investing in global research, from both a local and global perspective. There are numerous examples of research in developing countries that ultimately had widespread benefits, including research on the hepatitis B virus, human papillomavirus, and drug-resistant tuberculosis.

The last 2 decades have witnessed unprecedented growth in global health training and research programs. This explosion originated largely from the development of potent HIV medications that allowed rollout of treatment in Africa through programs such as the Presidents Emergency Plan for AIDS Relief (PEPFAR). The immediate benefits and success of programs aimed at addressing the global AIDS epidemic have subsequently generated interest in a variety of other health conditions, including trauma and chronic diseases.

The return on investment in global research is evident. There are examples of tropical diseases that have been eradicated (eg, smallpox), nearly eradicated (eg, polio), or reduced to a small number of countries (eg, malaria). Progress in HIV has been substantial, with research establishing effective prevention and treatment programs.

The cross-national collaborations that occur in global health research have the potential to be highly effective. US scientists bring expertise and technology that can be applied to local health concerns. They can therefore provide mentorship where lacking, and enable access to funding that would otherwise not exist. Local scientists give perspective on the local problems that should be prioritized when designing research. These partnerships can be durable and often expand over time.

The success of research and treatment programs in HIV/AIDs and other infectious diseases has led to improved survival and shifted focus to a variety of noncommunicable diseases, including injury. Road traffic injuries alone are projected to rise to become the third leading cause of death and disability by 2030, surpassing HIV/AIDs, malaria, and tuberculosis. This emphasizes the need for trauma surgeons to engage in global health and explore the opportunities for international collaboration. It is important that training programs provide exposure to global health across a variety of specialties, including orthopaedic surgery, to foster these interests. Ultimately, these efforts will help to increase funding and thereby build local capacity to conduct research and address the growing epidemic of trauma.


In medicine, we commonly focus on the optimization of care for the individual patient we are treating. Ideally, our research is focused on questions that are aimed at changing clinical practice. In contrast, public health takes a broader, population-based approach. This research tends to be broader in scope and aims to change policy at the government level or evaluate the success of large-scale public health programs. Understanding this distinction is a first step in understanding the type of evidence necessary to make larger scale impact (see Fig. 1, Supplemental Digital Content,

The type of research most familiar to physicians typically evaluates the effectiveness of 1 treatment strategy relative to another in a comparative design. However, before conducting a comparative study, the most effective research programs are able to first establish the magnitude of the problem. The incidence, duration, and severity of a condition help to establish the burden of a disease. The World Bank has attempted to do this on a global scale with the global burden of disease Project, which uses disability-adjusted life years (DALYs) to establish the total morbidity and mortality of all disease conditions worldwide.1 DALYs are a product of the severity of a condition on a scale from 0 to 1 and the expected duration of the condition in years. By multiplying the DALYs of a disease by the total number of people affected by the disease, the World Bank has created a rank order of diseases to prioritize funding for research and treatment programs.

After establishing the impact of a condition, the strategies to address it can be explored and assessed for their effectiveness. Studies in medicine can be graded using the evidence-based pyramid, ranging from high-quality randomized controlled trials (level 1) to expert opinion (level 5) (Fig. 1).2 High-quality studies are less subject to bias and thereby more likely to be incorporated in practice guidelines and affect clinical practice. In addition to comparative clinical research, economic studies aid in prioritizing investment in research programs by quantifying the return on investment for a treatment strategy. These studies are particularly relevant at a broader policy-making level, where decisions about coverage for different treatments are determined or when investment in health programs must be weighed against programs unrelated to health.

The hierarchy of evidence.

Once evidence has been generated, it is important that there are effective methods to synthesize all available evidence from multiple sources. Commonly used methods are systematic reviews and meta-analyses. A systematic review uses an exhaustive search strategy to identify all available literature on a topic and presents it in a concise review. A meta-analysis, in contrast, uses a similar search strategy but takes an additional step and pools the data to achieve a more precise estimate of the effect of a given treatment.

In assessing and pooling evidence for policy makers, it is important that context be considered, particularly when research is aimed at developing countries, for which the availability of infrastructure and human resources to implement programs effectively must be considered. Results are often not generalizable to resource-limited settings, where the relative risks and benefits of different treatment strategies may be altered.

