2013.04.12

2012 (Ju) 293

Minshu Vol. 67, No.4

Judgment concerning the information necessary for securing the "safety that the product ordinarily should provide," as prescribed in Article 2, paragraph (2) of the Product Liability Act, in the case of an ethical drug, and the method of providing such information

Case to seek damages

Judgment of the Third Petty Bench, dismissed

Tokyo High Court, Judgment of November 15, 2011

1. In the case of an ethical drug, in order to secure the "safety that the product (the drug) ordinarily should provide," as prescribed in Article 2, paragraph (2) of the Product Liability Act, the information on the drug's side effects that are foreseeable at the time of its delivery must be described appropriately on its package insert.

2. In the case of an ethical drug, whether or not the information on the drug's side effects as necessary for securing the "safety that the product (the drug) ordinarily should provide," as prescribed in Article 2, paragraph (2) of the Product Liability Act, is described appropriately in the drug's package insert, should be judged by taking into consideration various factors concerned, including the details and degree of the side effects that are foreseeable at the time of the drug's delivery (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.
(There are concurring opinions concerning 1 and 2.)

Article 2, paragraph (2) of the Product Liability Act, Article 52 of the Pharmaceutical Affairs Act, Article 18-4-2 of the Ordinance for Enforcement of the Pharmaceutical Affairs Act (prior to the revision by Ordinance of the Ministry of Health, Labour and Welfare No. 89 of 2003), Article 42, paragraph (1) of the Ordinance for Enforcement of the Pharmaceutical Affairs Act

Product Liability Act
(Definitions)
Article 2
(2) The term "defect" as used in this Act shall mean a lack of safety that the product ordinarily should provide, taking into account the nature of the product, the ordinarily foreseeable manner of use of the product, the time when the manufacturer, etc. delivered the product, and other circumstances concerning the product.

Pharmaceutical Affairs Act
(Matters to Be Described in Package Insert)
Article 52
A drug must be accompanied by a package insert or contained in a container or package which describes the matters set forth in the following items; provided, however, that this shall not apply where otherwise provided for by Ordinance of the Ministry of Health, Labour and Welfare:
(i) the dosage and administration, and any other precautions necessary for using and handling the drug;
(ii) in the case of a drug listed in the Japanese Pharmacopoeia, matters that are required to be described in its package insert or on its container or package under the Japanese Pharmacopoeia;
(iii) in the case of a drug subject to standards established pursuant to Article 42, paragraph (1), matters that are required to be described in its package insert or on its container or package under such standards; and
(iv) in addition to what is set forth in the preceding items, matters specified by Ordinance of the Ministry of Health, Labour and Welfare.

Ordinance for Enforcement of the Pharmaceutical Affairs Act (prior to the revision by Ordinance of the Ministry of Health, Labour and Welfare No. 89 of 2003)
(Drugs Specified by Ordinance of the Ministry of Health, Labour and Welfare)
Article 18-4-2
The drugs prescribed in the second sentence of Article 14, paragraph (3) of the Act (including the cases where applied mutatis mutandis pursuant to paragraph (7) of said Article) shall be the drugs set forth in the following items (excluding drugs intended exclusively to be used in disease diagnosis which are not directly used for the treatment of an animal's or human’s body or which are applied to an animal's or human’s skin, drugs manufactured by a pharmacy operator using the facilities and equipment situated at his/her pharmacy, drugs for which the prefectural governor is to administer the affairs under the authority to approve as provided in Article 15-4 of the Order, and drugs intended exclusively to be used for animals):
(i) drugs whose active ingredients and routes of administration differ from those of drugs listed in the Japanese Pharmacopoeia and drugs for which approval for manufacturing or import has already been granted (excluding new drugs prescribed in Article 14-4, paragraph (1), item (i) of the Act for which the investigation period prescribed in said item (if this period has been extended under paragraph (2) of said Article, the period thus extended) has not yet expired on or after the day on which approval for manufacturing or import was granted, and drugs subject to the instruction given by the Minister of Health, Labour and Welfare as prescribed in paragraph (1), item (ii) of said Article for which the period designated by the Minister of Health, Labour and Welfare as prescribed in said item has not yet expired);
(ii) ethical drugs prescribed in Article 1-5, item (i), (b) of the Order (hereinafter referred to as "ethical drugs") (excluding those set forth in the preceding item).

Ordinance for Enforcement of the Pharmaceutical Affairs Act
(Drugs or Medical Devices for Which Data Are Collected and Compiled According to Standards Set by the Minister of Health, Labour and Welfare)
Article 42
(1) The drugs specified by Ordinance of the Ministry of Health, Labour and Welfare as prescribed in the second sentence of Article 14, paragraph (3) of the Act (including the cases where applied mutatis mutandis pursuant to paragraph (7) of said Article) shall be the drugs set forth in the following items (excluding drugs intended exclusively to be used in disease diagnosis which are not directly used for the treatment of an animal's or human’s body or which are applied to an animal's or human’s skin, drugs manufactured and sold at a pharmacy, drugs for which the prefectural governor is to administer the affairs under the authority to approve as provided in Article 80 of the Order, and drugs intended exclusively to be used for animals):
(i) drugs whose active ingredients and routes of administration differ from those of drugs listed in the Japanese Pharmacopoeia and drugs for which approval for manufacturing and sale has already been granted (excluding new drugs prescribed in Article 14-4, paragraph (1), item (i) of the Act for which the investigation period prescribed in said item (if this period has been extended under paragraph (2) of said Article, the period thus extended) has not yet expired on or after the day on which approval for manufacturing and sale was granted, and drugs subject to the instruction given by the Minister of Health, Labour and Welfare as prescribed in paragraph (1), item (ii) of said Article for which the period designated by the Minister of Health, Labour and Welfare as prescribed in said item has not yet expired);
(ii) drugs specified by the Minister of Health, Labour and Welfare as ethical drugs (hereinafter referred to as "ethical drugs"), except for those set forth in the preceding item.

