Understanding the clinical trial phases
It often takes years for researchers to develop and test new medical interventions, first in a laboratory setting and then as part of a clinical trial. With objectives for safety, ethics and efficiency in mind, researchers break the process down into smaller parts, typically known as phases.
Every phase is an important opportunity for researchers to gather information, evaluate risks and benefits, and move the intervention further towards approval and wider use.
Below, we explain the most common phases used in Australian clinical trials, including investigator-led or initiated trials. These phases apply to – but may differ between – trials for different interventions, from medical drugs and devices to diagnostic tools.
Clinical trial phases: A quick summary
- clinical trials are run in different phases
- there are four key phases, each with a different goal
- the phases of a clinical trial may vary for investigator-led trials due to budget constraints and access to resources.
Read on to learn about clinical trial phases in more detail.
What is a clinical trial?
Put simply, a clinical trial is designed to test the safety and effectiveness of a new medical intervention – from new drugs to medical devices and surgical techniques – using human volunteers.
In Australia and around the world, clinical trials are an important tool that investigators use to understand and improve people’s health and wellbeing. In the past they have led to breakthroughs for a number of serious conditions, including heart disease, cancer and asthma.
At each stage of a clinical trial, researchers will gather information to determine whether they can proceed to the next step. Not every trial will proceed through all possible phases.
Pre-trial exploratory studies
Clinical trials are focused on the observation and treatment of living patients, rather than laboratory or theoretical research. However, many clinical trials have an early phase that may involve clinical or non-clinical research, from small human studies to animal testing.
This research is usually different to the Phase 1 or pilot stages of a trial. Depending on the nature of the study and intervention, it may be referred to as an early phase, exploratory phase or Phase 0 trial.
In a clinical trial for a new drug, the earlier stage is often known as a Phase 0 trial. As part of this early clinical research, a small number of people, usually 10-15 participants, receive a small dosage for a limited period.
In a clinical trial for a new medical device, pre-clinical testing is common, particularly due to the potentially invasive nature of devices. This testing may involve engineering analysis, computational simulation, biocompatibility testing or animal testing.
Trial phases: medications and treatments
The below four-phase structure is commonly used in clinical trials, particularly those testing new drugs, vaccines or other treatments.
Clinical trial phase 1
The main goal of Phase 1, also known as Phase I, is to determine the safety of a new intervention and how well people tolerate it.
This is usually the first time the medicine or treatment is tested on humans. Researchers assess whether it is safe to use, what the correct dosage should be, and if there are any side effects. They may also check how it works alongside other medicines or food.
- Number of participants: 20 –80
- How it works: The intervention is administered to a small number of people, either patients or healthy volunteers. They are given a fixed dose and monitored for side effects.
- Design and length: These trials are usually short but may involve an overnight stay in the hospital. Participants are closely monitored. The new treatment may benefit them in some ways, but significant improvements are uncommon.
Clinical trial phase 2
The main goal of Phase 2, also known as Phase II, is to determine safety and efficacy – that is, whether the intervention is an effective response to the disease or condition it is designed to treat.
The intervention was already found to be safe in a Phase 1 trial but now requires further testing with more people.
- Number of participants: 100 – 300
- How it works: The medication or treatment is given to a larger group of people. These participants usually have the condition or disease that the intervention is designed to target.
- Design and length: A Phase 2 trial may be a randomised controlled trial, where participants are randomly allocated to two or more groups and given different treatments, or a non-randomised trial, where all participants receive the new treatment. Similar to the Phase 1 trial, this process is usually short, with no overnight stay required. Participants are closely monitored.
Clinical trial phase 3
The main goal of Phase 3, also known as Phase III, is to determine overall safety, efficacy and effectiveness.
A Phase 2 trial has already proved that the potential benefits of an intervention outweigh the risks. Researchers now want to know if it is preferable to the standard treatment already available. They will look at various factors, including side effects and quality of life for participants.
If the third phase is successful, the new medication or treatment may be approved for use by regulatory bodies, e.g. Australia’s Therapeutic Goods Administration (TGA).
- Number of participants: 300 – 3,000
- How it works: The medication or treatment is given to several hundred or even thousands of people.
