ICH and EU regulatory framework and the role

of the European Medicines Agency (EMA)

GCC Workshop on Similar Biological Medicinal Products (Biosimilars)

19-20 April 2011, Riyadh

Falk Ehmann MD, PhD, MSc - Scientific Support & Projects, European Medicines Agency (EMA) An agency of the European Union
 Outline

• Overview ICH and the Global Cooperation Group

• European Medicines Agency (EMA)

• European Regulation of Medicinal Products

• Procedural Aspects (Centralised Procedure)

2
 Agenda: International Conference on Harmonisation (ICH)

• To provide a brief overview of ICH

• Explain the role of the Steering Committee
– Responsibilities
– Membership
– Function
• Report on the mandate of the Global Cooperation
Group
– Shift from information-sharing to training
– Membership (RHIs*, DRAs*)

*RHI: Regional Harmonisation Initiatives

*DRA: Drug Regulatory Authority

3
 ICH
INTERNATIONAL CONFERENCE ON
HARMONIS/ZATION
of
Technical Requirements
for the Registration of
Pharmaceuticals for Human Use
http://www.ich.org
Hosted by ICH Secretariat
IFPMA, Geneva, Switzerland
4
 ICH Background
Unique harmonisation project involving the regulators and
research-based industries of US, EU and Japan
 started in 1990

• WHO, Canada, and EFTA* are observers

Objectives:
• to improve efficiency of new drug development and
registration process
• To promote public health, prevent duplication of clinical trials
in humans and minimise the use of animal testing without
compromising safety and effectiveness

Accomplished through the development and implementation of

harmonised guidelines and standards

* European Free Trade Association (EFTA) is an intergovernmental organisation set up for the promotion of free trade
and economic integration to the benefit of its four Member States: Iceland, Liechtenstein, Norway and Switzerland.
5
 ICH Membership
Europe
EU EFPIA
Japan
MHLW JPMA

United States
FDA PhRMA
Observers: WHO, Canada, EFTA
6
ICH Steering Committee Responsiblities

• The body that governs ICH

• Determines ICH policies and procedures

• Decides on the adoption of ICH projects

– Selects topics for harmonisation
– Endorses the creation of Expert Working Groups

• Monitors and facilitates the progress of Expert Working

Groups

• Signs off ICH documents

7
 ICH Structure

8
Steps of ICH Harmonization
After adoption of a topic by the Steering Committee

STEP 5--Implementing
Guidelines in ICH Regions

STEP 4--Adopting
Harmonized Guidelines

STEP 3--Consulting with Regional

Regulatory Agencies—Comment Period

STEP 2--Agreeing on Draft Text

STEP 1--Building Scientific Consensus

9
 ICH Outcomes
• Over 50 guidelines on technical requirements on:
Quality, Safety and Efficacy
• Efficacy - 14 topics/17 guidelines
• Safety - 8 topics/16 guidelines
• Quality - 9 topics/23 guidelines
• Electronic Standards for the Transfer of Regulatory
Information
• Common Technical Document (CTD & eCTD)
• Maintenance of ICH Controlled Terminology Lists
• Medical dictionary for adverse event reporting and coding
of clinical trial data (MedDRA)
• Scope of ICH products now extends over the product life
cycle and beyond new drugs (OTC and Generics)
10
 ICH: Keys to success
• Effective management and administration
– Through ICH Secretariat and Steering Committee

• Joint participation of regulators and industry

• Science based and consensus driven

• Frequent, concurrent meetings of SC and Working Groups that are

outcomes based

• Commitment of all parties to implement harmonized guidelines

• Well-defined process and procedures

11
 ICH Implementation Process Flow
Process Implementation Step Actions
Good guideline topic Guideline must be value-
selection Topic Selection added and ‘implementable’

Targeted via meetings

Active distribution Publication Non ICH Groups

Formal communication ‘Roll out’ Using

process Dissemination multiple avenues

‘Early, often, all’ within and

Educating users
Training across organizations

Putting guideline ‘theory’ Integrated process; address

into ‘practice’ Implementation questions/issues

Active monitoring
12 of utilization Management Feedback to ICH SC
 Operating Procedures

• The work product of ICH has grown more complex over time -
not simply “new topics”

• ICH Steering Committee adopted a Procedures document that

outlines and defines the variations of work “categories”
– Defines roles and responsibilities
– Updated every fall to reflect current harmonisation activities

