What is IRESSA
 Is an anticancer drug for non-small-celllung cancer.

 Has a novel mechanism of action(inhibition of EGFR).
→”molecularly targeted drug”

 Has been extensively promoted as a
1

Approval of IRESSA“safe anticancer drug with few adverse
reactions.”

Phase II Approval [Does this reflect your intended
meaning? Or do you mean “II. Approval Phases”?]

Approved with exceptional speed

Guidelines for Methods of Clinical Evaluation for
Anticancer Drugs (prior to 2005 revision)

1.25.2002 Application for importation
approval
7.5.2002
Approved (global first)↑
4.2004
Transfer of approval operations
to the Pharmaceuticals and Medical
Devices Agency

Phase I Clinical Trials
Phase II Clinical Trials・・・Tumor-shrinkage effect(small-scale)
Approval

Approval Conditions for
IRESSA“Performance of a domestic randomized
comparative clinical trial having asufficient sample size, with the objectiveof further elucidating the efficacy andsafety of this drug in the treatment of
non-small cell lung cancer (unresectable

Post-

Phase III Clinical Trials・・・Survival benefit approval（large-scale）

Occurrence of suffering due toadverse reactions
Starting immediately after approval, there were
multiple cases of adverse reactions of serious
interstitial pneumonia and acute lung injury.
7.5.2002 Approval
7.15 First reported fatality
10.15 Urgent Safety Information Report
26 events 13 deaths「Targeted attack of only cancer cells」

or recurrent)”

1

Deaths reported due toadverse reactions

Total number of treatedpatients is unknown

2002 180 deaths (July – December)2003 202 deaths
2004 175 deaths
Subtotal 557 deaths
2005 80 deaths
2006 51 deaths

As of March 2010, 810 deaths
had been reported.

 1.2005

AstraZeneca reported
cumulatively approx. 86,800 patientstreated Iressa as of Dec. 28, 2004.

3.2005 Revised to approx. 42,000 patients.

7

Adverse reactions at theapproval examination stage

Overlooked adverse reactions (10 typicalcases)
Patient No.

Overview (Interstitial pneumonia cases)

No. of adverse reaction cases reported up to preparation of
the examination report before the approval(3 in Japan)
 3 in domestic clinical trials
 4 in overseas adverse reaction reports(4 overseas)Overlooked cases of adverse reactions
 196 cases up to approval 10 of those cases were typical lung damage

Additionally reported cases of adverse reactions(10 typicalcases)(3 additional
cases) 9










Severity

OutcomeRespiratory failure

Fatal

Fatal

Ｂ3-63

55 y.o. M

Respiratory failure

Life-threatening

Unresolved

Ｂ3-67

38 y.o. F

Pulmonary infiltration ＮＯＳ

Life-threatening

Unknown

Ｂ3-79

68 y.o. F

Respiratory failure

Life-threatening

Recovered

Ｂ3-11568 y.o. F

Dyspnea ＮＯＳ

Ｂ3-13254 y.o. M

Dyspnea NOS, pulmonary hemorrhage

Ｂ3-14063 y.o. M

Pulmonary infiltration ＮＯＳ, respiratory
failureＢ3-15239 y.o. F

Pulmonary infiltration ＮＯＳ，
allergic pulmonary alveolitis

Ｂ3-16462 y.o. F

Ｂ3-17273 y.o. F

Fatal

Fatal

Life-threatening

Unresolved

Fatal

Fatal

Life-threatening

Unresolved

Respiratory failure, lactic acidosis

Fatal

Fatal

Pulmonary infiltration NOS

Fatal

Fatal

Not classified as “Interstitial pneumonia”; thus overlooked.
10

focusing on the 3 domestic cases.

4 overseas cases ＋ 3 additional cases: 4 deaths ５７％
10 overlooked typical cases: 5 deaths
５０％
2 Japanese EAP cases: 1 death

Risk trends for JapaneseAdverse Reaction

51 y.o. F Only the relevance was investigated,

High mortality rate

Patient

Ｂ3-54

Handling of adverse reaction
reports in the examination

Risk apparent from adverse reaction cases
reported before the approval8 Only the existence of reports of 4 overseas

cases was noted.