The final appeal is dismissed.
The appellants of final appeal shall bear the cost of the final appeal.

Concerning Chapter III of the reasons for petition for acceptance of final appeal argued by the appeal counsel, SHIRAKAWA Kiyosumi, et al.
1. The appellants of final appeal are the surviving family members of patients of terminal lung cancer, etc. who developed interstitial pneumonia and died after taking "Iressa 250 (tablets)" (hereinafter referred to as "Iressa"), an anticancer drug which the appellee of final appeal had imported with the approval for import obtained from the Minister of Health, Labour and Welfare in July 2002. In this suit, the appellants allege that Iressa had a defect as defined in Article 2, paragraph (2) of the Product Liability Act, such as an inappropriate description of its side effects in its package insert (hereinafter simply referred to as "defect"), and the abovementioned patients died due to such defect, and based on this allegation, the appellants seek damages against the appellee under Article 3 of said Act.

2. The outline of the facts legally determined by the court of prior instance is as follows.
(1) Cancer has been the most frequent cause of death of Japanese people since 1981. Among all types of cancer, lung cancer has killed the largest number of people because this disease at an early stage rarely causes symptoms that patients can be aware of, and it is often the case that it has already advanced to a considerable stage when patients become aware of its symptoms. With regard to non-small-cell lung cancer, which accounts for more than 80% of lung cancer cases, the five-year survival rate among patients at Stage IIIB, which is basically an inoperable stage, is 3 to 18%, and the five-year survival rate and the one-year survival rate among patients at Stage IV are about 1% and about 30 to 50%, respectively; thus, it is a refractory type of cancer with an extremely poor prognosis. Non-small-cell lung cancer at these stages or a recurrent case of such cancer is considered to be eligible for chemotherapy (drug therapy), but as compared to other types of cancer including small-cell lung cancer, non-small-cell lung cancer is less sensitive to chemotherapy and it is therefore not curable by this therapeutic approach which is effective only to a very limited extent in prolonging the life of patients with non-small-cell lung cancer. Furthermore, about 70% of patients with non-small-cell lung cancer have already reached either of the abovementioned stages when they are diagnosed with this disease. Under such circumstances, progress in chemotherapy to cure this disease had been desired eagerly.
(2) A. In July 2002, a person who wished to import drugs was required to obtain approval from the Minister of Health, Labour and Welfare as provided in Article 14 of the Pharmaceutical Affairs Act (prior to the revision by Article 1 of Act No. 96 of 2002; hereinafter referred to as the "Act") as applied mutatis mutandis pursuant to Article 23 of said Act, and in order to apply for this approval, the applicant was required to attach data of clinical trial results and other data to the application form (Article 23, and the first sentence of Article 14, paragraph (3) of the Act). With regard to new drugs like Iressa, regulations concerning trials to be conducted to collect such data were enacted, including the Ministerial Ordinance on Good Clinical Practice for Drugs (Ordinance of the Minister of Health, Labour and Welfare No. 28 of 1997), which had been drafted in accordance with internationally agreed standards. And also in 2002, guidelines for the standard methods of conducting clinical trials of anticancer drugs were made available in the form of "Guidelines for Clinical Evaluation Methods of Antineoplastic Drugs" (Notice Yaku-Shin-Yaku No. 9 of February 4, 1991, issued by the Director of the New Drug Division of the Pharmaceutical Affairs Bureau, Ministry of Health). According to these guidelines, clinical trials of an anticancer drug were supposed to be conducted in three phases: Phase I, where trials are conducted for in-patients having a type of cancer for which ordinary therapy is not effective or there is no generally recognized standard therapeutic method, mainly for the purpose of examining the toxicity of the drug; Phase II, where trials are conducted in order to detect carcinomas for which the drug is expected to be effective and examine the drug's safety when used for such carcinomas, and to determine the dosage and administration of the drug to be used for those carcinomas and ascertain the level of its efficacy and safety; and Phase III, where trials are conducted in order to confirm and verify the efficacy and safety of the drug and establish its usefulness. It was generally admissible to submit the results of Phase III trials after obtaining the abovementioned approval from the Minister of Health, Labour and Welfare.
B. In addition to Article 52 of the Act which specifies the matters to be described in a package insert of a drug, points for describing these matters in relation to ethical drugs as instructed by the Minister of Health, Labour and Welfare were provided by means of the relevant notices, respectively titled, "Points in Preparing Package Inserts of Ethical Drugs" (Notice Yaku-Hatsu No. 606 of April 25, 1997, issued by the Director-General of the Pharmaceutical Affairs Bureau, Ministry of Health), "Points in Describing Precautions for Use of Ethical Drugs" (Notice Yaku-Hatsu No. 607 of the same day, issued by the Director-General of said Bureau), and "Points in Preparing Package Inserts of Ethical Drugs" (Notice Yaku-An No. 59 of the same day, issued by the Director of the Safety Division of said Bureau). In these notices, it is required that a package insert be prepared by providing sections as necessary for describing instructions, explanations and other relevant matters (hereinafter the points mentioned in these notices shall be collectively referred to as the "Points for Description").
According to the Points for Description, the "Warning" section of a package insert should be filled in "in cases where the drug may produce a fatal or extremely severe and irreversible side effect, or where a side effect produced by the drug is likely to lead to an extremely serious incident and special attention is called for." The "Precautions for Use" section, designed to provide physicians, etc. with the necessary information, should contain the "Side Effects" section, which is divided into "Serious Side Effects" and "Other Side Effects," and "side effects of the drug that call for special attention" should be described as the former type of side effects. Further, according to the voluntary standards set by the Japan Pharmaceutical Manufacturers Association, a private organization consisting of pharmaceutical companies, the abovementioned "side effects of the drug that call for special attention" should be described in reference to the most serious grade (Grade 3) among the three grades of severity indicated in the notice titled "Standards for Grading Severity of Side Effects of Drugs, etc." (Notice Yaku-An No. 80 of June 29, 1992, issued by the Director of the Safety Division of the Pharmaceutical Affairs Bureau, Ministry of Health; hereinafter referred to as the "Severity Grading Standards"). The side effects to be classified as Grade 3 based on the Severity Grading Standards are defined as "side effects considered to be severe, or more specifically, side effects which have the risk of causing patients who have taken the drug to suffer permanent functional failure to a level where they would die or have difficulty in their daily lives depending on factors such as their physical constitution or their conditions when the side effect occurs." Interstitial pneumonia is categorized as a Grade 3 side effect.
