What is a clinical trial?

How clinical trials test new treatments to find better ways to prevent, detect or treat disease.

• What is a clinical trial?
• Why do we need clinical trials?
• Phases of clinical trials
• How clinical trials work
• Who can be part of a clinical trial?
• What happens when a trial is complete?

What is a clinical trial?

Clinical trials are research investigations in which people volunteer to test new treatments, interventions or tests as a means to prevent, detect, treat or manage various diseases or medical conditions. Some investigations look at how people respond to a new intervention* and what side effects might occur. This helps to determine if a new intervention works, if it is safe, and if it is better than the interventions that are already available.

Clinical trials might also compare existing interventions, test new ways to use or combine existing interventions or observe how people respond to other factors that might affect their health (such as dietary changes).

The World Health Organization (WHO) definition for a clinical trial is

‘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’.

Clinical trial interventions include but are not restricted to:

• experimental drugs
• cells and other biological products
• vaccines
• medical devices
• surgical and other medical treatments and procedures
• psychotherapeutic and behavioural therapies
• health service changes
• preventive care strategies and
• educational interventions.

Researchers may also conduct clinical trials to evaluate diagnostic or screening tests and new ways to detect and treat disease.

*The word ‘intervention’ will be used to refer to interventions, treatments and tests throughout this website.

Why do we need clinical trials?

Clinical trials are essential to the development of new interventions. For example, without clinical trials, we cannot properly determine whether new medicines developed in the laboratory or by using animal models are effective or safe, or whether a diagnostic test works properly in a clinical setting. This is because computer simulation and animal testing can only tell us so much about how a new treatment might work and are no substitute for testing in a living human body.

Clinical trials also permit testing and monitoring of the effect of an intervention on a large number of people to ensure that any improvement as a result of the intervention occurs for many people and is not just a random effect for a one person.

Most modern medical interventions are a direct result of clinical research. New interventions for most diseases and conditions — including cancer, heart disease, high blood pressure and asthma — have been developed through clinical research. Clinical trials often lead to new interventions becoming available that help people to live longer and to have less pain or disability.

Clinical trials can also help to improve health care services by raising standards of treatment. Doctors and hospital staff involved in clinical trials are continually trained to provide best practice patient care. Australian clinical trials are recognised internationally for including very high-quality patient care.

Phases of clinical trials

Clinical trials of biomedical interventions typically proceed through four phases.

Phase I Clinical Trial

Phase I clinical trials are done to test a new biomedical intervention for the first time in a small group of people (e.g. 20-80) to evaluate safety (e.g. to determine a safe dosage range and identify side effects).

Phase II Clinical Trial

Phase II clinical trials are done to study an intervention in a larger group of people (several hundred) to determine efficacy (that is, whether it works as intended) and to further evaluate its safety.

Phase III Clinical Trial

Phase III studies are done to study the efficacy of an intervention in large groups of trial participants (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions (or to non-interventional standard care).  Phase III studies are also used to monitor adverse effects and to collect information that will allow the intervention to be used safely.

Phase IV Clinical Trial

Phase IV studies are done after an intervention has been marketed. These studies are designed to monitor the effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use over longer periods of time.  They may also be used to investigate the potential use of the intervention in a different condition, or in combination with other therapies.

Other Clinical Trials

Researchers may also conduct exploratory studies, sometimes referred to as ‘Phase 0 trials’ or ‘pilot studies’.  These come before Phase I trials and are used to test how the body responds to an experimental drug. In these studies, small doses of the new drug are given once or for a short time to a very limited number of people.

Clinical trials of diagnostic tests are sometimes divided into exploratory phases, challenge phases and advanced phases to see how effective and how accurate the tests are.

How clinical trials work

Researchers may first test new interventions in the laboratory and in animal studies. The most promising experimental interventions are then moved into clinical trials where they are tested in humans. During a clinical trial, more information is gathered about the effectiveness and safety of a new intervention.

In a clinical trial, the new intervention will usually be compared against something else, called a control. The control can be either a placebo (a substance containing no medication) or an established intervention that is already in use.

In Australia, clinical trials are governed by national ethics guidelines and codes of conduct. For further information on requirements, see the National Statement on Ethical Conduct in Human Research and the Australian Code for Responsible Conduct of Research

Clinical trials of unapproved substances and devices also must comply with the requirements of the Therapeutic Goods Administration (TGA) and with international guidelines, as adopted by the TGA.

