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Information gathered from preclinical tests are used to apply for permission to conduct clinical trials. In the UK, applications have to go to the Medicines and Healthcare products Regulatory Agency (MHRA) who assess the preclinical data, including safety data, and decides if the evidence supports allowing clinical trials in volunteers and patients to go ahead; the National Research Ethics Service (NRES) who ensure that the rights, safety, dignity and well being of clinical trial participants are protected; and other organisations. A clinical trial can only start when all the necessary approvals have been granted by these bodies. The organisation conducting a trial (usually known as the Sponsor) is also expected to register the trial on a public, searchable database. This helps to keep track of all the trials being conducted across the world at the same time, and also can help people find out where a trial is being conducted, in case they would like to volunteer (via their doctor) to participate.
The stage of testing new medicines in people is called clinical trials. Although a potential new medicine has been tested carefully before it is first given to people, occasionally unexpected effects occur, so testing must take place in stages using information gathered from each stage to decide what to do next.
Phase 1 clinical trials
The first stage of testing is often done in volunteers. These are usually people who are healthy and so would receive no benefit from the medicine, so they are often paid for their time and inconvenience. They will usually be given very small doses of the medicine and blood and urine samples will be taken to find out what has happened to the compound in their bodies. They stay in the testing centre, which may be attached to a hospital, for several hours or even overnight, and will be looked after by doctors and nurses. They will also be monitored to see what effect the medicine has - for example on their blood pressure and heart rate - and they will be asked if they have any unexpected side effects such as headaches.
Over a few days or weeks larger doses will be given to different volunteers to investigate what effect the medicine has in larger doses, up to the type of dose that might be required to treat the disease. In the end 50 or so people will have taken the medicine and a lot of information will have been gathered.
Phase 2 clinical trials
The aim of these studies is to identify the dose of the medicine that is required to treat the disease without causing too many unwanted side effects. So these trials are carried out in patients suffering from the disease the medicine is intended to treat. Usually around 200 patients will be treated in this phase.
The new medicine is tested against the best available treatment or, sometimes, a placebo - which looks like the medicine but contains no active ingredients. It is important that neither the patient, nor the doctors who are treating them, know whether they are taking the new medicine or not. These are often called randomised-controlled trials, or double-blind trials. That way they cannot be biased in their recording of the results of the trial - how well the medicine worked and whether the patient suffered any side effects.
Phase 3 clinical trials
This is the main stage in clinical testing of a new medicine. Thousands of patients will take the new medicine, or the best alternative treatment, and the data from these trials will decide if the new medicine is safe and effective enough to be prescribed by doctors for the general population.
All patient records from the trials are checked by scientists as it is important that side effects are picked up, as well as seeing how well the medicine has treated the disease. The data is carefully recorded so that it can be analysed in comparison with data from other treatments for the disease. A new medicine must show benefits over existing treatments.
Also at this stage evidence of the economic benefits of treatment will be gathered; information on this aspect of the development of a medicine is given on page 8 of this resource.
All the information that the company has gathered during preclinical and clinical testing is pulled together and sent to the organisation responsible for approving new medicines. In the UK this is the Medicines and Healthcare Products Regulatory Agency (MHRA). The Agency has to decide if enough evidence has been submitted to show that the medicine is effective, relatively safe and of good enough quality that it can be given to patients.
Some medicines work better in some people than in others. The company developing the medicine may know early on that this is likely to be the case, or they may find out during clinical trials in different populations around the world. This may lead to recommendations on which groups are more likely to benefit from the medicine.
In some cases a test may be available to identify those people for whom the medicine will work best. An example of this is the breast cancer treatment trastuzumab, more commonly known as Herceptin. One specific type of cancer cells have high levels of a particular protein on their surfaces (HER2 protein), Herceptin is much more likely to work if the cancer cells have high HER2 levels. Tests are available to measure the HER2 levels of the tumour cells and, if they are high, Herceptin is likely to be an effective tretment. This approach leads to the idea of 'personalised medicines' which are designed to work for people who have specific genetic profiles.
Post-marketing trials (Phase 4)
Once a new medicine is on the market and doctors can prescribe it, studies will still continue as there is more to learn about the medicine.
Probably earlier trials will not have included young children so, if the disease is one that children also get, the medicine will need to be tested in children to identify the best dose to give and to ensure the medicine is safe for them to take.
Also many people will take several medicines at once, sometimes these can interfere with each other. For instance if two medicicines are both broken down by the liver, they may be broken down more slowly which may mean that lower doses of one, or both, should be given. This will affect the dose that should be used. The most common medicines that are likely to be taken at the same time as the new medicine will have been considered during earlier trials, but not all possible combinations will have been tested.
There may be other diseases that the medicine might be able to treat, these will also be investigated through further studies.
They may include studies that look at how the new medicine improves clinical practice (eg shorter time in hospital clinics) or patient outcome (eg shorter stays in hospital) which help the NHS make cost savings.
In phase 2-4 clinical trials patients receive medicines which are expected to treat their illness, but there are other types of clinical studies.
Often these involve groups of people being observed to see if they develop a disease, or patients who have a disease are studied to see if past exposure to something might have led to them getting the disease. These are called observational clinical studies and are important in finding out more about what factors are linked to a disease such as heart disease or diabetes.
Clinical trials can also assess treatments that do not involve medicines. For instance new medical devices, such as cochlear implants for deafness, have to undergo trials to compare their effectiveness against conventional hearing aids; or a new form of keyhole surgery has to be trialled in comparison with traditional surgery before it can be recommended for widespread use.
Trials may also compare the effectiveness of educating patients about their condition, or about how to improve their illness through lifestyle changes. For example one group of patients may be given a leaflet about how healthier eating could help them lose weight; another group might attend sessions where they were shown how to prepare healthy food. These two groups could be commpared to see which method has been more effective. Although these trials cannot be double blind, allocation of patients to the different treatment groups would still have to be random to remove any bias.
Once a new medicine is on the market many more people will take it than the few thousand who have been involved in trials. It is very likely that new adverse effects will be identified and the company who sells the medicine needs to be made aware of these so that it can, if necessary, warn doctors and patients about these effects.
Information about how this data is gathered is given on page 8 of this resource.