Issue 18 Understanding Science

Clinical Trials – Part One: Medical Research

🕒 13 min

There are no such things as incurable, there are only things for which man has not found a cure.”

Bernard Baruch, 30 April 1954

What is medical research?

Medical (biomedical) research, sometimes referred to as experimental medicine, comprises different types of research, from basic, to clinical, applied research. Different scientific fields are usually included and range from biology, medicine, physics, computational science, mathematics, chemistry, and pharmacology. The overarching intention of such research is to improve human health and well-being.

History of medical research

The history of medical research and clinical trials is complex but rather interesting, involving a variety of challenges, from scientific to ethical, legal, and regulatory. While medical research as a term may cover basic research and epidemiological research as well as clinical research, the history of each branch is rather complicated and there are quite a number of interesting historical scientific experiments, often accidental, that enabled science to develop to the place it is today. Think of Mendel’s peas, Jenner’s smallpox experiment, Fleming’s accidental discovery of penicillin, or DNA structure discovery by Franklin, Watson, Crick, and Wilkins.

When we discuss medical research and clinical trials specifically, many would be surprised to discover that the first clinical trial was described in The Bible, in the Book of Daniel. According to the text, king Nebuchadnezzar unintentionally conducted an uncontrolled medical experiment. As an experienced military strategist, he ordered soldiers to only eat meat and only drink wine, thinking this is an optimal diet for good physical condition. Some of the soldiers of royal background, and used to a plant-based diet, objected and the king allowed them to retain their diet but only for 10 days. After 10 days passed, the soldiers on the plant-based diet were in better physical shape compared to the soldiers on a meat-based diet and they were allowed to resume eating their standard diet.

Fast forward to the modern era, physician James Lind is considered a pioneer of what we deem today to be an established controlled clinical trial. Lind’s famous scurvy trial in sailors is a well-known example among researchers. He discovered that a diet with oranges and lemons caused sailors to recover from scurvy within a week, while others, whose diet was without “vitamin C”, were not improving. Out of 12 sailors, i.e. the research participants:

  • Two were given a quart of cyder a day,
  • Two were given 25 drops of elixir vitriol 3x a day,
  • Two were given spoonfuls of vinegar 3x a day,
  • Two, that were having the worst case of scurvy were given a course of seawater,
  • Two got medicine from the ship’s surgeon, and
  • The remaining two received 2 oranges and a lemon a day.

The rest of the diet was identical among the sailors. This was described in May 1747.

One century later, placebo was first introduced, when in 1863 the US physician Austin Flint planned the first clinical study to compare a dummy treatment (highly diluted herbal tincture) to an established active treatment in patients suffering from rheumatism. There were no significant differences between the arms.

The first double-blind trial was conducted in 1943-1944 by Medical Research Council (MRC) in the UK to investigate patulin as a treatment for the common cold. It was subjected to a rigorous schedule to keep patients and physicians blinded to the treatment given. The nurse allocated the treatment in a separate room to keep the others unaware of the treatment given. The results did not demonstrate any benefit of using patulin.

In 1946, the first randomized trial was conducted, again by MRC in the UK to look at the effect of streptomycin on pulmonary tuberculosis. The patients were either randomized to be treated by streptomycin and bed-rest (S case) or by bed-rest alone (C case). Prior to joining, patients were previously untreated by streptomycin (due to limited supplies overall in the UK) and they did not know which treatment they would get. The trial was also known for its meticulous design and conduct as well as for the use of unbiased outcome measures (x-ray interpretation by blinded experts).

In the modern era, the evolution of various study designs, as well as the establishment of the regulatory framework, is relevant for our consideration. While, in a nutshell, the ethical and moral frameworks can be traced back to the Hippocratic Oath of not harming patients, during World War II, this principle was often disregarded. Such a situation led to the development of ethical standards in medical experiments, namely the International Guidance developed in 1947 known as the Nuremberg Code, that highlighted the importance of voluntary participation. In 1964, other guidelines were developed to describe the principles of use of human subjects in medical research. This was the Helsinki Declaration, which has been renewed since then consistently, with the latest update being in 2008.

In 1996, Good Clinical Practice (GCP) was published by the International Conference on Harmonization (ICH) of technical requirements for registration of pharmaceuticals for human use, which is the universal, globally accepted gold standard for the ethical conduct of clinical trials.

Types of medical research

Medical research is generally split into primary and secondary research.

According to the areas being researched, studies in medical research can be generally split into:

  1. Basic (experimental) research
  2. Epidemiological research
  3. Preclinical research
  4. Clinical research

Clinical and epidemiological studies can be further classified into interventional and non-interventional. It is often not easy to definitively classify an individual study into only one of the four groups, given that the studies may be complex, lengthy, and have elements of all four types of medical research (see Figure 1).

