I Foresight Training Course (Pavia, 2-4 settembre 2008) European Centralised Procedure and Paediatric Regulation.

1. 1ST FORESIGHT TRAINING COURSE
In collaboration with
“Master in Regulatory Sciences - GIANNI BENZI” (University of Pavia)
“Master in Scientific and Regulatory Assessment of New Medicines” (Tor Vergata
University – Rome)
with the support of
Italian Society of Regulatory Affairs (SIAR)
Task-force in Europe for Drug Development for the Young (TEDDY)
Consortium for Biological and Pharmacological Evaluations (S. Maugeri Foundation
and University of Pavia)
and an educational grant from FARMINDUSTRIA
EUROPEAN CENTRALISED PROCEDURE
AND
PAEDIATRIC REGULATION
Pavia, 2-4 September, 2008
Fondazione Salvatore Maugeri Via Maugeri, 4 – Pavia (Italy)
1st Topic: European Centralised procedure from A to Z

2. CHMP and Centralised
Procedure:
future challenges
Eric Abadie
CHMP Chair / EMEA and
General
Directorate/AFSSAPS
1
Overview of presentation
A. Product Evaluation
-
Centralised Procedure (CMA, EC, AA)
SAG’s
Transparency and B/R
B. Interaction CHMP/other Committees:
PDCO as an example
C. Projects
2

3. Product Evaluation
• Acce t New Medicines
Access to
icines
• SAGs
• Transparency and Risk Benefit
3
CHMP Opinions 2006 - 2007
Outcome of initial-evaluation applications (EU market)
70
60
50
40
30
20
10
0
58
51
8
2006
Positive opinions
9
4
7
2007
Applications w ithdraw n prior to opinion
Negative opinions
4

4. CHMP Opinions 2006 - 2007
Positive opinions per therapeutic area (by ATC code), 2006 - 2007
4
10
7
3
15
13
15
35
1 5
23
Alimentary tract
Cardiovascular
Hormonal
Immunotherapy and oncology
Respiratory
Various
Blood
Genito-urinary
Anti-infective
Neurology/Central nervous system
Sensory organs
5
Rapporteurs from
October 2006 – June 2008
UK
DE
40
NL
SE
35
ES
FR
30
DK
PT
IE
25
BE
HU
20
FI
IT
15
AT
NO
EE
10
SL
LT
5
PL
CZ
GR
0
UK
DE
NL
SE
ES
FR
DK
PT
IE
BE
HU
FI
IT
AT
NO
EE
SL
LT
PL
CZ
GR
6

5. Co-Rapporteurs from
October 2006 – June 2008
UK
DE
NL
SE
20
18
ES
FR
16
DK
PT
IE
14
12
BE
HU
10
FI
8
IT
AT
6
NO
EE
4
SL
LT
PL
CZ
2
0
UK
DE
NL
SE
ES
FR
DK
PT
IE
BE
HU
FI
IT
AT
NO
EE
SL
LT
PL
CZ
GR
GR
7
Peer Review from October
2006 – June 2008
45
40
35
30
25
20
15
10
5
0
DE
SE
FR
DK
EE
NL
PT
ES
IE
CZ
NO
Apr 2005-June 2008
UK
AT
HU
FI
MT
LU
PL
LT
BE
IT
IC
GR
Oct 2006-June 2008
8

6. Conditional Marketing Authorisation
(CMA) Requirements
Art 4: a conditional approval may be granted where although comprehensive
clinical data have not been supplied, all of the requirements (a)-(d) are met
•
(a) The risk-benefit balance of the medicinal product, as defined in Article
1(28a) of Directive 2001/83/EC is positive
2001/83/EC,
•
(b) It is likely that comprehensive data can be provided
•
(c) Unmet medical needs will be fulfilled (no satisfactory methods or major
therapeutic advantage)
•
(d) Benefits of immediate availability outweigh risks due to additional data to
be provided
p
In case of emergency situations only, also non-clinical or pharmaceutical data
may be missing
Art 5: specific obligations….to confirm that R/B balance is positive
Fulfilment of Specific Obligations: lifting of CMA
9
Directive 2001/83/EC as amended, Annex
I, Part II (Exceptional Circumstances, EC)
The applicant can show that he is unable to provide comprehensive data
on the efficacy and safety under normal conditions of use, because:
• The indications for which the product is intended are encountered so
rarely
• In the present state of scientific knowledge
• Contrary to generally accepted principles of medical ethics
Specific obligations. These obligations may include the following:
• Identified programme of studies
studies…. basis of a reassessment of the
benefit/risk profile,
• Restricted use
• Medical information shall draw the attention …
Specific obligations – inform B/R – improve safe/effective use
Fulfilment of spec obligation ≠ Lifting of EC
10

