Japanese CTD/eCTD Basics
Lifecycle
of the regulated medicinal products
in Japan
1.
Discovery
2.
Preclinical
3.
Clinical
4.
Dossier
5.
Authorities
6.
Approval
7.
Manufacturing
8.
Export & Import
9.
Pricing & Reimbursement
10.
Marketing
11.
Postmarketing
12.
Reevaluation and reexamination
Note: The Table above represents the twelve phases of the lifecycle of the medicinal
products (medicines, quasi-medicines, cosmetics and medical devices)
regulated in Japan. The documents from the Japan regulatory process
milestone series - or Milestone documents provide concise up-to-date
description of each phase. Further details could be found in the Key and Basic
documents available in the JKS Document Store or by enquiring directly to JKS
at regulatory@jouhoukoukai.com.
Common Technical Document (CTD) and
Electronic Technical Document (eCTD)
Table of Contents
1. Brief history
2. Legislation
2.1 Notifications concerning the current legislation on the
preparation of Gaiyo
2.2. Notifications concerning the CTD
3. Concept and specifics of the Japanese CTD
3.1. Differences in the scope
Table 1. Scope of CTD (for Japan)
3.2. Differences in the content
3.3. Differences in the technical execution
3.4. Differences in the data correlations
Table 2. Relations between the Gaiyo parts and CTD modules
4. CTD and e-CTD
4.1. Architecture of e-CTD
4.2. Specifics of the Japanese e-CTD
Table 3. Acceptable electronic carriers for e-CTD
5. Development and timeline for implementation
5.1. Participants in the development of the CTD from Japan
5.2. Timeline for implementation of CTD in Japan
5.3. Implementation status
Table 4. Implementation status of CTD in Japan
As a party to ICH process Japan is fully involved in the development and
implementation of the Common Technical Document (CTD).
1. Brief history
The idea for harmonization of the documentation required for submission
for approval of new medicinal products had been discussed at the earlier
meetings of the ICH initiative. However, at the meeting in Tokyo, October 1990
the Steering Committee concluded that agreement of uniform format of
application might be feasible only after reaching a practical solution for the
reporting of the results of the clinical studies.
The efforts in this direction led to the ICH-wide adoption of the ICH
Guideline (E3: Step 5) "Structure and Content of Clinical Study Reports". In
Japan the E3 Guideline was adopted in May 1996 by PAB/PCD Notification
No. 335. The implementation of the guideline allowed a simplified compilation of
worldwide clinical study reports, thus providing more uniformity of the data
included and the submission to the regulatory authorities.
Defining moment for the further harmonization - both in terms of regulatory
requirements and technical detail of the data presentation was the adoption of
the ICH Harmonized Tripartite Guideline: "Ethnic Factors in the Acceptability of
Foreign Clinical Data" on the acceptance of data generated in foreign countries
for submission in Japan. The two regulatory documents - PMSB Notification
739 (August 11, 1998) "On the Handling of Clinical Data on Pharmaceuticals
Generated in Foreign Countries" and the PMSB/ELD Notification 672 (August
11, 1998) "On Ethnic Factors in the Acceptability of Foreign Clinical Data" not
only legalized the bridging trials in Japan, but created a platform for the
integration of foreign datasets into Japanese dossier.
It should be noted that the harmonization between European and North
American regions is and it is expected to proceed with fewer difficulties
compared with the process of harmonization between Japan and either EU or
US. Aside from the obvious cultural and ethnical differences, another significant
obstacle is the use of different language and scripting system. The significance
of the problem became evident during the development of the Japanese version
of MedDRA - MedDRA/J. It is believed that the expertise gathered since the
introduction of MedDRA/J in 1999 would be utilized in testing and
implementation of CTD.
Within the architecture of the ICH topics the CTD belongs to topic M
(Multidisciplinary Topics) and is codified as M4. The safety part - M4S Safety:
The non-clinical section of the application is the CTD domain where the
Rapporteur is from Japan - the Topic Leader of the Expert Working Group is from
JPMA.
