Medicinal product development and phases of clinical trials
Compounds that may become new, useful medicinal products are discovered daily in laboratories across the world. To discover a compound believed to contain the necessary properties (a candidate molecule or medicinal product), selection is made from among 15,000 to 20,000 molecules.
In some cases, candidate molecules are targeted when knowing the disease occurrence mechanism, a compound is sought which will target and have an appropriate effect at a specific site in the human body and thus prevent disease occurrence or development. Alternatively, new candidate medicinal products may be discovered incidentally, when positive effects are observed as a result of using compounds in different trial models.
SYNTHESIS AND SELECTION OF A FORMULATION
After identifying a candidate molecule, it is necessary to determine formulation through which it will be most efficient (solution, tablet, capsule, etc.) and administration route of the future medicinal product (orally, intravenously, subcutaneously, etc.). The formulation that will reach the targeted part(s) of the body in a sufficient dose and its appropriate and easy use needs to be selected.
Candidate molecules are first laboratory-tested using different chemical and biochemical probes, cell cultures and animal models. Data on safety, efficacy, mechanism of action and pharmacological activity of the medicinal product are closely monitored and gathered. This phase usually takes several years.
After sufficient data indicating good efficacy and safety of a medicinal product are gathered in nonclinical trials, the medicinal product is ready for its first use in humans within clinical trials. Approximately, only one out of 10,000 molecules tested in nonclinical conditions reaches the clinical trial phase.
Clinical trials are conducted in four phases* and the first three must be completed prior to obtaining a marketing authorization (registration of a medicinal product). The overall clinical development of a medicinal product may take ten years or more.
4 phases of clinical trials
Phase 1 clinical trials begins with the first application of a medicinal product in humans. They are conducted on a small number of trial subjects (20 – 100) who are generally healthy volunteers. Only medicinal products expected to be more toxic, such as chemotherapeutic agents, are tested on patients. In this phase, the action of the medicinal product on the human body, its availability and potential adverse reactions are investigated. As this phase usually involves healthy subjects, its purpose is not to treat disease but to determine the dose range needed for a medicinal product to reach specific targets in the body. The obtained dose range will be used in future trials. Data on tolerability and the nature of adverse events/side effects is also important. Phase 1 trials are mainly conducted in a single or in several trial sites, and usually require hospitalization for intensive reaction monitoring. This is the only clinical trial phase where subjects are paid to participate. After the dynamics of a medicinal product in the body and its reasonable safety are established in a phase 1 trial, phase 2 of the trial can start.
Phase 2 clinical trials (often referred to as therapeutic-exploratory) are designed to investigate the efficacy of a medicinal product on a larger number of subjects (generally up to several hundred) suffering from a particular disease. In this phase optimal effective doses are determined and efficacy is compared to that of the standard available treatment or placebo. In addition, important information is gathered about the safety and the behaviour of the medicinal product in bodies of people suffering from the disease, which may be different from healthy people. The purpose of this trial phase is to determine whether a medicinal product has the desired therapeutic effect and whether or not the adverse reactions are acceptable.
Phase 3 clinical trials (often referred to as therapeutic-confirmatory) follows phase 2 trials in order to demonstrate that the treatment with an investigational medicinal product is equal to or better than the present standard treatment. This phase is used to confirm the information obtained in phase 2 and usually involves a larger number subjects (several hundred to several thousand) in numerous sites and countries across the world. The efficacy and safety of a medicinal product compared to the present treatment standard (and/or placebo) is usually investigated in two or more parallel trial groups. Unlike in phase 2, a medicinal product in this phase is usually administered over a longer period of time, to patients having different degrees of disease severity, sometimes in combination with other medicinal products, etc.
After the trial is completed, the data are processed and analysed and the trial results are published. The data on medicinal products that were found to be effective and having an acceptable safety profile (when the possible benefits exceed the potential harm from treatment) are then submitted for review in the form of registration dossiers to regulatory authorities in different countries. In the case the review is positive, a marketing authorization (medicinal product registration) is granted and the medicinal product becomes available for treatment of patients worldwide.
After a medicinal product is approved for use, further clinical trials are conducted on a larger number of people (several thousands) in order to gather further detailed information on the safety of the medicinal product, especially on those serious adverse events which occur in rare cases. This type of trial is often referred to as a post-marketing trial or observational trial.
The overall development of a medicinal product therefore frequently takes 10 – 15 years and requires substantial funds. It is believed that, over the past decade, the development cost for a new medicinal product has risen to over a billion US dollars.
* The concept Phase 0 clinical trial has been introduced in recent years, in which subjects (usually 10 – 15 of them) are given, on the basis of nonclinical trials, small doses of an investigational medicinal product to see if the medicinal product will behave in the body as expected. Since very small doses are used, this type of trial does not provide efficacy and safety information, but is aimed at accelerating a medicinal product’s development.