Explainer: What is a clinical trial? | Science News for Students

Explainer: What is a clinical trial?

Countless numbers of people volunteer for research studies to help answer medical and health questions
Aug 24, 2018 — 6:30 am EST

Volunteers who take part in clinical trials usually start by answering a host of questions about their health and habits. Those who qualify to take part may be asked to take experimental drugs, experimental therapies (such as acupuncture to treat headaches), new food supplements or exercise regimens.


Let’s say your doctor prescribes some medicine. Perhaps it’s a pill. If you live in the United States, Europe or many other parts of the world, that medicine will have undergone tests. Before that medicine makes it into your hand, researchers will have ensured that it works well and is safe.

And they did this through clinical trials.

Such research trials always involve human volunteers. The people can be any age, from babies to the elderly. It all depends on who might benefit from a new treatment or behavioral change. Scientists refer to what is being tested in these studies as an intervention.

A clinical trial generally divides its volunteers into two or more groups. As its name implies, one group — the “intervention group” — always receives the intervention. Other groups may receive a different amount or type of treatment. Yet another group may receive no treatment at all. These other comparison groups are known as controls. Researchers compare what happens to the people in the intervention group against what happens to the controls.

New medicines or vaccines are one type of intervention. But there are many others. Talk therapies, such as what a psychiatrist might use, are another type. So are diets, exercise regimens and the educational videos that may be shown to teens.

Or researchers may want to assess how well a medical device works. For instance, will some new “pen” that injects the drug epinephrine (Eh-pih-NEF-rin) halt a potentially life-threatening allergic reaction fast enough? Medical acupuncture trials may test at which sites on the body the needles should be inserted.

Each new clinical trial builds on existing knowledge. This can come from other clinical trials, from studies of people that don’t involve interventions and from research in animals. It might even build on research in cells or tissues in the lab, or on computer analyses of the shape and properties of new molecules.

For new drugs or vaccines, the early work begins in a laboratory. That’s where the ingredients all come together. When researchers want to understand how something will function in people, they may first use animals as a stand-in. Why animals? One reason is that they tend to be shorter-lived. Probing the life-long effects of some treatment may take only days or weeks in short-lived insects. To study the same thing in rodents may take only a few years. To assess the same impacts in people, however, could take decades.

Those early steps can uncover a lot about how a treatment might work, or whether it might cause unwanted effects. Data from these trials also may suggest how much or how often a treatment might need to be used. And researchers can use such data to help figure out who might benefit most. Only then will they be ready to start testing the intervention in people.

How a clinical trial works

Consider a recent clinical trial that looked at depression and insomnia in youth.

Depression is a mood disorder. Its victims can feel persistent or recurring bouts of sadness. Some may feel hopeless. Very often, depressed people may have trouble falling asleep. If they awaken in the middle of the night, they may be unable to get back to sleep.

Greg Clarke wanted to see if it was possible to reduce symptoms of depression by treating someone’s sleep problems — insomnia — as well as the depression. As a clinical psychologist at the Kaiser Permanente Center for Health Research in Portland, Ore., Clarke studies depression, insomnia and anxiety.

child psychologist and child talking
Even children may participate in clinical trials. And those trials may involve medicines or even talk therapy, such as the treatment shown here.

Earlier clinical trials had shown promising results in adults. Now Clarke and his colleagues wanted to know if the sleep therapy would help younger patients, too.

They recruited 41 people, all 12 to 20 years old. Each was assigned to a group at random. (Usually this is done by a computer program.) Such “randomization” is an important step. It helps reduce differences between the groups. Without randomization, all of the people most likely to benefit from treatment could end up in the intervention group. That could make the treatment appear more effective than it really is.

“When you finally finish the study,” Clarke says, “you should really have only one thing different between the two groups.” And that would be “the treatment that they were exposed to.”

All recruits in Clarke’s trial received therapy for depression. For the intervention, some of these people also received therapy for insomnia. Not the control group. They just received instructions on good sleep habits.

By the end of the study, people in the intervention group slept, on average, 40 minutes longer than did those in the control group. A higher percentage of people in the intervention group also recovered from depression — and they recovered faster.

Many clinical trials also are “blinded.” This means that the people involved in the trial do not know which of them are receiving the intervention — and which are not. By being “blind” to these details, people cannot influence the outcome of the trial. When the participants don’t know which group they are in (intervention or control), the trial is known as single-blinded. In a double-blinded study, both the participants and the researchers are kept in the dark — until the entire study is over.

The information is collected in stages

Research on drugs or treatments can take place in four phases, designated by the Roman numerals I to IV. Each phase is a separate type of clinical trial.

Phase I trials are small. They typically include only 20 to 80 people. These trials test the safety of a treatment, usually in healthy people. They also help to figure out the right dose of a drug or therapy. According to the U.S. Food and Drug Administration, roughly seven in every 10 drugs move on from a phase I to a phase II clinical trial.         

