Clinical Trials: what are they?

Clinical trials are a fundamental phase in the development of a therapy. Their importance lies in determining the effectiveness of a treatment by comparing it with other available options and evaluating any potential side effects. To mark International Clinical Trial Day, aimed at raising awareness on this topic, we have gathered essential information worth knowing about them.

What are Clinical Trials?

Clinical trials, or clinical trials, are an important phase of scientific research in which tests are conducted on volunteer patients to evaluate the effectiveness and safety of a therapy. This treatment can involve drugs, medical devices, vaccines, and other medicinal products, including the use of diagnostic equipment.

In most cases, trials involve the safety and efficacy of a new therapy, but they can also investigate the administration methods or timing of an existing drug, protocols for early diagnosis of a disease, or lifestyle interventions for patients, such as specific diets or exercise programs.

Clinical trials can be promoted by companies (known as profit studies) or by groups, societies, associations, or independent individuals (known as non-profit studies), involving either a single research centre or collaborations among multiple centres, both nationally and internationally.

The first clinical trial

The first controlled clinical trial was conducted in 1747 by Dr. Lind, a ship’s surgeon in the British fleet. Determined to find a cure for scurvy, a disease that decimated long-haul sailors until the mid-18th century, he conducted an experiment. He divided the sailors into groups of two and administered different preparations based on the knowledge of the time to each group. The pair of sailors who received a preparation based on oranges and lemons recovered from scurvy, unlike the others. This led to the discovery that scurvy was caused by a lack of fresh citrus in the diet, which provides vitamin C.

Preclinical trials

Today, times have changed: clinical research is much more advanced, and trials are more targeted. Before a new therapy can be administered to patients, it is essential to demonstrate the scientific hypotheses that led to its creation through rigorous controlled procedures and laboratory simulations. This preliminary phase, known as preclinical research, aims to provide evidence of the potential effectiveness of the treatment against the disease.

Preclinical studies, also known as preclinical trials, consist of tests conducted before administration to patients. These include in vitro tests conducted in the laboratory on cells, including those taken from individuals affected by the disease, and in vivo tests involving the use of animals when reliable in vitro tests are not available. During this phase, tests are also conducted to evaluate the chemical stability of the molecule and technical studies to define the formulation and optimal dosage for human application. The duration of preclinical studies extends on average for three to five years or more. If the preclinical tests yield positive results, the clinical trial phase, involving direct testing on humans, follows. About 50% of the tested molecules pass the preclinical tests.

Phases of clinical trials

The time required to conduct a clinical trial can be extremely prolonged, especially when testing a new drug. This is due to the need for caution and the need to carefully consider the peculiarities of the disease and its progression over time. Some diseases have a chronic course with relapses over the years, making it inappropriate and risky to draw hasty conclusions about the effectiveness of a treatment. Additionally, some drug side effects may only manifest after a long period. Therefore, it is sometimes necessary to follow patients for several years.

Clinical trials consist of four phases.

Phase I of clinical trials

Phase I of a clinical trial is dedicated to evaluating the action and safety of the drug under investigation. The drug is administered in progressively increasing doses, starting from the lowest possible dose to a very limited group of individuals, usually less than 80, most of whom are healthy volunteers, except in oncology studies. The main aim of this phase is to investigate the tolerability of the drug, its pharmacokinetics, metabolism, and pharmacodynamics. It seeks to identify any side effects that may not have been evident during preclinical studies conducted on cells and laboratory animals, to determine the maximum tolerated dose.

It is important to note that Phase I is primarily aimed at obtaining knowledge and not at therapeutic purposes. It provides crucial information to establish analogies and differences with the data obtained during preclinical studies, offering indications on future therapeutic activity and the appropriate dosage for human use. Phase I typically lasts about 1-2 years. If the results of this phase are positive and the drug is considered safe, the Ministry of Health and Regulatory Health Authorities may authorize the transition to Phase II, involving a larger sample of people. About 70% of drugs successfully pass this initial testing phase.