2. Legislation
2.1 Notifications on the regulations for the preparation of Gaiyo
There was a number of notifications from the MHLW specifying the details
about the content and technical preparation of the documentation set to be
submitted with the application for approval. The key guideline was
* PAB/NDD Notification No. 21 (dated March 31, 1992)
"The Guiding Principles for Preparing the Document Summary
(GAIYO) of Applications for Approval of New Drugs"
In 1998 several notifications were issued to reflect the major change
brought by the allowance to use foreign data for submission in Japan and the
impact and evaluation of the ethnic factors:
* PMSB Notification No. 739 (August 11, 1998)
"On the Handling of Clinical Data on Pharmaceuticals Generated
in Foreign Countries"
* PMSB/ELD Notification No. 672 (August 11, 1998)
"On Ethnic Factors in the Acceptability of Foreign Clinical Data"
The specification of the documents necessary to prepare and submit an
Application for Manufacture and Import Approval was further formulated in the
following notifications from MHLW:
* PMSB Notification No. 481 (dated April 8, 1999)
"Applications for manufacturing and import approval of medicinal
products"
* PMSB/ELD Notification No. 666 (dated April 8, 1999)
"Items to be noted in applications for manufacturing and import
approval of medicinal products"
as the above Notification No. 481 became the basic regulatory document
for the preparing of documents for submission until mid-2001.
The later amendments were enforced by the
* PMSB Notification No. 663 (dated June 21, 2001)
Handling of the documents which should be attached to
approval application of medicinal products
The Notification No. 663 was issued simultaneously with the Notification No.
899 (see also below). During the transitional period until July 2003 no other
changes were introduced in the requirements for preparing the Gaiyo, and the
applicants who have opted to submit the format of Gaiyo followed the prescribed
in Notification No. 663 standard. At the same time applicants who have decided
to submit simultaneously their documentation in CTD format followed the
standards specified below.
2.2. Notifications concerning the CTD
The following is a list of the notifications from the authorities to the Public
Health Bureaux of the Prefectural Governments and to the industry associations
(FPMAJ, etc. ) in relation with the introduction of the CTD in Japan:
Notifications from MHLW
* PMSB/ELD Notice (dated March 15, 1999)
"Results of the ICH Japan-US-EU meeting in Brussels (Steering
Committee/Expert Working Groups meetings)"
* PMSB/ELD Notice (dated October 12, 1999)
"Results of the ICH Japan-US-EU meeting in Washington
(Steering Committee/Expert Working Groups meetings)"
* PMSB/ELD Notification No. 1673 (dated December 1, 1999)
"Draft of the Guideline for the preparation of the Evaluation
Reports in the CTD"
* PMSB/ELD Notification No. 1835 (dated December 22, 1999)
"Draft of the Guideline for the preparation of the Summary of the
non-clinical tests reports in the CTD"
* PMSB/ELD Notification No. 932 (dated August 7, 2000)
"Draft for the Guidelines for CTD"
* PMSB/ELD Notification No. 136 (dated February 27, 2001)
"Problems in the selection of control groups in clinical trials"
* PMSB/ELD Notification No. 350 (dated April 10, 2001)
"Handling of the documents to be attached to the approval
applications for new medicinal products"
* PMSB Notification No. 663 (dated June 21, 2001)
Handling of the documents which should be attached to
approval application of medicinal products
* PMSB/ELD Notification No. 899 (dated June 21, 2001)
"On the organization of application dossier appended to new
pharmaceuticals application (NDA) for approval"
* PFSB/ELD Notice (dated October 22, 2001)
"Specific Q & A on CTD - Quality Guideline for Japanese
Submission"
* PFSB/ELD Notice (dated April 30, 2002)
"e-CTD (draft)"
* PFSB/ELD Notice (dated August 13, 2002)
"Mock-up to compile general source of active
substance/preparation for CTD quality guidelines"
* PFSB/ELD Notice (dated November 8, 2002)
"Q&A on ICH CTD - Topic M4"
