Clinical trials are studies conducted in human patients to investigate whether a therapy is safe and effective. Early trials focus on safety. As the therapy is determined to be safe, more participants are recruited for further trials. Researchers begin to investigate the efficacy of the therapy together with more specific questions about dosage, effect duration, and side-effects. Researchers are required keep the relevant regulatory bodies informed of their findings and of any unforeseen adverse events.
Why are clinical trials necessary?
There are several reasons why a therapy might undergo clinical trials.
- The therapy is new and has not been tested in humans yet. As part of their development, novel therapies must undergo closely monitored tests in humans to ensure their safety and efficacy. These tests are referred to as clinical trials. At this stage, the treatment is often referred to as an investigational treatment. Patients who are considered suitable candidates for a new drug may be invited to take part in a clinical trial, under the supervision of a team of healthcare professionals.
- The therapy has been approved to treat a specific medical condition in patients within a specific demographic; for example, the initial trials of a novel drug will often be conducted on participants living with the target medical condition, and between 18 and 65 years of age. Researchers must conduct further clinical trials to assess whether it is appropriate for use in other groups (for example, in young children, people who have co-existing conditions, or people who are receiving other ongoing medical treatment).
- The treatment has been approved for a specific purpose or disorder, and researchers are investigating whether it can also be beneficial in other situations or for other disorders (for example, to see if a licensed therapy with anti-inflammatory effects can be used to safely and effectively treat inflammatory disorders). These studies must also be validated through clinical trials. In this context, the treatment may also be described as investigational, even though it has regulatory approval in other clinical contexts.
- The treatment has been approved, and researchers are investigating a new method for administering the treatment (for example, as a pill, gel, injection, etc.). Even if the therapy has gone through the regulatory process and been authorised for clinical use, the new mechanism for delivering must go through clinical trials before it can be used routinely in the clinic.
Therapies which are being investigated through clinical trials may be referred to as ‘investigational therapies’. They may also be called an ‘unproven therapy’, as they have not yet been validated for clinical use. However, they should not be confused with ‘unregulated therapies’, which are not supported by research or scientific findings. Clinics offering unregulated therapies may be taking advantage of legal loopholes to avoid maintaining safety standards, or may provide regulators with inaccurate or misleading information, and so are not subject to the same oversight as regulated, investigational therapies. You can read about the risks of unregulated therapies here.
What are the different phases of a clinical trial?
In order to bring a therapy ‘from the lab to the clinic’ – a process known as translational research - researchers must complete a closely monitored series of clinical trials to assess its efficacy and safety. There are several distinct phases to this process. If any phase reveals that the therapy does not have the desired effect, or that it carries an unacceptably high risk of adverse effects, the trial is halted.
This section offers a brief, general description of the clinical trial process. If you would like to find more information about on-going research around a particular disorder or organ system, you can find more detail in our Current and Potential Uses section. You can find a more detailed description of the clinical trials process below.
The earliest stages of clinical trials – the pre-clinical phase – are conducted in a lab setting, using human cells and tissues. This allows researchers to investigate how human cells will react to a therapy, and to begin gathering information about safety and efficacy in a very controlled environment. Our Methods and Tools section contains more information about how scientists can create ‘models’ of human tissue in the lab.
The next phase of pre-clinical trials is to conduct studies in animal models. Researchers investigate whether the therapy has the desired medical effect in a living animal, a much more complicated setting than a single cell model. Researchers also assess the safety of the therapy, noting effects of different doses, and whether there are any side-effects. Studies may be repeated in different animals to refine the findings before progressing to clinical trials in humans.
Clinical trials are divided into several phases, each designed to obtain clear, accurate and specific information about the safety and efficacy of the therapy under investigation. The number of trial participants is gradually increased if the therapy is shown to be safe and effective.
Phase 0: Some new experimental therapies are tried on a very small number of healthy volunteers before starting the trial in patients. The goal is to confirm that the therapy acts as expected in the human body. This stage is also referred to as ‘Pre-Stage 1’ or ‘Proof-of-concept’ trial.
Phase 1(I): Participants (patients or healthy volunteers) receive different doses of the therapy. The goal of this stage is to determine the safety of different dosages, and to understand how and at what rate it is metabolised by the body.
