Essential Considerations for Requestinga Clinical Trial In-Country Representative<For Foreign Sponsors>

Japan CRO Association
Policy Committee
Monitoring Working Team

Date of Issue: June 30, 2017
Date of Revision: March 01, 2020

We do not undertake any responsibility for troubles, loss,
damage, and so on caused by using this document.
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Foreword

The following points are the most important to be understood and followed with regard to clinical trials
conducted in Japan. The regulatory authority in Japan has expressed significant concerns regarding thefollowing items, which must be performed without fail.

1.

In any clinical trial in Japan, safety information is reported to the regulatory authority no later than 7
calendar days, in the earliest case, after first knowledge of incidence. Reporting obligations arise at thetime of submitting a notification of a clinical trial plan.

2.

For safety information, the date the information is obtained by a foreign sponsor or by the ICCC,
whichever is earlier, is regarded as the date for obtaining initial information.

3.

A foreign sponsor and the ICCC must always include items on reporting safety information in any
contract between them after understanding the description above. If there is an affiliate company inJapan, the extent of its involvement must be confirmed.
In association with the guidance documents “Essential Considerations on
Requesting a Clinical Trial In-Country Representative <For Foreign Sponsors>
issued by Japan CRO Association, June 2017

Table of contents

Chapter 1.
Chapter 2.
Chapter 3.

Aim and scope of this document ..................................................................... 1
Items that should be checked at the time of outsourcing duties to ICCC ........ 1
Items that Foreign Sponsors need to understand when ICCC conducts
duties .............................................................................................................. 2

Chapter 1.

Aim and scope of this document

As globalization of drug development progresses, companies that do not have branches or subsidiaries inJapan are increasingly planning clinical trials in Japan. There is a regulatory system for these companies(hereinafter referred to as foreign sponsors) to promote drug development in Japan through outsourcing theoperations of clinical trials to Contract Research Organizations (CROs). The following is described in the
Ministerial Ordinance on Good Clinical Practice for Drugs (hereinafter referred to as J-GCP: Attachment 1-1).
(Clinical Trial In-Country Representative)
To take necessary measures to prevent the occurrence or spread of health hazards due to investigational
products, the person who intends to sponsor a clinical trial and resides outside Japan shall appoint a
person eligible for sponsoring the clinical trial on behalf of the person who intends to sponsor a clinical
trial from among persons residing in Japan (including the head of a Japanese business office of a foreigncompany) to have him or her (hereinafter referred to as “Clinical Trial In-Country Representative*”)conduct the procedures for sponsoring the clinical trial (J-GCP Article 15).
*: Clinical Trial In-Country Representative is referred to as an In-country Clinical Caretaker(ICCC) in this document.
ICCC, in place of the foreign sponsor, conducts all the procedures for the regulatory authority, medical
institutions, and so on; however, the final responsibility for the clinical trial resides in the foreign sponsor.
In contrast, along with the establishment of the Sakigake Designation System,* the need for CRO services isrecently increasing from venture companies outside Japan that have little experience in drug development inJapan. Thus, it is increasingly important for ICCCs to explain the Japanese environment including regulatory
requirements. This document describes the points that foreign sponsors should understand and follow, thedifferences in systems outside and inside Japan, and the unique regulatory requirements in Japan when a
CRO enters into a contract with a foreign sponsor to perform the duties of ICCCs. We hope that this guidance
document is useful for foreign sponsors.
*: Strategy of Sakigake by the Ministry of Health, Labour and Welfare (MHLW). Please referto the following link for further information.
http://www.pmda.go.jp/english/review-services/reviews/advanced-efforts/0001.html
While this document focuses on the considerations of clinical trials for drugs containing new active ingredients,
this can also be applied to clinical trials for medical devices and regenerative products, though some of therules differ.

Chapter 2.

Items that should be checked at the time of outsourcing duties to ICCCs

When a foreign sponsor outsources duties to an ICCC, items that should be considered come down to thefollowing two categories. If it is judged that a clinical trial that a foreign sponsor plans to outsource does notsatisfy the regulatory requirements in Japan, it is necessary for foreign sponsors and the ICCC to fully discuss
the foreseeable problems and measures before starting the duties.
➢

Organization and system in foreign sponsors: Foreign sponsors must have a system to be a sponsor
for clinical trials, including securing professionals with adequate expertise, establishing standard
operating procedures, and building processes on safety evaluation and on reporting to the regulatory
authority based on the rules in Japan, as specified in J-GCP Article 4.