* PFSB Notification No. 1115003 and 1115004 (dated November 15,
2002)
"Partial revision of the standards about the range of medicinal
products [Revised related notifications 00910406, 00910408,
00900684, 00980358, 20000481, and 20010374]"
* PFSB/ELD Notice (dated January 28, 2003)
"Regarding Q & A on how to produce data submitted with
application forms for the approval of manufacturing or import of
new drugs [related notices on Topic M4 and Notice 20011009]
* PFSB/ELD Miscellaneous Communication (dated June 4, 2003)
"On the soliciting opinions and information in relation to the "Use of
electromagnetic tags and electronic signatures in the process of
application for manufacture or import approval of new drugs (draft)"
* PFSB/ELD Notification No. 0604001 (dated June 4, 2003)
"Electronic Common Technical Document Specification" [corrected
by Notice 20030787]
* PFSB/ELD Notice (dated June 4, 2003)
"Q & A related to the "Electronic Common Technical Document
Specification"
* PFSB/ELD Notice (dated June 6, 2003)
"On the proper preparation of the Electronic Common Technical
Document (draft)"
* PFSB/ELD Notice (dated June 13, 2003)
"Revision of the Electronic Common Technical Document
Specification" [revised notice 20030676]
* PFSB/ELD Notification No. 0701004 (dated July 1, 2003)
"Partial revision of 'How to produce data submitted with application
forms for the approval of manufacturing or import of new drugs'"
[divisional input part 1/5] (main text)
* PFSB/ELD Notification No. 0701004 (dated July 1, 2003)
"Partial revision of 'How to produce data submitted with application
forms for the approval of manufacturing or import of new drugs'"
[divisional input part 2/5] (Annex 1)
* PFSB/ELD Notification No. 0701004 (dated July 1, 2003)
"Partial revision of 'How to produce data submitted with application
forms for the approval of manufacturing or import of new drugs'"
[divisional input part 3/5] (Annex 3)
* PFSB/ELD Notification No. 0701004 (dated July 1, 2003)
"Partial revision of 'How to produce data submitted with application
forms for the approval of manufacturing or import of new drugs'"
[divisional input part 4/5] (Annex 4)
* PFSB/ELD Notification No. 0701004 (dated July 1, 2003)
"Partial revision of 'How to produce data submitted with application
forms for the approval of manufacturing or import of new drugs'"
[divisional input part 5/5] (Annex 5)
3. Concept and specifics of the Japanese CTD
There are no differences in the perception in Japan of CTD as an
internationally adopted convention for harmonization of the format for reporting
to the authorities of the approval data. However, certain differences and specifics
can be identified in term of the content and technical execution:
3.1. Differences in the scope
As ICH parties agreed it, initially the scope for implementation of CTD
would be
Table 1. Scope of CTD (for Japan)
Targeted
Remained out of scope
Prescription medicines
New Chemical Entities &
Biologicals (1)
New biologics (2)
New administration route (3)
New indications (4)
New dosage forms (5)
New doses (6)
Additional formulation
Generics
Non- prescription medicines
All
Note: The number is brackets represent the prescription medicines in term
of categories for submission according to the Attached Table 2 (1) -
Displayed by category (class)
3.2. Differences in the content
so far two outstanding differences can be seen in relation to the contents of
CTD:
A) Module 1 - the difference and national specifics of the Module 1
are pre-determined by the concept of CTD. As decided and
described in ICH Harmonized Tripartite Guideline "Organization of
the Common Technical Document for the Registration of
Pharmaceuticals for Human Use" - recommended for adoption at
Step 4 of the ICH Process on November 8, 2000 by the ICH
Steering Committee. According to the pyramid-like organization of
the CTD, Modules 2, 3, 4 and 5 comprise the CTD itself, while the
"top" Module l is nationally-specific, as its content is to be prepared
under the national or regional requirements. The data to be
included in Module 1 are equivalent to the data at present required
to be included in Part "A" of Gaiyo - see Table 2 below.