(3) A. Conventional anticancer drugs which were effective for lung cancer were cytocidal drugs aiming to shrink the tumor by impeding the division of abnormally growing cancer cells, and due to their mechanisms of action, these drugs unavoidably impeded the division of healthy cells and resultantly caused side effects such as hematologic toxicity, gastrointestinal toxicity, and alopecia. Among these anticancer drugs, the six major types of drugs approved for manufacturing in the 1990s and thereafter, as a result of Phase II trials, were suspected of having caused interstitial pneumonia as a side effect at a frequency of 1.0 to 4.9%. Among these six types of drugs, two drugs caused two deaths each from interstitial pneumonia as a side effect, and one drug caused one death suspected of being due to interstitial pneumonia, whereas no deaths from interstitial pneumonia were reported with regard to the other three drugs.
Also among the six types of anticancer drugs, with regard to the two drugs for which deaths from interstitial pneumonia as a side effect were reported in Phase II trials, the package insert contained a description in the "Warning" section that the drug must not be used for patients with interstitial pneumonia, and a description in the "Contraindication" section that the drug, when used for patients with interstitial pneumonia, may lead to a fatal case, respectively. However, with regard to the drug for which a fatal case suspected of being due to interstitial pneumonia was reported, the package insert contained descriptions of interstitial pneumonia in the "Careful Administration" section of the "Precautions for Use" section and in the "Serious Side Effects" section of the "Side Effects" section, but did not describe that the drug may lead to a fatal case, nor did this package insert contain any description of interstitial pneumonia in the "Warning" section.
B. On the other hand, in July 2002, drug-induced interstitial pneumonia was a common side effect caused from the administration of drugs that were effective for specific types of diseases or symptoms, such as anticancer drugs and antirheumatic drugs, and it was a type of disease generally involving the risk of death. Therefore, at that time, it was known at least among physicians engaged in anticancer therapy targeting lung cancer that when interstitial pneumonia occurred due to the administration of these drugs including anticancer drugs, it could lead to a fatal case.
(4) A. Iressa (containing gefitinib as its active ingredient) is a molecular targeting drug which is effective in shrinking a cancer tumor by selectively blocking the signaling pathways of the epidermal growth factor receptor (EGFR) associated with cancer cell growth. As its mechanism of action is different from those of the conventional cytocidal drugs, it rarely causes side effects such as hematologic toxicity that occur almost without exception when the conventional anticancer drugs are used.
B. Among the 133 clinical trials conducted in Japan before approval for import of Iressa was granted, three cases developed interstitial pneumonia in which the association of the disease with Iressa cannot be denied, but all of these cases took a turn for the better with successful therapy. Looking at the clinical trials conducted abroad, three cases developed interstitial pneumonia in the two types of clinical trials conducted in the United States, both for which more than 1,000 cases had been registered, and another two cases developed interstitial pneumonia in other clinical trials, and four of them led to deaths. However, in all of these death cases, there was only a possibility or suspicion about the causal relationship between the administration of Iressa and the patient's death, because of the facts that cytocidal drugs were used in combination with Iressa and that the cancer itself progressed to an advanced stage.
In addition, according to the Expanded Access Program implemented in the United Kingdom for allowing for the administration of investigational drugs to patients who were ineligible to participate in clinical trials, Iressa was also administered to patients who had not been allowed to participate in the abovementioned clinical trials, including those who had not responded sufficiently to standard therapy and those who had been unable to receive other types of whole-body anticancer drug therapy. The number of such patients who were given Iressa under this program had reached about 15,000 persons worldwide by July 2002. If a hazardous incident took place with any of these patients receiving Iressa, it was supposed to be reported to the appellee's parent company (a UK corporation), which had synthesized and developed Iressa (the information concerning hazardous incidents thus reported shall hereinafter be referred to as the "EAP side effects information"). According to the EAP side effects information, 15 cases were reported as cases in which the occurrence of interstitial pneumonia as a side effect of the administration of Iressa cannot be denied, and 11 cases of them led to deaths. However, in two cases out of these death cases, there was no causal relationship between the administration of Iressa and the patient's death, and in the other nine cases, a causal relationship between the administration of Iressa and the patient's death cannot completely be denied but it would be too much to affirm such causal relationship. Furthermore, unlike side effects information obtained through clinical trials, the EAP side effects information is not subject to monitoring or anything similar, while only the case reports prepared by the physicians in charge are sent to the abovementioned parent company, and for this reason, there are problems with the EAP side effects information such as that verification between the case reports and the medical records (primary source materials), correction of errors through mutual inspection among physicians, or confirmation of consistency is not conducted.
In the cases of occurrence of interstitial pneumonia reported in the abovementioned clinical trials and in the EAP side effects information, the period after the administration of Iressa until the occurrence of the disease was 2 to 148 days, and in the death cases in which the causal relationship between the administration of Iressa and the patient's death cannot be denied, the period after the occurrence of the disease until the patient's death was 0 to 30 days. Thus, all of these cases did not imply that Iressa could cause interstitial pneumonia as its side effect which would occur at an early stage and progress rapidly.
(5) In January 2002, the appellee filed an application for approval for import of Iressa, with the results of clinical trials until Phase II attached, and on July 5, 2002, the appellee obtained approval for import of Iressa from the Minister of Health, Labour and Welfare, as a drug which is effective for inoperable or recurrent non-small cell lung cancer and which is to be administered orally in a dose of 250mg once daily (this approval shall hereinafter be referred to as the "Approval for Import"). Upon granting the Approval for Import, the minister designated Iressa as a powerful drug (Article 44, paragraph (2) of the Act) and as a drug dispensable on direction or prescription (Article 49 of the Act; meaning the prescription legend drug under the Pharmaceutical Affairs Act currently in force; the same shall apply hereinafter), and also designated it as an ethical drug which must be accompanied by a package insert according to the Points for Description.