Phase II of clinical trials

Phase II of clinical trials is dedicated to evaluating the effectiveness of the drug and its short-term side effects. During this phase, a larger group of people is involved compared to Phase I, primarily consisting of patients rather than healthy volunteers. The molecule is administered for the first time to the subjects for whom it was formulated. The number of participants can range from about 25 to 300, depending on the frequency of the pathology being studied.

The primary objective of this phase is to establish the minimum dose of the drug that has therapeutic activity against a particular disease. About 33% of drugs pass this phase and advance to the next one. The results obtained from Phase II studies are submitted to global health authorities for approval for commercialization. It is important to note that there is a risk in this phase that drugs with high therapeutic potential but intended for a small number of patients with rare conditions, known as orphan drugs, may be discontinued in the commercialization process.

Phase III of clinical trials

During Phase III of clinical trials, the evaluation of side effects and the risk/benefit ratio is carried out. Additionally, the molecule is compared with other standard therapies (or placebo if no treatment exists) to demonstrate and confirm the superiority of the new treatment over previous therapies. Different dosing regimens are also tested for commercialization, and potential interactions with other drugs are analyzed.

In Phase III studies, the effectiveness and safety of the treatment are evaluated on a large scale, involving a variable number of patients between 1000 and 3000. The selection of patients is extremely rigorous, aiming to ensure they are representative of the population affected by the disease, identifying the type of patient most suitable for the treatment, and excluding at-risk subgroups. These studies are usually conducted simultaneously at multiple sites, often internationally, in academic or hospital settings, following rigorous protocols. Phase III typically lasts 4-5 years. About 25% of drugs successfully pass this phase. The company that developed the drug can then apply for marketing authorization from competent authorities, such as the EMA for Europe. Subsequently, in Italy, the AIFA will evaluate whether the authorized drug can be reimbursed by the National Health Service.

Phase IV of clinical trials

Phase IV of clinical trials consists of monitoring the drug after its commercialization. Some side effects, even severe ones, may only manifest when the drug is taken by a large number of people in everyday practice. Therefore, it is crucial to continue monitoring the treatment by collecting information on the drugs and their potential long-term side effects. This phase is commonly known as pharmacovigilance and is essential for promptly identifying any problems related to the use of the drug and taking necessary measures to ensure public safety.

Types of clinical trials

There are two main types of clinical trials:

Experimental studies. Also known as interventional studies or clinical trials. These studies aim to test the effectiveness and safety of a therapy through specific tests. Participants are required to take a particular treatment following precise rules.
Observational studies. As the name suggests, these studies focus on long-term observation of diseases, exposure to a particular substance, or lifestyle to identify the benefit/risk ratio or potential improvement solutions. These studies are divided into:
Prospective studies. The patients involved are followed throughout the study to evaluate the intervention.
Retrospective studies. Events that occurred before the start of the study are investigated.

Additionally, based on the type of clinical question being investigated, there are the following types of clinical studies:

Prevention studies. Useful for researching the best way to prevent a certain disease in healthy people or to prevent the disease from recurring.
Screening studies. Essential for investigating the best way to detect certain diseases.
- Diagnostic studies. Conducted to find which tests or procedures are best for diagnosing a particular disease or condition.
- Treatment studies. Conducted to investigate the safety and effectiveness of a new treatment, or surgical/radiotherapy procedure, for a specific disease or condition.

Who participates in a clinical trial?

A clinical trial consists of:

volunteer patients (or healthy volunteers for the first phase of clinical trials);
the research team consisting of doctors, nurses, and other healthcare professionals;
experts in statistics, data analysis, and informatics to analyze study results;
the sponsor who funds the study.

A clinical trial can take place in hospitals, clinics, medical centers, universities.

The clinical trials sponsor

Clinical trials can be funded by various sources, including pharmaceutical industries, foundations, scientific societies, and voluntary groups such as patient associations. Studies funded by research institutions or receiving public funding are called independent. Participation in this type of clinical trial can offer benefits such as evaluating long-term risks or rare adverse effects of treatments, comparing different therapeutic options, and verifying improvements in daily life.

