Clinical trial of pharmaceutical agents is the necessary step required for development of any new drug or for expansion of indications for application of already known drugs. In the initial stages of drug development chemical, physical, biological, microbiological, pharmacology, toxicology and other studies are conducted in tissues (in vitro) or in laboratory animals. These are so called preclinical (non-clinical) studies, which are intended to establish and evaluate (using the scientific methods) the efficacy and safety of experimental drugs. However, such studies could not provide reliable information on how the drug will act in humans, since the animal organisms differ from human organisms in both pharmacokinetic characteristics and in body organs and systems response to drug exposure. Therefore, it is necessary to perform clinical trials of drugs in humans.
So, what is the clinical trial (study) of pharmaceutical agent? A clinical trial is defined as the systematic investigation of pharmaceutical agent in humans (patients or healthy volunteers) to evaluate its safety and/or efficacy and to establish and/or to confirm its clinical, pharmacological, pharmacodynamic properties and to evaluate absorption, distribution, metabolism, excretion and/or drug interactions as well. A clinical study is initiated by Sponsor, who is responsible for its organization, monitoring and/or financing. Investigator (a person or a group of persons) has the responsibility for the practical conducting of the study. The Sponsor of a study is usually the pharmaceutical company which performs the development of the new pharmaceutical product, however, the Investigator may act as Sponsor if the study is performed on his/her own initiative; in such case he/she has the overall responsibility for conducting the study.
All clinical trials should be performed in compliance with the underlying ethical principles of the Declaration of Helsinki, GCP (Good Clinical Practice) guidelines and all applicable regulatory requirements. Before a clinical study is initiated, foreseeable risks should be weighted against anticipated benefit for the study subject and society. The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. Subjects can be enrolled in the clinical study only on the basis of voluntary informed consent (IC) obtained after detailed explanation of the trial.
Clinical study should be scientifically sound, and described in a clear detailed protocol. Assessment of risk/benefit ratio as well as reviewing and approval of study protocol and other study relevant documentation is the responsibility of Institutional Review Board / Independent Ethics Committee (IRB/IEC). After approval by IRB/IEC is obtained, the clinical trial can be started.
Types of clinical trials
A pilot study is intended to obtain preliminary data important for planning future trials (such as determining possibility of conducting study in a larger number of subjects, sample size and power of further trials etc.)
Randomized clinical study is the trial in which subjects are randomly allocated to treatment groups (randomization procedure) and have an equal probability of receiving investigational or control study drug (comparator or placebo). In non-randomized trial randomization procedure is not performed.
Controlled (sometimes synonym “comparative” is used) clinical study is the trial in which the investigational drug whose efficacy and safety are not fully studied is compared with the agent whose efficacy and safety are well known (comparator drug). Comparator can be placebo, standard therapy or no treatment at all. In a non-controlled (non-comparative) study no control/comparative group (in which subjects are given comparator drug) is used. In a more comprehensive sense, a controlled study is meant as any trial in which potential sources of systematic biases are controlled (i.e. minimized or excluded, as possible) and which is conducted in strict compliance with the study protocol, is monitored etc.
In parallel studies, the subjects of different groups are given either only investigational drug or only comparator drug/placebo. In crossover studies, each patient receives both compared drugs (usually in a random sequence).
A clinical study can be designed as open study in which all parties involved are aware which drug is being used for which subject or as blinded (masked) study in which one (single-blind study) or more parties (double-blind, triple-blind or full-blind study) involved in the clinical study are unaware of the treatment assignment. Prospective study is a trial in which subjects are divided into groups that are exposed or not exposed to an investigational drug before the outcomes have occurred. In contrast, a retrospective study investigates the outcomes of previous clinical trials, i.e. the outcomes have occurred before the study commenced.
Depending on the number of sites where studies are conducted according the same protocol, the studies are called single-center or multicenter studies. A study is called International if it is conducted in different countries.
Parallel Group trial is a study that compares two or more groups of people concurrently, one or more of which receive the investigational drug and one of which is a control group. Some parallel studies compare different treatments without including a control group. (Also called independent group design).
Cohort study is an observational study in which a defined group of people (the cohort) is followed over time. The outcomes of subjects in subsets of this cohort who were exposed or not exposed (or exposed at different levels) to treatment with investigational drug are compared. A prospective cohort study assembles participants and follows them into the future. A retrospective (or historical) cohort study identifies subjects from past records and follows them from the time of those records to the present.
Case control study (synonym: case referent study) compares people with a specific diseases or outcome of interest (cases) to people from the same population without that disease or outcome (controls), and seeks to find associations between the outcome and prior exposure to particular risk factors. Case series (synonyms: anecdote, case history, single case report) is a study reporting observations on a series of individuals, usually all receiving the same treatment, with no control group. Case study is a study reporting observations on a single individual.
At present, it is preferred such type of study design that provides the most reliable data, e.g. controlled prospective randomized comparative and desirably double-blind studies.
Recently, the role of clinical trials of pharmaceutical agents has gained increased importance in view of implementation of principles of Evidence-Based Medicine in practical health care. And the main principle is to make specific clinical decision on patient treatment based on rigorously proven scientific findings; and such data can be obtained from well-designed controlled clinical trials.