COMMON TECHNICAL

DOCUMENT (CTD)

&

EUROPEAN MEDICINES

AGENCY (EMEA)

Index

1. What is it?

2. Significance

3. Scope

4. Diagrammatic representation

5. CTD-Q basic structure

6. Regulatory Communication

7. Maintenance/Implementation

8. eCTD

9. Issues

10. Conclusions

11. References

COMMON TECHNICAL DOCUMENT (CTD)

WHAT IS IT? IT IS :

A common harmonized FORMAT for applications for preparing marketing authorizations in

the three ICH regions.

A TEMPLATE for presenting data in the dossier.

IT IS NOT:

A statement of data requirements for applications.

SIGNIFICANCE OF CTD:-

To provide for a well structured harmonized common format/template for the submission

of technical requirement to the regulatory authorities (FDA) that is acceptable in all 3 ICH

regions.

A common format will significantly reduce the time and resources used to compile

applications for registration of human pharmaceuticals.

It will ease the preparation of electronic submissions.

Facilitate simultaneous submission in three regions.

Facilitate exchange of regulatory information among regulatory authorities.

More efficient assessment.

Faster availability of new medicines.

To avoid generating and compiling different registration dossiers.

SCOPE:-

Addresses the format/structure of applications for MAs of active substances and their

corresponding drug products.

NTA Guidance : The text following the section titles is intended to be explanatory and

illustrative only i.e. It merely indicates the location where information has to be provided.

The actual content of these sections in the dossier should include relevant information

described in existing CHMP- and CHMP-ICH guidelines.

The section Regional Information addresses information unique to this region.

diagramatic representation

CTD-Q basic structure

MODULE 1

Admin and Regional Specific Information

Don‘t forget molecular structure aspects re: Similarity (1.7)

- Although these are outside the main quality/safety/efficacy benefit-risk evaluation for an

authorization.

Administrative Regional Information

• 1.1 Table of Contents

• 1.2 Application forms

• 1.3 Product Information, SPC/Labelling/ Package Leaflet

• 1.4.1 Expert declarations & signatures for the QOS

• 1.5 ‗Specific Requirements‘ for types of application

bibliographic, generic, biosimilar, informed consent etc.

• 1.6 Environmental Risk Assessment (GMO? )

• 1.7 Orphan issues, structural similarity

• 1.8, 1.9 Pharmacovigilance and Clinical Trials

MODULE 2

CTD Summaries

– Quality Overall Summary (2C) – QOS

This is probably what EU assessors will read first

• Quality Overall Summary

– Written text summary following the outline and scope of the ‗Body of Data‘, Module 3 .

– Not required to be critical

– No formal tabulated summary structure

– Key parameters of the active substance & product which may have an impact on efficacy or

safety should be emphasised

– Relevant tables/figures could be incorporated

– External Drug Master File (ASMF Open part ) will be summarized here. Closed/Restricted

part should be in the ASMF itself.

MODULE 3:- CTD-Q ( guideline )

Main body of Quality Data

i.e. The Q dossier will be basically modules 2.3 & 3

Note : Same structure for ‗ NCE ‘ & ‗ Biotech ‘ products Scope of the guidance , i.e. format

• 3.1 Table of Contents – helpful to assessors

• 3.2Body of Data ‘

• 3.2.S Drug Substance

External Drug Master File ( ASMF ) should also follow this structure for both the Open and

Closed/Restricted parts.

• 3.2.P Drug Product

– 3.2.A Appendices

• A.1 Facilities and equipment ( biotech)

• A.2 Adventitious Agents contamination

• A.3 Excipients ( novel )

Example of a ‘network’: Polymorphism

• Cross reference between section P2 (Pharm. Development) and relevant sections in S (Drug

Substance) and in P (Drug Product)

– S 1.3 Properties of the active substance

– S.2 Manufacture

– S 3.1 Studies on Polymorphism (experimental data)

– S 4.1 Specifications relating to control of physical forms

– S.4.3 Analytical methods used

– S 4.5 Justification of Specifications

– P 2: Influence of the polymorphic forms on product characteristics – dissolution, stability ,

etc.

– P 5.1 Product Specifications, need to control polymorphs?

– P 5.6 Justification of Specifications

Regulatory Communication (1) ICH has sought to enhance regulatory communication through the development of:

– Standardized data elements, example: E2B

– Controlled vocabularies, example: MedDRA

– Common format for drug registration: CTD

– Electronic specifications and standards for the transmission of such

information, example: ESTRI and eCTD

Regulatory Communication (2) Benefits:

Speak same language: promotes communication

Quality, accuracy and consistency of information

Improve timeliness of communications (electronic transmission)

CTD/eCTD reduces delays and costs associated with registration of drug applications

Regulatory Communication (3) Status of CTD/eCTD implementation:

As of July 2003 CTD mandatory in EU and Japan, ‗highly recommended‘ in US and

Canada

Integration of CTD in existing regulatory frameworks

No significant difficulties encountered

New era: eCTDs now being submitted in all ICH regions

Regulatory Communication (4) New: M5: Data elements and standards for drug dictionaries:

– For use in describing medicinal products and active ingredients

– Controlled vocabulary includes units, routes of administration, pharmaceutical

forms

– Electronic message specifications to be developed

Maintenance/Implementation (1) Critical aspects of the ICH harmonization process considering need to ensure

– continued relevance and improvement of an ever-growing number of guidelines

– consistent and intended use by regulators and industry

Tools/mechanisms:

– Qs and As, addenda, revisions, points to consider

– Change control and maintenance processes: eCTD, E2B(M) and Q3C

– New: maintenance of ICH controlled terminology lists

Maintenance/Implementation (2) Tools/mechanisms:

– MedDRA maintenance and support service organization (MSSO)

– Creation of implementation working groups (e.g., for CTD/eCTD, E2B(M))

and implementation tool (new)

– Implementation standing item on ICH Steering Committee agenda

– General procedures and roles/responsibilities under development

eCTD Part 1 Tutorial

Section 1.0 eCTD Tutorial Table of Contents.

