1 Introduction to Global Health Research
Global health is the study and practice of “improving health and achieving equity in health for all people worldwide” (Koplan et al. 2009). The determinants of ill health and inequality are as far-reaching and complex as this definition is ambitious, and, the search for global health solutions spans many disciplines:
- Public health
- Social behavioral sciences (e.g., economics, psychology, anthropology)
- Biomedical engineering
- Public policy
Global health research is multidisciplinary and interdisciplinary by design (Merson, Black, and Mills 2011). It is multidisciplinary in the sense that no one field can solve the great global health challenges of our time and interdisciplinary in the recognition that solutions can be reached through collaboration on new approaches that integrate ideas from different academic and clinical traditions.
Its multidisciplinary nature means that global health research is a vast, sprawling enterprise that involves many stakeholders. Let’s survey the landscape of global health research before establishing some fundamentals about scientific research.
The term “stakeholders” can refer to a wide range of people and organizations. Typically, it means donors (i.e., the public and private organizations that fund research programs), policy makers (i.e., government officials and bureaucrats at national or international bodies like the CDC or the WHO), and program implementers (e.g., organizations like Doctors Without Borders) that actually deliver services to beneficiaries (i.e., individuals, populations, or patients), and it even extends to scholars who study a particular topic or policy issue.
1.1 Who Funds Global Health Research?
Billions of dollars are spent on global health research every year.1 This funding comes from public institutions such as the National Institutes of Health (NIH) in the United States and private philanthropy organizations such as the Bill and Melinda Gates Foundation.
In 2015, the international community disbursed $36.4 billion in development assistance for health, down from a peak of $38 billion in 2013 (Institute for Health Metrics and Evaluation 2016). Although Figure 1.1 does not present total research dollars contributed, per se, it does show the sources of global health financing, the channels through which they flow, and the areas on which they focus (see here for an interactive version).2
The United States Government contributed one-third of all development assistance for health in 2015 ($13 billion). More than half of USG funding was directed to HIV/AIDS, malaria, tuberculosis, and other infectious diseases. Noncommunicable diseases received <1% of resources, despite accounting for 7 of the 10 leading causes of death globally (Figure 1.2).
1.2 Who Produces Global Health Research?
Academic centers around the world, like the Duke Global Health Institute, are major contributors to global health research. Public and private donors like the USG, the Bill and Melinda Gates Foundation, and the World Bank make grants to university-affiliated faculty members who partner with colleagues inside and outside governments to plan and conduct research. Donors also channel research support to nonprofit research organizations such as FHI 360 and RTI International, who work in a similar fashion.
Interesting hybrid models include the Abdul Latif Jameel Poverty Action Lab (JPAL) and Innovations for Poverty Action (IPA). JPAL is a global network of university-affiliated professors from more than 40 universities that uses randomized evaluations (i.e., experiments) to answer policy questions related to poverty alleviation. The JPAL website, http://www.povertyactionlab.org, contains excellent resources regarding the methods used in randomized evaluations, as well as links to published studies and policy briefs. IPA is a sister organization that is also a leader in the use of randomized evaluations to study important policy questions about global poverty.
1.3 Where is Global Health Research Published?
Global health research is published in medical journals (e.g., The Lancet and JAMA), general science journals (e.g., Science and PLOS ONE), discipline-specific journals (e.g., The Journal of Immunology and Epidemiology), and disease-specific journals (e.g., AIDS and Malaria Journal). Journals specializing in global health include The Lancet Global Health, BMJ Global Health, Global Public Health, and Global Health: Science and Practice.
1.4 What Constitutes Global Health Research?
Like any scientific endeavor, global health research begins with basic research founded in principles of hard science. This is only the beginning, however; basic research constitutes only a small portion of the overall body of ongoing research. The areas of applied exploration built on this foundation include the clinical arenas from which important global health changes emerge.
1.4.1 BASIC RESEARCH
Basic research—or “pure” research—is the pursuit of fundamental knowledge of phenomena. For example, scientists conduct laboratory experiments to understand the parasitic life cycle and how parasites interact with humans at different stages. Likewise, basic ecology research seeks to understand plant species diversity. The information generated by basic science becomes the universally acknowledged background for more advanced research—applied science.
1.4.2 APPLIED RESEARCH
Basic research is different than applied research, which focuses on specific problems or applications in several ways. For instance, an applied research question might be, “How can we increase the coverage and use of bed nets that prevent malaria transmission?” The basic science, such as the behavioral habits of the mosquito and the transmission conditions for malaria, have already been determined by entomologists and epidemiologists.
In contrast, applied science takes many different forms, including clinical research. Clinical research is a broad field that encompasses patient-oriented research, epidemiological and behavioral studies, outcomes research, and health services research.3 Basic research provides the foundation for all clinical research.
