Drug-induced Disaster Due to IRESSA
Masato Sekighchi

1. What is IRESSA?
IRESSA is an anticancer drug indicated for unresectable or recurrent
non-small cell lung cancer. Developed as a molecularly targeted drug witha mechanism of action that differs from conventional cytotoxic anticancer
agents, IRESSA was rapidly approved on July 5, 2002 after anextraordinarily short period of only about 6 months after the submission of
the approval application. This approval, complying with the guideline atthat time, was granted based on the data up to Phase II clinical trials
obtained at the time of application, with the condition that Phase III
clinical trials should be executed to confirm the survival benefit after itsapproval.
2. Occurrence of suffering due to adverse reactions
Starting immediately after the approval of IRESSA, there were multiple
cases of adverse reactions of serious interstitial pneumonia and acute lungdisorder, and an Urgent Safety Information Report was issued on Oct. 15,
2002, a mere 3 months after approval. Cases of the lung disorder continuedto occur thereafter; as of September 2009, there had been 799 deaths
reported due to adverse reactions. This number of deaths is unbelievably
high compared to the past anticancer drugs.
3. Error in evaluation at the examination stage
This issue of suffering due to adverse reactions to IRESSA was not
unpredictable. Even at the time of the approval examination process, there
had been 20 cases recognized by the government. Moreover, 9 of those
events were deaths, representing a high mortality rate. The Ministry of
Health, Labour and Welfare was also aware of the occurrence of interstitial
pneumonia. However, they focused on that disease name and failed to look
into the symptom of the cases, thus ended up overlooking many otherevents that had been reported under different disease names. They also
neglected events that occurred outside of clinical trials, and thus ended up
underestimating the risk associated with IRESSA.

- 1 -4. Efficacy
The many cases of adverse reactions were not the only problem
surrounding IRESSA. After the approval of the drug, four overseas clinical
trials failed one after another to prove the survival benefit of IRESSA. On
the basis of these results, the US FDA prohibited, in principle, theadministration of IRESSA to new patients, while in the EU, AstraZeneca
itself withdrew its approval application. In contrast, in Japan, although adomestic Phase III clinical trial (V1532) carried out as a condition forapproval failed to prove the survival benefit of IRESSA, no review of thecontents of the approval of IRESSA was performed. This shows theproblems associated with accelerated approval with certain approvalconditions.
5. Promotional Advertising
Behind the ballooning problems surrounding IRESSA lies AstraZeneca’s
clever marketing strategy. AstraZeneca-sponsored articles were publishedin medical journals, and specialists heaped praise on IRESSA. Press
releases from AstraZeneca emphasized the efficacy and safety of IRESSA,
and numerous articles appeared in newspapers and other mass media,introducing IRESSA as a novel anticancer drug with few adverse reactions.
None of these articles touched upon the fact that there had been cases offatal interstitial pneumonia as an adverse reaction prior to approval of thedrug. This sort of reporting began even before IRESSA had been
approved—AstraZeneca was able to circumvent the strict regulations
regarding advertising for ethical drugs, and the company succeeded increating an image of IRESSA as an innovative drug with few adversereactions.
6. Inadequate warning statements
The initial version of the package insert for IRESSA did not include a“Warnings” column. Moreover, although there was a statement regarding
interstitial pneumonia in the “Clinically Significant Adverse Reactions”
column, it was not clearly stated that this adverse reaction could belife-threatening, or that deaths had actually occurred. This type ofstatement was completely insufficient as a warning of fatal risk, and the- 2 -image of IRESSA as a “safe drug” that had been created by AstraZeneca’s
marketing strategy clearly prevailed in the minds of physicians andpatients.
7. Conflict of interest
Specialists who recommended IRESSA in various media played a large rolein the creation of the image of IRESSA as an “innovative drug.” Many ofthese specialists had economic ties with AstraZeneca, receiving speaking
fees, donations, or honoraria for participating in the IRESSA clinical trials
or cooperating in research.
8. Lawsuits regarding drug-induced suffering due to IRESSA
Lawsuits regarding drug-induced disaster due to IRESSA were initiated in
2004 in the Osaka District Court and the Tokyo District Court, and they
will be concluded on July 30 in the Osaka District Court and on August 25
in the Tokyo District Court. Prior to that, the plaintiffs formed a unified
plaintiffs’ group in March and have strengthened the movement andpresented demands for an overall settlement including the following 5elements: (1) an apology, (2) compensation, (3) review of the approval ofIRESSA, (4) establishment of a relief system for deaths and injury due toadverse reactions to anticancer drugs, and (5) verification and preventionof recurrence.

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