Characteristics of safety information obtained from postmarketing observational studies for re-examination in Japan

Abstract

Background: In Japan, postmarketing surveillance (PMS) studies are required for newly approved drug products to further collect safety information in clinical settings. "PMS study" is a general term encompassing both postmarketing observational (PMO) studies and postmarketing intervention studies for re-examination. Each PMS study is conducted under contracts between the pharmaceutical company and medical institutions in accordance with Good Postmarketing Study Practice. It has been reported that the safety information collected postmarketing is limited because of underreporting. The objective of this investigation was to identify differences among profiles of the drug product safety information collected through intervention studies and observational studies before and after approval. Our study addressed whether the issue of underreporting, generally considered as associated with observational studies, occurs in PMO studies for re-examination. In addition, we considered potential causes of such underreporting.

Results: The overall adverse reaction rate was lower in PMO studies than in intervention studies before approval in almost all cases. The adverse reaction rate in intervention studies exhibited similar profiles regardless of whether they were conducted prior to or following approval. In addition, we found that one reason for a lower adverse reaction rate in PMO studies was that the number of reports of adverse reactions that had occurred frequently prior to approval decreased postmarketing.

Conclusions: Underreporting was observed even in PMO studies for re-examination under the Japanese regulation. Although it was suggested that expected and common adverse reactions were more likely to be subject to underreporting, further investigation is warranted to explore the reasons for the under-reporting in PMO studies.

Keywords: Package insert; Pharmacovigilance; Postmarketing surveillance; Re-examination; Safety.

Fig. 1

Scatter plot of the adverse reaction rate in clinical studies for NDA (ARR-NDA) and the adverse reaction rate in PMO studies for re-examination (ARR-PMO) (176 drug products, 206 sets). Vertical axis ARR-NDA adverse reaction rate in clinical studies for NDA. Horizontal axis ARR-PMO adverse reaction rate in postmarketing observational studies for re-examination

Fig. 2

Scatter plot of the adverse reaction rate in clinical studies for NDA (ARR-NDA) and the adverse reaction rate in PMI studies (ARR-PMI) (45 drug products, 48 sets). Vertical axis ARR-NDA adverse reaction rate in clinical studies for NDA. Horizontal axis ARR-PMI adverse reaction rate in postmarketing intervention studies

Fig. 3

Relationship between: the difference of incidence rate of the most common adverse reaction in clinical studies for NDA and that in PMO studies; and the difference of the overall adverse reaction rate in clinical studies for NDA and that in PMO studies (162 drug products, 192 sets). Vertical axis difference of the overall adverse reaction rate in clinical studies for NDA and that in PMO studies for re-examination (ARR-NDA–ARR-PMO). Horizontal axis difference of incidence rate of the most common adverse reaction in clinical studies for NDA and that in PMO studies for re-examination