However, many clinical trials are sponsored by the pharmaceutical industry and aim to demonstrate the efficacy and safety of new treatments for regulatory approval. Knowing who funds a clinical trial is essential to understand the study’s objectives and make informed decisions. Conflicts of interest can arise when researchers receive financial compensation from pharmaceutical companies interested in the ongoing study. These conflicts should be declared and carefully evaluated to ensure the objectivity and integrity of the clinical trial.

What is a Study Protocol?

Clinical trials result from a complex organization involving various professionals and require careful coordination between research teams at national and international levels. Before the study begins, a plan, known as a study protocol, is defined. This protocol details all aspects of the study, including

research purposes and objectives;
valutation criteria;
inclusion and exclusion criteria for patient selection;
the clinical test e their frequency;
the therapeutic plan, that is the modalities and the administration period of the experimental drug;
the involved centres.

This protocol provides detailed guidelines for all aspects of the study, ensuring rigorous standardization and allowing for an accurate evaluation of the results obtained.

Who undergoes clinical trials

Clinical studies involve voluntary patients who are carefully informed about the type of experimentation they will undergo. Depending on the nature of the study, volunteers may be individuals with specific conditions or certain characteristics.

In the initial phase of studies on a new drug, aimed at examining potential toxicity and identifying the maximum tolerable dose, healthy volunteers without pre-existing medical conditions may also be involved. However, for ethical reasons, healthy volunteers will not be administered treatments that could be toxic, such as oncological drugs.

Conditions indicating the reliability of a study

A clinical study is considered reliable when it is controlled, randomized, and at least double-blinded. The presence of all these conditions ensures the study’s rigor.

Controlled study

A controlled study involves dividing patients into two distinct groups. One group will receive the experimental treatment, while the other group will receive standard treatment or a placebo, which is a formulation without an active ingredient. The second group is termed the control group. All other conditions of the study, including examinations and clinical checks, will be uniform for all volunteers. This approach makes it easier to identify differences caused by the type of treatment administered, thus ensuring an accurate comparison between the two groups.

Randomized clinical study

In randomized clinical studies, two types of drugs are compared. Therefore, participants are divided into two distinct groups, and each group is assigned one of the two drugs under study. This assignment occurs randomly to avoid any interference in the results and to ensure that there is no bias in the selection of treatments. This way, each participant has an equal chance of receiving the experimental treatment.

Randomized clinical trials represent the gold standard in clinical research, especially when evaluating the effectiveness of an innovative treatment. However, it is not always possible to conduct a randomized clinical study due to factors such as financial issues, lengthy timelines, or ethical reasons.

Blind or masked study

A clinical study is masked when it is not known which drug a particular patient is taking. The masking conditions can vary:

Single-blind or single-masked study: the patient does not know which of the comparison drugs they are taking and may receive a placebo.
Double-blind or double-masked study: neither the patient nor the doctor knows which treatment is being administered.
Triple-blind or triple-masked study: in addition to the patient and the doctor, the data analyst is also unaware of the patient’s group assignment, ensuring an impartial assessment of the results.

Masking is essential to prevent influences on the judgment of results, ensuring that observations of both negative and positive treatment effects are objective.

If all treatment information is known, the study is referred to as open-label.

Characteristics of a reliable clinical study

The characteristics of a reliable clinical study are fundamental to ensuring the integrity of the research and the safety of the participants. In summary, these characteristics include:

Ethics: The clinical study must be designed and conducted with the aim of improving and innovating in the treatment of medical conditions. All decisions made during the study must be guided by ethical principles that prioritize the well-being of the participants.
Independence: The study must be independent and free from conflicts of interest. It must solely address the needs and safety of the participating patients and must not be influenced by commercial, academic, or career interests.
Transparency: All research results must be made public and accessible. This includes not only positive results but also negative or neutral ones. Transparency is essential to ensure that the scientific community and the public can accurately assess the study results.
Approval: The clinical study must be pre-approved by an independent ethics committee. Additionally, participants in the study must be aware of the risks and benefits of the study and must provide their informed consent before participating.