➢

Appropriateness of conducting a clinical trial: At the time of conducting an outsourced clinical trial,
the sponsor should have completed the necessary studies including studies on the quality, toxicity, andpharmacological effects of its test drug.
Particularly in cases of foreign sponsors with little experience in drug development in Japan, studies on
the Japanese population are sometimes insufficient. Thus, an evaluation needs to be performed basedon the Basic Principles on Global Clinical Trials (Attachment 1-2), Basic Principles on Global Clinical1Trials (Reference Cases) (Attachment 1-3), Basic Principles for Conducting Phase I Trials in theJapanese Population Prior to Global Clinical Trials (Attachment 1-4), and Guidance for Establishing
Safety in First-in-Human Studies during Drug Development (Attachment 1-5). If the studies are
insufficient, consultation with the Pharmaceuticals and Medical Devices Agency (hereinafter referred toas PMDA) is recommended for the appropriateness of the Complete Clinical Data Package.
As for the timing of nonclinical safety studies enough to conduct clinical trials for pharmaceuticals, refer
to ICH M3 (R2) (Attachment 1-6).
If it is difficult for foreign sponsors to examine the above-mentioned items on their own, the examination canbe outsourced to a CRO.

Chapter 3.

Items that foreign sponsors need to understand when an ICCC conducts
its duties

It is important for foreign sponsors to have common grounds with the ICCC before starting duties tosufficiently understand Japanese systems and then to smoothly conduct clinical trials through building good
relationships with the ICCC. Major items necessary to achieve this are described below.
➢

Responsibilities of the ICCC: Responsibilities of the ICCC are not limited to submitting a notification of
the clinical trial plan or the Clinical Trial Notification (CTN) (see Attachment 2) and reporting adverse drug
reactions to the regulatory authority. It is necessary to understand that the foreign sponsor, through the
ICCC, is expected to take necessary measures to prevent the occurrence or spread of health hazards
due to investigational products. The ICCC is appointed as a person eligible for sponsoring the clinical
trial on behalf of the person who intends to sponsor a clinical trial (J-GCP Article 15: Attachment 1-1).
To do this, a foreign sponsor needs to agree with the ICCC in writing on a system that is necessary for
the ICCC to perform its duties and on the assignment of duties.
If a foreign sponsor has an affiliate company in Japan, it is recommended to reach a mutual agreement
including the ICCC for the roles and responsibilities of the affiliate company as necessary.

➢Handling of safety information: Obligations to report safety information arise on the day of submitting
initial CTN and lasts until obtaining approval or submitting notification for discontinuation of development.
Therefore, it is important to establish processes including providing information to the ICCC among
foreign sponsors, medical institutions, and ICCCs before submitting the CTN so that safety information isreported appropriately within the period specified by the law. The following points should be considered.
(For details, see Attachment 3, Collection, Reporting, Notification, and Definition of Seriousness for
Safety Information as well as Reporting Time Frames for Safety Reports.)
✓

✓

✓

✓

The date the information is obtained by a foreign sponsor or by the ICCC, whichever is earlier, isregarded as the date for obtaining initial information. It is reported to the regulatory authority within
7 to 15 days of this date depending on the situation.
All safety reports to the regulatory authority in Japan require the use of a specified form. Meretranslation of the Council for International Organizations of Medical Sciences (CIOMS) Form is not
accepted; therefore, the information needs to be customized for reporting to the regulatory
authority. Also, opinions of foreign sponsors, which are not described in the CIOMS Form, need tobe reported. Therefore, the reporting procedure must be agreed upon with the ICCC so that thereports can be submitted within the reporting deadline.
Other than individual case reports, reports of actions outside Japan and drug research reports are
submitted to the regulatory authority. Therefore, the scope and the operating procedure need to be
decided.
The definition of “known” and “unknown” can sometimes differ between Japan and the country of aforeign sponsor. Events to be reported and reporting deadlines must be checked so that there is2

no missing report to the regulatory authorities inside and outside Japan [Enforcement Regulations
for Pharmaceuticals and Medical Devices (PMD) Act Article 273/ reporting adverse drug reactions
and so on related to clinical trials for drugs].
Refer to ICH E2F for the Development Safety Update Report (DSUR) [Notification 1228 No. 1 of the
Evaluation and Licensing Division (ELD), Pharmaceutical and Food Safety Bureau (PFSB), Ministry of
Health, Labour and Welfare (MHLW), dated December 28, 2012: Attachment 1-7].
➢