According to PMSB/ELD Notification No. 899 the Japanese
Module 1 has to contain information and data organized into the
following structure:
Module 1 (Administrative Information and Prescribing Information)
1) Module 1 Table of Contents
2) NDA Application Form (Format based on Articles 17,
and 27, of the Enforcement Regulations of the
Pharmaceutical Affairs Law)
3) Certificates (including statement by responsible person
supervising collection and preparation of application
data, documents related to GLP and GCP, copy of a
written contract of co-development)
4) Patent Status Information
5) Origin, background of the discovery and research, and
development history
6) Conditions of use in foreign countries
7) List of other pharmaceuticals with similar
pharmacological effect(s) and/or indication(s)
8) Draft Package Insert (Labeling)
9) Documentation of non-proprietary name
10) Format for designation of poisonous/deleterious
pharmaceutical ingredients
11) Draft protocol for Post-Marketing Surveillance (if
necessary)
12) List of information/documents complied in the dossier
13) Others
Another difference in the content and requirements is related to the
environmental risk assessment reports - unlike EU and US regions, the reports
are not required to be included in the Japanese Module 1 contents.
B) Module 5
Although the CTD modules 2 to 5 are envisioned as for global use and thus
much more standardized, there are provisions allowing inclusion of data
(information, description) which regional authorities have considered
unacceptable to remove from the application documentation. One example is the
provision that fro NDA submission in US the Integrated Summary of Safety (ISS)
and the Integrated Summary of Effectiveness (ISE) would be included along with
the NDA summary. However, as in the case with the US-specific requirement for
inclusion of SAS datasets (see below), those regional inclusions might be
omitted when the CTD modules are used for global submission.
Similarly, in Japan there are some regional requirements determined by the
use of Japanese language (described in detail below in the part for e-CTD) and
by the regulatory framework. The Notification No. 899 provides the outline for
the additional requirements derived from the Japanese regulations and mostly
related to Module 5 - the Part 5.3.7 Patient Data Listings:
- Patient data listing in the pivotal studies for dose selection and
efficacy confirmation.
- Patient data listings of the subjects with adverse reactions in all
the clinical studies included (submitted).
- Patient data listings of the subjects with serious adverse events
in all the clinical studies included (submitted).
- Patient data listings of the subjects with abnormal laboratory
values in all the clinical studies included (submitted).
- The charts showing the changes of laboratory values in all the
clinical studies included (submitted).
Briefly, the Japanese requirements mandate submission of tabulated
listings of all subjects of the trials.
3.3. Differences in the technical execution
Regarding the language requirements, the tabulation and figures in the Part
5.3.7 Patient Data Listings should be presented in Japanese. However, a
representation in English is acceptable as long as comprehensive glossaries of
terms and abbreviations are prepared from existing databases in English. In
principle, the only other than Japanese language acceptable is English and if the
source database is compiled in other language, it should be consider
presentation only in Japanese.
3.4. Differences in the data correlations
At present the data to be included in Gaiyo are to be organized and
grouped according to the requirements as stipulated in the Attached Table 1:
A. General
B. Physico-chemistry, tests, assays
C. Stability
D. Toxicity
E. Pharmacology
F. ADME
G. Clinical trials
Although the regulations have been amended (see the Legislation above)
to specify requirements for different classes of prescription medicines - such as
radiopharmaceuticals or to describe the data, which might be omitted in the
application, the basic groups from A to G have been preserved.
Starting with the implementation of the CTD the data should be rearranged
in different order, detailed in the Notification No. 899 . The Table 2 gives a
schematic overview on how the parts of Gaiyo are related to the structure of
CTD.