On July 16, 2002, the appellee started import and sale of Iressa. The package insert attached to this drug at that time (hereinafter referred to as the "First Edition of the Package Insert") did not contain a description of interstitial pneumonia as a side effect in the "Warning" section but described this disease in the "Serious Side Effects" section following three side effects, namely, "severe diarrhea (less than 1%), diarrhea with dehydration (1 to 10%)," "toxic epidermal necrolysis, erythaema polymorphe (frequency unknown)," and "impaired liver function (1 to 10%)," while providing the following descriptions: "interstitial pneumonia (frequency unknown): The use of this drug may cause interstitial pneumonia. Conduct close observation, and if any abnormality is observed, discontinue use and offer proper treatment." However, there was no clear description to the effect that interstitial pneumonia could be fatal. According to the Severity Grading Standards, the symptoms mentioned in the "Serious Side Effects" section, namely, "severe diarrhea," "diarrhea with dehydration," and "toxic epidermal necrolysis," are all categorized as Grade 3 together with interstitial pneumonia, and among cases of impaired liver function, the "case where severe changes in liver function test values are observed," which was designated in the First Edition of the Package Insert as a case where the use of Iressa should be discontinued, is also categorized as Grade 3.
(6) A. During the period of about three months after the launch of the sale of Iressa until October 11, 2002, a total of 34 cases of interstitial pneumonia as a side effect were reported to the appellee or the Ministry of Health, Labour and Welfare. In at least three cases of these reported cases, the occurrence of interstitial pneumonia was denied in the follow-up reports submitted no later than said date, and among the other 31 cases, 17 cases were death cases.
B. On October 15, 2002, as directed by the Ministry of Health, Labour and Welfare, the appellee issued a letter of emergency safety information regarding acute lung injury and interstitial pneumonia caused by Iressa (hereinafter referred to as the "Emergency Safety Information").
The Emergency Safety Information stated that among 7,000 patients (estimate) who had used Iressa since the launch of its sale, 22 cases were reported as having developed lung injury, including interstitial pneumonia, in which the association between the occurrence of the disease and the administration of Iressa cannot be denied (including 11 cases in which the association between the patient's death and the administration of Iressa cannot be denied), and that in some of these cases, the disease appeared at an early stage after the patient started taking the drug (within 14 days in 12 cases) and progressed rapidly. Accordingly, said information provided the following descriptions: "1. The administration of this drug may cause acute lung injury or interstitial pneumonia. Conduct close observation such as by performing chest X-ray study, and if any abnormality is observed, discontinue use and offer proper treatment."; "2. Serious side effects such as acute lung injury and interstitial pneumonia may occur and have a fatal course. Upon using this drug, closely observe the clinical conditions (respiratory conditions, whether the patient has coughing or fever, etc.), and perform chest X-ray study regularly."
C. On the same day, the appellee prepared the third edition of the package insert of Iressa (hereinafter referred to as the "Third Edition of the Package Insert"), and in the "Warning" section, additionally provided at the beginning of the package insert, and in the "Important Basic Precautions" section of the "Precautions for Use" section, the appellee provided descriptions to the same effect as those provided in the Emergency Safety Information mentioned above, and also at the beginning of the "Serious Side Effects" section, the appellee stated, "Acute lung injury or interstitial pneumonia may occur."
Furthermore, on December 25, 2002, the appellee prepared the fourth edition of the package insert of Iressa following the outcome of the study at the Gefitinib Safety Council of the Ministry of Health, Labour and Welfare, and in the "Warning" section of this package insert, the appellee added the following description: "Acute lung injury or interstitial pneumonia often occur at an early stage after the administration of this drug and have a fatal course. Therefore, be sure to have the patient stay in the hospital or under similar control for at least four weeks after starting the administration of this drug, and conduct close observation to detect any sign of serious side effects such as interstitial pneumonia."
D. The number of cases reported to the Ministry of Health, Labour and Welfare in which the patient's death was suspected of being due to the side effect of Iressa changed from 180 cases in 2002 to 202 cases in 2003 and 175 cases in 2004, and then decreased by half to 80 cases in 2005, and further dropped to 34 cases in 2009.
(7) According to data including the results of clinical study conducted after the Approval for Import was granted, the incidence rate and the death rate of interstitial pneumonia as a side effect of Iressa were 5.81% and 2.26% at the highest, respectively. General risk factors for incidence of and death by this disease include complication or history of interstitial pneumonia, past or present smoking habit, being a male, and poor health conditions for the whole body, but no knowledge currently available has clarified the pathogenesis of this disease.
(8) A. P, a child of Appellant X1, was diagnosed with non-small-cell lung cancer at Stage IV in September 2001, and started receiving chemotherapy in December 2001, but as he/she showed symptoms of side effects such as nausea, anorexia, and alopecia, chemotherapy was discontinued with the last administration performed on July 1, 2002. On August 15, 2002, P started to take Iressa, and as he/she showed positive reactions such as improved subjective symptoms and shrinkage of the shadow of the lung cancer, he/she was temporarily discharged from the hospital on September 21, 2002, and continued taking Iressa at home. However, since an abnormal shadow was observed in his/her lung upon his/her visit to the hospital on October 3, 2002, the use of Iressa was discontinued and P was admitted to the hospital again, but his/her respiratory conditions later deteriorated quickly, and he/she finally died on October 17, at the age of 31.
B. Q, the father of Appellant X2, was diagnosed with non-small-cell lung cancer at Stage III in May 2002, and started receiving chemotherapy. However, this therapy was later discontinued because it did not work but rather caused side effects such as pain, fever, and anorexia. Q had already been treated for interstitial pneumonia for some time, and along with the progression of his cancer, interstitial pneumonia became slightly worse and he therefore received oxygen administration. On September 2, 2002, Q started taking Iressa, but this did not prove to be effective in reducing the tumor but it was rather suspected of causing the cancer to become worse. On October 9, 2002, his interstitial pneumonia became worse, and in the evening on October 10, the interstitial pneumonia became worse acutely to a level to make Q unable to breathe, and he finally died on the same day at the age of 67.

