Phases of Clinical Trials

Before a clinical trial can be completed, there are several different phases it must go through. Each phase will uncover more information about the trial which helps researchers to deliver a more effective treatment. Most often, clinical trials are divided into three phases, but some trials require stages zero and four.

To help you better understand the phases of clinical trials, we’ll discuss how clinical trials work, the steps involved, and how they differ from one another.

How do clinical trials work?

Clinical trials are designed to determine whether a new type of treatment, drug, or prevention is safe and effective for people. Most trials will be split into groups, offering alternative treatments to establish which one works best. Sometimes, a treatment is compared against no treatment (a placebo).

The entirety of a clinical trial is divided into phases that follow strict guidelines, especially around those who can participate in the trial. Participants are most often randomly assigned to one of the treatments in the trial, ensuring any differences are genuine and not due to differences in the people of each group.

Each phase aims to answer specific questions outlined at the beginning of the trial. These can include questions about whether the treatment works, if it works better than current alternatives, and whether there are any side effects.

Through clinical trials, researchers can also establish information about the cost-effectiveness of a treatment, its clinical value, and how it could improve the quality of life for people with the condition they are researching.

Steps in a clinical trial

Clinical trials can be better understood using the various steps involved from a general perspective. Here are the key steps involved in the majority of clinical trials.

Initiation

Prior to a clinical trial starting, researchers need to conduct extensive laboratory research. This is necessary to help establish potential treatments and their benefits before human trials can begin.

Design

Once a potential treatment has been identified, a protocol or detailed plan can be created. This outlines what will happen during the trial, how it will be conducted, and the reasons for this. It also describes the objectives of the trial, participation selection criteria, the schedule of tests and procedures, drugs and their dosages, and how long the study will take.

Implementation

Once a clear outline for the trial has been established, participants can be selected and treatments administered. This part of a clinical trial also involved data collection which is essential for deciding whether the treatment is a success. During implementation, trial participants will be given specific instructions to follow throughout the trial duration. They will also receive regular health checks to ensure their safety and assess the effect of the treatment.

Analysis and reporting

Once the trial has been completed and all data collected, researchers will analyze this data. During this stage, analysts will determine the effectiveness of the treatment or drug and any side effects experienced. They will then decide whether the treatment should be approved for wider use.

Publication

The results discovered in the analysis stage will be published in scientific journals, no matter whether they are positive or negative. This ensures the scientific community and the public have extensive knowledge about the research findings. If a treatment is found to be successful, it will also be submitted to the relevant governing body to begin the approval process for public consumption.

Clinical trial phases

Each clinical trial phase has a different purpose designed to provide researchers with answers to the questions laid out at the beginning of the trial. Here, we’ll explore each phase of a clinical trial in depth.

Phase 0 clinical trials - Exploratory trials

Not all clinical trials involve phase 0, but in some cases, they will be used to establish whether a drug behaves the way researchers expect it to. The main differentiator between phase 0 studies and other phases is that phase 0 trials have no therapeutic intent. They’re often used in cancer trials.

Phase 0 trials typically include a small number of people and only small doses are offered to establish whether the drug reaches the place it’s supposed to, what happens to the drug in the body, and how cells react to it. For example, researchers in cancer studies will seek to find out whether the drug reaches the cancer cells and how they respond.

Phase 1 clinical trials - Safety Trials

Phase 1, or phase i clinical trials as they’re often known, are typically the first to involve human subjects. In this phase, researchers seek to establish whether a new treatment or drug is safe and how it is best delivered - e.g. by mouth or vein. They also aim to find out what the drug or treatment does in the body and how the body reacts to it.

Often, participants will receive a very low dose of the treatment. They will be monitored carefully and regularly to check for side effects. If adverse effects are minimal, dosages will be increased. This process will continue until researchers determine the dose that’s most likely to deliver the best results with the least side effects.

Phase 1 studies are usually conducted in large healthcare centers so that participants can be monitored more closely. This is possible due to the small number of participants. However, with such small numbers, any rare side effects are unlikely to occur until later in the trial when more people receive the treatment.