The final stage in changing practice or policy that is often least familiar to orthopaedic surgeons is the process of dissemination and advocacy. Journal publication is commonly considered the endgame for the dissemination of clinical research study results. Although this may be effective in some cases, true policy change is unlikely to occur without a more directed approach, which includes identification of key stakeholders, such as professional organizations, hospital leadership, or government policy makers, and provision of a summary of the problem and evidence supporting the proposed solution.

Orthopaedic surgeons should recognize that research does not change practice or policy as an afterthought. Research programs that establish burden of disease and conduct comparative and economic analysis of treatment strategies can generate the necessary evidence. However, it is only through successful summarization of the data, using systematic reviews or meta-analysis and subsequent dissemination of these results to the relevant stakeholders that the desired impact can occur.


International clinical research in middle-income and developing countries has many benefits over research in developed countries, including access to large genetically diverse populations with a given disease, increased recruitment rate, a faster timeline to approval, and lower costs.3,43,4 However, conducting clinical research in such a setting comes with its own array of barriers that must be addressed. In developed countries, successful large-scale clinical research that consists of multiple individuals and research centers uses a collaborative group of investigators, who are both motivated and cooperative.5 These human resources might include principal and site investigators, research coordinators, and health care staff.6 Clinical research should furthermore have appropriate funding, a well-developed study protocol, a comprehensive manual of procedures, and methods to ensure that the trial is randomized and blinded.7 Finally, the study should have approval from the local ethics review committee, such that the recruitment and enrollment of study participants are ethically sound.7

In an international setting, these fundamental resource requirements become complicated, as nation-specific cultural, linguistic, institutional, and political issues may arise.8 Ideally, international clinical research should include community-based participatory research, which might translate to inclusion of local investigators who can contribute to protocol development and execution, as these investigators will not only be motivated to succeed but will have insight into the sociocultural context of the region and nation-specific health care priorities and challenges.3,63,6 Mbuagbaw et al6 reported on the issues encountered when conducting the Cameroon Mobile Phone SMS trial and found that a dedicated administrative officer was also crucial to the project success, as administrative holdups have the potential to delay studies and render them obsolete. Owing to differences in the research culture and health care system of the nation, one should furthermore be prepared for varying levels of training in the on-site investigators and support staff, and put resources in place to minimize any training deficits.4 For example, although there are more than half a million practicing doctors in India, fewer than 200 investigators have been trained in good clinical practice, which may stem from the perceived lower status of clinician researchers, making clinicians reluctant to participant in clinical trials.4,94,9 Finally, regional problems that may include language barriers, time zone differences, and a lack of general office support functions (including internet connectivity) should be considered at the outset and incorporated into the study protocol to minimize subsequent administrative challenges.3,63,6

Finally, and perhaps most importantly, there should be appropriate consideration of the relevant ethical issues, as a local institutional review board (IRB) or equivalent ethical review committee may not exist.6,106,10 Hyder et al11 surveyed 203 developing country researchers and found that 25% had conducted studies, which did not undergo any ethics review, whereas 44% had not undergone any type of review (technical, scientific, or ethical). Questions that should therefore be considered are as follows: Who will benefit from the research? Do potential study subjects have freedom of choice to participate or is participation influenced by local concerns, such as lack of access to ordinary health care services? Is there a potential for exploitation, and if so, how can this be avoided?3 The globalization of clinical research has great potential; however, clinical researchers must consider nation-specific challenges and concerns, and procure resources accordingly.


One of the key steps in any clinical research effort is selection of an appropriate study design and development of a research protocol. The choice of study design is dictated by a variety of factors, including the clinical question, ethical constraints, and available resources. This is particularly relevant in international collaborative studies, where available resources can vary widely, and the infrastructure, or lack thereof, may be a primary driving force behind the type of study chosen. At a minimum, it will affect aspects of the daily function of the study, when compared with a locally driven trial in a resource-rich environment. It is crucial for investigators to engage local partners to anticipate challenges in conducting clinical research before embarking on a study.

