Ethics and Pharmacovigilance activities in clinical trials: Differences between regulation and reality

Introduction: In clinical trials (CT), patient safety is a major concern for investigator, sponsor, and authorities, as well as the respect of fundamental rights of patients, under the control of the ethic committees (EC). How the ethical considerations interact with pharmacovigilance (PV) activities is a question of interest. Material and methods: The PV activities are detailed in the European and French regulations and guidelines. A literature review was conducted to understand the role and missions of the EC concerning the PV. The structures involved in this process have been identified: sponsor of PV team, members of ethics committees and safety board. An analysis of the ethical dimension of each PV activity in the real life in an institutional environment was performed, compared to the legal requirements. EC experts, lawyers and pharmacovigilants were interviewed. Ethical difficulties observed in CT are presented. Results: Ethical principles, with respect of autonomy, beneficence, least harm and justice have a place in activities performed before and after the beginning of a clinical trial: identification of expected risks, patient's information, collection and analysis of AE, redaction of safety report, signal detection and alert. EC members and PV experts highlighted differences between regulation and reality. Lack of time and staff dedicated to PV activities are the causes of the difficulties encountered in both the institutional teams and the EC in applying the regulations. The answers of the structures dedicated to help the PV team to act for safety and for patient's interest are often too slow to be effective. The PV decisions strongly impact the patients as illustrated by three studies: in premature infants with targeted reporting due to frequency and complexity of complications, in transplantation and hematology, detailing how the quality of the analysis may affect the future of CT. Discussion/Conclusion: Ethical principles and regulations frame the PV activities, but the effect of these important safety barriers could be reduced by technical and practical difficulties. The main risk is minimizing the patient's interest, but inappropriate safety results could also conduct to a premature discontinuation of CT, delaying the patient's access to innovative treatment. The recognition of the PV main role, the need of scientific and ethical qualified assistance are required. For both PV and EC, adapted procedures and appropriate resources are therefore necessary, for both PV and EC missions, given their impact on patients.