3. The appeal counsel argue that by referring to the information on interstitial pneumonia as a side effect of Iressa, which the appellee could have obtained by the time when the Approval for Import was granted, the appellee could have known that interstitial pneumonia caused as a side effect of Iressa might lead to a fatal case, and yet, the First Edition of the Package Insert did not describe this specifically or provide any appropriate description on interstitial pneumonia, and thus there was a defect in the instruction or warning given with regard to the side effects of Iressa.

4 (1) 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, and 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.
(2) From this standpoint, we examine whether the descriptions in the First Edition of the Package Insert available at the time when the Approval for Import was granted were appropriate.
A. According to the facts mentioned above, at the time when the Approval for Import was granted, no death from interstitial pneumonia as a side effect was reported in clinical trials conducted in Japan, nor was there any death case among cases of interstitial pneumonia reported in clinical trials conducted abroad and in the EAP side effects information, in which a causal relationship between the administration of Iressa and the patient's death can be positively confirmed, and under such circumstances, 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, the appellee 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. And considering that Iressa was at that time designated as a drug dispensable on direction or prescription which was effective for inoperable or recurrent non-small cell lung cancer, this drug was ordinarily expected to be prescribed or used by physicians engaged in lung cancer treatment. According to the facts mentioned above, physicians engaged in such treatment knew that anticancer drugs generally had a side effect of causing interstitial pneumonia which could lead to a fatal case. If that is so, 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. This is not affected by factors, such as the order of describing matters in the "Serious Side Effects" section, other side effects described in the relevant section, or the relevant articles in medical journals published by the time when the Approval for Import was granted.
B. On the other hand, according to the facts mentioned above, the letter of the Emergency Safety Information was issued following the reports of cases in which interstitial pneumonia appeared at an early stage after the patient began taking Iressa and progressed rapidly. 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.
Also in light of other circumstances, such as that Iressa was considered to be effective for inoperable or recurrent non-small cell lung cancer, which is a refractory type of cancer with an extremely poor prognosis, and that at that time it was admissible to obtain approval from the Minister of Health, Labour and Welfare only by submitting the results of clinical trials until Phase II, as well as that this approach of using Iressa as an anticancer drug would have been easily understandable to physicians engaged in treating this type of cancer, 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 on the basis of the fact that Iressa had a side effect of causing interstitial pneumonia which could become severe quickly.
C. According to the above, the description in the First Edition of the Package Insert cannot be deemed to be inappropriate as a description of a side effect that was foreseeable at the time when the Approval for Import was granted.
(3) It is clear that Iressa, which was later administered to P and Q, had been delivered from the appellee to the medical staff in charge at least when its administration started. 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.
Then, it follows that Iressa cannot be found to be defective at least in the relationships with P and Q.