Table 2. Relations between the Gaiyo parts and CTD modules
CTD Modules1
Corresponding
parts
Gaiyo2
1
Regional
administrative
Information
A. Data on the origin and
background of the discovery,
and conditions of use in
foreign countries, etc.
2
Table of
Contents
(No corresponding part in Gaiyo)
3
3.2.S 1-6
3.2.P. 1-7
B. Data on physical and chemical
properties, specifications,
testing methods, etc.
3.2.S 7
3.2.P. 8
C. Data on stability
4
4.2.1-4
D. Data on acute, sub-acute and
chronic toxicity, teratogenicity
and other types of toxicity
4.3.1-7
E. Data on pharmacological
effects
4.4.1-7
F. Data on absorption,
distribution, metabolism and
excretion
5
5.3.1
5.3.2
G. Data on results of clinical
studies
5.3.3-5
1 Based on the Reference Table 1-1 to PMSB Notification No. 899
2 Based on the Attached Table 2-1 to PMSB Notification No. 481
4. CTD and e-CTD
The Steering Committee signed a Step 2 for "Testing the electronic
Common Technical Document (eCTD)", which contains a specification document
and the DTD standard (Document Type Definition). This allowed the eCTD to
undergo "real case" testing by all 6 parties, as the v. 3 of the eCTD specifications
was adopted in Japan in July 2003 (see Table 4 below).
4.1. Architecture of e-CTD
The structure of the electronic submission in terms of organization and
navigation should be consistent with the modular structure of the Common
Technical Document. As defined in the Electronic Common Technical Document
Specification (ICH eCTD Specification v. 3) the DTD (Document Type Definition
- currently v. 3) describes the structure of e-CTD with the same relations
between Module (primarily national) and Modules 2 - 5 (primarily global) as in
CTD. Some of the global module may contain data not required for submission in
other regions: e.g. the SAS datasets required to be submitted with NDA in US
(according to the 21 CFR Section 314.50) are not necessary in Japan.
4.2. Specifics of the Japanese e-CTD
There are several characteristics of the Japanese e-CTD, which are more
related to the structure and the technical execution of the CTD, and in much
lesser degree indicate any differences with the general CTD concept.
* Multiple language support
The e-CTD specification allows use of multiple languages in the CTD
documents and use of multiple languages in the one and the same document.
From this point it is certain that the Japanese CTD-based submissions will
contain texts in multiple languages, since even now the current regulations
permit the use of English and other languages in the Application Assembly,
especially after the implementation for acceptance of foreign clinical data (see
above).
The language problem is further compounded due to the utilization of
different scripting systems - Chinese characters, Japanese syllabaries and Latin
alphabet, with two- and one-byte coding. In case the global modules have to be
used for submission in regions outside Japan, the texts should be translated in
English, what bring the question of the equivalency of the terminology.
* E-CTD templates
The e-CTD specification gives the definition of the e-CTD templates as
"...an empty directory structure with the recommended style sheets. It is an
illustration an eCTD Submission and it is ready to be populated with the sponsor
data." Some of the regulatory agencies in other regions have released demos or
templates - such as eCTD Template and EU-EFPIA Demo, and comparable
software is being developed in Japan as well. It was reported that the working
group from JPMA is actively contributing to the XML coding.
* Language codes
The language codes are two characters code from ISO-639 designated for
the purpose of creating file names:
Example:
hello-jp.pdf Japanese in PDF
hello-jp.xml Japanese in XML
* Media
Regulatory authorities in Japan are accepting e-CTD on electronic media
specified below:
Table 3. Acceptable electronic carriers for e-CTD
File size
Acceptable medium for
electronic transfer
Status in
Japan
Less than 10 Mb
3.5 inch DOS Formatted Floppy
Disks
Acceptable
Less than 7,000
MB
Standard CD-ROM (ISO 9660)
Acceptable
Over 7,000 MB
DVD, Digital Tape
Not decided
Preparing, packaging and sending the media should be done in such a way
to ensure that the delivered carriers are in usable condition. Similarly to the other
regions, the media should be physical delivered by a courier.