５０％

 Most cases were overlooked

All cases in clinical trials were Japanese (3/3)
3 domestic cases ＋ 4 overseas cases ＋ 3 additional
cases: 5 Japanese cases (5/10)
All 5 Japanese cases were serious or fatal.
These cases portended
the rash of adverse
reactions aftermarketing.

11

In The Second Section of Drug
Examination Committee the riskof Interstitial Pneumonia was noteven explained.

2

Insufficient consideration ofadverse events
Adverse event-related deaths in clinical trials:
34/677 patients (5.0%)
Only 2 (0.3%) of those were treated as deaths due toadverse reactions.
 Many cases of acute pulmonary damage due to
IRESSA were overlooked.
（Osaka: re-examination of witnesses Hama）



Efficacy

A portent of the riskof acute lung injury
14

Phase III clinical trials

Phase III clinical trials


INTACT １
2. INTACT ２
3. ISEL
4. SWOG0023
5. V1532（ Approval Conditions ）6. INTEREST
7. IPASSINTACT １，2
Coadministration of IRESSA with existing anticancer drugs

1.

→The median survival time showed no significant
difference between the IRESSA group and the placebogroup.
ISEL
The median survival time showed no significant difference
between the IRESSA group and the placebo group.



SWOG0023
Administration of gefitinib as maintenance therapy
following chemoradiotherapy + docetaxel chemotherapy

15→The median survival time was significantly inferior in the
IRESSA group (23 months) compared with the placebo 16
group (35 months).

Phase III clinical trials

V1532

 Repeated failure in placebo-controlled Second-line or third-line patientscomparative studies

 Comparison of survival times with IRESSA and Reduced survival time shown in SWOG0023

docetaxel Failure of the trial (V1532) conducted to satisfy

 Domestic clinical trial carried out tothe domestic approval conditions

satisfy the approval conditions

 Multiple cases of suffering due to adverse

reactionsNoninferiority of gefitinib to docetaxel withregard to the overall survival time was notproven.
Failure to prove a survival benefit

17

Dr. Nagahiro Saijo, witness“Statistical utility of IRESSA has not been proven.”
18

3

INTEREST

IPASS Second-line or third-line patients

 Patients with adenocarcinoma and no or only aslight history of smoking

 Comparison of survival times with IRESSA anddocetaxel Overseas clinical trial

 Comparison of IRESSA with doublet

chemotherapy using carboplatin/paclitaxel

 Primary assessment endpoint was the

progression-free survival time

Demonstration of noninferiority of gefitinib to
docetaxel? Failure of V1532 conducted in Japanesepatients? Docetaxel dosage larger than in V1532

Demonstration of superiority in the IRESSA groupover doublet chemotherapy using
carboplatin/paclitaxel
19

IPASS

20

欧米の状況
2003.5.5
2004.12.17

The IPASS patient cohort does not cover theJapanese indication
Japanese indication:“unresectable or recurrent nonsmall cell lung cancer”

2005.1.4

IPASS
subjects

In addition, the response rate in the EGFR
mutation-negative group was 1.1%.

2005.5.14
2005.6.17

FDAイレッサ承認
ISEL初回解析
FDA声明「回収するか、他に妥当な規制措置をとるかを決定する」
アストラゼネカ
EUへの承認申請を自ら取り下げ
SWOG0023中間解析
FDA、新規患者への投与を原則禁止

21

Handling of IRESSA in the
West

22

Handling of IRESSA in theWest

5.5.2003
12.17.2004

FDA approval
Initial analysis of ISEL
FDA statement: “A decision will bemade for recall or some other appropriate
regulatory measure.”
1.4.2005
AstraZeneca itself withdraws its
approval application to the EU
5.14.2005
Interim analysis of SWOG0023
6.17.2005
FDA
In principle, prohibition ofadministration to new patients

7.1.2009 Distribution approval granted in the
EU on basis of IPASS & INTEREST
However, restricted to “adult patients with
EGFR mutations and locally-advanced ormetastasized non-small cell lung cancer”