Compensation and legal liability: J-GCP Article14 states that the person who intends to sponsor aclinical trial shall beforehand take necessary measures such as purchasing insurance in preparation forcompensation to the subject in the event of trial-related injuries (including those attributable to the duties
performed by the contractor) (J-GCP: Attachment 1-1). The way of consideration for compensation andlegal liability sometimes differs between outside and inside Japan; therefore, to give compensation
appropriately, a system needs to be established by receiving sufficient explanation from the ICCC. The
main points are described below.
✓

✓
✓
✓
✓
✓
✓

A subject has the right to claim payment for damage based on legal liability from a sponsor, a
medical institution, and others even after obtaining compensation based on the compensation
rules of the sponsor.
Compensation consists of three parts: medical fee, medical allowance, and payment forcompensation.
A subject can receive compensation when the causality between the conduct of a clinical trial andthe health damage is not reasonably excluded.
Compensation for absence from work is not covered; however, this does not apply when healthypeople are studied.
Compensation is not offered for failing to offer expected effects by a drug or other benefits.
The process of paying compensation to a subject must be clarified.
An overview of compensation for explanation to a subject needs to be prepared beforehand andapproved by the IRB.

Note: It should be sufficiently understood that “compensation” and “legal liability” have the following
difference in meaning in Japan. As far as Japan CRO Association surveyed, no English translation
clearly differentiates between “compensation” and “legal liability.” Therefore, when a foreign sponsor
discusses with concerned parties in Japan, the meaning of the words in the context needs to be clarified.
In this document, each word is used according to the following meaning:
Compensation: To make up the loss due to damage, when something caused damage during alegal activity.
Legal liability:
To make up the loss due to damage when an illegal activity caused damage tothe others.
➢

Expenses for clinical trial — the point system: The point table is a unique pricing tool in Japan forclinical trial-related expenses. Since the contract of clinical studies and so on for drugs and the others innational university hospitals (notification) (July 2, 1999) has been issued, national university hospitals
have started using the pricing table. After that, many medical institutions followed, calculating expenses
based on the pricing table. Currently, this system is adopted by almost all the medical institutions inJapan as a standard system for calculating clinical trial-related expenses. The calculation method differsin minor details depending upon the management of each medical institution; thus, the same pricing
table is not necessarily used.

➢

Expenses for clinical trial — system for medical expenses combined with treatment outside
insurance coverage: In Japan, when medical treatment covered by health insurance (insurance
covered treatment) and the other treatment (treatment outside insurance coverage = self-financed
treatment) are combined, it is called mixed medical treatment. The mixed medical treatment is notallowed in principle by the regulation. If the mixed medical treatment is performed, expenses for all the
medical treatment including insurance covered treatment should be paid by a patient. System to define3the coverage of medical expenses combined with treatment outside insurance coverage permits
insurance coverage of the expenses that are common medical treatments (such as medical
examinations, tests, drug administrations, hospitalization fees) when the treatment outside insurance
coverage that is designated by the Ministry of Health, Labour and Welfare is combined with insurance
covered treatment.
In medical treatment in clinical trials for a drug, a sponsor pays all the expenses for examination andimaging diagnosis and expenses for administering or injecting study drugs as well as the same type ofdrugs with the same effects as that of the study drugs through the clinical trial period (from day of starting
administration of the study drug to the end of its administration).
This system, which clarifies assignment between medical insurance and responsibility of the company, isa unique rule in Japan.
➢

Procedure of clinical trials: Because of the unique clinical trial environment in Japan, foreign sponsors
should understand such procedures by receiving prior sufficient explanation from ICCCs. An agreementin the procedure with the ICCC needs to be reached beforehand. The main points are described below.
✓
✓

✓
➢

In performing clinical trials, the ICCC, not foreign sponsors, enters into a contract with a medical
institution and not with an investigator.
When entering into a clinical trial contract with a medical institution, the contents of the contract
need to satisfy items specified in J-GCP Article 13 (refer to Attachment 1-1, J-GCP). Sometimes a
medical institution asks to follow its rules including contract procedures and forms of contract.
Agreement regarding procedure for the review and approval of the contract must be reached with
the ICCC.
Because of the unique handling of clinical trial expenses in Japan, agreement regarding contents
and procedure for payment must be reached with the ICCC.

