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.
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 subjects or sub-groups of patients 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 subjects 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 patient group. For this reason, drugs which are considered to have a potentially high toxicity are usually tested on people from the target patient 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 subjects 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 subjects 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 subjects 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 subjects 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 subjects are involved, some may experience side effects which none of the subjects 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 subjects 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.
Last Updated: Friday 21 August 2009