Approval cannot be acquired in the case of an
indication that is not focused on patients who
have EGFR mutations (= the indication granted
in Japan)
23

24

4

Handling of IRESSA in Japan

Handling of IRESSA in Japan
1.25.2002
Approval application submitted to
the Ministry of Health Labour and Welfare
7.5.2002
Approval ←without waiting for the
INTACT results
8.19.2002
INTACT results reported
10.15.2002 Urgent Safety Information
12.25.2002 First Meeting to Discuss Gefitinib
Safety Issues
12.26.2002 Revision of package insert→ Warningstatement
25

Handling of IRESSA in Japan
2.1.2007

12.17.2004
1.2005 convened

Initial analysis of ISEL
Gefitinib Committee Meeting

Continued use of the drug was
permitted under the condition that the package
insert include a statement that, at the time of use,
reference should be made to the Japan Clinical
Guidelines for the Management of Lung Cancer. Nochanges were made in the approval content.
5.14.2005
Interim analysis of SWOG0023
7.25.2005
Revision of Clinical Guidelines for the26
Management of Lung Cancer

V1532

Initial analysis of V1532 announced

 Second-line or third-line patients

Safety Committee for Food and Drugs

 Comparison of survival times with IRESSA anddocetaxel

Safety Committee meeting held Domestic clinical trial carried out tosatisfy the approval conditions

Noninferiority of gefitinib to docetaxel withregard to the overall survival time was notproven.
27

Handling of IRESSA in Japan
2.1.2007

Failure to prove a survival benefit

Handling of IRESSA in Japan

Initial analysis of V1532 announced

What is meant by approval “conditions”?

Safety Committee for Food and Drugs
Safety Committee meeting held By when must they be satisfied?

“It was concluded that, in general, there is no basis for
actively selecting gefitinib over docetaxel for treatment of→ In the 4 years and 7 months from approval
until initial analysis

patients with unresectable or recurrent non-small cell lungcancer who have already been treated with one or two
chemotherapy regimens.” What is the effect if the conditions are not met?

“In consideration of the fact that the status of manifestation→Even if there is failure to prove a survival
benefit, no changes are made in the approved
items.

of adverse reactions is as stated in the most recent package
insert, etc.,…it is appropriate to continue to apply the current
safety measures.”

28

29

30

5

In the clinical setting and status of promotional advertisingCharacteristics of the defendant’s
promotional advertising

Promotional
advertisingContent

Methods• Emphasis on efficacy• Emphasize that there
are few adverse
reactions• No mention ofinterstitial pneumonia• Directed at allconcerned parties（doctors, patients, mass
media）• Use any and all media• Pretence of providing
scientific information(use specialists)• Predating approval

31

32

Medical Tribune Nov. 22, 2001
Interview with Dr. Nagahiro Saijo, National Cancer

医師を対象とした宣伝

CenterPresented by
AstraZeneca

“If a survival benefit is found, then since ZD1839
is a drug that shows little toxicity, I think that it
will probably be a very useful drug for thetreatment of non-small cell lung cancer.”“Since the toxicity of molecularly targeted drugs is
not very strong, it can be surmised that reported
patient deaths are probably due to administrationof the drugs to patients in whom administration is
not indicated ZD1839 also causes few adverse
reactions, and for that reason I worry that it mightalso be used in the same manner.”
34

Medical Tribune Oct. 25, 2001
Interview with Dr. Kazuhiko Nakagawa and others
Fourth Department of Internal Medicine, Kinki University
Faculty of Medicine“With regard to adverse reactions, it is said that skin rash isvery commonly seen. Are there any other adverse
reactions observed that require caution?”“Although their incidences are not very high, diarrhea andhepatic dysfunction can be raised as other adverse
reactions. However, those reactions show very rapid
improvement if drug administration is discontinued for acertain time, and for that reason I don’t think they present
much of a clinical problem.”* There was absolutely no mention of interstitial pneumonia.

Informed consent document forthe patients
These symptoms
recovered when IRESSA
was discontinued ortreatment using anotherdrug, etc., wasadministered.