Before initiating a clinical study, it is important to carefully evaluate whether there is a real need for research, whether there is uncertainty about the effectiveness of the new treatment compared to existing ones, and whether the study design is adequate to address specific research questions. This pre-evaluation helps ensure that the study is scientifically valid and ethically acceptable.

The risks of participating in a clinical study

Participating in a clinical study can entail some risks that are crucial to fully understand before making a decision. Among the main risks is the fact that desired treatment outcomes cannot be guaranteed, and in a randomized study, the patient cannot choose which treatment to receive. Additionally, it may be necessary to commit a significant amount of time to visits, tests, and hospital stays, and there may be exposure to unknown risks since the new treatment has not been extensively tested and some adverse effects may not have been identified yet.

However, it is important to remember that clinical studies are conducted and supervised by highly qualified doctors at centers of excellence. Patients are carefully monitored and undergo regular follow-up visits to promptly identify any complications or side effects.

The benefits of participating in a clinical study

Clinical studies represent a crucial decision for those affected by an illness. Participating in a clinical study can mean gaining access to innovative and potentially effective therapies for one’s medical condition. Additionally, the patient involved in the study undergoes regular visits and tests, ensuring constant monitoring of the disease and their health status.

Another important aspect not to be overlooked is that participating in a clinical study involves actively contributing to the development of fundamental knowledge that can improve the daily fight against human diseases. Personal contribution to medical research can not only bring direct benefits to the participating patient but can also positively influence the future treatment of patients with similar conditions worldwide. It is an act of altruism and solidarity that can have a significant impact on the health of many people.

How to participate to a clinical study

Participating in a clinical study typically starts with a recommendation from the treating physician, who provides the patient with all possible information through a written document called an informed consent form. This document describes in detail the study’s objectives, the planned tests and checks, possible side effects, benefits, and risks. It is up to the patient to decide whether or not to participate in the study, and signing the informed consent form is not binding to conclude the trial: at any time, a volunteer can suspend their participation in the study.

Increasingly, especially abroad, patients themselves, individually or through patient associations, actively seek clinical trials related to their disease, often via the internet. For this purpose, public registries of clinical studies have been created, online databases developed by research centers, scientific associations, and government agencies, listing ongoing or upcoming trials for a specific disease or condition.

Who takes care of the patient during the clinical trial?

During a clinical trial, the patient is entrusted to experienced and competent medical and paramedical staff within authorized hospital facilities, university research centres, or private institutions. This team will take care of the patient throughout the duration of the clinical trial, also requiring their active collaboration. For example, the patient may be asked to keep a diary to record specific data or any symptoms experienced during the trial. They may also be requested to complete questionnaires or provide regular feedback on their health status and the treatments received. The medical staff, on their part, will need to record any adverse events in specific safety databases, such as SafetyDrugs, in order to analyze their progression and evaluate the safety of the experimental therapy.

Furthermore, the medical team will continue to follow up with the patient even after the conclusion of the clinical trial, providing continuous assistance and support. Physicians, nurses, and other professionals involved in the study will be available to provide clarification and assistance at any time, both during and after the clinical trial, to both the patient and their family.

The period of observation during which the patient undergoes clinical and diagnostic tests is called the follow-up. This observation period allows for the evaluation of the effectiveness of the experimental treatment over time.

Laws and guidelines for patient protection in clinical trials

To ensure the protection of patients participating in clinical trials, various international and national laws, as well as ethical codes, have been enacted. Among these important regulations, we find:

The Helsinki Declaration. This document lists the fundamental ethical principles that must be respected in medical research involving human subjects. The Declaration emphasizes the principle of informed consent, the need to maximize benefits and minimize harm to patients, and the importance of independent and ethically approved review of clinical trials.
The Oviedo Convention. This Council of Europe convention establishes rules and principles regarding human rights and human dignity in medical and biological practices, including free and informed consent and the protection of patients’ personal data.
Good Clinical Practice (GCP). These are international guidelines that define standards for the design, conduct, recording, and reporting of clinical studies involving human subjects. GCP focuses on ethics, scientific quality, and participant safety in clinical trials.

