Clinical trials involve a series of studies that test the safety and effectiveness of drugs and other medical treatments. To ensure research is carried out thoroughly and safely, there are several different stages of clinical trials.
In order to make sure the treatment is safe and effective for use in patients, it must successfully pass through every clinical trial phase.
Each phase is designed to assess the safety and/or the efficacy of the treatment in different ways, testing treatments firstly on a smaller number of healthy volunteer participants, progressing onto larger sample groups, involving patients.
There are typically 3 main stages of clinical trials: phase 1, phase 2 and phase 3. Some trials involve pre-clinical study phases (phase 0), and post-clinical study phases (phase 4).
Phases of Clinical Trials at a Glance
| Phase of Clinical Trial | Number of Participants | Main Aim of Trial | Is Trial Randomised? |
| Phase 0 | 10 – 20 people | To check if a novel drug or treatment is harmful at low doses | No |
| Phase 1 | 20 – 50 people | Finding out the most effective dosage without harmful side effects. Studying any side effects after taking treatment | No |
| Phase 2 | Participants can range from in the tens, to in the hundreds, depending on the clinical trial | Checking the most effective dosage from Phase I on a larger scale to gain more accurate data on side effects and how effective the treatment is. | Sometimes |
| Phase 3 | Hundreds of people, sometimes thousands of people depending on the trial | Comparing the new drug or treatment to the standard of other existing treatments, to determine if the new treatment has specific benefits or differentiators over those already on the market. | Most of the time |
| Phase 4 | Usually, a large sample size, but varies depending on the study. | Post-Approval for new drug or treatment. Finding out information on rare side effects and the long-term benefits/side effects. | No |
Different Phases Of Clinical Trials Explained
The three main stages of clinical trials are designed to ensure the treatment undergoes thorough testing before it is made available to patients. By staging the trial across different phases, researchers are able to determine whether it is safe to progress to the next stage of testing and, finally, safe to push to market.
Each stage of clinical development is governed by strict regulations to make sure no treatment progresses through research stages without being approved for safe use.
Early phases test the treatment on smaller numbers of participants, where researchers are able to identify any general adverse reactions or side effects. Later phases test on larger population groups, where researchers can identify any long-term or previously unknown side effects.
As well as participant group size, there are several other major differences between each phase, along with several types of clinical research.
Pre-Clinical Phase (Phase 0)
Some trials involve a pre-clinical study phase, often referred to as phase 0. This phase takes place at the earliest stage of research before the main study begins.
Phase 0 is unlike the main three stages of clinical trials (phases 1 to 3), in that only a small sample of the treatment is tested on a very small number of volunteers – usually around 10-20 people, due to not knowing what risks the new treatment poses to people.
The purpose of pre-clinical phases in clinical trials is to ensure that the small dosage of the drug results in no harm to humans before the research continues using larger doses in the main study phases. During phase 0 clinical trials, participants are made up of healthy volunteers, rather than people who might benefit from the drug, due to the unknown risk factor.
Pre-clinical phases are not always used, and are not a requirement for testing new drugs. Circumstances where phase 0 trials may be used could be to test if a treatment can successfully reach tumours during oncology research, or to see how the human body reacts to the drug.
The main benefit of conducting a phase 0 clinical trial is that researchers can test how the new treatment behaves and interacts with the human body. Additionally, phase 0 trials help to determine if a drug should be progressed to phase 1 trials, due to having more accurate human data, as opposed to animal data which can sometimes be inaccurate.
This early phase of clinical trials can help speed up the drug approval process, by providing additional supporting data to showcase the safety and effectiveness of the treatment.
Phase I: Safety
Phase 1 is the first main stage of the clinical trial process. For treatments that have not undergone a pre-clinical phase, phase 1 research will be the first time the treatment is tested on human volunteers – often referred to as first-in-human (FiH) studies.
What is the Purpose of a Phase 1 Trial?
Phase 1 trials are carried out in order to test the general safety of the new treatment. During this first phase, researchers will test different dosage levels in human participants to determine how much of the drug or treatment can be administered safely without adverse effects.
Phase I Trial Participants
Testing is carried out on a small number of volunteers (usually around 20 to 50 people). During this initial phase, volunteers are healthy individuals, rather than patients with the relevant condition. This is to firstly ensure that the new treatment is generally safe for use in the human body and that there are no major safety issues.
Typically, participants are dosed in smaller groups during phase 1 clinical trials, as this allows for the effects of one dosage level to be properly monitored, before moving on to a higher dosage. This prevents too many people from being dosed at once, as well as wasting money and time on recruiting participants for a later dosage if a lower dosage is deemed unsafe. So while the pool of participants is fairly small, it can take a long time for a phase I trial to be completed.
At this stage in clinical trials, researchers may be able to identify some of the potential side effects that may occur when taking the new treatment. Participants are given a low dosage of the test treatment to begin with and are monitored very closely.
Progressing From Phase I
If there are very few, or no side effects that occur with the low dosage, researchers then give a higher dosage to the following set of participants. This method is called dose escalation, and enables researchers to identify the optimal dosage that has the fewest side effects. With enough data to support the treatment’s general safety, the study can continue through to the next phase of research and test on more volunteers.
Around 70% of test treatments in phase I are approved for the next clinical trial phase.
Phase II: Efficacy
When a drug or treatment is evaluated as safe and approved for testing beyond phase 1, the research can progress through to phase 2.
What is the Purpose of a Phase 2 Trial?