5. We can affirm the determination of the court of prior instance that goes along with the above. We cannot accept the appeal counsel's arguments.

Therefore, the judgment has been rendered in the form of the main text by the unanimous consent of the Justices. There are concurring opinions respectively by Justice TAHARA Mutsuo and by Justice OKABE Kiyoko, and jointly by Justice OTANI Takehiko and Justice OHASHI Masaharu.

The concurring opinion by Justice TAHARA Mutsuo is as follows.
In view of the facts of the case, I would like to give supplementary comments on some points at issue as shown below, in relation to the court opinion.
1. The base time for finding a "defect" in a product, and the knowledge obtained ex post facto
The subject matter of this ruling to accept the final appeal is whether or not there was a "defect in the instruction or warning" given at the time when Iressa was placed on the market. Before discussing this point, I would first look at the relationship between the base time for finding a "defect" in a product and the knowledge obtained ex post facto.
Under Article 2 of the Product Liability Act, the term "defect" is defined as meaning that the product lacks the "safety that the product ordinarily should provide." Strictly, whether the product satisfies such safety standards should be determined as of the time when the product is placed on the market.
Where a product, at the time when it was placed on the market, was regarded in society as providing the "safety that the product ordinarily should provide," but it later turned out to be lacking such safety based on knowledge obtained ex post facto, such change in the circumstances cannot be the reason for finding retrospectively that the product had had a "defect" since it was placed on the market (while product liability may arise for continuing to place a product on the market after the product turns out to be lacking safety based on knowledge obtained ex post facto, a product placed on the market before that point in time does not give rise to the issue of product liability but only raises the issue of tort liability in general, arising in terms of the duty to recall defective products or to give warnings).
Academically, it is considered that in relation to Article 4 of said Act, the existence or nonexistence of a defect in a product in dispute should be determined based on the knowledge available at the time of the end of oral argument proceedings. However, this is only relevant to the issue of whether the product provided the "safety that the product ordinarily should provide" at the time when it was placed on the market.
Looking at the present case, when Iressa was approved, it was admissible to decide whether or not to approve anticancer drugs based on the results of Phase II trials, and accordingly, Iressa was approved based on the results of Phase II trials conducted according to said standards, on condition that Phase III trials should be conducted after this drug was made available to the public with such approval, while it would suffice to report the results thereof upon applying for reassessment (six years after approval).
Therefore, whether or not Iressa had any defect at the time when it was approved should be determined based on the knowledge obtained from the results of Phase II trials, which was available at the time of approval, and the knowledge that is presumed to have been obtained in Phase II trials, which later became available, and also based on the knowledge for which it later turned out that the knowledge could have been obtained before approval, and thus, nothing in the results of Phase III trials would affect the determination as to a "defect" in Iressa that was approved based on the results of Phase II trials. According to the case records, there are no circumstances suggesting the existence of any such defect in Iressa as requiring the Minister to refrain from granting approval at the time when Phrase II trials were finished.

2. Side effects of ethical drugs
Drugs, ethical drugs in particular, are taken for their medicinal effects although they are made of ingredients ordinarily not taken into the human body in daily life, and due to this nature, they could generally cause some side effects, including allergic reactions.
Among ethical drugs, those used for multiple purposes are required to provide a high level of safety, and the frequency or level of seriousness of their side effects should be extremely low. Drugs that meet these requirements can be deemed to be capable of providing the "safety that they ordinarily should provide."
Generally, ethical drugs that provide stronger medicinal effects could cause side effects at a certain rate accordingly. If physicians and other medical staff can prevent the occurrence of side effects of a drug or can properly respond to or treat the side effects after they occur by following the drug's prescribed usage, it may be justifiable to say that the "safety that the drug ordinarily should provide" can be secured by describing the possibility that the side effects could occur and the proper treatment thereof in its package insert.
However, in the case of drugs with very strong medicinal effects, it is a common view that however carefully and appropriately they are used, such drugs could unavoidably cause severe side effects at a certain rate. Even so, comparing the probability of side effects and the effect of the drug (including the availability of alternative drugs), the use of some drugs may still need to be approved. In that case, the "necessity of careful administration and the risk of unavoidable side effects" should be described in detail in the package insert, but yet I feel uncomfortable considering that the "safety that the drug ordinarily should provide" is secured just by describing these matters in the package insert (tort liability should arise for any deficiency in such description).
On the other hand, some drugs that pose such risk may still be necessary by reason of their medicinal effects, and in this context, it is unreasonable to find a "defect" in the drug only because the possibility of such severe side effects has become real.
If a drug could unavoidably cause side effects at a certain rate, the case should be considered as an issue of "acceptable risk," rather than an issue of whether the drug provides the "safety that the drug ordinarily should provide," and if patients suffer damage from side effects of a drug even though it has been properly used, the case should be considered as an issue of relief for drug-induced sufferings.

