What is a clinical trial?
A clinical trial is a biomedical/health-related research study into the effects on humans of a new medical treatment (medicine/drug, medical device, vaccine or new therapy), sometimes called an investigational medicinal product (IMP). Before a new drug is authorised and can be marketed, it must pass through several phases of development including trial phases in which its safety, efficacy, risks, optimal use and/or benefits are tested on human beings. Existing drugs must also undergo clinical testing before they can be used to treat other conditions than that for which they were originally intended.
European requirements for clinical trials
Organisations conducting clinical trials in the European Union must, if they wish to obtain marketing authorisation, respect the requirements for the conduct of clinical trials which can be found in the Clinical Trials Regulation (Regulation (EU) No 536/2014). This Clinical Trials Regulation came into application on 31 January 2022 and replaced the past EU Clinical Trials Directive 2001/20/EC and national legislation that was put in place to implement the Directive.
Under the Clinical Trials Regulation, all clinical trial applications for trials with medicinal products in humans have to apply through a Clinical Trial Information System (CTIS). CTIS is a single-entry point for sponsors and regulators of clinical trials for the submission and assessment of clinical trial. This is done to harmonise and streamline the processes for application and supervision of clinical trials throughout the EU. With CTIS, sponsors can apply for authorisations in up to 30 EU/EEA countries at the same time and with the same documentation.
The European Medicines Agency (EMA) sets up and maintains CTIS, in collaboration with the Member States and the European Commission. Information stored in CTIS are publicly available for transparency.
The Clinical Trials Regulation (Regulation (EU) No 536/2014) foresees a three-year transition period. From 31 January 2022, clinical trial sponsors can choose whether to submit an initial clinical trial application in line with the past system (Clinical Trials Directive 2001/20/EC) or via CTIS. From 31 January 2023, submission of initial clinical trial applications via CTIS becomes mandatory. It will also apply to trials authorised under the previous legislation if they are still ongoing on 31 January 2025, they will have to be transitioned to CTIS.
The European Medicines Agency (EMA) plays a key role in ensuring the standards of good clinical practice (GCP) are applied across the European Union. Guidelines to ensure that clinical trials are carried out in accordance with good clinical practice are contained in the “Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products” (also known as the Good Clinical Practice or GCP for short). This document provides more concrete guidelines and lends further support to the Clinical Trials Directive. In addition, EMA has published further guidance on clinical trial management during the COVID-19 pandemic. This covers how to deal with the extraordinary situations that the pandemic presents and specific advice on clinical trials for potential COVID-19 treatments.
EMA has also published additional, more specific guidelines which must also be respected. These include guidelines on inspection procedures and requirements related to quality, safety and efficacy.
Copies of the above-mentioned documents and the new Directive applicable on 31 January 2022 (available in 24 EU languages) can be found at: https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials-human-medicines
Types of clinical trials
Clinical trials can be categorised according to their objectives and also the way they are organised. For example, they might be prevention trials, treatment/drug trials or diagnostic and screening trials.
- Interventional trials (also called treatment trials or clinical drug trials) are clinical trials which set out to test treatments or combinations of treatments which have not yet been officially approved. For example, a pharmaceutical company may have developed a new drug which it believes would be effective in the treatment of Alzheimer’s disease but must first test it on human volunteers in accordance with strict and rigorous guidelines in order to ensure that it is safe and effective. Some drugs might be aimed at curing a particular condition, whereas others might be aimed at better controlling symptoms of a particular condition.
- Prevention trials involve tests to find ways to prevent particular medical conditions or if people have them already, to prevent them from reoccurring. The emphasis of these studies might be on medicines, vitamins and minerals or lifestyle changes.
- Observational trials investigate health issues in large groups of people. The participants in such trials do not receive any treatment but may be asked to provide information, blood samples.
- Diagnostic and screening trials are aimed at finding new ways to detect and diagnose medical conditions (e.g. a better test, a more effective procedure or a more sophisticated tool).
