Lessons from gefitinib-induced interstitial lung disease in Japan: Problems in approval, pharmacovigilance, and regulatory decision-making procedures

Abstract

Objective: The objective of this study was to identify problems in the approval, pharmacovigilance, and post-approval regulatory decision-making procedures involving gefitinib and to propose countermeasures to prevent further drug-induced suffering in Japan in the future.

Methods: We comprehensively reviewed reports regarding gefitinib published during the period from 2000 to 2006 by regulatory agencies, the manufacturer of the gefitinib-containing drug, cancer clinical study groups, and a scientific society.

Results: We identified the following major problems in the approval, pharmacovigilance, and regulatory decision-making procedures: 1) the results of animal experiments and pre-marketing clinical trials, and reports of adverse drug reactions from other countries were not properly reflected in the label; 2) indications for the drug were expanded without strict evaluation of the external validity of pre-marketing clinical trials; and 3) despite many serious cases of interstitial lung disease (ILD) being spontaneously reported, well-designed post-marketing surveillance was not immediately performed.

Conclusions: We propose a mandatory total registry of all drug users and surveillance (i.e. a prospective outcome study) as one of the rational solutions for preventing further drug-induced suffering in Japan.

Keywords: Decision making; Gefitinib; Japan; Lung diseases; Product surveillance; interstitial; organizational; postmarketing.

Figure 1

Frequency of cases of ILD and ILD-related deaths on a monthly basis after approval of gefitinib. (^†The West Japan Thoracic Oncology Group; ^††The Okayama Lung Cancer Study Group; ^†††The Japan-Multinational Trial Organization