Figure 1: Types of medical research (adapted from

Basic medical research

Basic medical research generally investigates mechanisms of diseases and tries to understand human health and complex physiological pathways. More specifically, it involves the investigation of and experimentation with behaviors, properties, and relationships of a given element (e.g. cell, molecule, genetic material, pathogen, compound, etc.) to build general knowledge and a foundation on which other types of research are built.

Basic research can be applied and theoretical, depending on the intention: i) solve problems under the investigation practically, ii) develop or improve methods that help to support applied research. A variety of disciplines can be involved in such research, ranging between statisticians, physicists, bioinformaticians, biologists, chemists, etc.

Crudely, basic research comprises cellular and molecular biology, neuroscience, immunology, and physiology and includes animal experiments, cell studies, physiological and genetic investigations, and can include investigation of drug properties. Basic research can also be utilized to improve/optimize analytical procedures, imaging technologies, and genetic sequencing.

This type of research is normally conducted at universities and research institutes and can be publicly or governmentally funded. The advantage of such research is that it can be done in a controlled environment, whereby plenty of variables can be controlled and an individual variable can be investigated. Such a level of control is artificial – however, as a consequence, it can promptly promote advances in understanding components of human health or disease.

Epidemiological research

Epidemiology is the method used to find the causes of health outcomes and diseases in populations. In epidemiology, the community is the “patient/subject” under investigation, and individuals are viewed collectively. Epidemiological research focuses on investigating the distribution, historical changes, and causes in the frequency of diseases.

In research, in contrast to clinical studies, which look at the effect of an intervention on the individual, epidemiological studies investigate patterns of disease in a population exposed to this intervention.

Epidemiological studies, like clinical studies, can be interventional and non-interventional. Interventional epidemiological studies imply having intervention by researchers as a part of the study design. Examples of interventional studies are field studies (region/country) or group studies (specific cohort). As an example, an intervention can be a bed-net sprayed with an insecticide used in the prevention of malaria infection. Here, bed nets would be distributed in one village and residents would be instructed to sleep under them as the mosquitos carrying Plasmodium falciparum, the infectious agent causing malaria, are mostly active at night. Another village, in the same region, but geographically separated, using their own standard method of protection from mosquitos, would serve as a control group. It is important that the villages are in the same region because that would imply the populations are somewhat similar. At the same time, it is relevant that the two villages are geographically separated to prevent the transfer of knowledge on the protective bed nets. This is the prerequisite for having adequate control. The described study is an example of a cluster-randomized trial design that can be used to investigate intervention between groups of people with similar baseline characteristics, as one of the essential prerequisites of clinical and epidemiological research.

The trial can be randomized on an individual or group level (individually or cluster-randomized study). In the example from before, it may not be ethical nor practical to implement individual randomization in the same village, due to the whole village being inevitably exposed to the knowledge of bed nets, causing the control group to potentially change their habits. On the other hand, the group that received bed nets may be potentially more protected from malaria infection compared to the control, which could have positive short-term consequences but would also compromise the study results, due to the absence of adequate independent control.

Observational studies, in contrast to interventional, are non-experimental and investigate associations between known exposures and outcomes. These can be cross-sectional, case-control, and cohort studies (see Table 1).

Observational epidemiological studiesDescriptionImportant definitions
Population data is collected at a single point in time (cross-section of time)
Prevalence studies (how many people have the disease at a given time)  
Case-controlStarts from an outcome and investigates exposure retrospectively in time
Case = instance of having an outcome/disease

Control = instance of not having an outcome/disease  
CohortObserves the group (cohort) over period of time (prospectively) to investigate exposure
Longitudinal studies (temporal relationship between exposure and outcome established)  

Incidence studies (how many people develop disease over a period of time)  
Table 1: Types of non-interventional (observational) epidemiological studies

Cross-sectional studies investigate the presence of certain diseases and exposures to potential risk factors in a snapshot of time in a population. They are often called prevalence studies because they look at how many people in a population in a given time point have the disease under investigation.

Case-control studies compare cases (= those with the disease) with controls (= those without the disease) over a period of time. Several exposure factors can be retrospectively investigated to see whether the duration of exposure or frequency of exposure (e.g. smoking) can be connected to the development of disease (e.g. lung cancer). Terms often used in these studies are the odds ratio (OR). OR represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure. The disadvantage of the case-control studies is that they cannot look at the incidence (how many new cases of the disease will emerge over a period of time).