Phase 2 clinical trials are designed to test whether the treatment actually works, whilst continuing to assess its safety. Since the first phase has approved the general safety of the drug, phase 2 trials involve more volunteers – usually several hundred.
During the second phase, researchers will assess how well the treatment delivers its intended effects. The intended effects might not always be to cure the condition. The intended effect could be to prevent further spread of the condition, or even to provide a better quality of life for the patient by relieving certain symptoms.
To assess how well the treatment works, researchers will determine an exact intended effect and measure how well the drug meets this need.
Unlike phase 1, this part of the research involves volunteer patients who suffer from the condition in order to analyse the treatment’s interactions with the condition. Research in this phase can take place over the course of several months, or in some cases, years.
Phase 2 Trial Participants
At this stage, patients can directly benefit from taking part in the trial, as it is possible that the treatment may start to show positive impacts on the test condition. Some doctors may even suggest clinical trial participation as an alternative treatment for patients with certain conditions.
With a larger volunteer group and a longer period of time having passed, phase 2 research helps uncover potential side effects that may not have been present during phase 1 trials. However, the volunteer sample size is still not large enough at this point to determine the overall safety of the medication, and it is not until phase 3 that a more definite evaluation of safety can be established.
Some phase 2 clinical trials can be randomised, which would see the selected participants assigned to random treatment groups. By placing the participants into randomised treatment groups, the data on the drug’s effects becomes more reliable, as there won’t have been any bias when selecting group members – such as people with overall better general health.
If this happened, it could potentially swing the results to appear to be more positive or negative than it actually is.
Progressing From Phase II
Around 33% of treatments are approved to progress beyond the phase 2 stage, which is less than half of the phase 1 trial’s approval rate of 70%. This is due to the more stringent testing on a much larger sample size. The increased sample size brings to light adverse side effects that might not have previously been seen in the smaller cohort.
Phase III: Comparison & Side Effects
When the treatment is approved for research beyond phase 2 trials, development continues through to phase 3.
What is the Purpose of a Phase 3 Trial?
The purpose of this third phase is to evaluate the effectiveness of the new treatment in comparison to the best available current treatments for the same condition. In order to progress beyond phase 3, research must show that the new treatment is at least as effective and safe as current treatments. This helps demonstrate whether the new treatment is useful for a specific population.
Phase 3 Trial Participants
Phase 3 trials provide the largest amounts of safety data. Studies in this third phase are longer in duration and involve hundreds, if not thousands, of participants. This means that results are much more likely to display any rarer side effects that did not appear in the earlier phases of research, as well as evaluate effectiveness across a more reliable sample size.
Phase III trials typically consist of randomised treatment groups, to help preserve the reliability of any data gathered about the drug or treatment being tested. One of the groups that participants can be assigned to is the control group. Anyone in the control group will receive the standard treatment that is available at the time, or a placebo dummy drug.
By doing this, data can be gathered which compares the new drug or treatment to the existing one, under fair and similar conditions. This helps with proving the effectiveness of the new drug compared to existing solutions, which is the primary focus of phase 3 trials.
Progressing From Phase III
Treatments that demonstrate effectiveness and safety throughout this phase will be eligible for regulatory approval, which, if successful, allows the drug to enter the market and become available for doctors to prescribe.
This extensive testing means that only around 25-30% of all the drugs in the clinical development process are approved to finally make it on to the market. To make it to market, the new treatment has to be proven to be more effective than the current standard treatment, and doesn’t cause adverse side effects.
When you combine this with how much time and money it costs to put a new treatment through clinical trials, you can see why as many as 90% of drug candidates will fail to be approved.
All the information of the entire trial process is submitted as a dossier to the relevant regulatory authority. This could be the Medicine and Healthcare products Regulatory Agency (MHRA) in the UK, the European Medicines Agency (EMA) in Europe or the Food and Drug Administration (FDA) in the USA. All of the data provided is scrutinised by the regulators who will ultimately decide if new treatment or drug can be approved to go on the market.
Post Market Safety Monitoring
Phases 1 to 3 are considered the main three stages of clinical trials and involve the largest amounts of research. However, beyond this, researchers continue to monitor the treatment after the drug has gone to market.
This final stage of monitoring is often referred to as phase 4, or the post-market safety monitoring phase. At this point, the test treatment has undergone regulatory approval for use and is available for doctors to prescribe to their patients.
Even after years of clinical trial research and regulatory approval, the safety of the drug is still a main priority for Clinical Research Organisations (CROs). For instance, researchers will monitor whether there are rarer side effects that were not present during the main trial phases, or whether side effects appear after a much longer period of taking the medication.
Why Monitor a Treatment After Approval?
It is important that research be still undertaken, even after a treatment has successfully passed through all the phases of clinical development, as once the treatment is available on the market, many more people will be prescribed it for their condition. This means that the sample size of potential data increases significantly, which can give an even more accurate portrayal of how the treatment works on a national or global scale.
The Phases Of Clinical Trials: Summary
Clinical trials are phased across three main stages in order to test new treatments thoroughly and identify possible safety issues. In summary, the purpose of these three main phases are:
- Phase 1 is the first stage of research, testing for general safety with a small volunteer group.
- Phase 2 tests how well the treatment works on a larger volunteer group.
- Phase 3 evaluates how effective the treatment is in comparison to current treatments.
Find Out How We Can Help
As an experienced Clinical Research Organisation (CRO), we are experts in clinical trials. From clinical trial data management to full phase clinical development, we’re here to help answer your questions.
Simply get in touch to speak with our team.
Alternatively, explore more of our blog, such as ‘What is Clinical Pharmacology?‘