Every clinical trial requires the approval of the competent national authority or authorities – in Switzerland, this is Swissmedic, the regulatory authority – and the Ethics Committees. Ethics Committees consist of experienced doctors, theologians, legal experts and lay people. They consider (on the basis of previous trials, etc.) whether and under what conditions the planned trial can take place from an ethical, medical and legal standpoint. They pay particular attention to protection of the trial participants. They also examine whether the medical facilities and doctors who will be involved in the trial are suitable.
Phase I – First-in-human investigation of tolerability
In this phase of drug development, small amounts of the new active substance are administered to several dozen healthy subjects who volunteer to take part in the trial. Since they are healthy, it is not possible to draw any conclusions about the efficacy of the new substance at this stage. The focus of this phase is whether the predictions in terms of tolerability, uptake, distribution, transformation and excretion that were made following the animal studies can be confirmed in humans. The reactions that occur at different dosages provide information about side effects in the human body and suitable dosages.
The data generated in this test phase are used to calculate the most suitable delivery form for the new medicine, such as tablets, capsules or drops. Once the best form for the product has been identified, production can start on a larger scale.
Phase II – Clinical trials of efficacy
Pharmaceutical companies and clinical research organisations cooperate with hospitals, such as university hospitals and other medical facilities, to enable sick patients to be included at this stage in the further development of new medicinal products. The doctors treating them inform them about the opportunity to take part in a trial and, if they are interested, look after them while they are receiving the study treatment. An average of 100 to 500 patients take part in a trial in this phase. It investigates the efficacy and tolerability of the medicine and also establishes the optimum dosage.
The most reliable way to make the necessary observations is to divide the patients into two groups. One group is given the new medicine, while the other group is given the standard treatment or a placebo – a medicine containing no active ingredient. Patients are assigned to the two groups by the doctors involved in the trial using a randomisation process; this means that patients are assigned by chance, not design. There are trials, known as double-blind trials, in which neither the patients nor the doctors know who is in each group. In these trials, the packs of medicine are identified solely by code numbers that are entered in the patients’ records. This enables the analysts to determine at a later stage who was given an active medicine and who was given a placebo. While the patients are being treated there is no way of knowing who is in which group. This approach is designed to prevent patients’ hopes and fears from influencing the effect of the medicine.
Phase III – Clinical tests to demonstrate treatment success
In this phase, the new medicine is tested in many thousands of patients to see if its tolerability and efficacy remain unchanged when it is used in a very large number of different people. In trials, it is frequently observed that a medicine works differently or not at all in different people. This is usually the result of the patient’s individual characteristics such as blood parameters or particular genetic features. Indicators like this that affect the action of medicinal products are known as biomarkers. Studies have identified certain characteristics in humans that are now known to affect the action of some medicines. Biomarker tests can be used to identify those patients who respond particularly well to a therapy.
In addition to testing efficacy in a large population, Phase III trials also investigate interactions with other medicines. At the end of the clinical phase, the results are evaluated against previously defined endpoints that describe the effect that the new medicine is expected to have. In infectious diseases, for example, the goal is for the infection to subside completely; in chronic diseases it is hoped that medication will extend the periods between exacerbations for as long as possible.