PHASES OF CLINICAL TRIALS

Medical research sets out to understand the disease mechanism. Therefore, researchers usually identify a way to influence this mechanism: block harmful molecules, kill germs, stimulate a favourable process. At this stage researchers create new compounds (molecules) that, theoretically, could act in a beneficial manner to disrupt the disease mechanism.

Subsequently, the compound goes through multiple stages to confirm its safety and efficacy. Firstly, computer models select potential molecular candidates (in silico), then appropriate lab testing is performed (in vitro). Tests are then conducted on laboratory animals selected as they show a reaction pattern similar to that of humans (in vivo or pre-clinical trials). In the late phases of the drug development process, clinical trials are finally implemented, and the medicinal product is administered to humans.

Only a small proportion of the compounds created by researchers reach this phase of clinical trials, most of them getting lost on this lengthy pathway as they do not prove to be as effective as expected.

Clinical research is divided into two main categories:

• EXPLORATORY clinical trials: Phase 1 and 2a clinical trials, where safety is tested and the first signs of efficacy are investigated
• CONFIRMATORY clinical trials: Phase 2b and 3 clinical trials, which confirm the optimal dose that shows effectiveness with minimal side effects.

Clinical trials go through the following phases, in chronological order:

Phase 0

It is a relatively recent form of optional exploratory trials. Phase 0 trials are called micro-dosing studies in humans as well and are intended to accelerate the development of promising medicines or imaging agents, establishing much faster whether the drug or agent works in humans as expected based on pre-clinical studies. Distinctive features of phase 0 studies include the administration of single sub-therapeutic doses of the investigational medicines to a small number of subjects (10-15) to collect preliminary data on the pharmacokinetics of the agent.

A phase 0 trial does not provide data on safety or efficacy, the dose being by definition too low to determine any therapeutic effect. Based on the data obtained during these trials, a decision is made whether to proceed or not with the drug development, based on relevant human models, instead of exclusively relying on sometimes inconsistent animal data.

Phase 1

Usually, the number of participants in such a trial varies from 20 to 100 healthy volunteers or volunteers with a certain illness/condition. The study lasts for several months. Investigational medicine is given to a small number of healthy volunteers to see which dose is safe, starting with a single dose administration. Different participants receive different doses to determine which dose is safer, then either multiple doses are administered to healthy volunteers and/or single/multiple dose(s) in volunteer patients with a condition (disease) possibly targeted by the investigational medicinal product. The information is useful for the design of phase II studies.

Phase 1 studies can be further divided as follows:

• Phase 1a (single ascending dose): In single ascending dose studies, small groups of subjects are given a single dose of the investigational medicine, while they are observed and tested for a period of time to confirm safety. A limited number of participants received the new medicine in sentinel dosing. This means that the first group of volunteers is composed of two participants from which one will receive verum and the other will receive placebo. If they do not experience side effects and the pharmacokinetic data are approximately consistent with the predicted safe values, the next participants will be dosed to complete the cohort which usually consists of 6-10 participants. After evaluation of safety parameters, the dose is escalated and a new group of subjects is then given a higher dose. This process continues until pharmacokinetic safety levels are met which fulfil the conditions of possible therapeutic doses. If unacceptable side effects are observed, then the dose escalation is discontinued and the current dose or possibly the previous dose is declared to be the maximum tolerated dose.
• Phase 1b l (multiple ascending dose): Multiple high-dose studies investigate the pharmacokinetics and pharmacodynamics of multiple-dose medicinal products by assessing safety and tolerability.

Phase 2

In Phase II trials, the investigational medicinal product is administered to a group of patients having the condition (disease) for which it has been developed. Typically involving several hundreds of patients, these studies are not large enough to show whether the investigational medicine is going to be beneficial. Instead, Phase II studies provide investigators with additional safety information. This data is used to design new Phase III research protocols.

Phase II studies can be further divided as follows:

• Phase 2a: Pilot studies designed to demonstrate clinical efficacy or biological activity ("proof of concept" studies)
• Phase 2b: Studies that aim to establish the optimal dose showing biological activity with minimal side effects (“definite dose-finding” studies).

Some studies combine Phase I and Phase II and test both efficacy and safety and tolerability.

Phase 3

The investigational medicinal product is administered to a much larger number of people (thousands of patients) over several years, in order to determine whether it continues to be effective or causes side effects, which only occur after a longer period of time and/or compare this investigational medicinal product to others already in use. If an investigational medicinal product is successful at this time, it could be approved for large scale use.

Phase 4

A treatment is often studied even after it has been authorized; these are called “post marketing studies”. These studies monitor the side effects or problems that could occur only after several years of use or test the treatment in different prevention or therapy settings.