Phase II trials enroll 100 to 300 people. Each recruit will have the illness or condition that might be helped by the treatment. These trials test how well the treatment works to help that condition. They also try to identify all side effects (nearly every treatment has some). Such trials can last for months to a few years. Roughly one in every three treatments tested this way will move on to the next type of trial.

Phase III trials scale up, recruiting some 300 to 3000 volunteers, all having the target condition. The larger numbers of volunteers provide more information. These trials compare the new treatment against existing treatments for the same condition to see which works better. These trials also continue to look for side effects. Phase III trials follow people for one to four years. Data from this stage might be used to get a new drug or treatment approved for widespread use in people with the condition. Only about one in every three or four drugs does well enough to move on to the final type of clinical trial.

Once a new drug or medical device is approved, medical professionals can prescribe it to the general public. But researchers often will continue to track it in what’s known as a phase IV trial. Here, researchers again want to confirm that the intervention is working. More importantly, they want to check that the long-term benefits greatly outweigh any side effects. These trials can follow thousands of treated people.

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A diagram showing the different phases of clinical trials
Research on drugs or treatments can take place in phases. Each phase is a separate clinical trial. The goal of these trials is to establish the safety and effectiveness of an intervention.
 AIDSinfo, U.S. Department of Health and Human Services (HHS)

Probing benefits of vitamins and more

The vast majority of clinical trials study the impacts of drugs and other therapies. But even the potential benefits of foods and nutrients might be studied in a clinical trial.

That’s what JoAnn Manson  at Harvard Medical School in Boston, Mass., and her colleagues are doing. They are directing a long-running trial known as VITAL. (Its name is an acronym for VITamin D and OmegA-3 TriaL.) Vitamin D is a nutrient that the body converts into a hormone to boost bone and muscle health. Omega-3 fatty acids are the heart-healthy fats in fish oil and some plants. This massive study, begun in 2010, has been following almost 26,000 U.S. men and women. Its main goal: to tease out whether high doses of  vitamin D and omega-3 fatty acids can prevent cancer, heart disease or stroke. This study will be on the lookout for signs of other benefits as well.

Data collected so far have led to a flurry of research papers. So far, Manson and her colleagues have been tracking the health of all of their recruits. These data will define the baseline, or starting point, of the volunteers’ health. Then the team can see whether people who get these daily food supplements end up healthier than people who don’t.

“A single study,” Clarke notes, “is not enough to draw a conclusion.” In fact, “sometimes even a dozen studies may not be enough” — especially if they did not include enough people. What’s more, he adds, it’s important that related studies all ask the same or similar questions. But when they do, the data they acquire should paint a picture of how valuable a new intervention can be.

Harvard researchers describe VITAL, the clinical trial they developed to study the potentially protective effects of certain dietary supplements on cancer, heart disease and more.
JoAnn Manson/Harvard University

Power Words

(more about Power Words)

acupuncture     A therapy that comes from traditional Chinese medicine, it stimulates various points on the body. This is usually done by inserting needles through the skin for a half-hour or more.

average     (in science) A term for the arithmetic mean, which is the sum of a group of numbers that is then divided by the size of the group.

behavior     The way something, often a person or other organism, acts towards others, or conducts itself.

blinding     (in research) The deliberate hiding of some important test information from a participant. For instance, a researcher might put a blindfold on participants before they eat something. This prevents them from being influenced by a food’s appearance. For a test of how well a drug works, researchers may give each person a capsule or shot. But only one group gets the real drug. Others might get an inactive “sugar pill” or injection of salt water. By not knowing if they got the real deal or an imposter, participants’ responses should not be biased for or against a particular result.

clinical     (in medicine) A term that refers to diagnoses, treatments or experiments involving people.

clinical trial     A research trial that involves people.

computer program     A set of instructions that a computer uses to perform some analysis or computation. The writing of these instructions is known as computer programming.

control     A part of an experiment where there is no change from normal conditions. The control is essential to scientific experiments. It shows that any new effect is likely due only to the part of the test that a researcher has altered. For example, if scientists were testing different types of fertilizer in a garden, they would want one section of it to remain unfertilized, as the control. Its area would show how plants in this garden grow under normal conditions. And that gives scientists something against which they can compare their experimental data.

depression      (in medicine) A mental illness characterized by persistent sadness and apathy. Although these feelings can be triggered by events, such as the death of a loved one or the move to a new city, that isn’t typically considered an “illness” — unless the symptoms are prolonged and harm an individual’s ability to perform normal daily tasks (such as working, sleeping or interacting with others). People suffering from depression often feel they lack the energy needed to get anything done. They may have difficulty concentrating on things or showing an interest in normal events. Many times, these feelings seem to be triggered by nothing; they can appear out of body does not work appropriately, leading to what might be viewed as an illness. This term can sometimes be used interchangeably with disease.

diet     The foods and liquids ingested by an animal to provide the nutrition it needs to grow and maintain health. (verb) To adopt a specific food-intake plan for the purpose of controlling body weight.

disorder     (in medicine) A condition where the body does not work appropriately, leading to what might be viewed as an illness. This term can sometimes be used interchangeably with disease.

double-blind study     A study in which neither the participants nor their doctors (or other people administering the study) know who is receiving a potentially therapeutic treatment.

epinephrine     A type of stress hormone, commonly called adrenaline, that is secreted by the adrenal glands. It constricts blood vessels. It also increases the force and rate at which the heart contracts.