• This FDA tutorial, consisting of seven PowerPoint presentations, provides overview of

FDA's eCTD guidance document and a comprehensive discussion on preparing the five

modules of an eCTD. Emphasis is placed on ensuring the successful submission of an

application and facilitating the review process.

Section 1.1 eCTD Module 1.

• This presentation provides information on:

o Archiving regional documents.

o Application management.

o Special regulatory programs.

o The legal and regulatory framework for the application/submission

Section 1.2 FDA Overview of the eCTD Guidance and its Implementation.

• This presentation helps the student on:

o Electronic submission guidances using eCTD specifications providing regulatory

submissions in electronic format for human pharmaceutical product applications and related

submissions.

• Includes NDA, ANDA, BLA, IND, DMF and associated submissions.

o Preferred format for submissions

Section 1.3 Ensuring an Effective Submission.

• This section discusses the top 10 eCTD issues for success:

1. PDF documents include TOCs.

2. PDF hyperlinks/bookmarks are correct.

3. XML must be standard components.

4. Documents conform to eCTD granularity.

5. MD5 checksum are correct.

6. Unneeded node extensions are removed.

7. Sequence numbers are 4 digit.

8. Application numbers are 6 digits.

9. eCTD submissions include Module 1.

10. Files referenced in the XML backbone(s).

Section 1.4 Guidance Compliant eCTDs Module 4.

• This section discusses Module 4 and the positions of its various components.

Section 1.5 Guidance-Compliant eCTDs- Module 5.

• Section 1.5 discusses the purpose and structure of Module 5:

o Provides framework for clinical documents submitted during drug development (IND); e.g.

protocols, protocol amendments, IND safety reports.

o One section contains all information to perform in-depth clinical pharmacology and clinical/

statistical BLA/NDA review.

o Permits comprehensive clinical pharmacology, clinical, statistical reviews.

o Majority of IND/BLA/NDA clinical content in section 5.3.

o A study report now comes in multiple files (E3) *different from the past.

o Datasets and CRF‘s organized by study, but still XPT and PDF, respectively.

Section 1.6 eCTDs Quality CMC Issues.

• This section outlines and describes the following issues:

o Historical FDA e-submission efforts.

o How to read the eCTD DTDs.

o Repeated sections.

o Location issues in Module 3.

o Topics appearing in multiple sections.

o Issues to be resolved.

Section 1.7 Prequel Template or Guidance.

• This presentation provides advice on:

o Background/Motivation.

o ICH CTD–General guidance on summaries–Annex: granularity document.

o Module 2: Summaries.

o Mapping from the CFR .

o Module 4: Safety.

Part 2 Guidances

Section 02 Guidance for Industry M4 The CTD - Efficacy Questions and Answers.

• This is one in a series of guidances that provide recommendations for applicants preparing

the Common Technical Document for the Registration of Pharmaceuticals for Human Use

(CTD) for submission to the U.S. Food and Drug Administration (FDA). This guidance

provides answers to questions that have arisen since the finalization of the harmonized CTD

guidance documents. This guidance specifically addresses questions related to efficacy. Other

question and answer (Q &A) guidances are under development to address general questions as

well as questions related to quality and safety. The questions and answers provided here

reflect the consensus of the ICH parties.

Section 03 Structure and Content of Clinical Study Reports.

• The objective of this guideline is to facilitate the compilation of a single core clinical study

report acceptable to all regulatory authorities of the ICH regions. The regulatory authority

specific additions will consist of modules to be considered as appendices, available upon

request according to regional regulatory requirements.

Part 3 Submissions

Section 04 Electronic Submission Guidances.

• PowerPoint presentation on providing regulatory submissions in electronic format including:

o Overview.

o Available guidances-traditional electronic submissions.

o Electronic submissions using eCTD specifications.

o eCTD guidance — changes from eNDA guidance–continuation of eNDA guidance.

o Submissions 101 references.

Section 05 Providing Regulatory Submissions in Electronic Format Using eCTD

Specifications.

• This is one in a series of guidance documents intended to assist applicants making regulatory

submissions to the FDA in electronic format using the electronic common technical document

(eCTD) specifications. This guidance discusses issues related to the electronic submission of

applications for human pharmaceutical products and related submissions, including

abbreviated new drug applications (ANDAs), biologics license applications (BLAs),

investigational new drug applications (INDs), new drug application (NDAs), master files (e.g.,

drug master files), advertising material, and promotional labeling. At this time, this does not

include applications supporting combination products.

Part 4 Technical Requirements.

Part 4 contains a number of specification, standards, definitions, presentations and checklists

for creating and maintaining an eCTD protocol within your company.

