Good Regulatory Practice

Definition and Goals of Drug Regulatory Affairs
and Good Regulatory Practice
ZAFES Curriculum
Regulatory Affairs (Module 11)
Dr. Christa Schrder

Paul-Ehrlich-Institut, Langen
Unit European Procedures
schch@pei.de
Content
Information on DRA
Legislation
Marketing Authorisation
Centralised procedure
Mutual recognition procedure
Decentralised procedure
Variations
Good Regulatory Practices
2
Dr. Christa Schrder, Paul-Ehrlich-Institut
1
Information on DRA
Legislation
Guidelines
Decisions / statements of key regulators
Comments / interpretations
Discussions at trade association meetings
will be found in
journals (Official Journal of the European Community (EU),
Bundesanzeiger (DE) , Regulatory Affairs Journal)
databases and
internet homepages, and is presented at
meetings
3
Regulatory Information published by authorities (1)

Official Journal of the European
Union
The Official Journal is comprised
of two series:
The L series contains EU
legislation including
regulations, directives,
decisions, recommendations
and opinions.
The C series contains reports and
announcements including the
judgments of the European
Court of Justice and the Court
of First Instance.
There is also a supplementary S
series containing invitations to
tender.
4
2
Regulatory Information published by authorities (2)
Bundesanzeiger
Der Bundesanzeiger ist neben dem
Bundesgesetzblatt ein weiteres
Verkndungs- und
Bekanntmachungsorgan der deutschen
Bundesbehrden. Es wird vom
Bundesministerium der Justiz
herausgegeben. Zustzlich ist der
Bundesanzeiger
Pflichtverffentlichungsblatt fr
gerichtliche und sonstige
Bekanntmachungen, fr alle
Handelsregistereintragungen sowie fr
gesetzlich vorgeschriebene
Verffentlichungen von
Jahresabschlssen und
Hinterlegungsbekanntmachungen der
Unternehmen. In den letzten Jahren wird
die herkmmliche Ausgabe auf Papier
mehr und mehr durch den im Internet
verffentlichten elektronischen
Bundesanzeiger ersetzt. Dabei erfolgen
Verffentlichungen blicherweise nicht
parallel in beiden Formen.
5
Regulatory Information published by commercial editors
Websites of different
associations e.g.
EFPIA - Europ. Fed. Of Pharm.
Industries & associations
http://www.efpia.org
VFA Verband Forschender

Arzneimittelhersteller
http://www.vfa.de
BPI - Bundesverband der

Pharmazeutischen Industrie
http://www.bpi.de
6
3
Regulatory Information published by commercial editors
Commecial databases e.g.
7
Information on DRA
Links to Key European Institutions
European Commission, Enterprise DG
http://ec.europa.eu/enterprise/pharmaceuticals/index en.htm
European Medicines Evaluation Agency EMEA
http://emea.europa.eu/
(National) Medicines Authorities in the European Union
http://heads.medagencies.org/
8
4
Information on DRA Mutual Recognition Product Index of
medicinal products approved through the MRP /DCP procedure
9
Website der HMA
10
5
Information on DRA - European Public Assessment Report
11
Information on DRA National lists of approved products
E.g. Rote Liste (Germany)
12
6
Hierachy of the Community texts
Pharmaceutical Law
1. Binding Legislation
Regulations (Verordnung) (e.g. 726/2004/EC)
directly binding
Directives (Richtlinie)
national law (e.g. 2001/83/EC 14. AMG Novelle)
2. Soft law not legally binding
Recommendations (Council, Parl.)
Guidelines (EU Commission, EMEA, CHMP, ICH, WHO)
Notice to Apllicants
13
Rules Govering Medicinal Products in the EU (Eudralex)
Volume 1 Community legislation

Volume 2 The Notice to Applicants (NtA)
Volume 2A Procedures for Marketing Authorisation
Volume 2B Presentation and content of the application dossier
Volume2C Regulatory Guidelines
Volume 3 - Guidelines Quality, safety, efficacy
Volume 4 - guide to Good Manufacturing Practice for
Medicinal products
Volume 5-8 Veterinary issues
Volume 9 Pharmacovigilance
Volume 10 Good Clinical Practice
14
7
Basic Classification of Medicines
Medicinal products / Medicinal devices for human or

veterinary use
New active substances / Generic medicinal Products
Biological Products / Biotechnology Products
Immunological Medicinal Products
Prescription / non-prescription
Herbal Medicinal Products / Traditional Herbal Medicinal
Products
Radiopharmaceuticals
15
Directive 2001/83/EC, Article 1 (2) Medicinal Product

