What are clinical trials? Phases, types, and how to participate

Depending on their purpose, clinical studies are generally divided into 2 main categories:

• interventional studies, in which researchers intervene by assigning specific treatments to groups of participants;
• observational studies, in which participants are observed without changing their treatment plans, with the aim of collecting information on the natural course of the disease or on the effects of treatments already in use.

Types of participant groups

Clinical studies are generally designed as controlled studies, meaning they involve comparison between 2 types of participant groups:

• experimental group, which receives the treatment under investigation;
• 1 or more control groups, which may receive a placebo (a substance with no active ingredient) or a standard therapy already in use.

The comparison between the experimental group and the control groups makes it possible to attribute the observed effects more accurately to the treatment being studied.

Randomization in clinical studies

To reduce the risk of bias in the results, randomization is often used, a process through which participants are assigned at random to the different study groups.

Blinding techniques in clinical studies

In many cases, “blinding” techniques are also adopted, meaning procedures aimed at concealing treatment allocation in order to reduce bias and subjective influence. These may be of 2 types:

• single-blind: in a single-blind study, the participant is unaware of the treatment received;
• double-blind: in a double-blind study, neither the participant nor the researcher assessing outcomes knows the allocation of subjects to study groups.

Subjects involved in clinical studies are selected according to inclusion and exclusion criteria defined in the study protocol, taking into account factors such as age, health status, presence of concomitant diseases, and use of other treatments.

Depending on the phase of the study, participants may be:

• healthy volunteers;
• affected by the disease under investigation.

In all cases, participation is voluntary and subject to signing an informed consent form, which ensures that the subject has an adequate understanding of the study’s objectives, risks, and benefits.

The clinical development of a new treatment is generally divided into 4 main phases:

• Phase I: conducted in a limited number of subjects; the main objective is to assess the safety and tolerability of the treatment previously developed in the laboratory (the so-called preclinical phase);
• Phase II: involves a larger number of participants, generally patients affected by the disease of interest, and aims to obtain the first evidence of efficacy, as well as to define the optimal dosage and safety profile;
• Phase III: characterized by large-scale studies conducted in broader and more representative populations. In this phase, the new treatment is compared with standard therapies in order to confirm its clinical efficacy and identify less frequent adverse events. To give an idea, to observe a rare adverse reaction with a probability between 0.01% and 0.1%, nearly 30,000 patients are required for it to be detected at least once; for an uncommon reaction (0.1–1%), about 3,000 patients are needed; for a common reaction (1–10%), about 300 patients; and for a very common reaction (>10%), only about 30 patients. Phase III results form the basis for for go-to-market authorization;
• Phase IV, also known as pharmacovigilance: includes studies conducted after treatment approval, with the aim of monitoring efficacy and safety in real-world clinical practice and identifying long-term or rare effects.

Although it must be noted that, despite methodological rigor, clinical studies may involve certain risks, including possible side effects of the treatment or efficacy not confirmed in all subjects, participation in a clinical trial offers concrete personal and collective benefits.

Participants gain access to new treatments or innovative therapies, often before they are available to the public, and receive continuous medical monitoring, with regular visits and specialist support. This allows physicians to follow the course of treatment and the patient’s response with great precision.

Participating in a clinical study at IRCCS Ospedale San Raffaele, an institution that integrates scientific research and clinical practice, offers the opportunity to access innovative therapies and highly specialized monitoring.

Clinical studies have a long history: as early as 1025, Avicenna, in his Canon of Medicine, formulated principles for systematically testing the efficacy of medicines.

Centuries later, in 1747, the Scottish physician James Lind, through what is generally regarded as the first controlled trial, demonstrated the efficacy of citrus fruits against scurvy, a disease caused by severe and prolonged vitamin C deficiency.

However, it was in the 20th century that shared methodological and ethical standards emerged.

The Belmont Report

In response to serious ethical violations that had emerged in earlier studies, such as the Tuskegee Syphilis Study, in which for decades African American patients with syphilis were observed without adequate treatment or informed consent, the Belmont Report was published in the United States in 1979. It was drafted by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, with the aim of defining the fundamental principles for protecting human subjects in biomedical research.

The principles defined by the Belmont Report are:

• respect for persons, translated into informed consent and protection of autonomy;
• beneficence, understood as maximizing benefits and minimizing risks;
• justice, concerning the fair selection of subjects and the distribution of the benefits and burdens of research.

These principles still form the basis of ethical regulations governing clinical studies internationally today.

Regulatory authorities today

The conduct of clinical studies today is regulated by national and international authorities, such as:

• Agenzia Italiana del Farmaco (AIFA) in Italy;
• European Medicines Agency (EMA) in Europe;
• Food and Drug Administration (FDA) in the United States.

These bodies are responsible for the scientific and regulatory evaluation of medicines and their authorization for commercialization:

• they analyze data on the quality, safety, and efficacy of medicines;
• they verify that studies have been conducted properly;
• they may request further investigation before granting approval.

Ethics committees

The approval and supervision of clinical studies also involve ethics committees, independent bodies that are essential for the protection of participants. Ethics committees are composed of professionals with different expertise:

• physicians;
• pharmacologists;
• biostatisticians;
• lawyers and experts in healthcare law;
• bioethicists;
• patient representatives or representatives of civil society.

This multidisciplinary composition ensures a balanced evaluation not only from a scientific perspective, but also from an ethical and social one. The main task of ethics committees is to verify that the rights, safety, and well-being of people involved in the study are always respected and remain the priority. In particular, they:

• evaluate the balance between risks and benefits;
• verify that the protocol is scientifically sound;
• ensure that informed consent is clear, complete, and understandable.

In other words, the ethics committee represents a guarantee of transparency and protection for participants, helping to strengthen trust in clinical research.

All of this takes place in compliance with shared international guidelines, such as Good Clinical Practice (GCP), which establish rigorous standards for the design, conduct, recording, and reporting of clinical studies.

Evidence-based medicine refers to an approach that combines the results of the best available scientific research with physicians’ experience and the specific needs of patients, in order to guide clinical decisions more consciously. In this context, clinical studies are fundamental in transforming research into concrete results: thanks to their rigorous design and regulatory oversight, every new treatment is carefully evaluated, creating reliable knowledge on which to base the medicine of the future.