In addition, clinical trials may be described as randomised trials, blind trials, add-on studies, open label trials or randomised double-blind placebo-controlled trials. These terms provide information about the way that the trial is organised which may have consequences for the participants (mostly with regard to the inclusion of a placebo group which is fairly common. A brief description of some of these terms is provided below:
|
Term |
Definition |
|
Participants |
The people who volunteer to take part in the study (sometimes called subjects but this is becoming less common). |
|
Randomised |
Participants are randomly assigned to different groups. |
|
Open label |
Participants and researchers are all aware of the drug being given. |
|
Blind |
The participants do not know which group they are in e.g. whether they are in the treatment group or the placebo group. |
|
Double blind |
Neither the researchers nor the participants know to which group the participants belong until it is revealed at the end of the study. |
|
Placebo |
A substance which does not contain the active ingredients of the experimental drug but looks the same (sometimes called a dummy drug). |
|
Add-on |
All participants receive an existing treatment but some then receive the additional experimental drug whilst others do not or are given a placebo. |
|
Single centre |
The study is carried out at one location. |
|
Multi-centre |
The study is carried out in several locations (i.e. different towns or even different countries). |
Phases of clinical trials
Testing an experimental drug or medical procedure is usually an extremely lengthy process, sometimes lasting several years. The overall procedure is divided into a series of stages (known as phases) which are described below.
Pre-clinical testing
Clinical testing on humans can only begin after a pre-clinical phase, involving laboratory studies (in vitro) and tests on animals, which has shown that the experimental drug is considered safe and effective. However, no animal is sufficiently similar to humans (even genetically modified ones) to make human testing unnecessary. For this reason, the experimental drug must also be tested on humans.
Whilst a certain amount of testing can be carried out by means of computer modelling and by isolating cells and tissue, it becomes necessary at some point in time to test the drug on a living creature. Animal testing is an obligatory stage in the process of obtaining regulatory approval for new drugs and medicines, and hence a legal requirement (EU Directive 2001/83/EC relating to Medicinal Products for Human Use). This applies to prescription and vaccine drugs but not to most over the counter drugs, off the shelf medicines and healthcare products (as the ingredients in them have usually already been tested). The necessity of carrying out prior testing on animals is also stated in the World Medical Association’s “Ethical Principles for Medical Research Involving Human Subjects.
In order to protect the well-being of research animals, researchers are guided by three principles which are called the 3Rs:
- Reduce the number of animals used to a minimum
- Refine the way that experiments are carried out so that the effect on the animal is minimised and animal welfare is improved
- Replace animal experiments with alternative (non-animal) techniques wherever possible.
In addition, most countries will have official regulatory bodies which control animal research.
The main phases of clinical trials
Clinical trials on humans can be divided into three main phases (literally, phase I, II and III). Each phase has specific objectives (please see below) and the number of people involved increases as the trial progresses from one phase to the next. General speaking the overall aims of the three phases are:
- Phase 1: determine safety
- Phase 2: determine whether the drug works
- Phase 3: determine how effective the drug is compared to currently available, effective drugs
Phase I trials
Phase 1 trials are usually the first step in testing a new drug or treatment on humans after successful laboratory and animal testing. They are usually quite small scale and usually involve healthy participants or sub-groups of participants who share a particular characteristic. The aims of these trials are:
- to assess the safety of experimental drugs
- to evaluate any possible side effects
- to determine a safe dose range
- to see how the body reacts to the drug (how it is absorbed, distributed and eliminated from the body, and the effects that it has on the body).
Dose ranging, sometimes called dose escalation, studies may be used as a means to determine the most appropriate dosage, but the doses administered to the participants should only be a fraction of those which were found to cause harm to animals in the pre-clinical studies.
The process of determining an optimal dose in phase I involves quite a high degree of risk because this is the first time that the experimental treatment or drug has been administered to humans. Moreover, healthy people’s reactions to drugs may be different to those of the target group. For this reason, drugs which are considered to have a potentially high toxicity are usually tested on people from the target group.
There are a few different approaches to phase I trials e.g. single ascending dose studies, multiple ascending dose studies and food effect.
In single ascending dose studies (SAD), a small group of participants receive a small dose of the experimental drug and are then observed in order to see whether that dose results in side effects. For this reason, trials are usually conducted on an inpatient basis. If no adverse side effects are observed, a second group of participants are given a slightly higher dose of the same drug and also monitored for side-effects. This process is repeated until a dose is reached which results in intolerable side effects. This is defined as the maximum tolerated dose (MTD).
