Lawsuit over side effects of anticancer drug Iressa

After taking an anticancer drug called Iressa, some lung cancer patients developed interstitial pneumonia and died. Regarding two deaths, surviving family members claimed for damages against the pharmaceutical company which imported and sold Iressa under Article 3 of the Product Liability Act on the ground that Iressa had lacked efficacy and usefulness (a defect in design) and a description of side effects on its package insert had been insufficient (a defect in the instruction or warning). After the appeal was fully rejected by a High Court judge, the surviving family members filed a petition for acceptance of final appeal to the Supreme Court.

The Supreme Court accepted the appeal in respect of determining a defect in the instruction or warning, but rejected in other respects, construing that it could not be said that the description of side effects had been inappropriate (Judgment by the Supreme Court on April 12, 2013 (website of the Supreme Court)).

• Page 53 of Hanrei Jiho No.2189

Summary of the case

Plaintiff / Appellant:

X, etc. (surviving family members of lung cancer patients A and B who died after taking an anticancer drug)

Defendant / Appellee:

Company Y (a pharmaceutical company which imports, manufactures and sells anticancer drugs)

Parties concerned:

A & B (lung cancer patients who died after taking an anticancer drug)
C (Japanese government; a party concerned in the first and second instances / The appeal concerning C was dismissed by the Supreme Court.)

Lung cancer patients A and B developed interstitial pneumonia and died after taking an anticancer drug containing gefitinib as its active ingredient (hereinafter called "Iressa"), which was imported and sold by Company Y with the approval for import from the Minister of Health, Labour and Welfare in 2002. Their surviving family members claimed for damages, asserting the following issues.

1. Against Company Y: Iressa lacked efficacy and usefulness as a pharmaceutical product (a defect in design) and a description of side effects on the package insert was inappropriate (a defect in the instruction or warning) under Article 3 of the Product Liability. The company neglected its duty to provide an appropriate description thereof (tort liability).
2. Against the Japanese government: The Minister of Health, Labour and Welfare granted the approval for import of Iressa and did not exercise regulatory authority after that, which was illegal under Article 1 (1) of the State Redress Act.

In the first instance, the court denied a defect in design of Iressa. With regard to a defect in the instruction or warning, however, the court construed that the first edition of the package insert at the time of import approval and delivery had been defective because there had been no description about interstitial pneumonia as a side effect in a warning section in the first edition of the package insert or in a "serious side effects" section at the top, and that it may produce a fatal case. It was construed that Company Y had recognized and considered that Iressa could have a side effect of causing the same level of interstitial pneumonia as that caused by other anticancer drugs in terms of the frequency of occurrence and the degree of severity, and sometimes could cause a fatal side effect, although Company Y had not assumed that the anticancer drug could cause acute interstitial pneumonia leading to poor prognosis. Moreover, the court recognized that the Minister of Health, Labour and Welfare had not exercised its regulatory authority to correct the insufficient description in the first edition of the package insert after approving the import of Iressa, which was illegal. The court partly affirmed the claim for damages against Company Y as well as the Japanese government.

In the second instance (original judgment), the court denied a defect in design as well as a defect in the instruction or warning on the ground that it had been known among physicians engaged in anticancer therapy that when interstitial pneumonia occurred due to the administration of an anticancer drug, it could lead to a fatal case, so it was hard to construe that the aforementioned physicians had considered that Iressa had no side effect when reading the description in the first edition of the package insert. The court denied liability of Company Y and that of the government.

The plaintiffs were dissatisfied with the original judgment and appealed the case to the Supreme Court. The Supreme Court accepted the appeal in respect of determining a defect by Company Y in the instruction or warning under the Product Liability Act, but did not accept the appeal in other respects.

Reasons

Drugs, due to the nature of being foreign to the human body, are considered to cause some hazardous side effects unavoidably, and the mere existence of side effects of a drug therefore cannot immediately be regarded as meaning that the drug is a defective product. Rather, the safety that a drug ordinarily should provide can be secured by appropriately providing the necessary information for using the drug as a product with regard to the drug's side effects that are foreseeable at the time of its delivery from its ordinarily expected manner of use, and in light of such relation, there may be cases in which the failure to provide such information on side effects appropriately could be a reason for finding a defect in the drug. According to the facts mentioned above, in the case of an ethical drug, such information on side effects should be described appropriately in its package insert.

It is reasonable to construe that whether or not the description in the package insert is appropriate should be judged by taking into consideration various factors concerned, including the details and degree of the side effects (including the frequency of occurrence), the knowledge and skill that the prescriber or user are ordinarily expected to have in light of the effect of the drug, and the format or style by which the side effects are described in the package insert, and then examining whether or not the risk of such foreseeable side effects is sufficiently disclosed to the prescriber or user.