Clinical Trial Notification:
✓
✓

✓
✓

In Japan, not the approval system but the notification system is used.
In case of CTN for drugs, which are administered to humans for the first time in Japan and with a
new active ingredient, a new administration route, and a new combination for medical treatment, it
will be under a 30-day investigation by PMDA as set by the law. It is necessary to answer theinquiries from PMDA within a limited time; therefore, it is desirable to establish a procedure
beforehand between foreign sponsors and the ICCC for answering the inquiries including roleassignment and translation works.
Even in the Nth submission of CTN, it is necessary to answer to the inquiries from PMDA within alimited time; therefore, it is desirable to establish the similar procedure mentioned above.
In case of submitting CTN, it is necessary to register the relevant information of clinical trial at
JRCT (Japan Registry of Clinical Trials). It is also required to register the results of clinical trials
within one year after completing the trial. (Refer to Attachment 1-8 on Registration of clinical trial
status.)➢ Labeling of study drug: A sponsor must indicate the following items in the Japanese language on thecontainer or package of the study drugs:
On the package✓ Statement of “For clinical trial use only”✓ Name and country of the sponsor as a foreign manufacturer and name and address of the ICCC
✓ Chemical name or identification code
✓ Manufacturing number or manufacturing code
✓ Information on storage method, expiration date, etc., if necessary

4The sponsor shall not indicate the following information in the documents attached to the study drugs, on
the study drugs, or on their containers or packages (including the inner packages):✓ Proposed brand name✓ Proposed indications✓ Proposed administration and dosage
When a study drug labeled in English is used in a multinational clinical trial, this is described in the
protocol, and approval from the IRB needs to be obtained (J-GCP Article 16) (refer to Attachment 1-1,
J-GCP).
When the description is in English, it is necessary to prepare another document in Japanese that
explains the dissolving method of the study drug and other handling methods (refer to J-GCP for
guidance).

5

Attachment 1
Guidelines, Guidances, and Others to Refer to for Judging the Validity of Conducting a Clinical Trial
1. J-GCP
Japanese version (Revised on January 22, 2016):
http://law.e-gov.go.jp/htmldata/H09/H09F03601000028.html
English version (December 28, 2012):
http://www.pmda.go.jp/files/000152996.pdf
2. Basic Principles on Global Clinical Trials
Japanese version:
English version:

http://www.pmda.go.jp/files/000157000.pdf
http://www.pmda.go.jp/files/000157900.pdf

3. Basic Principles on Global Clinical Trials (Reference Cases)
Japanese version:
English version:

http://www.pmda.go.jp/files/000157901.pdf
http://www.pmda.go.jp/files/000208185.pdf

4. Basic Principles for Conducting Phase I Trials in the Japanese Population Prior to Global Clinical
TrialsJapanese version:
English version:

http://www.pmda.go.jp/files/000157480.pdf
http://www.pmda.go.jp/files/000157777.pdf

5. Guidance for Establishing Safety in First-in-Human Studies during Drug Development
Guidance for Establishing Safety in First-in-Human Studies during Drug Development Q&A
Japanese version:
Japanese version:
English version:

http://www.pmda.go.jp/files/000208199.pdf
http://www.pmda.go.jp/files/000208200.pdf
http://www.pmda.go.jp/files/000208201.pdf

6. Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing
Authorization for Pharmaceuticals [ICH M3 (R2)] (timing of nonclinical safety studies for clinical trials
for pharmaceuticals)Japanese version:
English version:

http://www.pmda.go.jp/files/000156948.pdf
http://www.pmda.go.jp/files/000156908.pdf
http://www.pmda.go.jp/files/000156128.pdf
http://www.pmda.go.jp/files/000156455.pdf

7. Development Safety Update Report (PFSB/ELD Notification 1228 No. 1, dated December 28, 2012)
Japanese version:
English version:

http://www.pmda.go.jp/files/000156366.pdf
http://www.pmda.go.jp/files/000156623.pdf (ICH E2F)

