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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

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Evaluation and Regulation of Medicines & Health Products


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evaluation and regulation of medicines health products

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

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 ctd3

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 ctd4

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

Modular structure of CTD

Part IIPart III Part IV

Quality Non-clinical Clinical

  

Module 3 Module 4Module 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 ctd6

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 ctd7

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 ctd8

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

slide9

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

Module 2

Nonclinical

Overview

2.4

Clinical

Overview

2.5

Quality

Overall

Summary

2.3

Module 2-5 CTD

Nonclinical

Summaries

2.6

Clinical

Summary

2.7

Module 3

Quality

3.0

Module 5

Clinical

Study Reports

5.0

Module 4

Nonclinical

Study Reports

4.0

9

implementation of ctd

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

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

2C

2A

What is NTA ?

Volume 2 = NTA

* Volume 2A: Info on Procedures for MA(guidance, interpretation)

*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

2B

12

slide13

NTA - Volume 2BPresentation & Content

2B

2C

2A

“CTD”

5 Modules

Current EU format for submission of applications4 parts

Replace by newformat based on CTD - 5 Modules«4 parts may be presented as 5 modules»

Volume 2B

2C

2A

“NTA”

Revised NTA incorporating CTD: published 29 June 2001

13

slide14

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

Module 2

Nonclinical

Overview

2.4

Clinical

Overview

2.5

Quality

Overall

Summary

2.3

Module 2-5 CTD

Nonclinical

Summaries

2.6

Clinical

Summary

2.7

Module 3

Quality

3.0

Module 5

Clinical

Study Reports

5.0

Module 4

Nonclinical

Study Reports

4.0

14

nta ctd implementation

NTA CTD implementation

Topics to be addressed in EU

Give EU specific guidance in the Introduction

Defining scope & application types

AgreeonTime 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 implementation Time-Frames

NTA (CTD) Volume 2 published June 2001

July 2001 – July 2003 :TRANSITIONAL PERIODDossier can be presented using the * 1998 NTA Vol. 2 B edition, or* 2001 NTA Vol. 2 B editionMixtures of both formats between modules could be accepted, but not within parts/modulese.g. Q module 3 + S & E Parts III + IV

16

nta ctd implementation time frames18

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

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 scope20

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

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

Module 1 of Volume 2B (NTA)

1.1Overall 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

Module 1.2Application Form

Complete revisionby 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

Module 1.3SPC/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

Module 1.4Experts

Art. 12 of Directive 2001/83/EC

* experts must provide detailed reportson the Q, S & E data * duties of experts

Annex I to Directive 2001/83/ECSIGNED expert reports « critical » evaluation

25

module 1 4 experts26

Module 1.4Experts

Expert Reports Module 2 Overviews & Summaries

Signatures Module 1.4

Info on experts Module 1.4(education, experience)

26

module 1 5 specific requirements

Module 1.5Specific Requirements

1.5 Specific requirements for different types of applications1.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

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

slide29

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

Module 1Annex

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

Questions & Answers

General CTD questions & Module 3-5 : IFPMAhttp://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

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 answers33

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 answers34

EU Questions & Answers

Q2: Need to reformat ‘old’ dossiers?NOClinical, non-clinical = not usefulQuality = recommended, encouraged -> complete Quality part (incl.DMF if applicable) - > signed declaration from the MAH - > no need for Quality Summary

34

eu questions answers35

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 answers36

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 answers37

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

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 initiatives39

Other EU initiatives

EC: Revision of Legislation

Update of Annex I to Dir 2001/83/EC to reflect CTD format & terminology  implement by July 03Will 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

CTD Applications receivedJuly 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

slide41

EMEA ExperienceGeneral 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

slide42

EMEA ExperienceGeneral 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

slide43

EMEA ExperienceGeneral 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

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

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

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#top

46