Gefitinib-Induced Suffering

1. Emergence as a “breakthrough” cancer drug

Iressa® (Gefitinib) is a molecularly targeted anticancer agent developed for advanced lung cancer. Unlike conventional chemotherapy, it acts selectively on molecular pathways driving tumor growth. Although developed overseas, Japan approved it in July 2002 through a “priority review,” becoming the first country in the world to authorize its use—even before approval abroad. This accelerated process was partly intended to address Japan’s so-called “drug lag,” the delay in introducing new medicines compared with other countries. The drug was widely publicized as a “dream therapy”—effective, orally administered once daily, suitable for outpatient use, and supposedly mild in side effects. For patients facing terminal illness, it was a beacon of hope. Doctors prescribed it even during the interim before public insurance coverage was finalized, and some patients used it at home without close clinical supervision. However, as use spread, numerous reports of acute lung injury and interstitial pneumonia associated with Iressa® reached the Ministry of Health, Labour and Welfare (MHLW). In October 2002—only months after approval—the Ministry ordered AstraZeneca (the pharmaceutical company) to issue an “emergency safety information” and revise the package insert. Nevertheless, deaths continued. In December 2002, the Ministry convened the Gefitinib Investigative Committee and required additional revisions, mandating informed consent regarding potential adverse effects and close monitoring during treatment. Although these measures gradually reduced new deaths, by March 2010, there had been 1,916 reported cases of interstitial lung disease and 734 deaths linked to Iressa®. Meanwhile, an international clinical trial found no statistically significant survival difference between patients receiving Iressa® and those receiving placebo, leading the European Union to withdraw the drug’s marketing authorization in 2005.

2. Litigation and the backlash from medical and governmental circles

In 2004, families of deceased patients filed lawsuits in Osaka and Tokyo District Courts, seeking to hold both the government and AstraZeneca accountable for approving and marketing an unsafe drug. The Gefitinib drug-induced suffering lawsuit raised issues different from those in earlier drug-induced suffering cases: how to assess severe adverse effects in critically ill cancer patients when some patients were still benefiting from the drug, which remained on the market? In 2011, both district courts issued mediation proposals recognizing the responsibility of the government and AstraZeneca (the pharmaceutical company) for deaths that occurred before the first safety alert was issued. The plaintiffs accepted the proposal; however, the defendants rejected the settlement. The proposal triggered backlash within the medical community. Some professional associations argued that the ruling could discourage pharmaceutical innovation and restrict access to new drugs. Subsequent investigation revealed that the MHLW itself had prepared internal documents supporting this opposition, exposing collusion between regulators and professional organizations. On appeal, higher courts overturned the earlier decision. They held that the package insert had already listed “important adverse reactions” and that doctors, therefore, should have been aware of the risks, absolving both the government and the pharmaceutical company of liability. The Supreme Court dismissed the plaintiffs’ final appeal, resulting in a complete defeat for the victims.

3. Broader implications for modern drug safety

Although the Iressa® case was not officially recognized by the government as “drug-induced suffering,” it raised the following critical questions that continue resonate today. First, it exposed the risks of approving and distributing new drugs without adequate post-marketing surveillance. Second, it demonstrated that pre-approval clinical data provide only limited knowledge of safety, underscoring the necessity of continuous monitoring of adverse reactions after approval. Third, the case has highlighted the human cost of accelerated approval systems that prioritize access over safety. In 2017, Japan introduced the conditional early authorization system, allowing drugs for rare or life-threatening diseases to be marketed before the completion of clinical trials. While this policy seeks to accelerate access to therapies, it also reopens the ethical challenge highlighted by the Iressa® case: the issue of how to balance the promise of innovation with the responsibility to protect patients from unrecognized risks.

References

1. Doi, Osamu, 2019, 「戦後の薬害事件の概要と教訓」 (https://www.pmrj.jp/publications/02/shiryo_slides/yakugai_shiryo_sengo.pdf).
2. Hanai, Jugo. 2023,「イレッサ薬害――国が薬害と認めない薬害」Hongo, Masatake, and Sato, Akihiko Tetsuhiko (eds.) (2023). 『薬害とはなにか――新しい薬害の社会学』, Minerva Shobo, (ISBN 9784623095292).
3. Association of Victims of Iressa-Induced Suffering, 2020, “Iressa.” (http://hkr.o.oo7.jp/yakugai/forum/forum22-data/Iressa.pdf).
4. The Pharmaceutical and Medical Device Regulatory Science Society of Japan (2012),『知っておきたい薬害の教訓――再発防止を願う被害者からの声』YAKUJI NIPPO, (ISBN 4840812136).
5. The Pharmaceutical and Medical Device Regulatory Science Society of Japan Pharmacopoeia Association (2011), 『知っておきたい薬害の知識』Jiho, (ISBN 4840741743).