3. Assessment of interstitial pneumonia as a side effect
As mentioned in the court opinion, after Iressa was approved under the Pharmaceutical Affairs Act and made available to the public, cases in which patients developed interstitial pneumonia at an early stage after taking this drug and then became worse and died were reported one after another, and under such circumstances, the letter of the Emergency Safety Information was issued in October 2002.
However, according to this information, among more than 7,000 patients (estimate) who used Iressa, there were only 22 patients who developed interstitial pneumonia or other lung injury (0.31%) and 11 patients who died from such disease (0.16%). Also, with regard to the research result showing the highest incidence rate of interstitial pneumonia (5.81%), mentioned in the court opinion, the judgment in first instance made a finding that in 22 out of the 140 cases, for which the primary source materials such as medical records had been obtained, the relationship in which interstitial pneumonia was induced by Iressa was denied. Supposing that such relationship is denied at the same rate for all cases in which the occurrence of interstitial pneumonia was observed in said research, the incidence rate would be 4.91%. This is almost equal to the frequency of occurrence of interstitial pneumonia due to Irinotecan (4.89%), one of the other anticancer drugs approved based on the results of Phase II trials (according to the finding of the judgment in first instance), and it cannot be deemed to be a particularly high rate.
In addition, as found in detail in the judgment in first instance, drug-induced interstitial pneumonia is itself regarded as a disease with a very high death rate and it may occur acutely, and it is therefore not always certain whether taking Iressa could immediately lead to the occurrence of acute interstitial pneumonia.
On the other hand, Iressa is supposed to be used for "inoperable or recurrent non-small cell lung cancer," and it is actually administered to patients in Stage IIIB or IV who have received other types of chemotherapy and suffered side effects or other problems that have made it difficult to continue the same chemotherapy (According to the facts found in the judgment in prior instance, in the case of the late P, his/her course of treatment had been deadlocked due to multiple metastases including metastasis to the brain, but after taking Iressa, he/she became better to a level where he could take food by mouth, and was discharged from the hospital temporarily. In the case of the late Q, he had been diagnosed with interstitial pneumonia two and a half years before being diagnosed with non-small-cell lung cancer, and along with the progression of the cancer, his course of treatment had been deadlocked by September 2002, but after taking Iressa, his pain was mitigated and his condition remained stable for about one week.) Therefore, when assessing the details and degree of side effects of Iressa, due consideration should be given to the fact that this drug is supposed to be administered to such patients (that is, patients who have few options for treatment except for Iressa).

4. Indication of side effects in the package insert
An indication in a package insert of a drug should be described so as to help the intended users of the drug gain better understanding of the drug. Since Iressa is a powerful drug which is designated as a drug dispensable on direction or prescription and which is effective for "inoperable or recurrent non-small cell lung cancer," the intended users of this drug are not clinicians in general but clinicians engaged in treatment of refractory cancers (it may be a little less accurate to refer to this type of clinicians as "specialists," as it was referred to in the judgment in prior instance.)
Presumably, these clinicians have conventionally used anticancer drugs. Since all of the conventional anticancer drugs have the potential to cause interstitial pneumonia as a side effect, it may be a matter of common knowledge to those clinicians that newly approved anticancer drugs could also have the potential to cause interstitial pneumonia as a side effect, and it may be recognized among them as well that once interstitial pneumonia occurs, it would be difficult to cure.
As is found in the judgment in prior instance, the indication of the "Serious Side Effects" section in a package insert refers to Grade 3 side effects. All of the symptoms described as "serious side effects" in the package insert of Iressa, such as severe diarrhea and impaired liver function, are categorized as Grade 3, and the occurrence of any of these side effects in severe cancer patients who are eligible for Iressa could cause them to die. Therefore, in light of the results of Phase II trials conducted before Iressa was approved, it may have been necessary and sufficient to describe "interstitial pneumonia" as one of the side effects of this drug (as pointed out in the court opinion, with regard to the two drugs among other anticancer drugs that were available at the time when Iressa was approved, interstitial pneumonia is described in the "Warning" section and in the "Contraindication" section, respectively; however, in both cases, the description is concerned with the administration of Iressa to "patients with interstitial pneumonia," not to such patients who have not yet contracted this disease).

The concurring opinion by Justice OKABE Kiyoko is as follows.
I would like to give some comments on the appellants' argument criticizing the determination of the court of prior instance regarding the causal relationship between the defect in the instruction or warning and the cases of side effects of Iressa.
As a defect in the instruction or warning regarding Iressa, the appellant alleges that the appellee should have taken but failed to take such measures as separately creating a "Warning" section in the First Edition of the Package Insert and thereby publicizing the drug’s risk of interstitial pneumonia via such section, or describing in the First Edition of the Package Insert that interstitial pneumonia caused by Iressa may lead to a fatal case. 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. Such foreseeability of side effects should not be determined only on the basis of the reported cases of side effects in which a clear causal relationship is found between the administration of Iressa and the symptoms considered as its side effects. It may be reasonable to give an instruction or warning of some symptoms as its side effects in light of the severity of the symptoms and the degree of possibility of the objective existence of said causal relationship. Therefore, the foreseeability of side effects must be determined by also taking into consideration the cases where causality cannot be denied. The explanation given by the court of prior instance on this point may not be appropriate as it might be misunderstood as meaning that only such cases as where causality is clearly found can be the basis for affirming the foreseeability of side effects. However, the court of prior instance also made a finding of the cases where the causal relationship with the administration of Iressa cannot be denied, and as the interstitial pneumonia observed in these cases is the same level of interstitial pneumonia as that caused by other anticancer drugs as a side effect, it should inevitably be said that what is foreseeable from said cases is also the same level of interstitial pneumonia as that caused by other anticancer drugs as a side effect. Interstitial pneumonia that occurs at an early stage after the patient takes a drug and becomes severer rapidly is a type of side effect that is very unique and is caused in a different way from the way in which interstitial pneumonia is caused by other anticancer drugs as a side effect, so it should inevitably be said that it was impossible to foresee such a type of interstitial pneumonia. It is true that since Iressa is a molecular targeting drug, which has a different mechanism of action from conventional drugs, and how it reduces tumors is yet to be clarified in detail, and what is more, it had not yet undergone Phase III trials, it may have been possible to foresee that this drug could cause some side effects but it is too much to say that it may have been possible to foresee that this drug could cause a different type of interstitial pneumonia from that caused by other anticancer drugs as a side effect. And as explained in the court opinion, the description given by the appellee in the First Edition of the Package Insert cannot be deemed to be inadequate as an instruction or warning regarding the possibility that Iressa could cause the same level of interstitial pneumonia as that caused by other anticancer drugs as a side effect, which is foreseeable from the reported cases.