8. Registration of clinical trial status (MHLW Notification dated March 26, 2018)
Japanese version: http://www.pmda.go.jp/files/000223575.pdf
English version: not available or not found6

Attachment 2
Notifications Related to a Clinical Trial (cited and translated from GCP Pocket References 2016)

Notifications related toa clinical trial
2. Notification ofchange in a clinicaltrial

1. Clinical trial plan
notification
Timing of notification(notification of plan toclinical trial agreement)
1. Clinical trial plan
notification--

3. Clinical trial
completion
notification

3. Clinical trial completion
notification (notification for
discontinuation of a clinical
trial/development)

If a drug with a new active ingredient/new administration route/new
combination ratio is administered to humans for the first time in Japan 30 days*
Other than above 2 weeks

Drug

New active ingredient, new administration route, new combination drug, newindication/effect, new dosage/administration, same active ingredient as the new
drug within reevaluation period, biological product, recombinant drug

Attachment

Protocol, informed consent document, (CRF sample)**, investigator’s
brochure, document describing scientific justification-

2. Notification of change
in a clinical trial

PMD Act Article 80-2 paragraph 2
PFSB/ELD Notification No. 0531-8

Timing of notification

Timing of notification-

Minor items: Submit all at once at a tentative deadline of 6 months after
change.***Other items: Notify before the change, refer to reference document (4)-2 fordetails.

Notify without delay at the following time points- Clinical trial completion notification: At the time of obtaining completion
notification and return of study drug at all the medical institutions- Notification for discontinuation of a clinical trial: At the time of
discontinuation of each clinical trial for each clinical trial plan notification- Notification for discontinuation of development: After the decision to
discontinu development of test product*:Around 30 days for microdosing studies**: Submission is unnecessary if items that should be described in CRF can be sufficiently understood from protocol***: Changes only in subinvestigators can be submitted 1 year after change. Change in the amount of study drugs and the number of subjects (the numberof subjects actually assigned in Japan) can be notified at the end all together.

Laws and regulations related to Clinical Trial Notification in Japan✓

Definition of a clinical trial [Pharmaceuticals and Medical Devices (PMD) Act Article 2 paragraph 17]
Among the data that should be submitted for approval of the application, this study aims to obtaindata on the test results in a clinical study (clinical trial is a unique legal term in Japan)✓

Submission of the Clinical Trial Notification (PMD Act Article 80-2, paragraph 2, Enforcement
Regulations for PMD Act Articles 268, 269, 270, and 271)✓

30-day investigation (PMD Act Article 80-2, paragraph 3)

7

Attachment 3
Collection, Reporting, and Notification of Safety Information; Definition of Seriousness for
Safety Concerns; and Reporting Deadline for Safety Reports(Cited and translated from GCP Pocket References 2016)
Collection and reporting of safety
information (clinical trials)- Inside and outsideJapan- Literature information- Academic meeting
information

SponsorCollecting
information-

Collection and evaluation ofsafety information
Discussing and performing
implementation measures

Adverse drug
reaction report(individual andperiodic reports)

Subjects

Adverse drug
reaction report(individual andperiodic reports)

SAE report
Initial report:
emergency report+ second report:
detailed report

Investigator
Reporting information
Revision of
ICF/Reconsent ofrevised ICF

Head of a medical
institution

When safety information is obtained from otherinstitutions and so on

Approval of clinical
trial continuation

IRB

When SAE occurs at the medical institutions
conducting the clinical trial

8[PMDA]- Collection, analysis, andevaluation of information[MHLW]- Planning and performing theimplementation of safetymeasures

SAE report

Notification

Reporting

Regulatory
authority

Exchanging
information

Safety information

WHO monitoring center
Regulatory authority ineach county

Notification of safety information
1. From a sponsor
Head of a medical
institution

Collection of safety
information[Serious adverse drug reactions
and so on]
Article 20, paragraphs 2 and 3[Information that affects decisions]- Annually: periodic report (unknown and known)[Within 3 months of the end of thereporting period][Serious adverse drug reactions and so on]*PMD Act Article 80-2 paragraph 6, Enforcement
Regulations Article 273
death/life threatening (unknown)
serious adverse reactions other than thoseabove (unknown)and death/life threatening (known)- Annually: periodic report (unknown and known)[Within 2 months of the end of the reporting
period]Article 54- Immediately: Checking for intention of continuation
and written records*- Quickly:
Revision of the informed consent
document and repeated consent of a
subject(requiring approval from the IRB)