Food and Drug Administration (or FDA)     A part of the U.S. Department of Health and Human Services, FDA is charged with overseeing the safety of many products. For instance, it is responsible for making sure drugs are properly labeled, safe and effective; that cosmetics and food supplements are safe and properly labeled; and that tobacco products are regulated.

insomnia     An inability to get to sleep and stay asleep long enough to become fully rested.

intervention     Deliberate action taken to bring about some anticipated outcome. (in medicine) A planned effort to prevent or treat a disease or other condition relating to health or well-being.

mental health     A term for someone’s emotional, psychological and social well-being. It refers to how people behave on their own and how they interact with others. It includes how people make choices, handle stress and manage fear or anxiety. Poor mental health can be triggered by disease or merely reflect a short-term response to life’s challenges. It can occur in people of any age, from babies to the elderly.

molecule     An electrically neutral group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O2), but water is made of two hydrogen atoms and one oxygen atom (H2O).

persistent     An adjective for something that is long-lasting.

psychiatrist     A medical doctor who spends many years learning to study and treat diseases of the human mind. Treatments may consist of talking therapies, prescription drugs or both. This medical field is known as psychiatry.

psychologist     A scientist or mental-health professional who studies the human mind, especially in relation to actions and behaviors. 

random     Something that occurs haphazardly or without reason, based on no intention or purpose.

randomize    (in study design) To assign people in one group or another based on no particular reason; indeed, researchers often use a computer to make the decision without knowing anything about the individual.

recruit     (noun) New member of a group or human trial. (verb) To enroll a new member into a research trial. Some may receive money or other compensation for their participation, particularly if they enter the trial healthy.

rodent     A mammal of the order Rodentia, a group that includes mice, rats, squirrels, guinea pigs, hamsters and porcupines.

side effects     Unintended problems or harm caused by a procedure or treatment.

therapy     (adj. therapeutic) Treatment intended to relieve or heal a disorder.

tissue     Made of cells, it is any of the distinct types of materials that make up animals, plants or fungi. Cells within a tissue work as a unit to perform a particular function in living organisms. Different organs of the human body, for instance, often are made from many different types of tissues.

vaccine     (v. vaccinate) A biological mixture that resembles a disease-causing agent. It is given to help the body create immunity to a particular disease. The injections used to administer most vaccines are known as vaccinations.


Website: U.S. National Institutes of Health. NIH Clinical Research Trials and You homepage.

Website: U.S. Food and Drug Administration. Guidance for Industry. E10 Choice of Control Group and Related Issues in Clinical Trials.

Journal: S. Rautiainen et al. Large-scale randomized clinical trials of bioactives and nutrients in relation to human health and disease prevention - Lessons from the VITAL and COSMOS trials. Molecular Aspects of Medicine. Vol. 61, June 2018, p. 12. doi: 10.1016/j.mam.2017.12.001.

Journal: C.M. Donlon et al. Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL): Effects on bone structure and architecture. Contemporary Clinical Trials. Vol. 67, April 2018, p. 56. doi: 10.1016/j.cct.2018.02.003.

Journal: D.R. Gold et al. Lung VITAL: Rationale, design, and baseline characteristics of an ancillary study evaluating the effects of vitamin D and/or marine omega-3 fatty acid supplements on acute exacerbations of chronic respiratory disease, asthma control, pneumonia and lung function in adults. Contemporary Clinical Trials. Vol. 47, March 2016, p. 185. doi: 10.1016/j.cct.2016.01.003.

Journal: J.H. Kang et al. Cognitive substudy of the vitamin d and omega-3 trial (VITAL-Cog): Design of a large randomized trial of omega-3 and vitamin d supplements in relation to cognitive change. Alzheimer’s & Dementia. Abstract #: P2-301. Vol. 11, July 2015, Supplement, p. P608. doi.org/10.1016/j.jalz.2015.06.843.

Journal:​ ​​G. Clarke et al. Cognitive-behavioral treatment of insomnia and depression in adolescents: A pilot randomized trial. Behaviour Research and Therapy. Vol 69, June 2015, p. 111. doi:  10.1016/j.brat.2015.04.009.