The classic hierarchy of study design for studies evaluating an intervention divides the different studies into levels of evidence (Fig. 1).2 At the top of the pyramid are randomized controlled trials, which randomly assign study subjects to each intervention. This creates 2 identical groups for comparison and reduces the risk of bias due to confounding. Although randomization is ideal, it may not always be feasible because of available resources or for ethical reasons. A key principle is that subjects cannot ethically be randomized to a treatment that is likely to be inferior. An example would be a study evaluating early debridement for open fractures. It would not be feasible to randomize a patient to a delay in treatment if early treatment is available.

Particularly in a setting where resources are limited, the feasibility of a study is an important question to address at the outset. Is there adequate funding? Are there enough subjects to achieve adequate sample size? In many developing settings, there is a large clinical volume, which diminishes the sample size issue; however, the infrastructure and resources to conduct the study may be correspondingly less. This may lead to the selection of a less rigorous study design to make completion of the study more feasible. A multicenter randomized controlled trial, while desirable, is not realistic in many settings. At the same time, it is important that the principles of quality design are not compromised because the study is being conducted in a low-resource setting.

When randomized trials are not possible, the next best alternative is a prospective cohort study. In this design, the patients are enrolled in the study before their treatment has been administered or an outcome determined. Patients are followed over time until the outcome transpires. In contrast, a retrospective study chooses patients for the study after the outcome has occurred. Because the patients are often no longer available for evaluation, this leads to a review of medical records. Obtaining accurate data is difficult in this approach, as the data may not have been recorded in the desired manner, if at all. This study design is particularly difficult in many developing settings, where record keeping is typically a paper charting system with variable amounts of detail recorded.

As a general principle, the highest quality study that can be feasibly and ethically performed should be the ultimate goal. In some cases, beginning with a small pilot study may provide the preliminary results necessary to compete for the funding to implement the desired study design. In addition, a pilot study will expose many issues in the study protocol before the definitive study is performed.


Global collaborations in orthopaedic surgery are becoming increasingly common, as they are essential to address many important clinical questions. By establishing international research networks, clinical studies gain improved recruitment ability and increased generalizability; however, for an investigator wanting to initiate international partnerships, there are several important considerations.

First, investigators must consider the geographical location of the proposed collaboration, as there may be variations in surgical practice, patient volume, level of research expertise, and availability of research personnel. There may also be important language and cultural differences. These factors are particularly relevant when considering collaborations with low-to-middle income countries (LMICs).

Second, it is vital to establish the role and responsibilities of the proposed international collaborator. A clear understanding of what expertise and infrastructure is needed and available, and what support you are able to offer (eg, study coordinator who speaks the local language) is also important. It is also essential to gauge the prospective collaborator's level of enthusiasm and dedication to the proposed research. Finally, it is imperative to be transparent about expectations, timelines, available funding, and authorship policies. Having a shared understanding of these important considerations enables both parties to feel confident regarding the success of the proposed collaboration.

There are multiple strategies that may be used to establish an international collaboration:

  1. Requesting a recommendation from a trusted colleague with established collaborative international networks is an ideal means of initiating a connection with potential collaborators. The benefits of this approach include an easy introduction between parties and the benefit of a “prevetted” international collaborator.
  2. Many successful collaborations are initiated through the natural networking that occurs at international professional association meetings or though professional travel abroad. Since these venues draw individuals together with similar professional interests, relationships are readily established.
  3. One may identify potential international collaborators based on their published research. An unsolicited invitation to collaborate is often relatively well received if your research interests are closely aligned. Despite initial enthusiasm between both parties, one must be initially cautious as the relationship develops to ensure a mutually beneficial dynamic is established.
  4. One can also use the services of a contract research organization (CRO) that has experience overseeing research activities in the desired geographical region. CROs typically have preestablished networks of local collaborators, and this approach works well in LMICs.

Once a relationship has been established, frequent communication is important to ensure its continued successes. This typically includes teleconferences (with a translator if necessary), email, and texting. In-person meetings, which may include site visits or attendance at professional association meetings, also provide opportunities to strengthen the relationship. It is also possible to engage collaborators through invitations to participate on study committees (eg, steering or writing committees). Finally, it is vital to ensure that collaborators are adequately funded and receive credit and thanks for their efforts.


In conclusion, it is possible to achieve strong and fruitful collaborations in both developed and LMICs. International collaborations are an essential and powerful way to answer important clinical questions.


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global health; orthopaedic surgery; international collaboration

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