A clinical study or a clinical trial is generally medical research, which requires the participation of volunteers, either healthy or sick, to analyze, identify and develop new therapeutic interventions aimed at the prevention, diagnosis, and treatment of diseases. Such clinical trials help in determining which approach works better to reach the endpoint of the study (with the endpoint being for example patient survival, disease-free survival or others, depending on the study). In addition, they might also help in detecting and defining which molecular, biological and/or clinical parameters (biomarkers) might predict response or toxicity of the existing and novel treatments in clinical practice.
Trials can be divided into two categories.
1. Observational Studies (Prospective or Retrospective)
- To describe the causes and consequences of diseases
- To identify factors that affect disease progression
- To assess the impact of diseases or conditions
2. Experimental Studies (Always Prospective):
- To identify new diagnostic and therapeutic strategies
Clinical trials, although complex, include only patients who agree to the terms of the study and sign an informed consent declaration following a detailed session of explanations by the study medical referents. Once enrolled in a trial, patients receive additional clinical visits, along with the routine assessments performed for standard treatment. The team following the patients and routine assessments provides information on the next steps and possible side effects. The attention to the safety of patients enrolled in these studies begins right at their enrolment as in fact the bodies in charge of granting the authorization for the implementation of a clinical study (e.g. FDA) do not only intervene in approving the trial but also examine and approve every single step of the entire process.
In light of the principles of personalized medicine, it is therefore very important to correctly select the subjects to be evaluated. One limitation of these studies is the fact that they are usually conducted on a quite homogenous sample patient population, which does not always reflect the complexity of the general population eventually receiving the treatment (e.g. comorbidity, advanced age, additional treatments, performance status, etc.).
It means that patients selected in clinical trials rarely mirror the general population of patients who should benefit of the treatment ― if approved in clinical practice ― as in fact patients in clinical trials are oftentimes fitter and with no comorbidities (rare event especially in the elderly population) and this affects the outcome of the trial. Therefore, the results must always be confirmed in the real-world setting.
Most clinical trials require approval by an Ethics Committee that hospitals and research centers have (Single Regional Committee) which evaluates the study and all related documents, like data collection, informed consent forms, and data privacy notes.
As per the European Regulation issued in 2014, the only exceptions are retrospective studies and studies that that do not involve active interventions on the subjects enrolled and are based only on the collection of clinical and biological data. In this case, the investigator informs the Ethics Committee which will acknowledge the issue.
It is also necessary that the process is carried out in compliance with the Declaration of Helsinki, the Oviedo Convention, the Guidelines of Good Clinical Practice (GCP), as well as with the national and international guidelines and recommendations.
A clinical study is therefore based on:
- Freedom, it should be performed in the interest of patients who participate voluntarily and not because of commercial, academic, or career interests.
- Disclosure of any conflict of interest.
- Transparency, all research results must be public and accessible.
- Approval by the Ethics Committee and approval of the participant who must be adequately informed before signing the consent.
Experimentation takes place in four phases:
PHASE 1: First evaluation of safety, toxicity and biological activity (phase Ib) of the drug or treatment plan to be tested. The endpoints of the study are the identification of the Maximum Tolerated Dose (MTD) and the Most Effective Biological Dose (MEBD). The population of the study is generally small and heterogeneous.
PHASE 2: Evaluation of disease response to the experimental treatment. Activity is the endpoint. The study population should be homogeneous and large. A control arm is not required.
PHASE 3: Evaluation of the efficacy of the experimental treatment versus the standard treatment (or control arm); Endpoint is efficacy that is superiority over the standard treatment for the disease. A large number of patients is generally involved in this phase, the population is very homogeneous and a standard-of-care control arm (best standard treatment available) is always necessary. Patients in the control arm can also receive either standard treatment or the so-called placebo (a preparation without any active ingredient) but this choice raises ethical and scientific concerns.
Patients are included into the intervention or control arm by special software (randomization).
PHASE 4: Evaluation of the drug that has been placed on the market with the aim of identifying any undesirable effects. The population must be heterogeneous and in real world.
Hence, well-conceived clinical trials represent the paramount groundwork for developing evidence-based medicine practice. Ideally, practice should be based on the best results obtained through the best designed clinical trials.
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