Evaluation and Regulation of
Medicines & Health Products
Implementation of the
CTD in Europe
&
EMEA Experiences
FFUL Lisbon Hilde Boone
29 May 2003 EMEA 1
Why CTD
Industry initiative/request discussed at ICH level
To provide for a common format/template for the
submission of information to the regulatory
authorities in the 3 ICH regions
“Common Technical Document” signed-off by ICH in
November 2000
2
Why CTD
Advantages / Objectives:
Resource saving for industry
Facilitate simultaneous submission in 3 regions
Facilitate exchange of regulatory information
Harmonised format to be further supported by
e-CTD
More efficient assessment; use of hyperlinks etc…
Faster availability of new medicines
3
Why CTD
However, CTD is only a FORMAT !
It’s not a “single” dossier, with a “single” content
since
Legal requirements differ in the 3 regions
ICH guidelines have not yet harmonised all
requirements
Pharmacopoeias are not harmonised
Applicant may have regional preferences
4
Modular structure of CTD
Part II Part III Part IV
Quality Non-clinical Clinical
Module 3 Module 4 Module 5
Module 2: written + tabular formats
( replaces expert reports)
Module 1: administrative, regional info
(not as such part of the ICH CTD) 5
Modular structure of CTD
Module 2: Quality Overall Summary
Non-clinical Overview
Clinical Overview
Non-clinical Summaries (tables)
Clinical Summaries (tables)
To provide a summary of the development plan
and of the Q, S and E data
To integrate the most important information
To facilitate the task of the assessor
6
Modular structure of CTD
Module 2 should provide (a.o.):
Integrated & critical analysis of the key-
parameters of the product
Summary and analysis of the main tox/clin data
Justifications for deviations from requirements
and guidelines
Non-clinical and clinical strategy used by company
Comment on GLP, GCP status of data submitted
Benefit/risk conclusions
Clear tabulated summaries of the tests/trials 7
Modular structure of CTD
Module 3-4-5: Body of data / Study Reports
+ references
Module 3 2 main parts:
3.2.S Drug Substance
3.2.P Drug Product
Module 4-5: similar structure to current format
8
Module 1:
Not Part of the CTD
Module 1
Regional Content to be determined
Information by EU, US, JP authorities
1.0
CTD Table of Contents
2.1
CTD Introduction
2.2
Module 2 Nonclinical Clinical
Overview Overview
2.4 2.5
Quality
Overall Nonclinical Clinical Module 2-5
CTD
Summary Summaries Summary
2.3 2.6 2.7
Module 3 Module 4 Module 5
Nonclinical Clinical
Quality Study Reports Study Reports
3.0 4.0 5.0
9
Implementation of CTD
Each region (US, EU, Japan) to introduce CTD into
legislation or guidance
As of July 2003 :
Mandatory use of CTD for EU, Japan (MHLW)
Highly recommended for US (FDA)
In EU: CTD reflected in Notice To Applicants
(NTA) and in Legislation
10
Why CTD implemented in
NTA ?
‘old’ Annex I to Directive 2001/83/EC:
« …. Application …. shall be presented in 4 parts…taking account
of guidance published by EC in Notice To Applicants ….. »
European Commission Publication (9 volumes):
“Rules governing medicinal products in the EU”
http://pharmacos.eudra.org/F2/eudralex/index.htm
Volume 1 = Community legislation
Volume 2 = Notice To Applicants
……
11
What is NTA ?
Volume 2 = NTA
* Volume 2A: Info on Procedures for MA
(guidance, interpretation)
2B * Volume 2B: Presentation and content of a
MA dossier (format template)
2C
2A
* Volume 2C: Regulatory guidelines
First published in 1986 - Regularly updated
http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm
12
NTA - Volume 2B 2B
Presentation & Content
2C 2A
“CTD” Current EU format for submission
5 of applications
Modules
4 parts
Replace by new format based on
CTD - 5 Modules
«4 parts may be presented as 5 modules»
Volume 2B
2C
2A
Revised NTA incorporating CTD:
“NTA” published 29 June 2001 13
Module 1:
Not Part of the CTD
Module 1
Regional Content to be determined
Information by EU, US, JP authorities
1.0
CTD Table of Contents
2.1
CTD Introduction
2.2
Module 2 Nonclinical Clinical
Overview Overview
2.4 2.5
Quality
Overall Nonclinical Clinical Module 2-5
CTD
Summary Summaries Summary
2.3 2.6 2.7
Module 3 Module 4 Module 5
Nonclinical Clinical
Quality Study Reports Study Reports
3.0 4.0 5.0
14
NTA CTD implementation
Topics to be addressed in EU
Give EU specific guidance in the Introduction
Defining scope & application types
Agree onTime frame for implementation
Defining Region-Specific items
Content of Module 1
Prepare FAQs document
Prepare amendment of Directive 2001/83/EC to
legally reflect CTD structure by July 2003 15
NTA CTD implementation
Time-Frames
NTA (CTD) Volume 2 published June 2001
July 2001 – July 2003 :
TRANSITIONAL PERIOD