Labeling of the media should assure identification of the media carrier itself
and its content. As additional regional requirements, the Japanese authorities
accept the description of the date of submission in two different ways:
- using the Gregorian calendar and the style DD-MMM-YYYY
- for example, 01-Jan-2001; or
- using the Japanese Imperial calendar in the style
YY/MM/DD - for example H13/01/01 - First of January of
the Thirteen Year of the Heisei Era.
The above electronic carriers can be accompanied in submission in Japan
by paper documents - cover letters, explanatory, etc.
* Specifications for PDF files
In Japan commercially available localized versions of Adobe Acrobat
software and freely available versions of Adobe Acrobat Reader software, as the
documents (PDF files) created by the Japanese version of the Acrobat
technologies do not differ from files created by using other language versions in
term of specifications. The major difference is the use of Japanese (two-byte)
fonts. Typically, the PDF files are generated by converting the documents
created by text editors and thus containing the text editors' default fonts (e.g.
from Japanese version of MS Word - MS Minchou). One known problem is that
even if the text of the source document is written entirely in English, the PDF
output might not be correctly displayable by non-Japanese Acrobat viewers.
5. Development and timeline for implementation
5.1. Participants in the development of the CTD from Japan
In Japan the development and implementation of the CTD is considered as
both a responsibility of the authorities and an industry-wide project.
* Authorities are represented by officials from:
- Evaluation and Licensing Division of the Pharmaceutical and
Food Safety Bureau of the MHLW
- Evaluation Division of the Pharmaceutical and Medical Device
Evaluation Centre, National institute of Health Sciences,
MHLW
* Industry associations - the most actively involved in the practical
matters of CTD is a working group created by the Japan
Pharmaceutical Manufacturers Association (JPMA) - an organization
which members are exclusively manufacturers of prescription
medicines. In contrast, the Proprietary Associate of Japan, PAJ
organizing the makers OTC products - and thus remaining out of the
scope of CTD, has shown no activity. The regional organizations
(Pharmaceutical Manufacturers' Association of Tokyo, PMAT, Osaka
Pharmaceutical Manufacturers Association, OPMA) and manufacturers
of generics are participating mostly in the educational activities.
The working group from JPMA is recognized for the contribution fro
solving technical problems related to XML and DTD. Most of its
members and especially those involved in international development
already have in-house advanced computer and network systems for
handling documentation such as templates, SOPs, data sets, etc.
5.2. Timeline for implementation of CTD in Japan
In Japan the implementation of CTD was planned and was being carried
out in three successive periods:
1. Preparatory period - until June 30, 2001. The purpose of the actions
undertaken by both the authorities and the industry groups was to
increase the awareness of the CTD, to disseminate information about
the CTD structure, implementation and importance, and to receive
feedback for the parties involved.
The followings were the main activities:
a) Education - MHLW and its affiliated organization - the Society of
Japanese Pharmacopoeia (SJP) organized from the beginning of
2001 a series of one-day meetings at two locations (Tokyo and
Osaka) where along with matters of changed regulations and the
approval process policy, the technical and regulatory aspects of the
CTD were presented and explained:
- MHLW Information meeting in February 2001 - "The Ninth
Briefing Session on the Evaluation of the New Medicinal
Products". This meeting was the beginning of the series of
educational gatherings related to CTD introduction in Japan
from July 2001. A lecture on "About the Policy of Use of CTD
Application" was delivered by a representative from the
Pharmaceutical and Medical Device Centre (PMDEC) of the
National Institute of Health Sciences (NIHS).
- MHLW Information meeting in May 2001 - in the program of the
meeting entitled "Important Matters Concerning the Evaluation
of the New Medicinal Products" (subtitle - "The Major Points of
Revision of the 14th Edition of the Japanese Pharmacopoeia",
one of the topics covered the policy of use of CTD.