Section 6 Comprehensive eCTD Table of Contents Headings and Hierarchy.

• This section includes the complete structure and numbering for content headings and the

hierarchy of Modules 1-5

Section 7 Conformance Review Checklist For NDAs.

• This document provides a checklist for

o General issues.

o Organization of folders.

o Organization of the electronic submission.

Section 8 eCTD Backbone Files Specification for Module 1.

• This document provides specifications for creating the electronic common technical

document (eCTD) backbone file for Module 1 for use with the guidance to industry: Providing

Regulatory Submissions in Electronic Format — Human Pharmaceutical Applications and

Related Submissions.

Section 9 eCTD Backbone Files Specification for Modules 2 through 5.

• This document provides specifications for creating the electronic common technical

document (eCTD) backbone file for modules 2 to 5 of the common technical document (CTD)

for use with the guidance to industry: Providing Regulatory Submissions in Electronic Format

– Human Pharmaceutical Applications and Related Submissions.

Section 10 eCTD Backbone Files Study Tagging Files.

• In order to help identify all of the files associated with a study, information is needed on

each document including the document title, subject matter (defined by the headings under

which the documents are located in the table of contents), relationship to other documents,

revision information, the location of the document and information on the submission that

included the document. This document outlines the eCTD backbone files which include many

of these information items. However, the eCTD backbone files do not contain enough

information on the subject matter of several documents (e.g., study report documents) to

support certain regulatory business rules. This additional information is provided in the STF.

The complete structure and contents of the STF files is presented in this section.

Section 11 eCTD Change Control Process v1.8.

• This document establishes the change control process for the eCTD Specification. Change

control for regional eCTD Module 1 specifications is the regional authority's responsibility.

Section 12 eCTD Change Request Form.

• This form should be used to request a change to the ICH eCTD Specification. The change

can be to fix a perceived ―bug‖, meet a new requirement or to enhance existing functionality.

Section 13 eCTD Specification v 3.2.

• This document describes the parts of the registration application that are common to all

regions and some of the lifecycle requirements for products. The parts of the registration

application that are specific to a region will be covered by regional guidance. However, this

backbone has been developed to handle both the regional and common parts of submissions.

Section 14 eSUBS and eCTDs: Practical Advice and Pitfalls to Avoid.

• PowerPoint presentation outlining the factors to be aware of when submitting an eDoc:

o Correct use of elements and leaf titles.

o Always Reference all Files in the XML Backbone(s).

o Include Module 1 in all eCTD Submissions.

o Make Sure All Application Numbers are 6 Digits.

o Make Sure all Sequence Numbers are 4 Digits.

o Do Not Use Node Extension.

o Verify That All MD5 Checksums are Correct.

o All Documents Should Conform to eCTD Granularity.

o All XML must use standard components.

o Be Sure All PDF Hyperlinks & Bookmarks are Correct

o Include TOCs In All PDF Documents.

Section 15 Evaluation and Research ISS/ISE: Where Do They Fit in the CTD-eCTD.

• PowerPoint presentation that provides advice on how to:

o Differentiate between ICH guidelines and FDA requirements for the CTD/eCTD.

o Identify the goals of the CTD/eCTD for both industry and regulators.

o Identify strategies to include the ISS/ISE in the CTD and eCTD submission formats.

Section 16 Future of Case Report Tabulation Submissions.

• PowerPoint presentation on case report tabulations including discussion of:

o Study data standards.

o Status of patient profile pilot.

o Medical review technology for an NDA safety database.

Section 17 Granularity Document Annex M4 Organization of the CTD.

• This is one in a series of guidances that provide recommendations for applicants preparing

the Common Technical Document for the Registration of Pharmaceuticals for Human Use

(CTD) for submission to the U.S. Food and Drug Administration (FDA). This annex to the M4

guidance on the organization of the CTD was developed by ICH in response to requests for

additional information after the harmonized CTD guidance documents were finalized in

November 2000.

Section 18 ICH eCTD Specification Document DTD 3.2.

• This section includes code for the XML submission that needs to be created and validated

according to the XML eCTD DTD standard.

Section 19 Module 1 Document Type Definition File.

• The ICH eCTD specification calls for a regional Module 1 document type definition file to

allow regional information to be submitted along with information from ICH Modules 2 to 5.

The section provided sample code for the FDA draft eCTD Module 1 DTD version 2.01

hierarchy.

Section 20 Placement of Integrated Summaries of Safety and Effectiveness (ISS/ISE) in

Applications Submitted in the eCTD Format.

• The tables in this document are examples of the various sections of the CTD that contain

sum mary and integrated discussions of efficacy and safety and the corresponding FDA

regulations, where applicable, that inform the content of those sections.

Section 21 Portable Document Format Specifications.

• These specifications are for submitting documents in Portable Document Format (PDF).

Section 22 Specification for Transmitting Electronic Submissions using eCTD

Specifications.

• This document provides specification for transmitting electronic submissions using eCTD

specifications. Details are included for transmitting the electronic submission on physical

media or electronically.

Section 23 Standards and Successful Document Creation.

• PowerPoint presentation on standards issues including:

o ISS/ISE placement one of the most frequently asked questions.

o ISS/ISE Represent Analysis–5.3.5.3 Reports of analyses of data from more than one

study–Module 5 provides necessary organization structures through STF.

o Module 2 Summaries–Critical and Concise Summaries–Page counts do not define what‘s

acceptable.