13
 Categories: ICH Harmonisation Activities

• New guideline topics under development

• Existing topics under revision

• Existing topics under maintenance

• Existing topics needing clarification for

implementation (Questions and Answers)

14
 ICH GCG: History
Interest beyond the 3 regions

1990 1999 2004 2008

RHI* Expanded
ICH GCG GCG

Initially focused on development of guidelines and standards

for use in the ICH “regions”

Growing interest in ICH products beyond ICH countries

*RHI: Regional Harmonisation Initiatives

15
 ICH Global Cooperation Group (GCG)
Created in 1999 as a sub-committee of ICH SC to:
• Facilitate dissemination of information on ICH
activities, guidelines and their use
• Promote a better understanding of ICH products
By:
• Information-sharing through literature and
presentations by GCG members at international
meetings

Same membership as ICH

16
 ….. Not enough
1990 1999 2004 2008

ICH Expanded
GCG RHI* GCG

More proactive approach was needed to respond

effectively to growing interest in ICH guidelines.
Decided to invite representatives from non-ICH
regions to be part of GCG.
*RHI: Regional Harmonisation Initiatives
17
 ICH6, Osaka, November 2003:
An Important Milestone
Endorsement by ICH SC of new Mandate &
Terms of Reference that call for:
• The ongoing participation of Regional
Harmonisation Initiatives
• More proactive approach
• Greater transparency

18
 Regional Harmonisation Initiatives
now part of GCG
APEC
• Asia-Pacific Economic Cooperation (21 member economies)
ASEAN
• Association of the Southeast Asian Nations (10 economies)
GCC
• Gulf Cooperation Council (6 Gulf states)
PANDRH
• Pan American Network for Drug Regulatory Harmonisation
SADC
• Southern African Development Community (15 countries)

19
 Adopted new GCG mission statement
2004 2008
1990 1999
Expanded
ICH GCG
RHI GCG

May 2005, Brussels:

“To promote a mutual understanding of regional harmonisation
initiatives in order to facilitate the harmonisation process
related to ICH guidelines regionally and globally, and to
facilitate the capacity of drug regulatory authorities and industry
to utilise them”

20
 Training: A Key Focus

Framework and mechanisms established:

• Strategy document lays out principles for effective, strategic use of
training resources

• Clearing house of training events created to identify opportunities

• Procedures and templates under development to improve efficiency

and effectiveness of process – including 2 year planning cycle

• Public access: all training materials to be posted on the ICH website

21
 Expanded GCG

1990 1999 2004 2008

ICH GCG RHI
Expanded
GCG

ICH has recognised the need for changes to mirror

global face of drug development.

In Oct 2007, the ICH SC decided to invite a number of

Drug Regulatory Authorities and Department of Health.

22
 How the ICH Week looks
Saturday Sunday Monday Tuesday Wednesday Thursday

ICH
ICH MedDRA Global
Regulator ICH Steering
Management Cooperati
s Forum Committee
Board on
Group

ICH Technical Working Groups

Complementary

23
Opening of ICH Technical Working Groups to
Experts from RHIs and DRAs/DoH
2010
1990 1999 2004 2008 Invitations of experts
from RHIs/DRAS/DoH
ICH GCG RHI DRAs to ICH EWGs/IWGS.

ICH has recognised the need for a new level of involvement of the GCG to
provide direct technical contributions to the work of ICH, a more global
perspective, and to advance implementation of ICH guidelines.
In November 2010, the ICH SC decided to invite RHIs and DRAs to nominate
technical experts as active members of ICH Expert Working groups.

24
 Beyond ICH: Regulatory Forum

• Regulators only

• ICH + China, India, Brazil, Russia,

Taiwan, Singapore, Australia

25
ICH: Keys to Success
• Well-defined process

• Effective management and administration

• Limited number of players with common focus

• Comparable regulatory, technical and financial capacity

• Commitment of all parties

26
EMA Efforts towards Harmonisation and Transparency
• Participation in SC and expert groups

• Public comments are collected and shared with ICH colleagues thereby
providing a conduit for non-ICH organizations’ input into the ICH Process

• Recent EMA-CHMP proposals adopted by the ICH SC: revision of the

guidelines for
– Genotoxicity,
– Carcinogenicity
– Preclinical Requirements for Clinical Trials

• Recent EMA CHMP proposals just adopted by the ICH SC: Addendum to the
guideline for Non-clinical testing of biotech products and Q&A on the
geriatrics guideline.