At the time when the approval for import was granted, there was a view that Iressa had a side effect of causing only the same level of interstitial pneumonia as that caused by other anticancer drugs in terms of the frequency of occurrence and the degree of severity. Based on this view, when preparing the first edition of the package insert, Company Y described interstitial pneumonia in the fourth place in the "serious side effects" section of the "precautions for use" section, which was created for the purpose of providing physicians with the necessary information, instead of creating a "warning" section in the package insert and putting this description in this section. When the abovementioned physicians read the relevant description in the first edition of the package insert, they obviously must have had no difficulty in understanding that Iressa had a side effect of causing the same level of interstitial pneumonia as that caused by other anticancer drugs and if patients who are eligible for Iressa develop interstitial pneumonia due to taking this drug, they could lead to fatal cases.

On the other hand, this type of interstitial pneumonia which became severe quickly cannot be regarded as the same level of interstitial pneumonia as that caused by other anticancer drugs as a side effect, nor was it possible to foresee this from the clinical trials conducted before the approval for import was granted. The description in the first edition of the package insert cannot be deemed to be inappropriate only because it did not include such description as that included in the third edition of the package insert, which was prepared and attached to the product three months after the approval for import on the basis of the fact that Iressa had a side effect of causing interstitial pneumonia which could become severe quickly.

There are no circumstances due to which the description in the first edition of the package insert had become inappropriate as a description of a foreseeable side effect during the period after the approval for import was granted and before the abovementioned administration of Iressa was started (August 15, 2002 or September 2, 2002). Then, it follows that Iressa cannot be found to be defective at least in the relationships with A and B.

Explanation

The abovementioned case represents the first judgment by the Supreme Court on the existence or nonexistence of product liability concerning an instruction or warning for an anticancer drug which had been administered to patients of terminal lung cancer. The Supreme Court pointed out that drugs have the nature of causing some hazardous side effects unavoidably, and that the mere existence of side effects of a drug therefore cannot immediately be regarded as meaning that the drug is a defective product. The court construed that the package insert of an ethical drug is required to include necessary information for using the drug with regard to the drug's side effects that are foreseeable at the time of its delivery from its ordinarily expected manner of use, and that whether or not the description in the package insert was appropriate should be judged by taking into consideration various factors concerned, including the details and degree of the side effects, the knowledge and skill that the prescriber or user are ordinarily expected to have in light of the effect of the drug. Therefore, the criterion for judgment was "foreseeability", which was probably a factor for determining a defect. Furthermore, the court denied the product liability of Company Y on the ground that the side effect of "interstitial pneumonia which becomes severe quickly" which was found out after sale of Iressa had not been foreseeable at the time of the approval for import, so it was unable to say that the description on the package insert had been inappropriate. The judgment was accompanied with concurring opinions by four justices. As they mentioned, in order to indicate an instruction or warning on the occurrence of such side effect as alleged by the appellants in the package insert upon the launch of sale, it must be possible at the time of launch of sale to give an instruction or warning and to foresee the occurrence of the side effect. This appears to be the reason for the denial of Company Y's product liability.

Defect liability under the Product Liability Act is not negligence liability, but strict liability^*. Considering the significance of drug efficacy, it might be possible to construe that "a drug had a defect in the instruction or warning" based on lack of description of a side effect in the instruction or warning when the drug generated a serious side effect which should have been described in the instruction or warning if the pharmaceutical company had known it in advance, even if the side effect was unforeseeable for the pharmaceutical company at the time of delivery.

In connection with the foreseeability based on which negligence was determined concerning a description in the instruction or warning, it may be possible to determine the existence or nonexistence of foreseeability based on the state of scientific or technical knowledge at the time when the manufacturer, etc. delivered the product, as stated in Article 4 (i) of the Product Liability, which provides for exemption from liability for damages.

Prior to the action brought to the Tokyo District Court for the first trial, a similar action was brought to the Osaka District Court, as a result of which the court affirmed part of the claim for damages against Company Y and dismissed the claim for damages against the government (reference precedent [3]). The appeal court decision by the Osaka High Court quashed the claim which had been partly affirmed by the Osaka District Court, so completely dismissed the claim for damages (reference precedent [4]). The plaintiffs appealed to the Supreme Court, but the Supreme Court decided to reject the claim for damages against Company Y as well as the government on the day when the above mentioned decision was made by the Supreme Court.

1. ^* Strict liability: liability for damages which legally arises even if there was no intention or negligence in the actions of the people responsible.

Reference precedents

1. Judgment by the Tokyo District Court on March 23, 2011
   (Page 202 of Hanrei Jiho No.2124 (the first instance judgment described on this article))
2. Judgment by the Tokyo High Court on November 15, 2011
   (Page 35 of Hanrei Jiho No.2131 (the second instance judgment described on this article))
3. Judgment by the Osaka District Court on February 25, 2011
   (Page 1132 of Shoumu Geppou Vol.58 No.3 (similar to the case described on this article))
4. Judgment by the Osaka High Court on May 25, 2012
   (Page 740 of Shoumu Geppou Vol.59 No.3)