Cold-like symptoms due
to pulmonary
inflammation: Interstitial
pneumonia (dyspnea)
has been reported.
366

Intense media coverage predating
approval

Press release“The important point is that these results indicate
success in not causing the severe adverse reactions
that are commonly seen in patients being treatedfor lung cancer. The main adverse reactions
associated with administration of ZD1839 are mild
to moderate skin reactions, such as rash, dry skinand itchiness, and diarrhea. Serious adverse
reactions are rare, and are usually associated with
progression of the disease.”* There is no mention of interstitial pneumonia.



11.2.2001 “Targeted attack of cancer cells”
With regard to adverse reactions, there have been some casesof rash and diarrhea, but compared with conventional drugs
there is great improvement. (Asahi Shinbun newspaper )

5.25.2002 “Novel lung cancer drug, gefitinib, to be approved
with exceptional speed.”A drug that is said to act directly on receptors involved incancer proliferation, to have no great effect on normal cells,
and to cause few adverse reactions. (Tokyo Shimbun
newspaper)

6.3.2002“Hey, cancer! Don’t overrate yourself!!”“Astounded.” “Amazing.” Comments made by specialists inregard to a novel cancer drug that was reported at a meetingof the American Society of Clinical Oncology last month. (Asahi
Shinbun newspaper)
38

37

Intense media coverage predating
approval

A search service was used to conduct acomprehensive search for past articles in thenational newspapers (Asahi, Yomiuri, Mainichi,
Sankei), local newspapers, specialist journals,
and business magazines.



85 articles were found regarding IRESSA(gefitinib, ZD1839) written prior to its approval(before July 5, 2002).



However, not even 1 mentioned interstitial
pneumonia.
This is because the defendant did not provide
information regarding interstitial pneumonia.

The fervent wish of a patientStatement from Mr. Akio Chikazawa, a plaintiff:

39“In mid-July of 2002, I found an Internet site that discussed
IRESSA. Expressions like ‘A novel drug that is like a dream,’‘An innovative lung cancer treatment that causes few
adverse reactions and can be easily taken in your own
home,’ etc., grabbed my attention.”“…There were numerous quotes from many oncology
specialists in articles in various magazines and newspapers,
all offering only praise of IRESSA, such as ‘Its response rate
is several fold higher than that for any previous anticancer
drugs,’ etc., and no matter where I looked I found notroubling information. If such a fantastic anticancer drug
were to become available, it would obviously be my wish to40
find a way to give it to my daughter.”Comparison of IRESSA package
inserts
Current

InitialInstructions and Warnings

41

42

7

Initial package insert(reverse side)

Problems with the initial package
insertInterstitial pneumonia (incidence
unknown):
Interstitial pneumonia may manifest,
and for that reason the patient should be
carefully monitored. In the case of any
abnormality, administration of the drug
should be discontinued and appropriate
measures should be taken.

Content
There isabsolutely nowarning thatinterstitial
pneumonia canbe fatal.

Note 1)Adverse reactions that occurred only instudies other than the Phase II
International Collaborative Trial and the
U.S.A. Phase II Clinical Trial (each ofwhich administered the drug in a 250
mg/day group) were classified as“incidence unknown”.
43

Statement
columns
No statement in
the Warnings
column.
44

Current statements in the
Warnings column“fatal cases”
“occurrence of fatal results”
“will be fatal”

“fatal results”“death rate”Manifestation of “life-threatening” interstitial pneumonia
Necessary testing for initial symptoms and early diagnosis ofinterstitial pneumonia
Restrictions on the medical care staff and medical facilities able
to use the drug
Hospitalization for a certain time period or equivalentmanagement is necessary
Idiopathic pulmonary fibrosis, etc., increase the risk of death
Sufficient explanation regarding efficacy and safety, andinformed consent
Coadministration with other anticancer agents and radiotherapy
is prohibited
Administration to patients meeting clinical trial exclusion criteria
is prohibited46

Defense witness in the Eastern Japan Lawsuit
Nagahiro Saijo (National Cancer Center
Hospital East, Vice Chairman)
Conflict of Interest

