The clinical trial phases
Before clinical trials in humans
Once an idea for a new medicine is born, several years of work in the laboratory proceeds before the medicine can be tested in human beings.
The first step in the development of a medicine is to prove the mechanism of action in a laboratory trial, a so-called in vitro trial, which means “in the glass”. This phase can last several years. If the results are convincing, the next step is in vivo trials where the medicine is tested in laboratory animals. Such trials must be approved by an animal ethics committee in the country concerned. These trials are called non-clinical trials or pre-clinical trials. They assess the medicine’s safety, efficacy and mechanism of action (which cells and/or processes of the body is affected by the medicine) as well as the pharmacokinetic properties in animals. Pharmacokinetic properties include absorption, distribution, metabolism and excretion, etc. This phase is extremely costly and time-consuming and could take several years. Many trials are stopped during this development phase because the results fail to show any effect or produce unacceptable side effects.
If the trial has demonstrated an adequate effect and there have been no signs of unacceptable side effects in the tested animal species, the next development phase can begin, which is testing the medicine in human beings.
Clinical trials of medicines in humans
This type of trial must be approved by the authorities in the country where it is to be conducted. The responsibility for obtaining this approval lies with the company or research group carrying out the trial (called the “sponsor” in the legislation). In Denmark, the Danish Medicines Agency, the Research Ethics Committee and the Danish Data Protection Agency must approve trials in humans.
First, the applicant must obtain an authorisation to manufacture the medicine. The authorisation is granted based on the outcome of an inspection carried out by the authorities. The purpose of the inspection is to verify that the company complies with good manufacturing practice (GMP). Here you can find a description of the Danish Medicines Agency’s control and inspection tasks.
Before the medicine is tested for the first time in humans (called a first-in-human (FIH) study), the Danish Medicines Agency assesses the results obtained in the laboratory trials and non-clinical trials. The Danish Medicines Agency’s doctors, toxicologists and pharmacists/biologists look at the efficacy, safety and the manufacture of the medicine. If the documentation is deemed insufficient, the Danish Medicines Agency will request further investigations to uncover all risks. The trial cannot be conducted before the results of those investigations have been approved by the Danish Medicines Agency.
FIH studies can be conducted in healthy volunteers, but they can also be conducted based on specific patient groups. Medicines with a significant potential for side effects, e.g. cytostatics for treatment of cancer which are cytotoxins (toxic to cells) are usually studied in patients whose cancer disease may benefit from the medicine’s potential effect.
The first phase of clinical studies (phase I) could be an FIH study, but it could also be a study where a known medicine is tested on a new disease/indication or patient group, e.g. children. Phase I trials typically involve an assessment of one or more of the following aspects of the investigational medicinal product: A preliminary assessment of the safety and tolerance, pharmacokinetic properties (absorption, distribution, metabolism and excretion), pharmacodynamics (the medicine’s mechanism of action in the body) and a preliminary measurement of the medicine’s effect.
In phase I, the medicine is usually only tested in a few people (approximately 10 subjects). If the medicine’s mechanism of action is new and might be particularly strong, the medicine is tested in one trial subject at a time to reduce the risk that several trial subjects are exposed to potentially unpleasant side effects.
If the phase I trial delivers positive results, phase II can begin. In phase II, the medicine is tested in a larger group of people who have the specific disease the medicine is targeting (approximately 100 subjects). In this phase, the medicine is tested in patients rather than in healthy individuals since the main purpose is to test the therapeutic effect of the medicine. Phase II also studies the medicine’s safety and tests which dose is most effective.
The next phase is phase III where the medicine is tested in a large group of patients under conditions more similar to everyday settings to confirm the medicine’s effect. In this large group of persons, we get a more detailed picture of the medicine’s effect and the possible side effects. A phase III trial usually takes several years and may include several thousands of individuals.Phase IV starts after the medicine has been authorised for marketing. Studies of the medicine’s therapeutic effect has a greater scope than the early documentation of the medicine’s safety, efficacy and dose determination. These studies often play an important role in the optimisation of the use of the medicine and discovery of possible side effects, e.g. those that could develop in patients who are treated with several different medicines.