Dossier can be presented using the
* 1998 NTA Vol. 2 B edition, or
* 2001 NTA Vol. 2 B edition
Mixtures of both formats between modules could
be accepted, but not within parts/modules
e.g. Q module 3 + S & E Parts III + IV 16
Mixed format applications All
All "Old" Q only NC only C Only Q + NC Q+C NC + C "New"
Part / NTA CTD CTD CTD CTD CTD CTD (CTD)
Module Content NTA
Part I Part IA X
Part IB X
Part IC:
- Quality E.R. X X" X" X"
- Pre-Clin E.R. X X" X" X"
- Clinical E.R. X X" X" X"
Part II X X^ X~ X~
Part III X X X X
See EC Part IV X X# X# X#
WebSite Module 1 ToC
Applic. Form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Product Inform. X X X X X X X
Signatures
- Signature Q X X X X
- Signature NC X X X X
- Signature C X X X X
Specific Inform. X X X X X X X
Annex: ERA:
- Non-GMO * X * X * X X
- GMO X * * X X * X
Module 2 ToC X X X X X X X
Introduction X X X X X X X
Q Summary X X X X
NC Overview X X X X
C Overview X X X X
NC Summary X X X X
C Summary X X X X
Module 3 X X X X
Module 4 X X X X 17
Module 5 X X X X
NTA CTD implementation
Time-Frames
As of July 2003 :
Mandatory for EU, Japan (MHLW)
Hihgly recommended for US (FDA)
Commission to amend Relevant EU legislation to
fully reflect CTD (Annex I to Dir. 2001/83/EC)
New Annex I to be published SOON !
18
NTA CTD implementation
Scope
Applicable to all types of EU procedures:
- Centralised procedure
- Decentralised (MR) procedure
- National procedures
Applicable to all types of products:
- NCEs
- Biologicals, biotech
- Herbal medicinal products specific guidance
will be provided
- OTC products 19
NTA CTD implementation
Scope
Applicable to all types of applications:
- Full, new applications
- Bibliographical applications
- Abridged, Generic applications
- Line-extensions & Variations
20
Regional (EU) specific
Information – Module 1
Requirements for content of EU application:
* Directive 2001/83/EC – Art. 8-12
* Directive 2001/83/EC – Annex I
Administrative and Scientific information
* required by EU legislation provide in
* but not reflected in CTD Module 1
21
Module 1 of
Volume 2B (NTA)
1.1 Overall Table of Contents
(complete application; modules 1-5)
1.2 Application Form = current IA-form
1.3 SPC, Labelling & Package Leaflet
1.4 Experts
1.5 Specific Requirements
Annex Environmental Risk Assessment 22
Module 1.2
Application Form
Complete revision by NTA group, to reflect
Principles agreed in Chapter 1 (Vol. 2A)
* Legal basis
* Annex II / Line-extension
Latest MS/EMEA requirements
NEW developments: Orphan Drugs, TSE,
Scientific Advice, GMOs
To be used in current & new dossier format
23
Module 1.3
SPC/Labelling/PL
* Based on EMEA/QRD Templates
* National templates may apply
(for MR or national procedures)
In line with SPC and Readability guideline
Standard headings and sentences
Available in 13 languages (EMEA Web)
* Mock-ups or Specimen of sales presentation
24
Module 1.4
Experts
Art. 12 of Directive 2001/83/EC
* experts must provide detailed reports
on the Q, S & E data
* duties of experts
Annex I to Directive 2001/83/EC
SIGNED expert reports
« critical » evaluation
25
Module 1.4
Experts
Expert Reports Module 2
Overviews &
Summaries
Signatures Module 1.4
Info on experts Module 1.4
(education, experience)
26
Module 1.5
Specific Requirements
1.5 Specific requirements for different types
of applications
1. Information for bibliographical applications
summary document on justification for
“well-established use” claim
2. Information for generics applications
summary document on evidence for
“essential similarity” claim
27
Well-established use
(bibliographical applications)
Intended for “Old” products; no Essential Similarity
Explain grounds for using publications
Literature to be included in Module 4 and/or 5
Discussion in Module 2 (overviews and summaries;
incl. WEU claims)
Summary of WEU demonstration in Module 1.5
addressing each indent of of Part 3I/4I of Annex I
to Dir. 2001/83/EC
28
Essential Similarity
(generic applications)
Module 1.5: to contain summary document on:
Active substance (« same »)
Overall S/E profile
Bio-availability , Bio-equivalence
Demonstrate « Essential Similarity » as defined
by the NTA (chapter 1)
Case-by-case validation decision by authorities
29
Module 1
Annex
ANNEX: Environmental Risk Assessment
(Separate binder)
Incl. Risk Assessment Overview
* Non GMO containing medicinal products
* Medicinal product containing/consisting of GMOs
There is no ANNEX II ! (orphan drugs) 30
Questions & Answers
General CTD questions & Module 3-5 : IFPMA
http://www.ich.org
ctd-related.question@ifpma.org
EU-specific Regulatory / Administrative questions
Questions on Module 1 : EC
http://pharmacos.eudra.org/F2/eudralex/vol-2/B/ctdqa_032003.pdf
?