Clinical trials









Private

47

V15-11 Trial 8.1998 – 5.2000 Efficacy and Safety Assessment Committee
V15-21 Trial 10.2000 – 5.2001 Efficacy and Safety Assessment Committee
V35-21 Trial 1.2001 – 10.2001 Efficacy and Safety Assessment Committee
V15-31 Trial 8.2002 – 4.2003 Efficacy and Safety Assessment Committee
V15-32 Trial 9.2003 – 10.2006 Post-production and distribution Clinical
Trial Coordination Committee
ＩＰＡＳＳ Trial 4.2006 Post-production and distribution Clinical
Trial Coordination Committee
Acted as an interlocutor for articles provided by AstraZeneca
Member of editorial committee of a magazine (SIGNAL) issued by
AstraZeneca
Attended numerous lectures sponsored by AstraZeneca, and received lecture
fees, etc.
48

8Defense witness in the Eastern Japan Lawsuit
Nagahiro Saijo (National Cancer Center
Hospital East, Vice Chairman)
Contributed to
IRESSA clinical
trials1.’01 – 10.’01

8.’98 – 5.’00

10.’00 – 5.‘01

Member of editorialcommittee of amagazine (SIGNAL)
issued by the
defendant
Lecturer, etc., for the
defendant

Defense witness in the Western Japan Lawsuit
Masahiro Fukuoka (Kinki University Faculty of
Medicine, Professor)

7.2002IRESSAapprovedFrom the development stage
 Attended IRESSA-related seminars (guidance fee of
100,000 Yen per session)Clinical trials
 Phase I clinical trial: Coordinating Investigator (contract
research fee: in excess of 10 million Yen)
 Phase II clinical trial: Coordinating Investigator(contract research fee: in excess of 10 million Yen)Donations to NPO, West Japan Thoracic Oncology Group（from Dec. 2000, Director; from May 2004, Chairman）
 Donation of approx. 20 million Yen each year

4.’06 8.’02 – 4.’03

9.’03 – 10.’06

1.’02 – 10.’06

11.’01 – 12.’06

49

50

51

52

53

54

9

55

56

Handling of IRESSA in Japan

Conflict of Interest

12.17.2004
1.2005 convened

7.25.2005
Revision of Clinical Guidelines for the57
Management of Lung Cancer

Members of the Guideline Planning Committee
clinical trials① N.Saijo
witness
WJTOG
clinical trials② M.Fukuoka witness
WJTOG
clinical trials③ S.Negoro
clinical trials④ S.Kudo
witness
clinical trials⑤ T.Tamura
WJTOG
clinical trials⑥ H.Tada
WJTOG
clinical trials⑦ T.Mitutomi witness
WJTOG⑧ H.Kato
WJTOG⑨ N.Yamamoto
58⑩ K.Hayakawa

Lawsuits regarding drug-induced
suffering due to IRESSA

Lawsuits regarding drug-induced
disaster due to IRESSA

 Western Japan Lawsuit Filed on July 15, 2004 (Osaka District Court) Plaintiffs・・・3 families, 1 survival victim
 To be concluded on July 30, 2010

1.

The Japanese government and AstraZeneca should recognize
their responsibility for the drug-induced suffering due to IRESSA
and issue an apology to the victims and their families.

2.

The Japanese government and AstraZeneca should pay
compensation to the victims and their families for the druginduced suffering due to IRESSA.
The re-examination to be started from July of this year should
review the contents of the approval of IRESSA.

Initial analysis of ISEL
Gefitinib Committee Meeting

Continued use of the drug was
permitted under the condition that the package
insert include a statement that, at the time of use,
reference should be made to the Japan Clinical
Guidelines for the Management of Lung Cancer. Nochanges were made in the approval content.
5.14.2005
Interim analysis of SWOG0023

3.

 Eastern Japan Lawsuit Filed on November 25, 2004 (Tokyo District
Court)
 Plaintiffs・・・3 families
 To be concluded on August 25, 2010
59

4.

A relief system for deaths due to adverse reactions to anticancer
drugs should be established, such as expanding the Relief
System for Sufferers from Adverse Drug Reactions.

5.

Verify the drug-induced suffering due to IRESSA and takeinitiatives to prevent recurrence of drug-induced suffering.

60

10