Any substance or combination of substances presented for treating
or preventing disease in human beings
Any substance or combination of substances which may be
administered to human beings with a view to making medical
diagnosis or to restoring, correcting or modifying physiological
functions in human beings
Article 2(2) In cases of doubt, where, taking into account all ist
characteristics, a product may fall within the definition of a
medicinal product and within the definition of a product covered
by other Community legislation the provisions of this Directive shall
apply
16
8
Acc. To Directive 2001/83/EC
Biological Product
A biological medicinal product is a product, the active substance of
which is a biological substance
Produced by or extracted from a biological source
That needs for its characterization and the determination of ist quality a
combination of physiochemical-biological testing, together with the
production process and ist control
The following shall be considered as biological medicinal products:
Medicinal products derived from human blood and human plasma as
defined, respectively in paragraphs (4) and (10) of Article 1
Medicinal products falling within the scope of Part A of the Annex to
Regulation (EEC) No 2309/93
Advanced therapy medicinal products as defined in Part IV of this Annex
17
Basic Classification of Medcines

Biotechnology Product (Annex to Regulation 726/2004/EC)
18
9
Marketing Authorisation
Options
Centralised Procedure
Mutual Recogntion
Mutual Recognition Procedure Centralised
Decentralised National
Decentralised Procedure
National Procedure
19
CENTRALISED PROCEDURE FOR MARKETING

AUTHORISATION APPLICATIONS EVALUATION
10
Optional Scope - Regulation (EC) No 726/2004
Article 3(1): mandatory scope
Article 3(2): optional scope
(a) new active substance not authorised; or
(b) significant therapeutic, scientific or technical innovation or

interests of patients at Community level.
21
Compulsory scope of Centralised procedure/

Therapeutic areas
Regulation 2004/726/EC: Medicinal products to be authorised by the
Community include medicinal products for human use containing a new
active substance which, on the date of entry into force of this Regulation,
was not authorised in the Community, for which the therapeutic
indication is the treatment of any of the following diseases:
-acquired immune deficiency syndrome

-cancer
-neurodegenerative disorder
-diabetes
and with effect from 20 May 2008:

-auto-immune diseases and other immune dysfunctions
-viral diseases
22
11
Overview of the Centralised Procedure
Day 0 - 120
Pre- Primary CLOCK
submission evaluation STOP
Day 121 - 210

Secondary Opinion/
Decision
evaluation
LAUNCH
Post authorisation
Activities 23
Quelle: EMEA
Landscape
CHMP
Committee for Medicinal Products for Human Use
Other
groups
COMP
Committee for
Orphan Medicinal Products
13 WPs
7 Scientific
Advisory Groups
Working Parties
24
Quelle: EMEA Dr. Christa Schrder, Paul-Ehrlich-Institut
12
CHMP Working Parties
Scientific Advice WP Scientific Advisory

Paediatric WP
Groups (SAGs
(SAGs))
- HIV/Viral Diseases
Safety WP - Anti-
Anti- Infectives (not HIV)
- Cardiovascular
Efficacy WP CHMP - Central Nervous System
- Diabetes & Endocrinology
- Diagnostics
Quality WP - Oncology
Pharmacovigilance Pharmacogenetics WP
WP Gene Therapy WP-
WP- Cell
based therapy WP
Biological WP
Vaccine WP
Blood Products WP
(Pre-
(Pre-)clinical WP on comparability
+ specific ad-
ad-hoc working groups or
Quality Review of Documents subgroup meetings when needed
25
Dossier Assessment
Dossier Assessment
Based on Assessment by Rapp/Co-Rapp
Peer Review
Precise and operational format
Reports to CHMP
Scientific MA
Advice MAA Post Authorisation
Initial MAA Pandemic flu Pharmacovigalance
List of Questions PMF MAA
Prior to Opinion (future)
VAMF
Possible Oral explanation
Variations
Line Extensions
Referrals
SAWP VWP PhVWP
BWP
Possible oral BWP
explanations VWP
+ BWP SWP
BWP VEG
VWP SAG
SWP Anti-infectives (not HIV)
QWP Diagnostics
central Nervous System
Cardiovascular
Diabetes / Endocrinology
SWP
QWP
26
13
Where to find Information about EMEA
27
Where to find WP and SAGs information
28
14
Pre-
Pre-Submission phase
Pre-
Pre-submission
-1 m
Request for
accelerated procedure
-7/-6 m
Appointment Rapporteurs +
Pre- submission meetings
- 18m/-12m
Filing strategy/ Confirmation Eligibility
Invented name review
Quelle: EMEA
- 12 to -36m
Orphan Drug Scientific Advice
designation 29
Submission / Validation Phase
10 working
days
Submission Acceptability D1
Application of application Start of
Modules 1-5 procedure
PTL (with relevant PTMs): check