In contrast to case-control studies, cohort studies can investigate incidence i.e. how often a specific disease occurs between two or more groups over time. This is a prospective investigation as it investigates the outcomes from a certain time point towards a time point in the future. Such studies often investigate relative risk or risk ratio (RR), which is the probability of an outcome (e.g. lung cancer) occurring in the group that is exposed vs. the probability of an outcome occurring in the group that is lacking the exposure (e.g. to smoking).

Epidemiological studies can be performed at the universities, hospitals, and different non-profit and governmental organizations, where epidemiologists often work. Besides that, they can be employed in for-profit organizations, such as the pharmaceutical industry. Epidemiologists can often be present “in the field” and are normally at the forefront when the public health danger, such as infectious disease outbreak, epidemic, or pandemic, is eminent.

Preclinical research

In pharmaceutical research, the clinical investigation is preceded by rigorous preclinical development. The clinical investigation starts with a “First Time in Human” (FTiH) exposure of a new intervention (treatment, vaccine, or medical device). To determine the starting dose and investigate the toxicology/harmfulness of a product, preclinical research is conducted, usually in an adequate animal model.

Depending on a class of product, a product may undergo different stages and types of preclinical development. Such studies include pharmacodynamics/PD (what a product does to the body), pharmacokinetics/PK (what a body does to the product in terms of absorption, distribution, metabolism, and excretion), and toxicology. Based on the results in vitro (in the cell) and in vivo (in animal models) subsequently, a safe initial dose for humans can be extrapolated allometrically (based on the shape, anatomy, physiology, behavior comparison).

The choice of an adequate animal model will depend on the possibility to extrapolate the results to humans. For example, primates may be an excellent model for a variety of diseases, but not so much for some viruses, as they are not always infected by the same viruses as humans. In this case, the closest animal model, that can be infected by the same virus as humans, is used. The similarity in metabolism, digestion, enzyme activity, and the similarity in anatomy and physiology are investigated to choose the most appropriate model. Lately, the use of animals in research is being limited due to ethical and cost reasons – however, in drug and vaccine development the need to use animal modes is driven by safety reasons. Regulatory authorities (such as US Food and Drug Administration; FDA and European Medical Agency; EMA) will usually not authorize the initiation of clinical trials in humans without the safety testing in at least two mammalian species.

The term “preclinical trials” applies to medicinal product development (drugs, vaccines, medical devices), which is most commonly conducted in pharmaceutical companies. Different types of scientists are included in such research, from those working in the laboratory to those analyzing the data.

Clinical research

Clinical research is conducted in human participants to evaluate the safety and efficacy of an intervention that is considered to be able to improve human health. While under the term “clinical trial” or “clinical study” we often consider an interventional trial, the study can be also non-interventional (NIS = non-interventional study), where the intervention of a researcher is reduced as much as possible. An example would be taking medicine according to the prescribing information and at the discretion of the treating physician while being a part of the investigational trial. This enables researchers to obtain real-world data on medicine using epidemiological approaches, rather than just data from a tightly controlled interventional study.

Interventional clinical research is especially highly regulated and a number of necessary steps are needed to ensure the safety of the participants, preciseness of study conduct, and the reliability of the research, the measured outcomes, and the conducted analysis. It presents a complex platform subjected to an array of legal and ethical requirements, without which a lot of drugs used every day to improve our health and longevity would have never reached the market.

To learn more on the topic of clinical trials, the complexity associated with conducting them, and to understand the difficulties of bringing a drug or a vaccine to the market, stay tuned for the “Clinical Trials – Part Two: Clinical Trials)”.


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Bhatt A. Evolution of Clinical Research: A History Before and Beyond James Lind, Perspect Clin Res. 2010 Jan-Mar; 1(1): 6–10.

Manja V. and Lakshminrusimha S. Epidemiology and Clinical Research Design, Part 1: Study Types, Neoreviews. 2014 Dec 1; 15(12): e558–e569.

Röhrig B. et al. Types of Study in Medical Research, Part 3 of a Series on Evaluation of Scientific Publications, Dtsch Arztebl Int. 2009 Apr; 106(15): 262–268.

Centers for Disease Control and Prevention (CDC). 2021. “Epidemiology.” Last edited on 17 June 2016.

OpenMD, 2021. “Types of Primary Medical Research.” Last edited on 2 September 2021.

Wikipedia. 2021 “Epidemiology.” Last edited on 12 October 2021

Wikipedia. 2021. “Medical research.” Last edited on 8 November 2021.

Wikipedia. 2021. “Preclinical development.” Last edited on 20 August 2021.

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