* In case of clinical trial for approval of partial change- Periodic report only for cases outside Japan (theother cases are managed by post-marketing reports)

Regulatory
authority

Sponsor- Immediately: individual report (unknown)- 7 days:- 15 days:

Article 32
Whether continuation of a clinical trial ispermitted or not

Investigator

Within 30 days

Article 40 paragraph 1

Subject

1. Serious adverse drug
reactions and so on

Direct notification is also possible

Revision of investigator’s brochure, protocol, and so on depending on content

Notification of safety information
2. From an investigator

Sponsor- Immediately: unknown and known(Emergency report and detailed report)

Article 32
Whether continuation of a clinical
trial is permitted or not[In case of adverse drug reaction and soon]*
PMD Act Article 80-2 paragraph 6,
Enforcement Regulations Article 273- 7 days:- 15 days:- Annually:[Information that affects decisions] Article 54

Subject

Investigator[SAE]
Article 48 paragraph 2

Article 31 paragraph 2- Immediately: Checking for intention ofcontinuation and written records- Quickly:
Revision of the informed consent
document and repeated consent
of a subject (requiring approval
from the IRB)

9

Regulatory
authority

Head of a medical
institution

2. Serious adverse event(SAE)

death/life threatening (unknown)
serious adverse reactions otherthan those above (unknown) anddeath/life threatening (known)
periodic report (unknown and known)[Within 2 months of the end of thereporting period]* In case of clinical trial for approval of partial change- Periodic report only for cases outside Japan (theother cases are managed by the post-marketing
report)Definition of Seriousness (Japan vs. ICH)
Enforcement Regulations
Articles 253 and 273

ICH

Death

Results in death

Disabling

Results in persistent or significant
disability/incapacity

Life-threatening cases

Life threatening

Cases that can lead to disabling
Cases that require hospitalization or
require prolongation of existing
hospitalization for treatment (InEnforcement Regulations Article 253,
cases listed in 3 or 4 above are excluded)

Requires inpatient hospitalization or
prolongation of existing hospitalization

Cases that are serious in accordancewith cases listed in 1–5 above

Other medically important conditions

Congenital disease or anomaly in adescendant

Is a congenital anomaly/birth defect10Safety Report: Reporting Time Frames
1. Reporting items to the regulatory authority (Regulations Article 273)
New active ingredientCases outside Japan
Expectedness

Cases inside Japan(clinical trials inJapan)(clinical studies outside
Japan, post-marketing
spontaneous reports
outside Japan, and soon)

Individual(no later than 7 calendar

Individual(no later than 7 calendar

days after first knowledge)

days after first knowledge)

Periodic (annually)
Individual

Periodic (annually)
Individual(no later than 15 calendar
days after first knowledge)(no later than 15 calendar
days after first knowledge)

Periodic (annually)
Individual

Periodic (annually)
Individual(no later than 15 calendar
days after first knowledge)
Periodic (annually)
Periodic (annually)(no later than 15 calendar
days after first knowledge)
Periodic (annually)
Periodic (annually)

Seriousness

Fatal orlife-threatening cases
Unexpected(unknown)
Other serious cases

Expected (known)

Fatal orlife-threatening cases
Other serious cases

The date the information is obtained by a foreign sponsor or by the ICCC, whichever isearlier, is regarded as the date for obtaining initial information.

11

2. Notification items to investigators and heads of medical institutions(GCP Ordinance, Article 20 paragraphs 2 and 3)
Cases outside Japan
Expectedness

Unexpected(unknown)

Cases inside Japan(clinical trials in Japan)

Seriousness

Individual(immediately)
Periodic (annually)
Individual(immediately)
Periodic (annually)
Periodic (annually)
Periodic (annually)

Fatal orlife-threatening cases
Other serious cases

Expected (known)

Fatal orlife-threatening cases
Other serious cases(clinical studies outside
Japan, post-marketing
spontaneous reports
outside Japan, and soon)

Individual(immediately)-*
Individual(immediately)
-*
-*
-*

*: Opinions and so on based on the total evaluation of accumulated cases for serious
adverse drug reactions and others in clinical studies outside Japan are described in theDevelopment Safety tside Japan are described in the Development Safety Update Report.

12