Title:Phase IV Studies: Some Insights, Clarifications, and Issues
Volume: 13
Issue: 1
Author(s): Bruno Mario Cesana and Elia Mario Biganzoli*
Affiliation:
- Department of Clinical Sciences and Community Health, Unit of Medical Statistics, Biometry and Bioinformatics "Giulio A. Maccacaro", Faculty of Medicine and Surgery, University of Milano, Milano,Italy
Keywords:
Phase IV, FDA and EMA guidelines, post-authorization drug safety, post-authorization drug efficacy, ethics committees,
explanatory trials and pragmatic trials, health technology assessment (HTA).
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.