One type of clinical research is a clinical trial. Drugs and vaccines have to pass through different phases of clinical trials before regulatory bodies, such as the Federal Food and Drug Administration (FDA), will approve their use with humans:
- Preclinical research
- Phase I
- Phase II
- Phase III
- Phase IV
Behavioral research (e.g., development and evaluation of parenting interventions) does not follow the same exact phases of vaccine and drug development, but the broad principles are the same.
Case study: Developing a malaria vaccine
The development of a vaccine for malaria provides a good example of the life cycle of a clinical trial. In 2015, after 30 years of research, a vaccine candidate called RTS,S, or Mosquirix™, made the news for having gotten one step closer to becoming a licensed vaccine after a successful Phase III trial.
Development of RTS,S began in 1984 through a partnership between the pharmaceutical company GlaxoSmithKline (GSK) and the Walter Reed Army Institute of Research. In 1987, a promising vaccine candidate entered preclinical research. During the preclinical phase, researchers performed tests on nonhuman subjects to collect data on how well the vaccine worked (efficacy), how much damage it could do to an organism (toxicity), and how the body affected the vaccine (pharmacokinetics).
Clinical research on humans began in 1992. To obtain regulatory approval, the vaccine had to complete three phases of testing. Doherty et al. (1999) conducted a Phase I safety and immunogenicity trial with 20 adults in The Gambia in 1997. This small sample size is typical of Phase I trials, where the main objectives are usually to determine a safe dosing range and to evaluate side effects. These researchers reported that the vaccine did not have any significant toxicity but did produce the expected antibodies.
Several Phase II studies conducted over the following decade (Phase IIa and Phase IIb) demonstrated the efficacy of the vaccine against several end points (or outcomes) (Moorthy and Ballou 2009). A Phase IIb trial began in Mozambique in 2003 with more than 2,000 children aged 1 to 4 years (Alonso et al. 2004). Each child was randomly assigned to receive 3 doses of RTS,S or a control vaccine. After 6 months, the prevalence of malaria was 37% lower in the treatment group than in the control group. A follow-up study with 214 infants also showed partial protection from malaria (Aponte et al. 2007). This Phase II trial was an important proof-of-concept study.
The final results of a large Phase III trial with more than 15,000 infants and young children in 7 African countries were published in The Lancet in 2015 (RTS,S Clinical Trials Partnership 2015). Children who participated in the study were randomly assigned to 1 of 3 arms: (a) 3 doses of RTS,S and a booster dose at month 20, (b) 3 doses of RTS,S and a booster dose of a comparator vaccine at month 20, or (c) 4 doses of a comparator vaccine. RTS,S reduced clinical malaria cases by 28% and 18% among young children and infants, respectively, over a 3–4-year period. This Phase III trial achieved its goal—to show that the treatment was efficacious.
On the basis of these results, the European Medicines Agency issued a “European scientific opinion” to help inform the decision of the WHO and African national regulatory authorities regarding their recommendation of the vaccine. If RTS,S is approved for use and eventually hits the market, researchers will likely conduct Phase IV trials to evaluate the vaccine’s long-term effects.
Implementation Science and Translational Research
The research on RTS,S, will not end there, however. The vaccine may be efficacious, but that does not mean it will be easy or cost-effective to produce and deliver at a scale of millions. Studies that assess how best to get efficacious treatments to the people who need them most fall under the domain of implementation science.
Many stumbling blocks face interventions in the process of moving from “bench to bedside.” Practitioners of translational research point to 4 key bottlenecks:
- T1: Translation from basic science to clinical research
- T2: Translation from early clinical trials to Phase III trials and beyond with larger patient populations
- T3: Translation from efficacy trials (i.e., Phase III trials) to real-world effectiveness through implementation science
- T4: Translation from evidence about delivery at scale to the adoption of new policies
Monitoring and Evaluation
Another arena of applied science in global health is monitoring and evaluation, or M&E.
In the United States, program evaluation became commonplace by the end of the 1950s and grew dramatically in the 1960s as the federal government expanded and introduced new social programs. Lawmakers wanted accountability, and the evaluation of social programs took off (Rossi, Lipsey, and Freeman 2003). But is program evaluation really research?
The United States and other modern nations should be ready for an experimental approach to social reform, an approach in which we try out new programs designed to cure specific problems, in which we learn whether or not these programs are effective, and in which we retain, imitate, modify or discard them on the basis of their effectiveness on the multiple imperfect criteria available (Campbell 1969).
But not everyone agrees. Some have argued that program evaluation is really designed for program implementers and funders, and that the messy nature of program implementation requires a loosening of research standards (Cronbach 1982) and simply evaluate the evidence, or “learn what you can.”
In their introductory text on evaluation, Rossi et al. (2003) strike a balance in views. Their answer is perhaps a bit unsatisfying but is arguably true nevertheless: It depends.
