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Background: Phase 1 clinical trials represent a critical phase of drug development because new candidate therapeutic agents are tested for the first time on humans. Therefore, international guidelines and local laws have been released to mitigate and control possible risks for human health in agreement with the declaration of Helsinki and the international Good Clinical Practice principles. Despite numerous scientific works characterizing the registered clinical trials on ClinicalTrials.gov, the main features and trends of registered phase 1 clinical trials in Europe have not been investigated. This study is aimed at assessing the features and the temporal trend of distribution of phase 1 clinical studies, carried out in the five largest European countries over a ten-year period (2012-2021), and to evaluate the impact of the Italian regulatory framework on the activation of such studies., Methods: The main data and characteristics of phase 1 clinical studies registered on the ClinicalTrials.gov database for France, Germany, Italy, Spain and the United Kingdom have been investigated and subsequently compared. The above-mentioned countries were selected based on similarities in terms of demographic and Gross Domestic Product (GDP) data available on official government websites. (3) Results: A total number of 6878 phase 1 clinical trials were registered for the five selected countries in the ClinicalTrials.gov database during the ten years analyzed; the studies were predominantly randomized (39.33%) and for-profit (76.64%). The most represented area of investigations was oncology (52.15%), followed by hematology (24.99%) and immunology (12.04%). The variability observed between the analyzed countries showed that the UK, Germany and France presented the highest reduction in the number of phase 1 clinical trials, while for Spain and Italy, a stable/increased trend was observed, although with a lower number of trials registered on the ClinicalTrials.gov database. (4) Conclusions: Italy displayed the lowest number of registered phase 1 clinical trials, even though it showed a stable trend over the years. In this regard, the Italian regulatory framework must urgently be adapted to that of other European countries (Spain has been the first country to implement the new Regulation (EU) No 536/2014) and streamline the process of clinical trial application to increase the attractiveness of the country. Moreover, nonprofit phase 1 clinical trials (which represent 19.81% of the total number of phase 1 clinical trials registered in Italy vs. 80.19% of profit phase 1 clinical studies) should be promoted and supported by the institutions, even from a financial point of view, to allow independent researchers to develop new therapeutic drugs.