The concurring opinion by Justice OTANI Takehiko and Justice OHASHI Masaharu is as follows.
As explained in the court opinion, Iressa has a side effect of causing interstitial pneumonia that becomes severer rapidly, and it was impossible to foresee such a side effect from clinical trials conducted before the Approval for Import was granted. Consequently, if it is considered to be necessary and sufficient to give an instruction or warning appropriately regarding side effects, the occurrence of which was concretely foreseeable, this would lead to the conclusion that there was no defect in the instruction or warning disputed in the present case.
Iressa is a molecular targeting drug which rarely causes side effects such as hematologic toxicity that occur almost without exception when conventional anticancer drugs are used, and it was therefore expected to be effective for inoperable or recurrent non-small cell lung cancer, which is a refractory type of cancer with an extremely poor prognosis and was considered to be less sensitive to the conventional type of chemotherapy. In the past, it was generally admissible to submit the results of Phase III clinical trials of a drug, which must be conducted in order to confirm and verify the efficacy and safety of the drug and establish its usefulness, after obtaining approval for import from the Minister of Health, Labour and Welfare, and accordingly, Iressa was approved based on the results of trials until Phase II, under certain conditions.
As mentioned above, although interstitial pneumonia was recognized as a side effect of Iressa at the time when the Approval for Import was granted, it was impossible to foresee that this drug could cause a type of interstitial pneumonia that becomes severer rapidly. During the period of about three months after the launch of import and sale of Iressa on July 16, 2002, a total of 34 cases in which interstitial pneumonia occurred as a side effect were reported (the occurrence of interstitial pneumonia was later denied in three cases), and among them, 17 cases were fatal cases. On October 15, 2002, the appellee issued a letter of emergency safety information regarding acute lung injury and interstitial pneumonia caused by Iressa.
It is generally anticipated that drugs that have been approved based on the results of trials until Phase II and imported and sold with such approval have a higher risk of having a side effect which may be found in Phase III trials conducted subsequently, as compared to those drugs that have undergone Phase III trials before being approved for import and sale. The severe side effect of Iressa that was later found, i.e. causing a type of interstitial pneumonia that becomes severer rapidly, is this latent risk becoming reality, and it may be possible to consider that this side effect was not concretely foreseeable but it was within the limits of general foreseeability. In the present case in particular, severe side effect cases were observed only three months after the launch of import and sale of Iressa, and considering that in all of these cases, interstitial pneumonia was caused, although with some difference in terms of severity, a doubt may arise as to the appropriateness of the First Edition of the Package Insert that described nothing about this point.
However, it cannot be said in the end that the description in the First Edition of the Package Insert was inappropriate, as concluded in the court opinion. Even when a package insert is required to describe the side effect in question, it would be inevitable for the package insert to provide only a general description of the side effect if the risk of the side effect is only generally foreseeable and cannot be concretely identified, and such a general description may not be regarded as an effective instruction or warning. With regard to such a generally foreseeable risk, it must be said that it cannot be helped, unless under special circumstances, that the package insert omits an instruction or warning on such risk on the assumption that the physicians who are in charge of treatment of lung cancer and are expected to use Iressa should understand that risk. Also, if the appellee is required to give a concrete description on the side effect based on the trial results that were later revealed, this would amount to asking the appellee to do the impossible and go against the purport of the Act.
Iressa was approved by the Minister of Health, Labour and Welfare based on the results of trials until Phase II for its efficacy for inoperable or recurrent non-small cell lung cancer, which is a refractory type of cancer with an extremely poor prognosis, and its import and sale was launched after it was designated as an ethical drug dispensable on direction or prescription. This was based on the administrative decision that the Minister had made while giving consideration to the balance between the patients' demand to use effective new drugs as soon as possible and the necessity to secure the safety of drugs, and as long as such decision is reasonable, it is inappropriate to strictly place responsibility on the manufacturer or importer of drugs for an outcome of the decision. On the other hand, where a drug has a severe side effect and its risk that latently existed at the time when approval was granted and import and sale was launched has become reality immediately thereafter, there is still a doubt about whether it is appropriate to force the patients who used the drug to endure their sufferings from the side effect. If the purpose of the Act is to define the drug manufacturers' responsibility and ensure protection of victims of side effects, and thereby contribute to improving the standards of people's living and promoting the sound development of national economy, it may be recommended that the risk of side effects to be caused by new drugs that are expected to be useful should be shared among a wide range of parties in the pharmaceutical industry, medical industry or society as a whole, aiming to ensure protection and relief for victims of side effects of drugs.

Justice TERADA Itsuro
Justice TAHARA Mutsuo
Justice OKABE Kiyoko
Justice OTANI Takehiko
Justice OHASHI Masaharu