Phases of clinical research
Clinical trials are conducted in four stages (phases). Each phase must end with positive results so that one may proceed to the next one.
The first stage – phase I
In the first place, the safety of a tested substance is pre-evaluated. In a group of several dozen healthy volunteers, its metabolism, absorption, excretion are being tested; the possible toxicity and interactions with other substances taken (foods, medicines) also are being verified. After completion of this phase it is possible to specify the dose of the investigated therapeutic agent. These studies are conducted in specialised centres that mostly belong to pharmaceutical companies or research institutions.
In the case of studies on substances for the treatment of cancer, phase I is combined with phase II in order not to expose the healthy volunteers on the operation of highly toxic compounds.
The second stage – phase II
At this stage, a clinical study determines whether a drug works in a particular group of patients and whether it is safe for them. Investigators also evaluate a dose-and-effect relationship for the substance at issue which results in determining the dose administered in subsequent phases of the research. The effectiveness and safety of the investigated drug is also being evaluated all the time. During phase II, subject to a detailed assessment are the data on absorption, metabolism and excretion of the drug related to the study participants’ age and gender. At this stage of the research the investigators compare the new drug with placebo, or with a medicine used to treat a particular condition. The comparison is being performed on the basis of the double-blind method, which is to ensure the most objective evaluation of the action of the new molecule. According to this method, neither the patient nor the investigator know whether the patient is given the substance that is the subject of the research, or placebo. The group involved in this study is chosen at random and comprises several hundred volunteers – in this case, patients suffering from the studied disease.
The positive evaluation of a phase II clinical trial is obtained when the benefit-to-risk ratio of using the investigated substance is clearly greater. After obtaining such a result, the transition to the next phase takes place.
The third stage – phase III
Phase III clinical trials aim to finally confirm the effectiveness of a test drug in the treatment of a particular disease. This phase includes examination of the relationship between drug safety and effectiveness, both during its short-term and long-term use. Phase III clinical trials tend to comprise groups reaching several thousand patients, and their duration time amounts to from one to several years. As in phase II clinical trials, the aforementioned double-blind method and random selection of patients are being implemented.
After positive completion of the phase III clinical study, the investigated drug can be registered and placed on the market.
The documentation about the investigated drug, which is submitted at an institution registering the medicinal product, encompasses all the data collected during preclinical and clinical trials (from phase I to phase III inclusive). It is a mandatory element of the documentation which can count up to several thousand pages. In order to accurately determine what data should be included in the documentation, drug manufacturers, before starting their research programmes, shall consult the issue with drug agencies in the countries concerned. This allows the manufacturers to precisely specify a group of patients to whom the investigated drug is to be targeted and reduces the risk of rejection of the discussed documentation due to the omission of relevant data.
The fourth stage – phase IV
The last phase of clinical trials concerns drugs registered and marketed, that is, available for sale. The aim of this phase is to determine whether the drug is safe considering all indications recommended by the manufacturer, and for all groups of patients. In this phase, the results obtained in previous phases are verified in addition. During the phase IV clinical trials, for example, new indications for the already registered drug also are being investigated.