Administrative part
Technical part (compliance with legal/regulatory
requirements)
Possible interaction with (Co-) rapporteurs to
discuss questions on admissibility
No scientific evaluation at this stage
30
15
Common Technical Document (CTD)
Not part of CTD
e1
1 e.g Environmental
ul
Regional risk assessment
od
Administrative Orphan
M
Information Exclusivity, Risk
Management
Nonclinical Clinica System
2
Overview l
y
ar
le
Over-
mm
Su y
u
all lit
view
2
d
er ua
Mo
Ov Q
Nonclinical Clinical
Summaries Summary
CT
D
3 4 5
Quality Data Nonclinical Data Clinical Data
Study Reports Study Reports Study Reports
Quelle: EMEA Raw Data

31
Primary Evaluation Phase
Stop
Clock
D 1 D 80 D 100 D 112 D 120

Rapp./Co- CHMP Peer review CHMP consolidated
rapp AR comments Tele- List of Questions
+ peer conference Approvability/non-
reviewer approvability
CHMP
EMEA Applicant Applicant
32
16
Secondary Evaluation Phase
Opinion
Benefi Risk
t
D 121 D 150 D 180 Day 181
Joint Rapp./ Hearing? Hearing D 210
Co-rapp. AR Opinion
D 170
Comments
CHMP
CHMP Consensus?
EMEA Applicant Vote?
33
Different type of MA
MA under Exceptional Circumstances Conditional MA
positive benefit-risk balance

Comprehensive data cannot be
comprehensive data likely to be provided
provided (specific situations
unmet medical fulfilled
foreseen in the legislation)
benefit to public health of immediate
availability outweighs risk inherent
Reviewed annually to reassess additional data is required
the risk-benefit balance
Authorisation valid for one year, on a
Will not (normally) lead to renewable basis
completion of the dossier and
become a normal market Once the pending studies are provided, it
authorisation can become a normal marketing
authorisation
34
17
Accelerated procedure
Scientific opinion in 150 days (instead of 210)
1st phase similar

Day 120 Opinion or List of outstanding issues
Day 121-150 Oral explanation if applicable + Opinion
35
Overview
Orphan Medicinal Products
Orphan Designation Orphan Designation
By COMP/EC mandatory access to CP
CHMP
Orphan Designation Protocol assistance Opinion
Procedure by SAWP
CP
Protocol assistance
procedure EC Decision
MA
Medicinal Products for the Community
CHMP Conditional Approval
Scientific Advice by SAWP Exceptional Circumstances
Opinion
Normal Circumstances
CP: Standard Evaluation or
Accelerated Procedure
Scientific Advice
Procedure EC Decision
MA
Compassionate Compassionate Compassionate Compassionate
Use Procedure Use Procedure Use Procedure Use Procedure
Medicinal Products for outside the community in collaboration with WHO

WHO Scientific
eligibilit Advice
y Scientific Advice Procedure by SAWP
CP
WHO CHMP
eligibility Opinion 36
18
Compassionate Use (Reg 726/2004/EC Art. 14 and Dir
2001/83/EC)
Supply of an unlicensed medicinal product to patients for

whom no standard alternative therapies are available
Usually reserved for the treatment of serious diseases
Takes place before or during the assessment procedure for

the granting of a MA and ends with the result of the
procedure
Enables innovative drugs to be made available to patients

during the development programme
37
Getting a MA for a new medicinal product
CHMP
Opinion(s) Translation to all other
19 official European
English languages + Bulgarian & Version
Romanian
(as signed off
by the Transmission
CHMP
Chairman)
Applicant(s)
M.S.
Commission
day 0 day 27
38
19
EPAR - European Public Assessment Report
= CHMP Assessment Report after deletion of information of

commercially confidential nature
Summary All readers
available in all authorised

EU languages presentations All readers
Patients
available in English Package Leaflet
Summary of Product
Health professionals
Characteristics
Labelling Pharmacists/patients
Authorisation Scientific community