Multiple ascending dose studies (MAD) are designed to test the pharmacokinetics and pharmacodynamics of multiple doses of the experimental drug. A group of participants receives multiple doses of the drug, starting at the lowest dose and working up to a pre-determined level. At various times during the period of administration of the drug, and particularly whenever the dose is increased, samples of blood and other bodily fluids are taken. These samples are analysed in order to determine how the drug is processed within the body and how well it is tolerated by the body.
Food effect studies are investigations into the effect of food intake on the absorption of the drug into the body. This involves two groups of participants being given the same dose of the experimental drug but for one of the groups when fasting and for the other after a meal. This allows researchers to see whether eating before the drug is given has any effect on the absorption of the drug by the body.
Phase II trials
Having demonstrated the initial safety of the drug (often on a relatively small sample of healthy individuals), phase II clinical trials can begin. Phase II studies are designed to explore the therapeutic efficacy of a treatment or drug in people who have the condition that the drug is intended to treat. They are sometimes called therapeutic exploratory trials and tend to be larger scale than Phase I trials. Many experimental drugs which fail tend to do so during the Phase II trials.
Phase II trials can be divided into Phase IIA and Phase IIB although sometimes both are combined.
- Phase IIA is designed to assess dosing requirements i.e. how much of the drug should patients receive and up to what does is considered safe. The safety assessments carried out in Phase I can be repeated on a larger subject group. As more participants are involved, some may experience side effects which none of the participants in the Phase I experienced. The researchers aim to find out more about safety, side effects and how to manage them.
- Phase IIB studies focus on the efficacy of the drug i.e. how well it works at the prescribed doses. Researchers may also be interested in finding out which types of a specific disease or condition would be most suitable for treatment.
Phase II trials can be randomized clinical trials which involve one group of participants being given the experimental drug and others receiving a placebo (dummy pill). Alternatively, they may be case series which means that the drug is safety and efficacy is tested in a selected group of patients. If the researchers have adequately demonstrated that the experimental drug (or device) is effective against the condition for which it is being tested, they can proceed to Phase III.
Phase III trials
Phase III trials are the last stage before clinical approval for a new drug or device. By this stage, there will be convincing evidence of the safety of the drug or device and its efficacy in treating people who have the condition for which it was developed. Such studies are carried out on a much larger scale than for the two previous phases and are often multinational. Several years may have passed since the original laboratory and animal testing.
The main aims of Phase III trials are:
- to demonstrate that the treatment or drug is safe and effective for use in patients in the target group (i.e. in people for whom it is intended)
- to monitor side effects
- to test different doses or different ways of administering the drug
- to determine whether the drug could be used at different stages of the disease.
- to provide sufficient information as a basis for marketing approval
Researchers may also be interested in showing that the experimental drug works for additional groups of people with conditions other than that for which the drug was initially developed. For example, they may be interested in testing a drug for inflammation on people with Alzheimer’s disease. The drug would have already have proven safe and obtained marketing approval but for a different condition, hence the need for additional clinical testing.
Post-marketing surveillance studies (phase IV)
After the three phases of clinical testing and after the treatment has been approved for marketing, there may be a fourth phase to study the long-term effects of drugs or treatment or to study the impact of another factor in combination with the treatment (e.g. whether a particular drug reduces agitation).
Usually, such trials are sponsored by pharmaceutical companies and described as pharmacovigilance. They are not as common as the other types of trials (as they are not necessary for marketing permission). However, in some cases, the European Medicines Evaluation Agency (EMEA) grants restricted or provisional marketing authorisation, which is dependent on additional phase IV trails being conducted.
Expanded access to a trial
Sometimes, a person might be likely to benefit from a drug which is at various stages of testing but does not fulfil the conditions necessary for participation in the trial (e.g. s/he may have other health problems). In such cases and if the person has a life-threatening or serious condition for which there is no effective treatment, s/he may benefit from “expanded access” use of the drug. There must, however, be evidence that the drug under investigation has some likelihood of being effective for that patient and that taking it would not constitute an unreasonable risk.