Phase 2(II): The therapy is administered to a larger group of patient participants. The aim is to assess the efficacy of the therapy on their symptoms and quality of life in the short term.
Phase 3(III): The new therapy is administered to a larger group of patient participants, ranging from a few hundred to a few thousand. The goal is to compare the new therapy to an existing treatment, to determine whether it is more effective than the standard and whether there are any important side-effects. (If no treatment exists, the therapy will be compared with a placebo – a treatment which should have no therapeutic effect, such as a sugar pill. This is to account for the placebo effect, a well-documented phenomenon where people who believe they are receive medical care feel better and experience alleviation of their symptoms. Participants will be informed at the beginning of a study that they may receive a placebo. Participants receiving a placebo are not likely to receive any direct medical benefit from participation in the trial.)
Phase 4(IV): The researchers continue to collect data on the therapy after it has been approved and is available for prescription. The goal is to assess the long-term effects of the therapy in a wide population. This phase is not required for all therapies.
Declining to participate in a clinical trial should not affect your standard of care. It is not typical for patients to pay in order to take part in a clinical trial.
Note: the phases of a clinical trial may be referred to using Arabic numbers or Roman numerals. For consistency, they are referred to using Arabic numbers throughout this website.
What are the challenges in clinical trials?
Participant well-being: Clinical trials can only proceed through the generosity of volunteer participants. Researchers have a duty of care to their participants, and have an ethical responsibility prioritise participant well-being over the research interests, or any other conflicting interests that may arise. This concept is referred to as the primacy of the human being.
Risk management: Clinical trials, although closely monitored, are by nature more uncertain than validated treatments. Participants may experience unforeseen side-effects. It may become necessary to withdraw a patient from a trial. If the clinical research team decides that the risks outweigh the potential benefits to patients, the trial may be halted without proceeding to the next phase. This is a valuable aspect of the clinical trials process, and prevents exposing further patients to unnecessary risk.
Trial limitations: Clinical trials are designed to investigate a therapy in specific cases, and the therapy can only be considered scientifically validated in these cases. A treatment which has been proven safe in one population (for example, young adults), must be considered ‘unproven’ for other populations with the same condition (such as children, or young adults with other, co-morbid disorders). Even if the existing evidence suggests that the treatment should be safe for patients in other demographics, the treatment must undergo further clinical trials in order to be considered proven safe and effective in this instance.
A long and uncertain process: The process of developing new therapies, or of confirming that existing therapies are safe for new treatments, is a long one. Gene and cell therapies undergo rigorous scientific and ethical review at the research and clinical trial stages of development. The path from ‘bench to bedside’ - from the development of a treatment in a lab to its regular implementation in the clinic - takes many years. Importantly, the aim of the process is to filter out therapies which are unsafe, ineffective, or unsuitable; in drug trials, fewer than 15% of drugs approved for phase 1 trials end up being licensed for clinical use. Even in successful cases, it may take many years for a therapy to receive full regulatory approval even when it has shown to be promising in during clinical trials. Furthermore, there may be a delay between a treatment’s approval and its availability on the market through a national public health service. You can read about the regulation of new therapies from a researcher perspective here.
Ethical Review
Studies involving laboratory animals or human participants require ethical approval before they can begin. Depending on local regulations, the ethical review board may be associated with the institution conducting the research (such as a university or hospital), or with a national healthcare service. Some studies may undergo ethical review by more than one committee – for example, if a trial is recruiting patients through a national healthcare service, they will need approval from both their institution’s ethical review board and a national health service ethical review board.
Review panels are usually composed of volunteers, and typically include both expert and lay members, including specialists such as pharmacists and statisticians. Their role is to ensure that a study is designed in such a way that valuable, meaningful data can be obtained with a minimum of distress, discomfort and inconvenience to participants, and that anything participants are asked to do is both reasonable and justified.
For studies involving living subjects, the review panel will have the opportunity to ask questions of the investigators in person. They may withhold approval until specific changes are made to the protocol or the patient-facing paperwork such as consent forms.
Pre-clinical research
The development of novel therapies begins in the lab – the pre-clinical phase of research. Cell and tissue models are used to gain an initial understanding of a therapy’s effect.
Simple models may consist of a single cell type. They are typically used at the earliest stages of investigation, to confirm that human cells will tolerate this therapy. It also allows researchers to examine the target cells in a controlled, simplified environment. By comparing later, complex models to these simple ones, researchers can assess what factors might change the effect of the therapy.