- MHLW Information meeting in June 2001 the meeting was
carried as "Fifth Brief Report Meeting on ICH". The attendees
were given a summary report on the overall progress in ICH
process, and in relation to CTD - on "Electronic forms of the
Common Technical Document (e-CTD)" and on use of CTD -
overall and safety, efficacy and quality parts.
- MHLW Information meeting in August 2001 one of the major
topics of the meeting entitled "Tenth New Drug Evaluation
Division Regular Presentation" was on the "Handling of
"Guideline for drafting parts related to CTD-Quality" as special
attention was put on the new requirement the general
pharmacology tests to meet the GLP standards.
The meetings were jointly sponsored by the Federation of Pharmaceutical
Manufacturers Associations of Japan (FPMAJ), Japan Pharmaceutical
Manufacturers Association (JPMA), Pharmaceutical Manufacturers'
Association of Tokyo (PMAT), Osaka Pharmaceutical Manufacturers
Association (OPMA), Japan Pharmaceutical Association (JPA).
b) Contribution to ICH activities
Japan hosted the ICH Steering Committee Meeting entitled "Paving the
Way for a Smooth Implementation of the Common Technical Document" in
Chiba, May 21-24, 2001. Simultaneously, the technical working groups
(CTD Implementation Working Groups, IWGs) held discussions on the
implementation of CTD. The followings are the main results of the meetings
related to CTD:
- Clarification of the regional implementation dates -
mandatory for Japan from July 2003 (see below)
- Refining the scope of the CTD
- Arrangements for variations and line extensions
explained
- Decision to widen the explanation and clarification efforts
and publication of educational materials in the form of
Questions & Answers
- Signing the Step 2 for Testing the electronic Common
Technical Document (eCTD)
- Agreement on the release of MedDRA 4.0 on June 15,
2001 (decision of the MedDRA Management Board)
c) Regulatory
Along with the regulatory communications (see 2. Legislation above) and
the series of educational meetings, the authorities undertook additional efforts
considering the truly international character of CTD and the expected difficulties
in the transitional period. All parts of Notification No. 899 are available in
English.
Secondly, the contact details of the officials in the MHLW and the working
group created by the JPMA were released and the members of the industry
associations encouraged sending feedback and enquiries.
2. Transitional period - from July 1, 2001 to June 30, 2003
The period of two years was expected to provide the industry with sufficient
time both for the preparation for the implementation of CTD (including
technologically), and for feedback to the authorities. From the other side, since
the applicants were encouraged to complement the customarily application
documentation with CTD, it was expected that such practice would benefit both
the authorities and the makers with the expertise.
It was reported that by end of July 2003 there were still few submissions
for medicinal products using CTD model. It is explained with the relatively short
period since the implementation and the lack of technical experience for
assembling the CTD dossier. Additionally, it is widely recognized - both by the
authorities and the industry that the majority of the reviewers have limited
experience in working with CTD-formatted documents and it might take certain
time to get fully accustomed with the new format.
3. Mandatory period - from July 1, 2003 - all new submissions from this
date are to contain CTD.
The deadline for requiring mandatory submissions of CTD was met in
Japan. However, the obstacles in front of the Japanese CTD are significant -
both from regulatory point and technologically (due to the different scripting
systems used in Japan). Therefore, many of pharmaceutical manufacturers in
Japan are reported that beside the support from the industry organizations have
created in-house task forces (groups) to tackle the CTD implementation.
5.3. Implementation status
The latest ICH Steering Committee and its expert working groups
meeting was held from July 15th to 18th, 2003 in Brussels, Belgium. Updated sets
of CTD "Questions & Answers" (Q&A) were reviewed by the Steering Committee
and now expected to be notified (see Table 4 below). In addition to their work on
the Q&As, the eCTD Working Group finalized the Change Control Process for
the eCTD specifications and reviewed a large number of change requests, and
the eCTD group also adopted an interim solution for Study Reports
specifications.
