Evaluation and Regulation of
Medicines & Health Products
Implementation of the
CTD in Europe
&
EMEA Experiences
FFUL Lisbon
29 May 2003
Hilde Boone
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
Clinical Summaries



(tables)
(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 keyparameters 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
Content to be determined
by EU, US, JP authorities
Module 1
Regional
Information
1.0
CTD Table of Contents
2.1
CTD Introduction
2.2
Nonclinical
Overview
2.4
Module 2
Quality
Overall
Summary
2.3
Nonclinical
Summaries
2.6
Clinical
Overview
2.5
Clinical
Summary
2.7
Module 3
Module 4
Module 5
Quality
3.0
Nonclinical
Study Reports
4.0
Clinical
Study Reports
5.0
Module 2-5
CTD
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
Volume 2
……
= Community legislation
= Notice To Applicants
11
What is NTA ?
Volume 2 = NTA
* Volume 2A: Info on Procedures for MA
(guidance, interpretation)
2B
2C
2A
* Volume 2B: Presentation and content of a
MA dossier (format template)
* Volume 2C: Regulatory guidelines
First published in 1986 - Regularly updated
http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm
12
NTA - Volume 2B
Presentation & Content
“CTD”
5
Modules
2B
2C
2A
Current EU format for submission
of applications
4 parts

Volume 2B
2C
Replace by new format based on
CTD - 5 Modules
«4 parts may be presented as 5 modules»
2A
NTA”
“
Revised NTA incorporating CTD:
published 29 June 2001
13
Module 1:
Not Part of the CTD
Content to be determined
by EU, US, JP authorities
Module 1
Regional
Information
1.0
CTD Table of Contents
2.1
CTD Introduction
2.2
Nonclinical
Overview
2.4
Module 2
Quality
Overall
Summary
2.3
Nonclinical
Summaries
2.6
Clinical
Overview
2.5
Clinical
Summary
2.7
Module 3
Module 4
Module 5
Quality
3.0
Nonclinical
Study Reports
4.0
Clinical
Study Reports
5.0
Module 2-5
CTD
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
Part /
Module
Part I
See EC
WebSite
All "Old" Q only NC only C Only Q + NC
NTA
CTD
CTD
CTD
CTD
Q+C
CTD
NC + C
CTD
Content
Part IA
Part IB
Part IC:
- Quality E.R.
- Pre-Clin E.R.
- Clinical E.R.
X
X
X
X
X
X"
X"
X
X
X
X
X#
X#
Module 1 ToC
Applic. Form
Product Inform.
Signatures
- Signature Q
- Signature NC
- Signature C
Specific Inform.
Annex: ERA:
- Non-GMO
- GMO
X
X
X
X
X
X
Module 2 ToC
Introduction
Q Summary
NC Overview
C Overview
NC Summary
C Summary
X
X
X
Module 3
Module 4
Module 5
X
Part II
Part III
Part IV
All
"New"
(CTD)
NTA
X"
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X"
X"
X"
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X^
X~
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X#
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*
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17
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
19
- OTC products
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
[email protected]
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 PreSubmission 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/vol2/home.htm#2b
FDA - Guidance on CTD
http://www.fda.gov/cder/guidance/4539O.htm
#top
46
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CTD module 1