1This video works across the research landscape. We start with the split between basic and applied research, move through the domains of clinical research and the phases a clinical trial passes through on its way to market, and close with the case of the first malaria vaccine.

2Global health research brings together scholars and practitioners from many different disciplines to tackle big challenges, so the methods of these disciplines are the methods of global health research. We can organize that landscape as a taxonomy, and over the next few minutes we'll work through it piece by piece.

3Here is the taxonomy. Don't worry if this diagram looks overwhelming at first — we'll work through it piece by piece. Here's the roadmap. Research is divided into two main categories, basic and applied, which you can see on the left side of the diagram. Within applied research, we have clinical research, including clinical trials, translational research, and implementation and policy research. Overlapping with applied research is monitoring and evaluation, which sometimes, but not always, qualifies as research. We'll start on the left with basic research and work our way across.

4Basic research, also known as pure or blue skies 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. Another example is the scientific investigation of the properties of cancer cells, to better understand how they grow and spread.

5The information generated by basic science becomes the basis for applied science. Harvard neurobiologist Dr. Rachel Wilson explains this beautifully. The new therapies of today, she says, were the prototypes of yesterday. And the prototypes of yesterday were previously just findings in laboratories, and before that they were just an idea. Unless we have new ideas, we're not going to have useful therapies. Great new therapies don't just fall like apples from a tree.

6While basic research expands our understanding, applied research focuses on specific problems or real-world applications. Much of global health research falls into the applied domain, because our mission is to improve health and achieve equity in health for all people worldwide. That's this block on the diagram, and everything nested inside it. Applied science takes many different forms.

7One of those forms is clinical research. Clinical research is a broad field that aims to understand human disease, develop better ways to detect, diagnose, prevent, and treat disease, and to promote health. That definition covers a lot of ground, so it helps to see the domains it spans.

8There are at least six I can think of. Treatment and prevention research tests new approaches for preventing or treating illness, and that includes clinical trials of drugs, biologics, devices, instruments, and behavioral interventions. Screening research develops and evaluates methods for detecting illness risk factors or markers. Diagnostic research develops and evaluates methods for identifying health conditions or illness. Genetic studies examine links between genes and disorders. Epidemiological studies study the patterns, causes, prevalence, and incidence of disease in a population. And health services research studies how people access healthcare services, healthcare costs, and outcomes.

9One type of clinical research is a clinical trial. If you've ever wondered why it takes so long for a promising treatment to reach patients, the phases of a trial help explain why. Here is that part of the taxonomy up close: preclinical work, then the numbered phases, then market.

10In the United States, drugs, biologics, devices, and instruments complete these phases prior to going to market. In the early phases of drug trials, the objective is to understand how the compound affects the body. What is a safe dose that could be effective? Preclinical research asks: are there signs that the drug candidate will have an effect in the lab? Phase 0 is an optional phase enrolling fewer than ten human subjects, What happens in the body — the pharmacokinetics — when a very low dose is administered to human subjects? Phase 1 enrolls tens of people. Is the drug safe? What is the best dose that balances possible effects with toxicity? Phase 2 enrolls hundreds and asks: when using this optimal dose, is there any effect of the drug on clinical markers or health outcomes?

11Phase 3 enrolls thousands. What is the effect of the drug on clinical markers or health outcomes when compared to an existing treatment or placebo in a randomized evaluation? Phase 3 trials put the optimal dose to the test, seeking to determine if the drug works and to quantify the size of the effect. Success at this stage is required for regulatory approval in some countries, and drugs that pass are typically approved for use by the governing regulatory body. Once a drug reaches market, Phase 4 asks a different question: are there long-term adverse effects of the drug once it is available on the market?

12In the United States, the FDA requires that most interventional studies of any regulated products with research sites in the U.S. be registered in the ClinicalTrials.gov trial registry. Many countries have their own registries, and the World Health Organization maintains a web portal that searches across registries.

13Trial registries are useful for researchers and patients alike. When my wife's Aunt Debbie learned she had an aggressive brain tumor, we searched ClinicalTrials.gov and identified several trials recruiting patients for experimental glioblastoma treatments. Debbie decided to take part in a Phase 1 trial that injected modified poliovirus into her tumor. She lived for another five years, and helped to advance the science of glioblastoma treatment.

14Healthy volunteers and patients like Debbie are the backbone of clinical research. Their sacrifices, combined with the ingenuity of scientists and research teams, have created thousands of medical breakthroughs. But for every new drug approved, there is a trail of failure. This figure traces the pipeline from basic research to FDA approval, and recent studies estimate that fewer than fifteen percent of candidates entering Phase 1 trials are ultimately approved by the FDA.

15The pipeline covers what the FDA regulates — drugs, biologics, devices, and instruments. Studies of behavioral interventions, social programs, and policies fall outside it. Nevertheless, we still design studies to estimate the efficacy of interventions, programs, and policies, and many of these tests meet the World Health Organization's definition of a clinical trial: any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.

16To see the whole pipeline in a single case, take the first malaria vaccine. In 2021, after more than 35 years of research, the World Health Organization recommended widespread use of a vaccine candidate called RTSS to prevent malaria in children. Development began in 1984, and soon after, a promising vaccine candidate entered preclinical research. Researchers performed tests on nonhuman subjects to collect data on how well the vaccine worked, how much damage it could do to an organism, and how the body affected the vaccine.

17Clinical research on humans began in 1992. Researchers conducted a Phase 1 safety and immunogenicity trial with 20 adults in The Gambia in 1997. The results suggested that the vaccine did not have any significant toxicity, but did produce the expected antibodies. That is the Phase 1 question from the table, asked of a real candidate: tens of participants, and safety before effect.

18Several Phase 2 studies conducted over the next decade demonstrated the efficacy of the vaccine against several endpoints. A Phase 2b trial began in Mozambique in 2003 with more than 2,000 children. Each child was randomly assigned to receive three doses of RTSS or a control vaccine. After six months, the prevalence of malaria was 37 percent lower in the treatment group than in the control group. This Phase 2 trial was an important proof-of-concept study.

19The results of a large Phase 3 trial with more than 15,000 infants and young children in seven African countries were published in 2015. Children who participated were randomly assigned to one of three arms: three doses of RTSS and a booster dose at month 20; three doses of RTSS and a booster dose of a comparator vaccine at month 20; or four doses of a comparator vaccine. The vaccine reduced clinical malaria cases by 28 percent among young children and 18 percent among infants, over a three to four year period. This Phase 3 trial demonstrated that the treatment was efficacious.

20On the basis of these results, the European Medicines Agency issued a favorable European scientific opinion. That led the health ministries in Ghana, Kenya and Malawi to authorize a pilot study in 2019, to assess the feasibility of administering the required four doses of the vaccine as part of routine childhood immunization programs. After more than 800,000 children were immunized under this program, the WHO recommended that countries with moderate to high transmission adopt the vaccine.