Ethical guidelines and giving consent for a trial

Clinical trials in Australia are regulated by laws and codes of conduct that aim to protect trial participants and the integrity of the research. All clinical research projects in Australia must be approved by a Human Research Ethics Committee (HREC), which checks that the research conforms to the requirements of the National Statement on Ethical Conduct in Human Research.

Anyone taking part in a trial must be fully informed about the objectives of the research, what is expected of them and any risks and potential inconveniences that may be experienced during and after the trial. If you are thinking of being part of a trial, you should be given a participant information and consent form that contains details of the trial and your participation as part of the process of informed consent.

Trials must follow a carefully controlled protocol, which is a plan that describes what researchers will do in the study. As a clinical trial progresses, researchers may report the results of the trial at scientific meetings, to medical journals and to various government agencies. When they do this, the names and personal details of trial participants are kept confidential and are not disclosed.

The trial protocol

Clinical trials follow a plan, or set of rules, known as a protocol to ensure that they are as safe as possible, that they measure the right things in the right way and that the results are meaningful. For example, a protocol describes:

• who is eligible to take part in the trial;
• the research methods, tests and procedures that will be used;
• the interventions that will be used and how they will be delivered; and
• the length of the study, what information will be collected and any follow up.

Control groups

If someone who is ill is given a medication and then gets better, it could be due to a natural recovery that would have happened anyway or to other factors. To determine if the intervention has worked, it needs to be compared to another intervention, non-interventional standard care or a placebo.

Participants in a clinical trial will therefore be put into one of two groups:

• a group that is given the new intervention being assessed; and
• a group that is given an established intervention that is already in use, other standard care or a placebo

The second group is known as the control group.

The aim of the trial is to compare what happens in each group. The results have to be different enough between the two groups to prove that the difference has not just occurred by chance.

If the individuals in the group being given the new intervention show a significant improvement, without any serious side-effects, over the control group, then the researchers may end the clinical trial early and seek to change the nature of the clinical trial to afford more patients the opportunity to receive the new intervention.

Comparing a new intervention with a standard intervention

A new intervention is often compared with a standard or commonly used intervention that is already known to be helpful. This makes it possible to determine whether the new intervention works better than one that is already being used.

Comparing a new intervention with a placebo

In some biomedical trials, a new intervention is compared with a placebo. A placebo is a ‘dummy’ treatment, such as a sugar pill, that looks the same or is used the same way as the interventional substance, but that has no known health effect. If the patients who received the intervention have a better outcome compared to patients who received the placebo, this suggests that the intervention was effective.

Placebos are not used if a patient would be put at risk, for example – in the study of treatments for serious diseases – by not being given effective treatment. Potential participants are told if placebos will be used in the trial before they agree to participate.

Placebo effect

It has been shown that if you think and believe you are going to get better, you are more likely to do so. If you take something you believe to be an effective medicine, your symptoms may improve. Reassurance from a doctor or other health care professional also helps some people to feel better. This is known as the ‘placebo effect.’ It is an effect that is poorly understood but that can, nonetheless, be quite real and powerful.

In clinical trials where it is used, a placebo appears to be the same as the new medication being studied, so you don’t know which one you are taking. Some people may feel better after taking the placebo because they think they are being given real medication. Researchers take the placebo effect into account when designing clinical trials, usually by ensuring that the number of people involved in the trial is large enough to compensate for any possible placebo effects.

Number of people in a clinical trial

The effect of an intervention may vary between people. This means that promising interventions have to be tested on a large enough number of people to ensure that the results can be analysed using statistics to see if any differences measured are statistically significant (i.e. real) and not due to chance.

For example, if seven out of ten people improve with a new intervention, this could be due to chance. However, if 700 out of 1000 people improve, then researchers can be reasonably confident that the new intervention is effective. Researchers can work out how many people are needed for a particular trial and whether the results are statistically significant by using mathematical calculations.

Later phases of trials require larger numbers of participants.

Randomisation

Many trials compare the effects of an intervention using two groups of participants. The two groups need to be as similar as possible except for the intervention received (or not received), so that any differences in outcomes are due to the differences between interventions and not the differences between groups.