Aim to maintain harmonised approach
Shared, common interpretation
Refinement of guidance 31
EU Questions & Answers
Q1: Guidance on Mixed format applications
Q2: Need to reformat ‘old’ dossiers?
Q3: Reformatting = variation? Fee?
Q4: Format of Variation applications?
Q5: Mixed formats allowed after July 2003?
Q6: Format of Line Extensions?
Q7: Format of Generic applications?
Q8: Module 2 for Generic applications?
Q9: Format of Herbal Medicinal Product applicat.?
32
EU Questions & Answers
Q10: Format of Mutual Recognition Applications?
Q11: Reformatting of MRP dossiers ?
Q12: Location of Certificate of Suitability?
Q13: Format of bibliographical applications?
Q14: Format of EDMFs in CTD applications?
Q15: Use of ‘old format’ EDMFs in CTD applications?
Q16: Format of variations to EDMFs?
33
EU Questions & Answers
Q2: Need to reformat ‘old’ dossiers?
NO
Clinical, non-clinical = not useful
Quality = recommended, encouraged
-> complete Quality part (incl.DMF if applicable)
- > signed declaration from the MAH
- > no need for Quality Summary
34
EU Questions & Answers
Q4: Format of Variation Application?
NO requirement to reformat ‘old’ dossier
- New Variation data = mandatory in CTD
- Cross-reference to ‘old’ data allowed
- Copies of approved docs to be provided:
take first variation opportunity to reformat
the doc / section concerned.
35
EU Questions & Answers
Q6: Format of Line Extensions?
NO requirement to reformat ‘old’ dossier
- New data = mandatory in CTD
- Always Module 1 + 2
- Cross-reference to ‘old’ data allowed
- Follow guidance on ‘mixed’ applications
- MAHs are encouraged to reformat ‘old’ quality
data (may not always be feasible)
36
EU Questions & Answers
Q10: Format of Mutual Recognition Applications?
If MRP starts after 1 July 2003
CMS will accept the submission of dossiers in
the ‘old EU’ -format until 31 December 2004
MAH to submit reformatted dossier to RMS
first.
-> no update of the RMS AR necessary
-> simple acknowledgement
37
Other EU initiatives
Training for EU EU and CADREAC Assessors
(~200): June – July 2001
Quality, Safety, Efficacy workshops
Update of CPMP Assessment Report Templates
(available on EMEA Website since March 2002)
Included list of CPMP/ICH guidelines as an
Annex to Modules 3-5
38
Other EU initiatives
EC: Revision of Legislation
Update of Annex I to Dir 2001/83/EC to reflect
CTD format & terminology implement by July 03
Will be published soon check EC’s Website !
Update of Directive 2001/83/EC as part of the
Review proposals:
‘expert reports’ ’detailed summaries’
39
CTD Applications received
July 01 – May 03
EMEA (Centralised Procedure):
16 new applications in full CTD format
6 new applications in mixed CTD+’old’ format
Of those, 5 concerned ‘Part A’ products
21 concerned ‘Part B’ products
9 line extensions (Q only; Q + C)
40
EMEA Experience
General issues
Experience so far is positive
Most questions & issues handled during Pre-
Submission contacts with Applicants or during
validation of the application.
So far, no feedback from assessors on any
difficulties encountered during assessment.
Issues encountered now clarified via Q&A on
Web
41
EMEA Experience
General issues
No deviations from headings & numbering
leave CTD headings & numbering unchanged
OK to introduce further sub-headings under
existing CTD headings
x other deviations refused
NO additions
NO deletions
NO re-numbering
42
EMEA Experience
General issues
Sections “not applicable” or cross-referring to
“old” data to be maintained in dossier
structure + commented in Overviews
No new Appendices or Annexes:
All information to be included in the relevant
sections of Modules 3-5 and not at the end of
the Module as new appendices not foreseen in
CTD (e.g. stability protocols, validation data).
43
Advice to Applicants
Follow CTD guidance; do not invent or adapt
Consult Q&A on ICH and Commission’s Website
In case of doubt: consult relevant Authority or
send questions to ICH / EC mailbox
EMEA provides assistance to applicants in the
pre-submission stage
44
Conclusion - Overall Benefit
Common format for applications, to be used in the
3 Regions
Requires commitment & (re-)organisation
Resource saving for industry Single dossier and
Possible simultaneous submissions in the 3 regions
Implementation of electronic CTD (e-CTD)
More consistent assessment
Accelerate availability of new medicines ? 45
Useful Websites
ICH – CTD Guidelines + Q&A + e-CTD:
http://www.ich.org/ich5c.html
EU – NTA incorporating the CTD + Q&A:
http://pharmacos.eudra.org/F2/eudralex/vol-
2/home.htm#2b
FDA - Guidance on CTD
http://www.fda.gov/cder/guidance/4539O.htm
46
#top