Phase 1 clinical trials aim to find out whether the drug or treatment works, which means they can also carry the most risk. If researchers determine that the treatment is safe, then the study can be moved to the next phase of the trial.

Phase 1a clinical trials

You may see Phase 1a clinical trials too, which are part of phase 1 clinical trials. In this stage, participants are given single ascending doses of the treatment. The first dose is monitored to check for side effects, and if none are established, those participants receive a higher dose.

Phase 1b clinical trials

Some studies also have phase 1b clinical trials which involve several groups of participants each receiving different doses. This is often a faster method of establishing whether a treatment works because researchers can test multiple dosages at the same time.

Phase 2 clinical trials - Efficacy trials

In phase 2 clinical trials, or phase ii trials, researchers aim to discover whether the treatment works. These trials typically involve larger numbers of participants than phase 1. The new drug or treatment is given to participants to establish whether the treatment is effective and to further study how safe it is.

In most cases, phase 2 clinical trials involve everyone getting the same dose. However, some phase 2 trials split participants into groups and alter how the treatment is given. This could include different dosages or administration methods. Researchers often do this to find out which dosage or method delivers optimal results with the least side effects.

Phase ii trials are often conducted at major healthcare centers, including large cancer centers and community hospitals. With larger numbers of participants, this phase of the trial usually uncovers less common side effects than those found in phase 1.

Phase 2 trials will sometimes be divided into phase 2a and 2b.

Phase 2a clinical trials

Phase 2a clinical trials are designed to assess and collect data about the dosing requirements. Researchers seek to establish how much of the drug should be given for optimal results and safety.

Phase 2b clinical trials

In phase 2b of clinical trials, researchers aim to find out how well the drug works at the given dose. Tests are conducted to determine how effective and safe the dose or treatment is. If both phase 2a and 2b are successful and researchers gain the information they need, the clinical trial can move on to phase 3.

Phase 3 clinical trials - Large-scale testing

Phase 3 clinical trials, also known as phase iii clinical trials, are often the last phase in a clinical trial - unless a phase 4 is required. In this phase, researchers will aim to find out whether the new drug or treatment is better than what is currently available for the condition they are researching.

Commonly, participants are split into two groups: the control group and the study group. The control group will receive the standard treatment (what’s already available) and the study group will receive the new treatment being tested. It’s important that phase 3 trials randomly assign participants so they can create a more unbiased trial to deliver more accurate results.

As the safety and efficacy will have already been tested in the previous phases, this stage of a clinical trial will often include large numbers of participants, often several hundred. A phase 3 clinical trial will typically take place in many geographic locations at the same time to ensure there is no location bias, and also to gather more participants from a larger pool.

Because phase 3 is often the last in a clinical trial, it usually takes much longer than the previous phases so researchers can gather as much data as possible to progress the drug or treatment further. Following a phase 3 trial, researchers can pass forward their findings for FDA approval if the drug or treatment is found to be successful.

Like other clinical trial phases, phase 3 trials are commonly divided into 3a and 3b clinical trials.

Phase 3a clinical trials

Phase 3a clinical trials aim to gather more information about the safety and effectiveness of the new treatment. The primary goal here is to establish and confirm the treatment’s therapeutic benefits while also identifying any long-term side effects. Data collected in this phase is crucial for demonstrating how safe and beneficial the treatment is.

Submission for FDA approval

Once phase 3 clinical trials have been completed and the treatment or drug is found to be successful, researchers can submit a New Drug Application (NDA) to the Food and Drug Administration (FDA) for approval. The application is thorough and detailed and should include all the clinical trial data obtained throughout each completed phase. 

When submitting an NDA to the FDA, researchers need to:

• Show that the benefits of the new treatment outweigh the negatives
• Outline the intended labeling for the drug
• Prove that the manufacturing process is suitable for strength and dosage preservation
• Once an application has been submitted, the FDA has 60 days to decide whether it will progress the application and review it further.