- Design and length: A Phase 3 trial always involves two or more test groups. Usually, the trial is a randomised control trial, where participants are randomly allocated to two or more groups and given different treatments. One is a control group, meaning they receive the standard treatment already available for the disease or an inactive placebo. The other group receives the new – also known as the experimental – intervention. Sometimes, the trial is ‘blinded’, meaning the participants and/or researchers don’t know which group is receiving the new intervention. Phase 3 trials usually run over a long period of time, often between three months and three years. The two or more groups of participants are closely monitored.
Clinical trial phase 4
The main goal of Phase 4, also known as Phase IV, is to assess how the medication or treatment is used by the wider population. They often incorporate health economic evaluations and outcomes research to assess the cost-effectiveness and impact of treatments on healthcare systems and patient outcomes.
Phase 4 trials happen after an intervention has been approved for use, made available for purchase and marketed widely. Researchers will monitor long-term benefits and risks, and potential alternative uses, for instance use by children.
The fourth phase is more common in commercially sponsored trials than in investigator-led trials.
- Number of participants: Thousands
- How it works: The medication or treatment is analysed in real-world settings, after it has been approved by the TGA and released.
- The design and length: Researchers will gather and study information about people already using the intervention. This shows them how it works in the long term and whether it can be effectively combined with other treatments.
Trial phases: medical devices
Clinical trials for medical devices may include testing devices such as surgical equipment, syringes, gloves, pacemakers, baby incubators, or implants.
Similar to trials for medicines and treatments, they also usually have three to four stages.
Pilot and feasibility phases
At the beginning of the trial, there are one to two earlier phases that involve a small group of participants (usually 10-30).
These exploratory phases provide important support for a future pivotal stage of the trial. They are designed to collect and assess data on the safety and performance of the new device and to help researchers understand whether the design is working or needs to be modified.
Pivotal phase
The pre-market pivotal phase involves a larger group, usually hundreds.
Researchers want to understand if the final design works safely and as intended on a larger group of patients. They also want to satisfy regulatory requirements ahead of the approval of the device for wider use.
Post-market phase
This phase takes place after the device has been approved for use.
Researchers may undertake a range of confirmatory investigations involving large groups, usually thousands of people. They want to further assess the performance and safety of the device when used more widely and across longer periods.
Trial phases: diagnostic tests
Diagnostic tests involve an examination of parts or products of the human body. These tests help diagnose and treat a range of diseases.
Common diagnostic tests include pathology testing, or the study of bodily tissues and fluid samples, and medical imaging, or the study of the body’s internal structures using x-rays, ultrasounds, and other techniques.
Clinical trials assessing the accuracy and effectiveness of diagnostic tests often involve three stages: exploratory phases, challenge phases, and advanced phases.
Do investigator-led trials have the same phases as commercially sponsored trials?
Investigator-led trials, also known as investigator-initiated trials, are not sponsored or initiated by commercial entities like pharmaceutical, biotechnical or medical device companies.
They are usually undertaken by health institutions or within an academic setting and funded through grants or sponsorship from government agencies and departments, research groups, foundations or charities.
Neither investigator nor industry-led trials have a fixed phasing structure. However, a number of factors will influence their length and scope.
Similarities between investigator-led and industry-led trials:
- Phases: Both types of trials follow similar structures. For trials involving medicines or treatments, these are Phase 1, Phase 2, Phase 3, and Phase 4.
- Goals: Each phase will assess similar goals regarding safety and effectiveness.
- Approval: All clinical trials require approval from a human research ethics committee to ensure research integrity and the safety and well-being of participants.
Differences between investigator-led and industry-led trials:
- Focus: Investigator-led trials often address niche research questions or test treatments for less common conditions, whereas industry-led trials focus on well-known, widely used medicines.
- Funding: Investigator-led trials also typically have less funding compared to trials sponsored by pharmaceutical companies. This often means the former are shorter and smaller in scope.
- Timeline: Due to funding and resource limitations, investigator-led trials may also take longer to complete each phase.
Frequently asked questions
From early pre-clinical studies through to post-market testing, the primary investigator, or key individual or group undertaking the trial, will need to adhere to a range of protocols and guidelines. They may be clinical and non-clinical in nature, and may involve consultations with stakeholders including human research ethics committees (HRECs), sponsors, and manufacturers. For more information on ethical conduct, please review the National Statement on Ethical Conduct in Human Research 2023.
For Australian researchers, a useful resource is the Australian Clinical Trial Handbook (2021 version), which provides guidance on conducting trials for unapproved therapeutic goods, including medicines and medical devices.