Section 24 Study Tagging File Workshop.

• PowerPoint presentation that deals with 2 tagging file problems:

o The maximum of only 256 characters that can be used.

• This is further limited by ICH to 230 characters to permit the ICH regulatory agencies space

for server and folders names to organize the submission.

• ICH guidance recommends that folder names not exceed 64 characters.

o Computer Displays that cannot readily display lengthy path and filenames.

• In many cases some filenames could be the same up to the ending making it difficult for

reviewers.

Section 25 Transformation of the Backbone from XML to HTML.

• eCTD the final ICH Step 4 eCTD specifications and draft specifications from the FDA to

enable the assembly of submission-ready documents, create the appropriate file/folder

structure, assign leaf document attributes, and then build the required XML backbone and

regional XML required in eCTD submissions.

Part 5 Training

Section 26 NDA Electronic Data Analysis Training.

• CDER has provided guidance to industry for sponsors to send case report form tabulations

and individual animal line listings as datasets. To help Center review staff use these electronic

datasets, the Office of Information Technology, in conjunction with review staff, has

developed NDA Electronic Data Analysis Training (NEDAT).

Section 27 NDA Electronic Submissions Training.

• In keeping with CDER's Electronic Regulatory Submission and Review (ERSR) goals,

electronic submissions are currently being placed on the CDER network for access and review

by CDER review staff. Currently, NDAs and their corresponding Amendments and

Supplements are the only submissions received in electronic format. Before these submissions

can be reviewed, CDER review staff must first be able to access an electronic submission

folder on the network save a drive path (map), copy the folders and files pertinent to their

discipline, and learn to use the features

available in Adobe Acrobat. Reviewer staff then can access these electronic files from

their desktop.

issues • Implementation not equal in all regions?

• Nothing to do with e-CTD ( although the e-CTD is of course based on the agreed CTD

structure )

• In EMEA, for publication purposes (EPARS) we still prefer to avoid ‗drug‘ Drug substance

becomes Active Substance

Drug Product becomes Medicinal Product

Conclusions

• Benefit for industry

– Format: yes, better utilisation of global resources

– Content: identical within the 3 regions but can it lead to an expectation of more data ?

• Benefit for regulators

– Format: yes, easy to evaluate in general

– Content: same as before really, no change.

• Benefit for the patient

– Expedited evaluation is a benefit, especially with a

positive conclusion and early marketing.

REFERENCES

1. Notice to Applicants , Eudralex Vol. 2B : ―NTA Guidance‖ June 2006 : Structure is

defined here. http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol- 2/b/ctd_06-2006.pdf

2. Q&A Document http://www.ich.org/LOB/media/MEDIA620.pdf

3. ‗Location issues‘ ( Quality ) - see CPMP/ICH/4680/02

4. ICH Updates http://www.ich.org

5. http://www.fda.gov/cder/regulatory/ersr/ectd.htm 6. http://esubmission.eudra.org/ 7. http://www.mhlw.go.jp/english/index.html 8. http://www.tga.gov.au/docs/html/eugctd.htm

http://www.tga.gov.au/docs/html/eugctd.htm http://www.tga.gov.au/docs/pdf/euguide/tgamod1.pdf

http://www.tga.gov.au/docs/pdf/euguide/ich/ctdm2quality.pdf http://www.tga.gov.au/docs/pdf/euguide/ich/ctdm2safety.pdf http://www.tga.gov.au/docs/pdf/euguide/ich/ctdm2efficacy.pdf

EUROPEAN MEDICINES

AGENCY (EMEA)

INDEX

1.Introduction

2. EMEA structure

3. EMEA organization

4. EMEA committee

5. The rules governing medicinal products in the european

union

6. Regulation of medicines in the european union

7. Role of the european medicines agency in the regulation

of medicines

8. Product information

9. Inspections - activities of the sector

10. EMEA certificates of medicinal products

11. Counterfeit medicines

12. Good clinical practice

13. Good laboratory practice

14. Good manufacturing practice

15. Process analytical technology

16. Product defects and recalls

INTRODUCTION

EUROPEAN MEDICINES AGENCY (EMEA)

The European Medicines Agency (EMEA) is a decentralized body of the

European Union with headquarters in London.

Its main responsibility is the protection and promotion of public and

animal health, through the evaluation and supervision of medicines for

human and veterinary use.

The EMEA is responsible for the scientific evaluation of applications for

European marketing authorization for medicinal products (centralized

procedure).

Under the centralized procedure, companies submit a single marketing

authorization application to the EMEA.

Once granted by the European Commission, a centralized (or

‗Community‘) marketing authorization is valid in all European Union

(EU) and EEAEFTA states (Iceland, Liechtenstein and Norway).

All medicinal products for human and animal use derived from

biotechnology and other high-technology processes, including advanced-

therapy medicines, must be approved via the centralized procedure. The

same applies to all human medicines intended for the treatment of

HIV/AIDS, cancer, diabetes, neurodegenerative diseases, autoimmune and

other immune dysfunctions, and viral diseases, as well as to all designated

orphan medicines intended for the treatment of rare diseases.

Similarly, all veterinary medicines intended for use as performance

enhancers in order to promote the growth of treated animals or to increase

yields from treated animals have to go through the centralized procedure.