Phase 3b clinical trials

While it might seem odd to complete a further clinical trial phase after an NDA has been submitted, phase 3b clinical trials are hugely useful to researchers. Phase 3b is usually carried out after a treatment or drug has received regulatory approval and is available for public consumption. It aims to continue evaluating the long-term safety and effectiveness of the drug or treatment in a real-world setting. It also gives researchers an insight into how the treatment impacts a patient’s quality of life.

In some cases, phase 3b trials also evaluate additional therapeutic uses, different dosages or formulations of the new drug or treatment, as well as comparisons with alternatives. The findings of phase 3b help researchers, healthcare professionals, and patients make informed decisions about their treatment.

Phase 4 clinical trials - Post-marketing surveillance

Phase 4 of a clinical trial is also completed after a new drug or treatment has been made available to the public. The aim here is to monitor and evaluate safety over a longer period. Researchers seek to discover whether there is anything else they need to know about the treatment or drug. Phase 4 trials can continue over many years, ensuring the new treatment or drug is completely safe and has the desired impact in the long term.

As the treatment or drug is already available to patients, this phase of a clinical trial can often involve thousands of participants. It can also help researchers understand other aspects of the treatment, such as its cost-effectiveness and how it impacts quality of life.

Differentiating between clinical trial phases

Although you might have an understanding of each phase in a clinical trial, it can be confusing when learning the differences between them as they tend to overlap in places, depending on the trial you are involved with. Of course, each phase in a clinical trial will have commonalities, such as regulatory compliance and ethical considerations. But there are some differences that set them apart too.

Phase 1 vs phase 2 clinical trials

When determining the key differences between phases 1 and 2 of a clinical trial, it’s all about the goals and procedures of each phase. Phase 1 clinical trials are designed to establish the safety and tolerability of a new treatment.

While phase 2 clinical trials lean on the data gathered in phase 1 to evaluate the efficacy of the treatment. Phase 2 also continues assessing the safety of the treatment and any side effects experienced.

Phase 2 vs phase 3 clinical trials

Like above, the differences in phase 2 and 3 of clinical trials lies in the objectives, but also the scale of the process. Phase 2 clinical trials work to assess the efficacy and safety of the treatment in a smaller pool of people.

In contrast, phase 3 clinical trials often involve a much larger group of participants and are carried out across multiple locations. Additionally, phase 3 trials seek to confirm the efficacy established in phase 2 on a larger scale, while continuing to monitor the side effects in a much bigger and diverse group of people.

Trials covering more than one phase

While most traditional clinical trials are carried out sequentially, with each phase being completed after the previous, some clinical studies combine phases. Trials spanning more than one phase at the same time are also known as ‘combined-phase’ trials. The goal of these trials is to speed up drug development by streamlining the traditional process and having phases carried out in tandem.

The main benefit of this type of trial is that there is a speedier transition between phases which can lead to the drug being approved much quicker. However, their nature means they can be complex to design and implement. Additionally, if early-stage data is misinterpreted, this can implicate the trial’s later stages.

Here, we’ll look at how combined-phase trials work in a little more detail.

Phase I/II trials

Clinical trials that overlap phases 1 and 2 of a study combine the initial safety assessments of the trial with the preliminary efficacy assessments. In phase I/II trials, researchers commonly design the study to discover the maximum tolerated dose through a dose-escalation stage, as well as the drug's activity via an expansion cohort where more participants are added to the study.

An example of how this works is an experimental cancer drug first being administered to a small group of participants to evaluate its safety and optimal dosage range. Following this, the trial is expanded with more participants to evaluate preliminary signs of its effectiveness against the tumor, while further monitoring safety. There is no pause between the two phases.

Phase II/III trials

In phase II/III clinical trials, researchers use adaptive trial designs to bridge the gap between the exploratory and confirmatory stages of drug development. Firstly, researchers examine the short-term safety and efficacy of the treatment, removing any low doses from the study that lack efficacy and any high doses that cause safety concerns.