• GCG: EMA opened certain CHMP working party meetings to GCG as training,
sends experts to regional workshops
27
 Conclusion on ICH
• Considerable progress to date in promoting a better
knowledge of ICH guidelines and the challenges faced by
other regions in their use

• GCG efforts have evolved from information sharing to

active dialogue to results-oriented actions

• Important new developments should further accelerate

progress

• Learning from each other, in a climate of trust and

cooperation, can greatly increase the strength of all
harmonisation efforts

• Moving towards more efficient regulatory systems and

increased availability of safe, effective and quality
pharmaceuticals on a global level
28
28
 Outline

• Overview of ICH and the Global Cooperation Group

• European Medicines Agency (EMA)

• European Regulation of Medicinal Products

• Procedural Aspects (Centralised Procedure)

29
 Introduction
• The European Medicines Agency (EMA) is a
decentralised body of the EU.

• The mission of the Agency is to foster

scientific excellence in the evaluation and
supervision of medicines, for the benefit of
public and animal health serving over 500
million users of medicinal products

• Responsible for centralised procedure and

co-ordination of EU network + plays a role
in stimulating innovation and research in
the pharmaceutical sector.

30
A networking Agency

• Member States have pooled their

sovereignty for authorisation of
medicines
• EMA is designed to coordinate the
existing scientific resources of Member
States

• EMA is not an FDA for Europe

• All parties linked by an IT network (EudraNet)

31
An interface of co-operation and co-ordination of
Member States’ activities
• Centralised procedure, eligible human and veterinary products
– Single marketing authorisation application valid throughout EU

• Six scientific Committees

• EU Network for scientific advice & expertise constitutes of

– 27 EU Member states
– > 40 national competent authorities
– 4,500 European experts

• Coordination of activities: Pharmacovigilance (new lex 2012), Inspection

• Referral or arbitration procedures for medicines approved via non-centralised

authorisation procedures

32
PATIENTS HCP
CHMP
(Committee for Human Medicinal Products)
Members: 1 per Member State + 1 alternate + 5 co-opted Members
Non voting members: ICE/NO; Chair : Dr. E. Abadie – Vice Chair: Dr. T. Salmonson

COMP
(Committee for Orphan Medicinal Products)
Members: 1 per Member State +3 additional Members + 3 Patient Organisations
Non voting Members: ICE/NO; Chair : Dr. K. Westermark – Vice Chair: Mrs. B. Byskov Holm

HMPC
(Committee for Herbal Medicinal Products)
Members: 1 per Member State + 1 alternate + max. 5 Co-Opted Members
Non-voting members: ICE/NO/possible intl. organisations; Chair: Dr Werner Knöss - Vice-Chair: Dr. I.
Chinou

PDCO
(Paediatric Committee)
Members: 5 CHMP, 1 per other Member States
3 HCP, 3 Patient Organisations + 1 Alternate per member Non voting members: ICE/NO; Chair: Dr. D.
Brasseur - Vice-Chair: Dr. G. Pons

CAT
(Committee for Advanced Therapies)
Members: 5 CHMP, 1 per other Member States
2 HCP + 2 alternates appointed by EC, 2 Patient Organisations + 2 alternates appointed by EC
+ MB/QRD/
Non voting members: ICE/NO; Chair: Dr. C. Schneider - Vice-Chair: Dr. P-A. Salmikangas

33 PCWP
Future PRAC
 S
Psy AG
SAG chi
atr
CVS Pharmacogenomics Biosimilars y

Radiopharmaceuticals Biostatistics

Ne
SAG

SA olo
Respiratory

ur
diagnostics

G gy
Gastroenterology
Blood Prod Patients & QWP*
Consumers Cardiovascular
Vaccines
CHMP SWP*
CNS
Urology
PhVig*
SAG
Cardiovascular Rheumatology
SAG Diabetes
Oncology Sci Adv BWP* Immunology
Vaccines
Infectious
Pharmacokinetics Diseases Working
parties
Oncology l
S A G t i v i ra Disciplines
n
SAG V /A Scientific
34 Anti-Infe HI Advisory Gps
ctives * 1 / MS representation
The EMA is not responsible for:

• Evaluation of all medicines in the EU Activities, e.g. pricing, reimbursement, are

under the responsibility of each MS in the EU

• Controlling, advertising of medicines

Article 1
• Research/development of medicines
“The provisions of EU Regulation shall not
affect the powers of Member States’
• Price and reimbursement authorities as regards setting the prices of
medicinal products or their inclusion in the
scope of the national health system or social
• Clinical trial approval security schemes on the basis of health,
economic and social conditions.
• Medical devices
In particular, Member States shall be free to
choose from the particulars shown in the
• EU healthcare policies marketing authorisation those therapeutic
indications and pack sizes which will be
covered by their social security bodies. “

35
The EU procedures of marketing
authorisations
Centralised Procedure Mutual Recognition Decentralised
(via EMA) procedure Procedure

Better Resource Utilisation

Harmonised Scientific Opinions
36 Harmonised Information to Doctors / Patients
The mutual recognition procedure

One initial National Authorisation

issued by:
-1 National Regulatory Authority
Agree
- recognised by up to 29 other
National Regulatory Authorities

Agree

37 Agree
The decentralised procedure evaluation
Collaborative Evaluation MS level without any pre-existing
National MA

Draft AR
SPC, PL
Labelling 30 days for RMS/
Agreement CMS to issue
National MA’s

120 days RMS 90 days CMS

to prepare AR to approve

REFERRAL
Serious risk to
public health
38
The centralised procedure

Regulatory review Process

• 1 Marketing Authorisation valid EU

• 1 Invented name (Tradename)

• 1 Common Labelling (22 languages identical)

– Summary of Product Characteristics
(SPC)
– User Package Leaflet &
Package Labelling
• Maximum time limit
– 210 days Evaluation  Opinion

39
The centralised procedure

Centralised Procedure = “reserved” procedure

• Not open to all products: dedicated to innovative products

- Some legally obliged to use CP
- Not for ‘old’ substances in established indications

• Example: aspirin for headache

May be open to ‘old’ substances in a new delivery system,
or in a new indication e.g. aspirin for Alzheimer's disease

Products eligible are defined in the legislation

Annex to Regulation (EC) 726/2004

40
Access to Medicines: Mandatory Scope

NAS
Auto-immune disease and
Other immune dysfunctions

AIDS Cancer Neurodegenerative

disorder

-Recombinant DNA Diabetes Viral

technology diseases
NAS / -Controlled gene
“known” expression
-Monoclonal AB Orphan Med Prod
AS? NAS / “known” AS
Reg. 2309/93 Reg. 726/2004

41
Access to Medicines: Optional Scope

Art. 3(2) of Regulation (EC) No 726/2004

Art. 3(2)(a) Art. 3(2)(b)

Significant
Innovation
Interest of
New Active
Patients at
Substances Therapeutic
Community
&/or
OR Level
Scientific
&/or
Technical

“known” AS
42
Structure of EU Marketing Authorization Applications (MAAs)
The Common Technical Document (CTD)
MODULE 1
Administrative and regional information, “Risk Management”, “Risk
Reduction” and Pharmacovigilance Plans

MODULE 2
Overviews and summaries of Modules 3 to 5

MODULE 3

Quality (manufacturing process, control methods, analytical tests)

MODULE 4
Pre- clinical investigations (animal models)

MODULE 5

Clinical investigation (Phases I to III)

43
 Centralised Procedure Assessment Procedure
PRE-
SUBMISSION
Joint Opinion,
Start Reports LoQ AR LoI CHMP AR EC
D0 D80 D120 D150 D180 D210 Decision

EPAR

Validation

Submission Responses to Responses to

LoQ D 121 LoI D181

AR: Assessment Report, EPAR: European Public Assessment Report, LoQ: List of Questions, LoI: List
of Outstanding Issues
Active time: evaluation

Clock Stop: i.e. time for the applicant to prepare responses

44
Regulatory processes throughout the EMA
Clinical Development
Preclinical Regulatory Post
Discovery Chemistry Evaluation
Development marketing
Ph I Ph II Ph III

8. Clinical trials
6. Certification

3. Classification/ Scientific recommendations

2. Briefing
5. Orphan Designation
Meeting ITF

1. SME 4. Scientific Advice/Protocol Assistance

Status
9. MAA
7. PIP Submission
Submission
Pre-submission
45
meeting
 Thank you for your attention!

Acknowledgements

• Patrick Le Courtois (Head of Development and Evaluation of Medicines, EMA)

• Spiros Vamvakas (Head Scientific Advice)
• Anthony Humphreys (Head Regulatory, Procedural and Committee Support)

An agency of the European Union