For medicinal products that do not fall under any of the abovementioned

categories, companies can submit an application for a centralized

marketing authorization to the EMEA, provided the medicinal product

constitutes a significant therapeutic, scientific or technical innovation, or

the product is in any other respect in the interest of patient or animal

health.

The safety of medicines is monitored constantly by the Agency through a

pharmaco- vigilance network. The EMEA takes appropriate actions if

adverse drug reaction reports suggest changes to the benefit risk balance

of a medicinal product. For veterinary medicinal products, the Agency has

the responsibility to establish safe limits for medicinal residues in food of

animal origin.

The Agency also plays a role in stimulating innovation and research in the

pharmaceutical sector. The EMEA gives scientific advice and protocol

assistance to companies for the development of new medicinal products. It

publishes guidelines on quality, safety and efficacy testing requirements.

Five scientific committees, composed of members of all EU and

EEAEFTA states, conduct the main scientific work of the Agency:

The Committee for Medicinal Products for Human Use (CHMP),

The Committee for Medicinal Products for Veterinary Use (CVMP),

The Committee for Orphan Medicinal Products (COMP),

The Committee on Herbal Medicinal Products (HMPC)

The Pediatric Committee (PDCO).

A sixth scientific committee – the Committee for Advanced Therapies

(CAT) – will be established at the end of 2008.

The EMEA is headed by the Executive Director and has a secretariat of

approximately 470 staff members in 2008. The Management Board is the

supervisory body of the EMEA, responsible, in particular, for budgetary

matters.

The Agency is also involved in referral procedures relating to medicinal

products that are approved or under consideration by Member States in

non centralized authorization procedures.

EMEA STRUCTURE

The EMEA began its activities in 1995, when the European system for

authorizing medicinal products was introduced,

European Medicines Agency (EMEA) is a decentralized body of the

European Union with headquarters in London.

Its main responsibility is the protection and promotion of public and

animal health, through the evaluation and supervision of medicines for

human and veterinary use.

The Agency brings together the scientific resources of the 25 EU Member

States in a network of 42 national competent authorities.

The EMEA has a role in both, but is primarily involved in the centralized

procedure.

Where the centralized procedure is used, companies submit one single

marketing authorization application to the EMEA.

A single evaluation is carried out through the Committee for Medicinal

Products for Human Use (CHMP) or Committee for Medicinal Products

for Veterinary Use (CVMP).

In 2001, the Committee on Orphan Medicinal Products (COMP) was

established, charged with reviewing designation applications from persons

or companies who intend to develop medicines for rare diseases (so-called

‗orphan drugs‘).

The Committee on Herbal Medicinal Products (HMPC) was established in

2004 and provides scientific opinions on traditional herbal medicines.

A network of some 3,500 European experts underpins the scientific work

of the EMEA and its committees.

EMEA MISSION STATEMENT

Developing efficient and transparent procedures to allow rapid access by

users to safe and effective innovative medicines and to generic and non-

prescription medicines through a single European marketing authorization

Controlling the safety of medicines for humans and animals,

In particular through a pharmacovigilance network

The establishment of safe limits for residues in food-

producing animals,

Facilitating innovation and stimulating research

Mobilizing and coordinating scientific resources from throughout the EU

To provide high-quality evaluation of medicinal products,

To advise on research and development programmes,

To perform inspections and to provide useful and clear

information to users and healthcare professionals.

EMEA organization

EMEA COMMITTEE

MANAGEMENT BOARD

It consists of:

A Chairman

Two members of European parliament

Two members of European commission

One representative of each country:

1. Austria

2. Belgium

3. Cyprus

4. Czech Republic

5. Denmark

6. Estonia

7. Finland

8. France

9. Germany

10. Greece

11. Hungary

12. Ireland

13. Italy

14. Latvia

15. Lithuania

16. Luxembourg

17. Malta

18. Netherlands

19. Poland

20. Portugal

21. Slovakia

22. Slovenia

23. Spain

24. Sweden

25. United Kingdom

Two representatives of

o Patients' organizations

o Doctors' organizations

o Veterinarians' organizations

One representative of observer countries:

o Bulgaria

Iceland

Liechtenstein

Norway

Romania

The Rules Governing Medicinal Products in the European Union

The body of European Union legislation in the pharmaceutical sector is

compiled in Volume 1 and Volume 5 of the publication ―The rules

governing medicinal products in the European Union‖.

Volume 1 – EU pharmaceutical legislation for medicinal products for

human use

Volume 5 – EU pharmaceutical legislation for medicinal products for

veterinary use

The basic legislation is supported by a series of guidelines that are also

published in the following volumes of ―The rules governing medicinal

products in the European Union‖:

Volume 2 - Notice to applicants and regulatory guidelines for medicinal

products for human use

Volume 3 - Scientific guidelines for medicinal products for human use

Volume 4 – Guidelines for good manufacturing practices for medicinal

products for human and veterinary use

Volume 6 - Notice to applicants and regulatory guidelines for medicinal

products for veterinary use

Volume 7 - Scientific guidelines for medicinal products for veterinary use

Volume 8 - Maximum residue limits

Volume 9 – Guidelines for pharmacovigilance for medicinal products for

human and veterinary use

Volume 10 – Guidelines for clinical trial

Medicinal products for paediatric use, orphan, herbal medicinal products

and advanced therapies are governed by specific rules.