Program evaluations should be as rigorous as logistics, ethics, politics, and resources permit—and no less. Surely a lower bound in terms of quality or what is worthwhile exists, but the line is so context dependent that a simple rule is best: “Don’t go beyond the data.” Every organization wants to claim “impact,” but not every evaluation can be based on the design and implementation.
Program monitoring is concerned with the implementation of programs, policies, or interventions. How are resources being used? Is the program being delivered as intended (or with fidelity)? How many people participate, and does the program reach the intended targets? These are all program-monitoring questions.
Accurate monitoring is essential for reporting data to funders, but it is also essential for all good evaluations. The reason is simple: If a program fails—that is, has no impact—the next question is why? Did the program fail because the idea or theory behind the program was wrong (theory failure)? Or was the implementation of the program so troubled that there was never a chance for success (i.e., implementation failure)? Every trial should include ongoing monitoring or a formal process evaluation to assess the impact of the program on a continual basis.
Koplan, Jeffrey P, T Christopher Bond, Michael H Merson, K Srinath Reddy, Mario Henry Rodriguez, Nelson K Sewankambo, and Judith N Wasserheit. 2009. “Towards a Common Definition of Global Health.” The Lancet 373 (9679):1993–5.
Merson, Michael H, Robert E Black, and Anne J Mills, eds. 2011. Global Health: Diseases, Programs, Systems and Policies. 3rd ed. Burlington, MA: Jones & Bartlett Publishers.
Institute for Health Metrics and Evaluation. 2016. “Financing Global Health 2015: Development Assistance Steady on the Path to New Global Goals.” Seattle, WA: IHME.
Doherty, JF, M Pinder, N Tornieporth, C Carton, L Vigneron, P Milligan, WR Ballou, et al. 1999. “A Phase I Safety and Immunogenicity Trial with the Candidate Malaria Vaccine Rts, S/Sbas2 in Semi-Immune Adults in the Gambia.” The American Journal of Tropical Medicine and Hygiene 61 (6):865–68. The American Journal of Tropical Medicine and Hygiene, 61(6)*](http://www.ajtmh.org/content/61/6/865.full.pdf+html.
Moorthy, V. S., and W. R. Ballou. 2009. “Immunological Mechanisms Underlying Protection Mediated by Rts, S: A Review of the Available Data.” Malaria Journal 312. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806383/.
Alonso, Pedro L, Jahit Sacarlal, John J Aponte, Amanda Leach, Eusebio Macete, Jessica Milman, Inacio Mandomando, et al. 2004. “Efficacy of the Rts, S/As02a Vaccine Against Plasmodium Falciparum Infection and Disease in Young African Children: Randomised Controlled Trial.” The Lancet 364 (9443):1411–20. http://www.ncbi.nlm.nih.gov/pubmed/15488216.
Aponte, John J, Pedro Aide, Montse Renom, Inacio Mandomando, Quique Bassat, Jahit Sacarlal, M Nelia Manaca, et al. 2007. “Safety of the Rts, S/As02d Candidate Malaria Vaccine in Infants Living in a Highly Endemic Area of Mozambique: A Double Blind Randomised Controlled Phase I/Iib Trial.” The Lancet 370 (9598):1543–51. http://www.ncbi.nlm.nih.gov/pubmed/17949807.
RTS,S Clinical Trials Partnership. 2015. “Efficacy and Safety of Rts, S/As01 Malaria Vaccine with or Without a Booster Dose in Infants and Children in Africa: Final Results of a Phase 3, Individually Randomised, Controlled Trial.” The Lancet 386 (9988):31–45. http://www.ncbi.nlm.nih.gov/pubmed/25913272.
Rossi, P. H., M. W. Lipsey, and H. E. Freeman. 2003. Evaluation: A Systematic Approach. Sage Publications. http://amzn.to/1TlIqoa.
Campbell, D. T. 1969. “Reforms as Experiments.” American Psychologist 24 (4):409. http://psycnet.apa.org/journals/amp/24/4/409/.
Cronbach, L. J. 1982. Designing Evaluations of Educational and Social Programs. Jossey-Bass. http://amzn.to/1L4gxwx.
The World RePort database from the NIH—the largest funder of health research in the world—lists health research projects totaling nearly $45 billion in 2015. It’s possible to filter on the country of the recipient organization, but this does not count money disbursed to US and European organizations working on global health issues.↩
Glossary of Terms for Human Subjects Protection and Inclusion Issues, based on the 1997 Report of the NIH Director’s Panel on Clinical Research, entry: “clinical research”. Available at http://grants.nih.gov/grants/peer/tree_glossary.pdf.↩
Campbell had an outsized impact on the field. It’s no surprise that an organization dedicated to synthesizing the best available evidence on social interventions, the Campbell Collaboration, bears his name.↩