These regulations and guidelines provide an ethical and legal framework for the conduct of clinical trials, ensuring that patients are treated respectfully, their rights are protected, and the information obtained from the studies is reliable and valid.

The role of the Ethics Committee

The role of the Ethics Committee is crucial in ensuring the protection of patients involved in clinical trials. This independent body is composed of a variety of qualified professionals, including physicians, patient representatives, ethics experts, pharmacologists, and statisticians, who carefully evaluate every aspect of the clinical study.

The Ethics Committee meticulously reviews all documents related to the study, including data collection forms, informed consent, and data privacy policies. Its primary priority is to protect the rights, safety, and well-being of study participants, and this consideration must prevail over any other interests, including those of science and society.

Depending on the assessment, the Ethics Committee may provide a favorable, unfavorable, or suspensive opinion. It may also request modifications to the study protocols to ensure greater patient protection. Obtaining the favorable opinion of the Ethics Committee is an essential requirement for initiating a clinical trial, confirming that ethical standards and patient safety have been adequately considered and respected.

In which ways is the patient actively protected?

The patient in a clinical trial is protected in several ways. Firstly, protocol approval is required: a clinical trial cannot include patients if the protocol has not been approved by the competent authorities and the Ethics Committee.

Moreover, before deciding whether to participate or not, the patient will be provided with all the information about the study in writing in the informed consent. Once the informed consent is signed, researchers are obliged to follow it scrupulously. The patient has the right to contact the Ethics Committee for any doubts or concerns and can withdraw from the study whenever they want.

Also, in terms of privacy, the patient is protected. Data will remain confidential and will not be included in the clinical trial report.

Lastly, the sponsor of the clinical trial is required to provide insurance to patients in case of adverse events.

Roles in clinical trials in Italy

Clinical research in Italy involves various actors, each with specific and complementary roles.

AIFA, the Italian national competent authority. Responsible for authorizing clinical trials and amendments to various phases. It plays a coordinating and directing role on all aspects related to experimental drugs, including safety and efficacy monitoring.

ISS, the Italian national Institute of Health. Provides advisory opinions on clinical trials, especially for phase I trials. It contributes to the scientific evaluation and approval of clinical trials, ensuring special attention to participant safety.

Ethics Committees. Operate within healthcare facilities where clinical trials take place. They assess the ethical merit of studies, ensuring they conform to good clinical practice standards and respect the rights and well-being of participants.

General directorates of healthcare facilities. Responsible for defining contracts and administrative management of clinical trials within healthcare facilities.

Promoters and Researchers. Directly involved in the organization and conduct of individual clinical trials. They are responsible for study design, data collection and analysis, and communication of results.

EMA with its EudraVigilance database. Handles reports of serious and unexpected adverse reactions (SUSARs) during the conduct of clinical trials. It contributes to monitoring the safety of experimental drugs.

Promoting awareness of clinical trials: the ECRAN project

The ECRAN (European Communication on Research Awareness Needs) project is a European Union initiative aimed at promoting knowledge and awareness of medical research among European citizens and making it more accessible and understandable. To achieve these goals, ECRAN has developed a series of educational and informational materials available in 23 European languages. These materials include a website, FAQs, and other educational content. All these tools are designed to provide clear and accessible explanations of both basic and advanced concepts in medical research, overcoming linguistic and cultural barriers.

Furthermore, ECRAN is committed to providing accurate and objective information about the benefits and risks of clinical trials, encouraging informed and aware participation by citizens. Through awareness-raising and education, the project aims to actively engage European citizens in medical research, thus promoting health and societal well-being.

International Clinical Trials Day

May 20th is International Clinical Trials Day. It is an important initiative aimed at raising public awareness of the importance of clinical research in promoting health and improving disease treatments. This day offers an opportunity to reflect on the challenges and opportunities of clinical research and to celebrate the progress made through clinical trials. For more information and to participate in International Clinical Trials Day initiatives, visit the official website.