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Italian Medicines Agency Agenzia Italiana del Farmaco

Clinical trials concerning medicinal products

Clinical trials concerning medicinal products

Clinical trials means any human study aimed at detecting or verifying the effects of a new medicine or of an existing medicine tested for a new therapeutic use, in order to establish its safety or efficacy. The trial is divided into several phases and is carried out first in laboratory and on animal models (pre-clinical trial) and then on humans (clinical trial).

Pre-clinical trial

This phase allows to observe the behaviour and the level of toxicity of the molecule on a complex living organism: what is its route of administration, how it is absorbed and subsequently eliminated.

At the beginning, “in vitro” studies are carried out in order to understand the characteristics of the substance from which a medicine is likely to be obtained.  The substance is placed in a test tube together with cell cultures or microorganisms and a series of tests is carried out in highly specialised laboratories.

Only once laboratory tests have established that the molecule has potential therapeutic effects, animal testing can be initiated. The purpose of “in vivo” studies is to verify whether the efficacy of the active substance demonstrated “in vitro” is confirmed in specific animal models of human diseases. These studies also aim to provide preliminary data on the behaviour of the investigational molecule - once it is introduced in the body - in terms of absorption, intra-tissue distribution, metabolism and excretion (pharmacokinetics), as well as to demonstrate its actual safety before human testing is initiated (toxicology).

 

Clinical trials

Phase 1

In Phase 1 studies, the active substance is tested in humans. The aim is to provide an initial assessment of the safety and tolerability of the medicinal product.

These studies are conducted in few selected centres on a limited number of healthy volunteers, who have proved not to have disease predisposition. The main objective is to assess the expected potential side effects, based on the results of previous studies on animals, and to establish how the medicine works and how it is distributed in the body.

Volunteers are divided into several groups. Each group receives a different dose of the medicine, to establish any undesirable effects in relation to the dosage administered. If the trial focuses on serious diseases, studies can be conducted directly on patients who are affected by such diseases and for whom the medicine is being developed.

If the medicine proves to have an acceptable level of toxicity in relation to the expected benefit (benefit/risk profile), the subsequent trial phases can be initiated.

Phase 2

In Phase 2 studies, the therapeutic activity of the potential medicine (i.e. its ability to produce the desired curative effects on the human body) is investigated. This phase also allows to understand the best dosage to be tested in the following phases, and to determine the effect of the medicine in relation to certain parameters (such as blood pressure), which are considered indicative of the patient’s health.

In phase 2 studies, the substance is administered to volunteers who are affected by the disease for which the medicine is being developed.

Subjects enrolled in the study are generally divided into several groups. Each group receives a different dose of the medicine and, when ethically possible, a placebo (a substance lacking therapeutic efficacy). To prevent placebo from affecting participants’ expectations, activity and safety parameters are assessed and the patient (single-blind study), or doctor and patient (double-blind study) are kept ignorant of the type of treatment received or administered.

This phase lasts about two years and helps to demonstrate the non-toxicity and the activity of the new investigational active substance.

Phase 3

Phase 3 studies allow to determine how effective the medicine is, whether it has any additional benefit compared to similar medicines already on the market, and the relationship between risk and benefit. In this case, the patients enrolled are hundreds or thousands

The efficacy of the medicine on symptoms, quality of life or survival is compared against placebo, other medicines already in use or no treatment.

The type of study used at this stage is the randomised controlled trial.This is a type of study in which patients are randomly assigned the new active substance or the control medicine (usually the standard treatment used for the investigated disease) and is very reliable in defining the effectiveness of a medicinal product.

The random assignment of the new medicine or of the control medicine ensures that the two groups have the same characteristics except for the medicinal product taken. Therefore, at the end of the trial, any differences in the participants’ health can be attributed exclusively to the treatment and not to errors or to chance.

During this phase, the onset, frequency and severity of undesirable effects are closely monitored. The duration of administration varies according to the trial objectives, but usually lasts months. The monitoring period of the medicine’s effects is often longer, sometimes reaching 3-5 years.

Phase 4

This is the clinical trial phase that includes studies conducted after the medicinal product has been approved, as part of the approved indications and in full compliance with the Summary of product characteristics (SmPC). It is called “post-marketing surveillance” because it is implemented after the product has entered the market.

During this phase, which may last a few years, additional and new information is acquired and the rarest adverse reactions are evaluated. These are the adverse reactions that could not emerge during clinical trials, but that can be detected with the mass use of the new medicine.

Clinical trial actors

Clinical research in Italy involves many actors: AIFA, for study authorisation and amendments to each phase; the Istituto Superiore di Sanità for consultative opinions on studies and amendments to Phase I; Ethics Committees for opinions within the health facilities where the clinical study is carried out; Directorates General of the health facilities for the definition of contracts; the Eudravigilance network for the reporting of serious and unexpected adverse reactions  during the trials; promoters and researchers directly involved in the conduct of each trial.

Thank to its role in the European network of competent authorities for clinical trials, AIFA coordinates and directs all aspects concerning investigational medicines.

 

Uffici di riferimento

Reference offices

Clinical Trials Office

Donatella Gramaglia

d.gramaglia@aifa.gov.it

Pre-Authorization Department

Sandra Petraglia

s.petraglia@aifa.gov.it

Nested Applications

Pre-Authorization Department

Reference offices

Pre-Authorization Department

Head:Sandra Petraglia


Clinical Trials Office

Reference offices

Clinical Trials Office

Head:Donatella Gramaglia


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