To answer more complex questions, researchers may employ more sophisticated models. These models can contain multiple cell types. They are often designed so as to reflect the physical and chemical properties of a tissue more closely than simple models. Researchers can use these models to investigate how a therapy will affect a target tissue, or how it may affect surrounding tissue or organs. These studies are said to be conducted ‘in vitro’ (‘in glass’, as early lab equipment for cell culture was made chiefly from glass). In vitro studies enable researchers to refine the treatment before exposing a living subject to it. Our Methods and Tools section contains more information about how scientists can create ‘models’ of human tissue in the lab.
If the results from in vitro studies are promising, the next stage of research is conducted using animal models. By studying a treatment in vivo (‘in a living body’), researchers can gain an understanding of how the whole body reacts to a treatment. Unlike studies conducted in vitro, these investigations can monitor downstream effects and the effect a therapy has on non-target parts of the body. The therapy, or mechanism of delivery, can be refined accordingly. A therapy may go through successive trials in different animal models, depending on the disease or organ system of interest.
The typical duration of pre-clinical trials is between 1-5 years, although it may take longer. When researchers have a thorough understanding of a therapy’s safety and efficacy in a relevant animal model, the investigation can apply to progress to the clinical phase of research.
The clinical trial process
Clinical research is conducted in human subjects to investigate a new therapy, or a new way of using an approved therapy. Clinical trials are divided into several phases, designed to obtain clear and accurate answers to specific questions at each phase. The number of participants is gradually increased as more information about the safety and efficacy of a therapy is obtained. Researchers must seek approval from a research ethics committee or ethical review board to proceed to a new phase of the trial. A typical clinical trial lasts for six to seven years in total.
Each phase of the trial includes a ‘control’ group. The members of this control group do not receive the therapy being studied. Instead, they receive either the existing standard therapy, if one exists, or a placebo therapy. The experience of the control group should be the same as the group receiving the therapy (the ‘treatment’ group), so that they do not know which group they are in; for example, they may be given sugar pills or injected with a non-therapeutic agent.
The data collected from the control group acts as a ‘baseline’ or reference point. If a difference is seen between the control group and treatment group, researchers can attribute this to the effect of the investigational therapy. If the results in both groups are similar, this suggests that the effect is caused by the placebo effect (ie., experiencing a positive effect on symptoms due to the belief that one is receiving medical treatment), rather than the investigational therapy.
Where practical, participants will not be told whether they are receiving the investigational therapy, or the placebo/standard therapy. This is referred to as a blinded trial, and is to prevent unconscious expectations from effecting the results. A double-blind trial is one where neither the participants nor the researchers administering the therapy and collecting the data know which treatment an individual is receiving while the study is ongoing.
Phase 0: In some cases, new experimental treatments are tried on a very small number of healthy volunteers before Phase 1 formally begins. The goal of this stage is to determine whether the therapy produces any effects in humans which were not predicted based on the results of animal studies, to safeguard against unforeseen adverse events. This is also referred to as ‘pre-stage 1’, ‘proof-of-concept’, or ‘first-in-human’ trials.
Phase 1
Phase 1 trials usually have fewer than fifty participants, and may have fewer than ten depending on the nature of the study or the rarity of the disorder in question. Participants may be healthy volunteers or patients. Different groups of patients have the therapy administered to them in different doses or concentrations.
The goal of this phase is to assess the safety of different dosages, to understand the rate at which they affect the body, and to determine at what rate they are metabolised. In this phase, researchers will determine the minimum effective dose (the lowest amount that needs to be administered to have a therapeutic effect), and the maximum dose (the dose above which there is no change in effect, or above which the therapy becomes unsafe or intolerable).
Phase 2
Phase 2 is conducted on a larger cohort of patients – typically between eighty to one hundred. Researchers assess the effect the therapy has on symptoms and signs of the disorder. This stage may also be used to assess the effects of varied dosages on the symptoms of the disorder.
The aim of this phase is to establish whether this therapy improves patient symptoms in the short term (within months, rather than over an extended period).
The tolerability of therapy and effect on patient quality of life are also assessed at this stage. As well as conducting conducting medical tests and assessing health outcomes, researchers may conduct patient interviews to ask about their personal experience of the therapy. This allows them both to refine the protocol, and to set reasonable expectations for future participants around potential benefits, side-effects, or inconveniences of participation.