Volume 2 of the publications “The rules governing medicinal products in

the European Union” contains a list of regulatory guidelines related to

procedural and regulatory requirements such as renewal procedures,

dossier requirements for Type IA/IB variation notifications, summary of

product characteristics (SPC), package information and classification for

the supply, readability of the label and package leaflet requirements.

The Notice to Applicants is presented in three parts:

Volume 2A dealing with procedures for marketing authorization;

Volume 2B dealing with the presentation and content of the application

dossier.

Volume 2C dealing with guidelines.

The Notice to Applicants was first published in 1986 and is regularly

updated.

Volume 2A - Procedures for marketing authorization

Chapter 1 - Marketing Authorization (updated version - November 2005)

Chapter 2 - Mutual Recognition (updated version - February 2007)

Chapter 3 - Community Referral (updated version - September 2007) - Pdf

Version - Word Version

Chapter 4 - Centralized Procedure (updated version - April 2006)

Chapter 5 - Variations (updated version - February 2004)

Chapter 6 - Community Marketing Authorization (updated version -

November 2005)

Chapter 7 - General Information (updated version - July 2008)

Volume 2B - Presentation and content of the dossier

Notice to Applicants, Volume 2B, incorporating the Common Technical

Document (CTD) (May 2008)

Application Form : Module 1.2 Application form - updated version,

revision 9- May 2008

- Module 1.2 Application form - pdf document (May 2008)

Volume 2B - Change Control Process for European eCTD Standarts

Change Control Process for European eCTD Standards - v1.1 (December

2006)

o Module 1.2 Application form - word document (May 2008)

Volume 2C - Regulatory Guidelines

Guidance on a new therapeutic indication for a well established substance

Volume 3 - Scientific guidelines for medicinal products for human use

Volume 3 of the publications ―The rules governing medicinal products in

the European Union‖ contains scientific guidelines prepared by the

Committee for Medicinal Products for Human Use (CHMP) in

consultation with the competent authorities of the EU Member States, to

help applicants prepare marketing-authorization applications for medicinal

products for human use.

Guidelines are intended to provide a basis for practical harmonization of

the manner in which the EU Member States and the EMEA interpret and

apply the detailed requirements for the demonstration of quality, safety

and efficacy contained in the Community Directives. They also help to

ensure that applications for marketing authorization are prepared in a

manner that will be recognized as valid by the EMEA.

Medicines for human use and its regulation

The regulation of medicines involves deciding whether or not new medicines

developed by the pharmaceutical industry are suitable to be placed on the

market for use by patients, and whether they continue to be safe for use once

they are on the market.

Regulation of medicines in the European Union

In the European Union (EU), a company that wishes to bring a medicine

to the market may submit a single application to the EMEA for a

'marketing authorization' (license) that is valid simultaneously in all EU

Member States, plus Iceland, Liechtenstein and Norway. This is called the

'centralized (or 'Community') authorization procedure', and is mandatory

for certain types of medicines and optional for others.

Other authorization procedures — 'national procedure', 'decentralized

procedure' and 'mutual-recognition procedure' — exist for medicines that

do not fall within the mandatory scope of the centralized procedure

Role of the European Medicines Agency in the regulation of

medicines

It is a fundamental requirement that decisions about the authorization of

medicines are based on an objective, scientific assessment of their quality,

safety and efficacy.

Conducting these assessments is the primary role of the EMEA. Through

its scientific committees, the EMEA assesses every medicine for which a

marketing-authorization application has been submitted (in accordance

with the centralized procedure), and prepares a recommendation (called an

'opinion') that is then relayed to the European Commission, which has the

ultimate responsibility for taking decisions on granting, refusing, revoking

or suspending marketing authorizations.

Besides preparing scientific opinions on marketing-authorization

applications, the EMEA is also involved in:

communicating authoritative and objective information about medicines to

patients, healthcare professionals and other audiences

promoting the availability of medicines

continuously monitoring and assessing the safety of medicines on the

market (a process known as 'pharmacovigilance')

the designation of medicines for rare diseases ('orphan' medicines)

providing special assistance to micro, small and medium-sized enterprises

involved in the development of medicines

assessing pediatric investigation plans (development plans) submitted in

support of marketing-authorization applications for medicines intended for

use in children

drafting regulatory and scientific guidance to assist companies in all areas

relating to the development and marketing of medicines

providing scientific advice and protocol assistance to companies seeking

to submit applications to the EMEA

Providing scientific recommendations on matters relating to medicines

referred to the Agency by EU Member States or by the European

Commission ('referral procedures').

Product information

Product information

Human Medicines

Veterinary Medicines

Safety Announcements

Product Withdrawals

Summary of Opinions

Opinions for Orphan Designation

Opinions for medicines used outside the EU

Authorized Medicinal Products for Human Use & veterinary medicines gives a list of

drugs which are authorized in European market.

Human Medicines - Product Safety Announcements given

Veterinary Medicines - No Product Safety Announcements posted

Market Authorization Withdrawals

Opinions - (CHMP) to give opinions, in cooperation with the World Health Organization

(WHO).

EMEA INTERACTION WITH PATIENTS' AND CONSUMERS' ORGANISATIONS

The Management Board has adopted a Framework on the Interaction between the EMEA

and Patients' and Consumers' Organization.