Scientific Basis Health professionals
Steps taken for the assessment

of the product Anyone interested
Steps taken after granting

Anyone interested
the Marketing Authorisation 39
European Public Assessment Report
40
20
Mutual Recognition Procedure
Decentralised procedure
Scope of MRP/DCP:
National Marketing Authorisation - (1)
new active substances (if not mandatory for the centralised

procedure)
generic medicinal products to national (and centralised)
authorised reference medicinal products (if not a
biotechnological medicinal product)
informed consent
bibliographic applications (well established use (WEU))
42
21
Scope of MRP/DCP:
National Marketing Authorisation - (2)
cont.
line extensions to national authorisations
known substances in new combination
homeopathics
traditional herbal medicinal products
43
MRP and DCP
Two routes to receive a MA
1. Mutual recognition procedure (MRP)

where the medicinal product has already received in a MS a MA at
the time of application
or
2. Decentralised procedure (DCP)

where the medicinal product has not received in a MS a MA at the
time of application
44
22
MRP and DCP
Procedures
45
Co-Ordination Group for Mutual Recognition and Decentralised

Procedures (CMD)
46
23
MRP DCP
Applicant
Dossier Dossier RMS
RMS
MA Dossier
CMSs
RMS 120 days
AR, SPC,
PL, label CMSs Draft AR,
SPC, PL
Proposal for Discussion

90 days 90 days
changes (CMSs) between all MSs
Update Final SPC, Final AR,

of AR PL, label SPC, PL
MA MA MA MA MA MA MA MA
RMS CMS CMS CMS CMS CMS CMS RMS
47
Marketing Authorisation EU
MRP DCP
First application to the Reference Only possible, if a national MA has
Member State and granting of a not yet been granted
national Marketing Authorisation Identical applications to be
(MA) Assessment Report (AR) submitted simultanously to RMS
For products with an existing and CMS
national MA the RMS has to update RMS prepares preliminary draft AR
the AR comments by the cMS
Identical applications to selected RMS distributes Draft AR
Concerned Memeber States (CMS) If agreement is reached after 90
If agreement is reached after 90 days subsequent national
days subsequent national Authorisations in the RMS and CMS
Authorisations in the cMS (Authorisation dates different)
(Authorisation dates different) If no agreement is reached further
If no agreement is reached further 60 days negotiation phase in the
60 days negotiation phase in the Coordination Group (CMD)
Coordination Group (CMD) 1 SPC, Package leaflet, labelling;
1 SPC, Package leaflet, labelling; different brand names possible
different brand names possible
48
24
Variations
Definition of a Variation
Any amendment to the documentation which is the legal

basis for the Marketing Authoristion of the medicinal
product archived at the competent authority
49
Classification of Variations
Acc to Regs 1085/2003/EC and 1084/2003/EC Annexes
Urgent safety restrictions: immediate information of the

EMEA / competent authorities
Type IA and IB (minor variations): Notification Decision by

RMS
Type II is an approval procedure e.g. additional therapeutic

indication
Extension Application leads to a Marketing Authorisation
50
25
Good Regulatory Practices
Good Regulatory Practices (GRP) can be defined as:
M. Korteweg, EMEA:
A quality system to ensure that the users of medicinal
products, the applicants, the regulators are satisfied with the
scientific advice, opinions, the establishment of Maximum
Residue Levels, inspection and assessment reports and
related documents, taking into consideration legal
requirements and guidance in order to protect and promote
human and animal health.
51
Good Regulatory Practices in a growing network of authorities
1988 ICH Conference in Japan: harmonisation of technical

requirements for registration of pharmaceuticals in human
use
Authorities worked more and more together (CTD, exchange
of information, etc) EU enlargement
Implies a common understanding of technical /regulatory
requirements and consistency in interpretation and
application whether in the area of assessments, inspections
or pharmacovigilance
Need to ensure quality, consistency in a growing EU
establishment of management systems
52
26
Tools
Paul-Ehrlich-Institut: Peer Review
Medicines Agencies Network: Benchmarking
53
The Peer Review Group as a tool to drive Good Regulatory