Phase 3
In Phase 3, the new therapy is administered to a larger group of patient participants, ranging from a few hundreds to a few thousands.
The new therapy is administered to a larger group of patient participants, numbering in the thousands. The goal is to compare the new therapy to an existing treatment (or to a placebo, if none exists), to determine whether it is more effective than the standard and whether there are any important side-effects.
Phase 4
Phase 4 is conducted after the therapy has been approved and is available for prescription. It is not a requirement for all therapies.
In Phase 4, the researchers continue to collect data about the therapy from patients who have been prescribed it as part of their routine care. The goal is to assess the long-term effects of the therapy, including duration of positive effects and whether any adverse effects appear over the longer term.
An appropriate time-frame for the on-going collection of data is typically discussed with and approved by a research ethics committee.
Ongoing clinical trials
Researchers are currently investigating a range of novel gene and cell therapies, both in the lab and in clinical trials. For more information about research into a specific disease or tissues, please see our condition-specific factsheets.
If you are offered a place on a clinical trial, it is important that you take as much time as you need with the decision, and that you are comfortable with your choice. If you have any questions or concerns about a treatment you have been offered, you may find these questions helpful in starting a discussion with your healthcare provider. The research team should also provide you with the opportunity to ask questions about the study. You may also find it beneficial to connect with patient support organisations and ask members about their experience of taking part in a clinical trial.
Declining to participate in a clinical trial should not affect your standard of care. It is not typical for participants to be asked to pay to participate in a clinical trial.
Why have I been offered an unlicensed or investigational therapy?
Clinical trials are conducted to answer very specific research questions. Tis means that when a therapy completes the clinical trials process, it is only licensed for use in these specific cases. There are a number of legitimate reasons why a patient might be offered a product which is not yet approved for treatment of their condition.
Investigating the effects of an approved therapy in a new patient population.
Some clinical trials may need to be repeated in different sub-populations, to confirm that they are safe and effective. For example, a therapy approved for use in older adults is not automatically validated for use in children. Clinical trials may be conducted iteratively to allow for more complex patient profiles, to assess the treatment’s safety and efficacy in patients with multiple health issues.
Novel delivery mechanisms for approved therapies.
In order to research new methods for delivering a therapy, the clinical trial process must be repeated. This is to confirm that the effects and their duration are comparable to the validated method, and to identify the nature and frequency of any side-effects associated with the new method.
Investigating whether a therapy approved for one disorder can be used to treat another condition.
A therapy may be repurposed for treatment of another disorder. This may be because the two disorders present similar symptoms, or have similar mechanisms of action. It may also be because a secondary effect of the therapy could be beneficial in another context.
When a clinically validated therapy is being investigated for a novel purpose, the researchers may be granted permission to omit Phase 1 of clinical trials, as the safety profile has already been established.
'Unproven' and 'unregulated' therapies
Unfortunately, some organisations will exploit the ambiguity around the idea of ‘unproven’ or ‘investigational’ treatments, and offer patients therapies which are not supported by scientific evidence. ‘Investigational therapies’ are those which have not received market authorisation, and are currently completing clinical trials with the ultimate goal of regulatory approval. ‘Unproven therapies’ is a broader term, covering all therapies which have not received marketing authorisation.
‘Unregulated therapies’ are therapies which have not gone through the formal process of peer review, or have not complied with the regulatory authority’s requirements. These therapies do not benefit from the same regulatory and ethical oversight as investigational therapies. You can read in more detail about the risks of unregulated therapies here.
A note on 'off-label' use of medical products
A clinician has the freedom to prescribe their patient any licensed medical product as part of their treatment, even if the product is not authorised for use in their specific circumstances. This use may be well-established in the medical literature (for example, in published case studies) and regarded as safe and appropriate within the medical community. Medical products may be widely used ‘off-label’ for a particular purpose before this use is formally investigated in a clinical trial. One well-known example is the use of beta-blockers, a type of drug licensed for treating high blood pressure and cardiac arrhythmia, to treat anxiety. As these products have completed the clinical trials process and been assessed by the relevant regulatory and ethics authorities, off-label use of a product is not considered to be an unregulated therapy.
