Phase IV Studies: Some Insights, Clarifications, and Issues

Abstract

Background: There is an increasing need to face regulatory aspects as well as ethics and scientific ones in the pharmaceutical research phase after the authorization of a drug. Traditionally, Phase IV studies, after the authorization of a drug to be marketed by the Competent Authority like the Food and Drug Administration (FDA) (in Europe, European Medicine Agency - EMA- through National Procedures or Community Procedures) have been considered mainly aimed to the assessment of the new drug safety profile. However, the sample size calculation for such aim is still an open issue. Moreover, the benefit/risk assessment is a compelling global need.

Methods: This editorial aims to give a fairly exhaustive overview of the main topics currently present in the pharmaceutical research phase after the authorization of a drug. FDA and EMA guidelines are considered under a comparative perspective with a focus on the perspective of "Post Authorization Safety Studies (PASS)" and "Post Authorization Efficacy Studies (PAES)" with critical considerations. Then, the approach of "Explanatory Trials" and "Pragmatic Trials" is proposed under the horizon of Health Technology Assessment (HTA).

Conclusion: Critical remarks are raised against the pure commercial perspective in the proposal of PASS and PAES and on the design of registries which should be planned with relevant objectives to be pursued by appropriate statistical analyses reported in the Statistical Analysis Plan (SAP) of the study protocol. Finally, a particular focus is placed on the work of the Ethical Committees regarding the approval of the observational studies on the safety and the efficacy of the drugs in their pragmatic clinical use.

Keywords: FDA and EMA guidelines; Phase IV; ethics committees; explanatory trials and pragmatic trials; health technology assessment (HTA); post-authorization drug efficacy; post-authorization drug safety..