In order to enable the Agency to establish contacts with the appropriate patients‘ and

consumers‘ organizations on a transparent basis, the Agency together with the

EMEA/CHMP Working Group with Patients' Organizations prepared a set of criteria to be

fulfilled by patients‘ and consumers‘ organizations prior to involvement in the EMEA

activities. Based on these criteria, a questionnaire has been prepared to collect all necessary

information in order to evaluate if your organization fulfils the defined criteria, and

therefore can be involved in EMEA activities.

One can contact EMEA through this e-mail ID: patients-consumers@emea.eu.int

SME Office: Addressing the needs of small and medium-sized enterprises

(SMEs)

Specific provisions aimed at promoting innovation and the development of new medicinal

products for human and veterinary use by SMEs was adopted by the European

Commission on 15 December 2005.

The Agency has launched an 'SME Office', which is dedicated to addressing the particular

needs of smaller companies.

Any queries, feedback or comments are welcome.

Contact point smeoffice@emea.eu.int

INSPECTIONS - ACTIVITIES OF THE SECTOR

Coordination of the verification of compliance with the principles of Good Manufacturing

Practice (GMP), Good Clinical Practice (GCP) and Good Laboratory Practice (GLP)

Co-ordinating any inspection requested by the CHMP or CVMP

Pharmacovigilance (PhV)

Vaccine Antigen Master File (VAMF) and Plasma Master File (PMF) certification.

The Sector organizes and chairs regular meetings of European Economic Area (EEA) GCP

and GMP inspectors

Implications of PAT

Sampling and Testing Programme.

Communication and action by Member States in response to suspected Quality Defects

Responsibility for issuing Certificates of Medicinal Products in accordance with WHO

requirements

Mutual Recognition Agreements (MRA) that have been negotiated between the European

Community and non European countries.

Whilst most scientific activities of the Agency are divided between medicinal products for

human and for veterinary use, the tasks of the Inspections Sector are typically common to

both types of products.

EMEA CERTIFICATES OF MEDICINAL PRODUCTS The EMEA certification scheme is based on World Health Organization

recommendations.

EMEA Certificates are issued by EMEA, on behalf of the European Commission, to

confirm the Marketing Authorization status of products

EMEA issues certificates within 10 working days following receipt of a valid

application form.

COUNTERFEIT MEDICINES Counterfeit medicines are substandard pharmaceuticals - medicines manufactured below

established standards of safety, quality and efficacy. They are deliberately and fraudulently

mislabeled with respect to identity and/or source.

Counterfeiting can apply to both branded and generic products and counterfeit medicines

may include products with the correct ingredients but fake packaging, with the wrong

ingredients, without active ingredients or with insufficient active ingredients.

The most frequently counterfeited medicines in wealthy countries were new, expensive

lifestyle medicines, such as hormones, steroids and antihistamines. In developing countries

the most counterfeited medicines have been those used to treat life-threatening conditions

such as malaria, tuberculosis and HIV/AIDS. As the phenomenon spreads, more and more

medicines are counterfeited, including expensive ones, such as anti-cancer drugs, and

those highly in demand, such as antiviral.

Regulators and industry are equally concerned about the rise in counterfeits.

EMEA seeks to support anti-counterfeiting activities in close cooperation with the

Commission and national medicines agencies by facilitating information sharing and

coordinating actions (including recalls and testing) in the case of centrally authorized

product counterfeits.

Good Clinical Practice - Human Medicinal Products Good Clinical Practice (GCP) is an international ethical and scientific quality standard for

designing, recording and reporting trials that involve the participation of human subjects.

Compliance with this standard provides public assurance that the rights, safety and well

being of trial subjects are protected; consistent with the principles that have their origin in

the Declaration of Helsinki, and that the clinical trial data are credible.

Clinical trials included in any marketing authorization application in the EU are required

to be conducted in accordance with GCP

The sector is involved in the preparation of new and revised guidance on GCP topics, co-

ordination of advice on the interpretation of EU GCP requirements and related technical

issues, and on the development of community-wide procedures relating to GCP

inspections.

Europe has adopted the ICH-GCP in July 1996

Good Clinical Practice - veterinary medicinal products For clinical trials of veterinary products, Europe has adopted the VICH GCP

It provides guidance on the design and conduct of all clinical studies of veterinary

products in the target species.

It is directed at all individuals and organizations involved in the design, conduct,

monitoring, recording, auditing, analysis and reporting of clinical studies in target species

and is intended to ensure that such studies are conducted and documented in accordance

with the principles of Good Clinical Practice (GCP).

Good Laboratory Practice The principles of Good Laboratory Practice (GLP) define a set of rules and criteria for a

quality system concerned with the organizational process and the conditions under which

non-clinical health and environmental safety studies are planned, performed, monitored,

recorded, reported and archived.

The Procedure describes the co-ordination of GLP inspections of the non-clinical safety,

toxicological and pharmacological studies proposed in human and veterinary applications

for marketing authorizations under the centralized system.

EMEA Inspections Sector has advised the CHMP and CVMP that pivotal studies for

centralized products should be inspected to assess their compliance with the Principles of

GLP.