In order to ensure that there is no bias during the selection of the different groups for a clinical trial, participants are allocated to each group in a way that doesn’t involve a decision by anyone involved in running the trial. This process is called randomisation and is usually done by a computer.

Blinding

If a clinical trial is ‘blinded’ or ‘masked’, it means that the participants and/or the researchers don’t know who is receiving the new intervention and who is not.

If a clinical trial is ‘single blind’, it means that the participants in the trial do not know which intervention they are receiving, but the researchers and medical staff do.

If a clinical trial is ‘double blind’, it means that neither the researchers organising the trial nor those taking part in the trial know who is receiving which intervention.

Blinding helps to reduce the effects of bias when comparing the outcomes of the interventions. If either researchers or participants know who is receiving the new intervention, this knowledge can influence what they report. Participants who think that they are receiving a new intervention may be very hopeful about its effects or may not want to let down the researcher. For this reason, they may exaggerate benefits and minimise side effects. Likewise, researchers may allow their hopes for a new intervention to unconsciously influence how they record the effects.

In the event of an emergency where you doctor needs to know which intervention you are receiving to provide the care you need, the blinding can be ‘broken’ and they can find this out.

Who conducts clinical trials?

Researchers conducting clinical trials can be part of hospitals and other medical institutions, specialised research groups, universities, or pharmaceutical, medical device and biotechnology companies, or a combination of these.

A clinical trial team includes doctors and nurses and may also involve other health care professionals, social workers, biostatisticians and trial coordinators and monitors. At the beginning of the trial, the clinical team take initial measurements and a medical history from the participant and give them clear information about what to expect in the trial and what they need to do. During the trial, each participant is monitored carefully by members of the trial team.

Who funds clinical trials?

Clinical trials are sponsored or funded by various organisations or individuals, including government departments and agencies, research groups, foundations, charities, and pharmaceutical, medical device and biotechnology companies.

Who can be part of a clinical trial?

Due to the wide variety of trials taking place, almost anyone can take part in a clinical trial. Trials can involve people of all ages, from children to the elderly, and with all types and stages of a disease or condition. Taking part in a trial is completely voluntary and participants can withdraw at any time with no adverse effects on the quality of their medical treatment or relationship with their doctor.

Some trials need healthy participants to test the safety of new interventions or tests, particularly in early stage trials. In these trials, healthy participants can be compared with patient participants. They receive the same test, procedure or drug that the patient group receives and researchers can compare the effects and side effects of the new test, procedure or drug between the two groups.

Many trials need participants who have the disease or condition that the new intervention targets. Patient participants test the new intervention to see what effect it has on their disease or condition.

Why you might not be able to take part

All clinical trials have guidelines about who can take part. These guidelines are called inclusion and exclusion criteria. Criteria that must be met in order to allow someone to take part in a clinical trial are ‘inclusion criteria’; criteria that prevent someone taking part are ‘exclusion criteria’. The criteria may be based on age, gender, the type and stage of a disease or condition, previous treatment history and other medical conditions. Inclusion and exclusion criteria aim to ensure that the trial will produce useful and reliable results and contribute to the safe conduct of the study.

Sometimes, it is not possible for a volunteer to be involved in a particular trial. For example:

• some trials seek people with certain diseases and conditions, while others need healthy people
• the disease or condition may need to be at a particular stage
• participants may not be allowed to receive another treatment at the same time
• some trials need people of a certain age
• there may already be enough people in a particular category who have joined the trial.

Medical tests

Before participants join a trial, they may need to have tests (such as a blood test) to see if they can take part. These tests may also allow the researchers to know more about a person’s health before they start trial treatment, so that, at the end of the trial, they can tell if there has been an improvement. During the trial, participants are likely to have more tests to see whether the treatment is working.

What happens when a trial is complete?

After a clinical trial is completed, the researchers examine all the information collected during the study. Researchers can then determine whether the results mean that the new intervention should continue to the next phase of clinical trial, or, when applicable, seek approval for general use by the relevant authorities. Once a new intervention has been proven to be safe and effective, it may become part of standard treatment for the disease or condition.

Examination and analysis of the information can take some time. Therefore, there may be a delay before the results of a clinical trial are known, particularly with larger trials that can involve thousands of people and that may take place over several years.

If you have taken part in a trial, the researchers should make the results available to you directly (if you have indicated that you wish to know the results). It is also expected that results of all completed studies will be made available in reports or papers published in scientific journals.