Secondly, the participant group will be adjusted to ensure the best results can be obtained and trend statistics are adaptively chosen based on the estimated dose-response curve in the clinical endpoint of the first-stage patients. Researchers then use the data uncovered in both stages to establish dose-response and identify the lowest effective dose.

As an example, a clinical trial for a new cancer drug starts with a phase 2 component that assesses multiple dosages for their effectiveness against early-stage disease makers. Once a specific dosage shows positive results, the trial can seamlessly transition into phase 3, with the chosen dosage being tested on a larger group of participants for safety and efficacy.

Phase I/II/III trials

Clinical trials that combine all three main phases of a trial are very rare but have been done. These trials often use complex adaptive designs and usually expand cohorts or change the treatment arms as more data is collected. They require a huge amount of organization and personnel to ensure the data collected is accurate and there are enough people to analyze it.

To explain further, let’s say a potentially groundbreaking drug for a rare genetic disorder has been uncovered. The trial could start with a small cohort but as safety is established, more participants are added to gauge efficacy. If positive signals continue, the trial can progress to a large group of participants for a more definitive assessment of the drug’s efficacy.

Phases of clinical trials for medical devices

With technology advancing rapidly, it’s important to discuss how clinical trials work for medical devices specifically. Most often, clinical trials for medical devices are divided into distinct phases that systematically evaluate the safety and efficacy of the device. 

The first phase, often called the pilot or feasibility phase, comprises preliminary testing on a small cohort. This stage aims to assess the device’s basic safety and functionality. The second phase expands the study into a larger group of people. In this phase, researchers evaluate the device’s performance, specifically looking to identify any potential risks or adverse effects. Finally, the third phase includes more rigorous testing on a larger and more diverse group of people. This stage helps to confirm the overall safety, effectiveness, and reliability of the device.

After each phase of medical device testing has been successfully completed, the device can be submitted for regulatory approval just like any other clinical trial. Medical devices are subject to the same approval process and standards as drugs and other treatments. This ensures anything available to the public is safe and beneficial for the condition it aims to support or treat.

Finding the right phase of clinical trial for you

Understanding the different phases of clinical trials is one thing, but deciding which phase is right for you takes a lot of consideration. You’ll need to think about what is more appropriate for your condition or situation, as well as where to find a trial that suits your needs. Selecting the appropriate phase of a clinical trial that aligns with your health goals and comfort level is critical.

If you’re looking to access a novel treatment in its initial safety assessment, phase 1 would be a good fit, depending on the trial type and your condition. However, if you’re seeking efficacy and greater safety data, phase 2 could be a better choice. Phase 3 clinical trials would be a good fit if you’re looking to join a more established treatment with a wider participant pool.

If you’ve missed the boat for a clinical trial in the early stages, you might also consider phase 4 clinical trials where you can take part in post-market surveillance and long-term effects. This is possible if you’ve been prescribed and are already using the treatment or drug.

How to find a clinical trial

If you’re keen to join a clinical trial in any phase, there are several ways you can find the ideal trial for your needs. Firstly, it’s a good idea to speak to your healthcare practitioner as they may have information on relevant clinical trials that they are aware of. They may also be able to offer you resources for finding reputable trials.

Secondly, there are a plethora of online databases and platforms that specialize in clinical trial listings. Many of these websites enable you to search based on a variety of criteria including your condition, location, and phase. This helps you to find a trial that suits your condition needs, travel limitations, and the phase you’re interested in.

Finally, you could contact patient advocacy groups and organizations that are relevant to your condition. These groups will often have information on upcoming clinical trials specifically for your condition. Furthermore, group members and leaders may also be able to help guide you through the process of finding and applying for the trial as they’ll have experience doing it already.

Conclusion

Whether you’re new to clinical trials and simply want to gain an understanding of how they work, or you’re actively searching for a clinical trial to join, our guide should have helped you get to grips with the different phases of clinical trials.