Good Manufacturing Practice Good Manufacturing Practice (GMP) is defined as ―That part of Quality Assurance which

ensures that products are consistently produced and controlled to the quality standards

appropriate to their intended use.‖

The principles and guidelines for GMP are stated in two Directives; Directive for

medicinal products and investigational medicinal products for human use and Directive

concerning veterinary medicinal products

Process Analytical Technology The term "Process Analytical Technologies (PAT)" has been used to describe "a system

for designing and controlling manufacturing through timely measurements (i.e. during

processing) of critical quality and performance attributes for raw and in-process materials

and also processes with the goal of ensuring final product quality".

This part of the dossier focused on a comprehensive analysis of the active substance, the

choice of the composition, the manufacturing method, as well as the identification of the

critical process parameters and the development of suitable analytical methods

In order to support the PAT activities in EU, an EMEA PAT team was created in

November 2003.

Aim to review the implications of PAT and to ensure that the European regulatory

framework and the authorities are prepared for and adequately equipped to conduct

thorough and effective evaluations of PAT-based submissions.

Product Defects and Recalls In order to protect public health and animal health, it may become necessary to implement

urgent measures such as the recall of one or more defective batch(es) of a medicinal

product during its marketing period.

The authorization holder is required to notify the relevant Competent Authority of any

defect or abnormal restriction that could result in a recall.

Competent Authorites should ensure that information concerning the recall of medicinal

products is notified rapidly to other Member States, if the nature of the defect presents a

serious risk to public health. This information is communicated using the Rapid Alert

Procedure.

Sampling and Testing of Centrally Authorized Products The EMEA implements every year a sampling and testing programme, aimed at

supervising the quality of the Centrally Authorized Products (CAPs) available on the

European market.

EMEA is supported by other institutional partners and by the marketing authorization

holders; each of these plays an important role in the success of the programmes.

Annual reports on the outcome of the sampling and testing programme have been

published starting with products submitted for testing in 2003.

EU Enlargement Activities in the Pharmaceutical Sector

The EMEA has opened up a new area for this topic with a view to providing information and

guidance to applicants and marketing authorization holders during the run up to accession of

Bulgaria and Romania as of 1st January 2007 and future candidate countries.

The intention is to provide a variety of information on topics specific to the EMEA‘s activities

and help applicants/marketing authorization holders prepare for those phasing in processes and

transitional processes.

EMEA IMPLEMENTATION OF THE NEW EU PHARMACEUTICAL

LEGISLATION

These new provisions provide tools to speed up patients‘ and healthcare professionals‘ access

to medicinal products in the Community. They also introduce measures for better safety

monitoring of medicinal products for human and veterinary use

New name for the EMEA As a consequence of the revised EU pharmaceutical legislation, the name of the EMEA

changed from the 'European Agency for the Evaluation of Medicinal Products' to the

'European Medicines Agency'.

The acronym 'EMEA', however, remains unchanged.

New composition of the Management Board The composition of the EMEA Management Board has changed to reflect the enlargement

of the EU to 25 Member States: whereas previously there were two representatives per

Member State on the Board, there is now only one.

Also new is that the Board will include two representatives of patients' organizations, one

representative of doctors' organizations and one representative of veterinarians'

organizations. The selection process for these representatives is ongoing; it is expected that the

full composition of the Board will be settled shortly.

As before, the Management Board continues to have two representatives of the European

Parliament and two representatives of the European Commission, plus one observer from

each of the EEA-EFTA states Iceland, Liechtenstein and Norway.

Each member of the Management Board has an alternate.

New composition of CHMP and CVMP Now have one representative per EU Member State instead of two, plus one representative

for Iceland and one representative for Norway. Each committee member has an alternate.

Possibility of appointing up to five co-opted members each, to gain additional expertise in

particular scientific areas.

New scientific committee: HMPC The HMPC was inaugurated in September 2004.

The role of the HMPC is to provide the Member States and the European Institutions with

the best-possible scientific opinions on questions relating to herbal medicinal products.

New scientific advice working parties (SAWPs) The new legislation gives the EMEA the responsibility of setting up structures and

procedures for providing scientific advice to undertakings on the conduct of the various

tests and trials necessary to demonstrate the quality, safety and efficacy of medicinal

products.

The CHMP and CVMP have each set up a Scientific Advice Working Party to fulfill this

responsibility by providing scientific advice and protocol assistance to sponsors,

companies, research institutes, etc.

New scientific advisory groups (SAGs) The role of these SAGs is to provide, on request from the committee concerned, an

independent recommendation on scientific and technical matters relating to products under

evaluation or any other scientific issues relevant to the work of the respective committee.

While views expressed by the SAGs are taken into account, the ultimate responsibility for

final opinions rests with the respective scientific committee.

SAGs to provide expertise on oncology, diagnostics, anti-infective and

endocrinology/diabetes. The establishment of SAGs for HIV/viral diseases,

CNS/psychiatry, and cardiology is planned for 2005/2006.

EMEA ROAD MAP TO 2010 European Medicines Agency (EMEA) has developed a long-term strategy that will contribute

to better protection and promotion of public and animal health, improve the regulatory

environment for medicinal products, and help to stimulate innovation, research and

development in the EU.

The Road Map takes a realistic view of the challenges facing the Agency and the EU

regulatory system as a whole, while offering viable proposals as to how those challenges can

be met. The ultimate objective of the Road Map project is to ensure that, building on the solid

achievements of the past 10 years, the EMEA and its partners in the EU medicines system

adequately prepare the ground for further success in the years to come.

Reference www.emea.eu.int