Practice
PEI Peer Review Group: Definition
The PRG is a PEI-internal scientific panel, which by

discussion of assessment reports
widens the scientific basis of decisions made by internal and external

assessors,
provides assistance in critical / controversial issues.
...provides access to regulatory memory
54
Quelle: C. Schneider Dr. Christa Schrder, Paul-Ehrlich-Institut
27
Regulatory Peer Review why?
Regulatory decisions should include the following principles:
Based on science
At least for biological and biotechnological medicinal products: Bridging quality

non-clinical clinical part
Consistency with previous regulatory decisions

for similar active substances from the same class
for active substances based on a similar
mechanism of action
for similar clinical indications
Requirements for Applicants should be similar
55
Quelle: C. Schneider Dr. Christa Schrder, Paul-Ehrlich-Institut
The Peer Review Group as a tool to drive Good Regulatory

Practice
PRG meeting mandatory if:

PEI is Scientific Advice/Protocol AssistanceCo-ordinator
PEI is (Co-) Rapporteur in centralised procedure
Scope recently extended:

PEI is Reference Member state in a MRP/DC
Referrals if induced by PEI
National Procedures
(except certain cases, e.g. not virus-inactivated blood
components for transfusion, parallel imports, )
Quelle: C. Schneider 56
28
EU Medicines Network
What is
BENCHMARKING
Of
EUROPEAN MEDICINES AGENCIES
BEMA?
Compare
To enrich, to learn, to find best practices, which are
(cost)-effective, efficient, feasible
57
BEMA - Aim
Identify and share best practices across the network of EU

and EEA medicines agencies
Comparing individual management systems or processes
with the aim of learning from one another
Carried out by colleagues from another competent authority
who are fulfilling the same responsibilities under legislation
in different and complementary ways learning from
one another
The purpose of BEMA is to enable mutual exchange of
information, with a view to introducing improvement
measures within agencies
58
29
Thank you very much!
59
30

Good Regulatory Practice

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Good Regulatory Practice

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Definition and Goals of Drug Regulatory Affairs

and Good Regulatory Practice

Dr. Christa Schrder

Regulatory Information published by authorities (1)

Regulatory Information published by commercial editors

VFA Verband Forschender

BPI - Bundesverband der

Commecial databases e.g.

Links to Key European Institutions

European Commission, Enterprise DG

European Medicines Evaluation Agency EMEA

(National) Medicines Authorities in the European Union

Website der HMA

Information on DRA National lists of approved products

E.g. Rote Liste (Germany)

Rules Govering Medicinal Products in the EU (Eudralex)

Volume 1 Community legislation

Medicinal products / Medicinal devices for human or

Basic Classification of Medicines

Directive 2001/83/EC, Article 1 (2) Medicinal Product

Basic Classification of Medcines

CENTRALISED PROCEDURE FOR MARKETING

Article 3(1): mandatory scope

Article 3(2): optional scope

(a) new active substance not authorised; or

(b) significant therapeutic, scientific or technical innovation or

Compulsory scope of Centralised procedure/

-acquired immune deficiency syndrome

and with effect from 20 May 2008:

Day 121 - 210

Scientific Advice WP Scientific Advisory

Where to find WP and SAGs information

Submission / Validation Phase

PTL (with relevant PTMs): check

Not part of CTD

Quelle: EMEA Raw Data

Primary Evaluation Phase

D 1 D 80 D 100 D 112 D 120

positive benefit-risk balance

Scientific opinion in 150 days (instead of 210)

1st phase similar

Day 121-150 Oral explanation if applicable + Opinion

Medicinal Products for outside the community in collaboration with WHO

Supply of an unlicensed medicinal product to patients for

Usually reserved for the treatment of serious diseases

Takes place before or during the assessment procedure for

Enables innovative drugs to be made available to patients

Getting a MA for a new medicinal product

= CHMP Assessment Report after deletion of information of

Summary All readers

available in all authorised

Authorisation Scientific community

Steps taken for the assessment

Steps taken after granting

European Public Assessment Report

new active substances (if not mandatory for the centralised

MRP and DCP

Two routes to receive a MA

1. Mutual recognition procedure (MRP)

2. Decentralised procedure (DCP)

Co-Ordination Group for Mutual Recognition and Decentralised

Proposal for Discussion

Update Final SPC, Final AR,