The present status of implementation of CTD/eCTD is Step 5 globally, as
the details for the adoption of the individual documents in Japan is shown at
Table 4.
Table 4. Implementation status of CTD in Japan
Topic
MHLW
Status
M4 ORGANIZATION
Including the Granularity document that provides guidance on document
location and paginations
M4 Organization
with Annex: Granularity
Adopted - PFSB/ELD Notification No.
0701004 dated July 1, 2003
Step 5
Edited documents adopted May 2001,
PMSB/ELD Notification No. 899
dated June 21, 2001
Adopted - PFSB/ELD Notice dated
January 28, 2003
General Q & A
updated July 2003
To be notified
Step 5
M4Q QUALITY
The section of the application covering chemical and pharmaceutical data
including data for biological/ biotechnological products
M4 Quality
Adopted - PFSB/ELD Notification No.
0701004 dated July 1, 2003
Step 5
Edited Documents adopted May 2001,
PMSB/ELD Notification No. 899
dated June 21, 2001
The Quality Q & A
updated July 2003
To be notified
Step 5
M4S SAFETY
The non-clinical section of the application
M4 Safety
Adopted - PFSB/ELD Notification No.
0701004 dated July 1, 2003
Step 5
Edited documents adopted May 2001,
PMSB/ELD Notification No. 899
dated June 21, 2001
The Safety Q & A
updated July 2003
To be notified
Step 5
Table 4 (cont.)
Topic
MHLW
Status
M4E EFFICACY
The clinical section of the Application
M4 Efficacy
Adopted - PFSB/ELD Notification No.
0701004 dated July 1, 2003
Step 5
Edited documents adopted May 2001,
PMSB/ELD Notification No. 899
dated June 21, 2001
Efficacy Q & A
updated February 2003
Adopted - PFSB/ELD Notice dated June
27, 2003
eCTD ELECTRONIC
The Electronic CTD
e-CTD Specifications v.3
Adopted - PFSB/ELD Notification No.
0604001 dated June 4, 2003
Step 5
The eCTD Q & A and
Change Request
Tracking Table
updated July 2003
To be notified
Step 5
eCTD Q&A/Change
Request Form
Submit to Your Regional ICH Member for
eCTD Questions or Change Requests
Disclaimer
This study is based on information obtained trough its own
research and from sources available to public and it is not a
complete analysis of every material fact. Statements of fact
have been obtained from sources considered reliable but no
representation is made as to their completeness or accuracy.
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Note: ICH, International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use.
Note: The current Pharmaceutical and Food Safety Bureau, prior to 1997 as
Pharmaceutical Affairs Bureau, and now defunct Pharmaceuticals and Cosmetics
Division.
Note: The current Pharmaceutical and Food Safety Bureau, prior to 2003 as
Pharmaceutical and Medical Safety Bureau.
Note: ELD, Evaluation and Licensing Division.
Note: Gaiyo stand for synopsis in Japanese and also is often translated as "Document
summary" or "Summary of findings". It is a dossier with summarized registration data. It
must be enclosed in the Application Assembly for approval of new medicinal products, for
post-approval changes and submissions for re-evaluation of the medicinal products. Gaiyo
was the standard for preparing the Japanese NDA dossier prior July 2003.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: Federation of Pharmaceutical Manufacturers Associations of Japan.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: See in the JKS Document Store the JKS document 4_D_K002.
Note: See in the JKS Document Store the JKS document 4_D_K001.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: At the Ninth Brief Report Meeting on ICH held on August 28, 2003 in Tokyo.
Note: Source ICH.
Note: Source ICH, as of September 2003.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Note: See in the JKS Document Store the JKS document 4_D_K003.
Medicinal products lifecycle Japan regulatory process milestone series
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