7. EMEA / CHMP Imposed on
MAH
+ve CHMP
opinion
“normal” MA
100
+ve CHMP
opinion
Adequate
Data
Exceptional
Circumstances
Time
11
Conditional Approval
(Cancer, HIV !)
Sutent
Impaqtiv
Prezista
Cancer
L
Sunitinib
HIV
J
Darunavir
Diacomit
Epilepsy
N
Stiripentol
Isentress
J
Raltegravir
Tyverb
HIV
Breast
Cancer
L
Lapatinib
Vectibix
MCR cancer
L
Panitumumab
Intelence
HIV
L
Etravirine
12

8. Exceptional circumstances
(Orphan diseases !) to June
2008
Atryn
Congenital
Antithrombin
deficiency
Elaprase
Hunter Syndrome
A
Idersulfase
Increlex
IGFD
H
Mecasermin
Evoltra
ALL
L
Clofarabine
Pandemrix
Pandemic
R-Antithrombin
alfa
Flu vaccine
13
Accelerated Assessment
When ?
•Reserved products
major therapeutic
interest
•Public health
•Therapeutic
innovation
Justification
major benefits
expected
•Unmet needs vs
available methods
•Extent of major
Extent
ajor
impact (medical
practice, added
value)
14

9. January 2006 – June 2008
N = 21
Positive = 8
Negative = 13
15
HIV (2/5)
Dar…
Dar
NL / UK
- ve
Atr…
DE / FR
- ve
Cel…
SE / PO
+ ve
Ise…
UK / FR
+ ve
Etr…
FR / PO
- ve
16

10. Oncology (1/6)
Gen…
Gen
ES / FR
- ve
Das…
DK / PO
- ve
Len…
FR / SE
- ve
Tor…
T
DE / NL
- ve
The…
Vid…
UK / FR
NL / ES
- ve
+ ve
17
Miscellaneous (2/6)
Anaemia
FR / DE
Epo…
- ve
PNH
ES / FR
Sol…
+ ve
GvHD
SE / ES
Orb…
- ve
NMB
FI / SE
Bri…
- ve
Angioedema
SE / UK
Fir…
+ ve
VTE
SE / DE
Xar…
- ve
18

11. Scientific Advisory Groups (SAGs)
• Deliver independent recommendation to specific
questions put by CHMP
• Rapporteur/Co-R
Rapporteur/Co-Rapporteur will attend
t
ill tt d
– To present the issues
– To provide any additional information on the
dossier
• Possible hearing from applicant
• SAGs “advise”, CHMP “decide”
• SAG position reflected in CHMP Assessment Report
• Concerns: only one SAG really works
(Oncology+++)
19
Timings of SAG meetings
Experience to date
Products
Initial MA
Tarceva
180 - 210
Nexavar
120 - 121
Sutent
Oncology
120 - 121
Avastin
180 - 210
Vectibix
re-examination
Mylotag
180 - 210
Ceplene
180 - 210
Lenalidomide
Gliolan
180 - 210
180 - 210
Genasense
re-examination
Cerepro
re-examination
Tyverb
180 - 210
20

12. Timings of SAG meetings
Experience to date
SAG Categories
HIV/Viral
Initial MA
Post Authorisation samples
Celsentri
180 - 210
Tysabri
121 - 180
Valdoxan
Pre+post 210
Endocrinology
-
-
CVS
-
-
Arixtra + Angiox
Diagnostics
Luminity
150 - 180
Gadolinium contrast agents
+ NSF
-
-
Cubicin
Mycograb
Pre+Post 210
CNS
Anti-Infectives
Guidelines
Referral Art.30 Lamictal
Nutropin AQ
Actos
Avandamet
21
Interactions
CMDh
PDCO
CHMP
COMP
WP’s
HMPC
SAWP/
Pharmacovigilance
CAT
SAG’s
PhVWG
Cttee
22

13. Interactions CHMP/PDCO
• PDCO/C
PDCO/CHMP: regular meetings C
e
r ee gs Chairs,
role CHMP members at PDCO
• PDCO/SAWP: COMP model
• PDCO/other CHMP WP: improving their
coordination on overlapping topics, j
pp g p , joint
WP, PDCO to provide full input into
CHMP guidelines
23
B/R assessment: how to improve transparency
and consistency of our opinions ? Results of B/R
CHMP working group
DISCUSSION OF DRAFT REPORT OF
DISCU
ON
WORKING GROUP BY CHMP
22 JANUARY 2007
DEADLINE FOR COMMENTS
13 FEBRUARY 2007
ADOPTION FOR RELEASE FOR PUBLIC
CONSULTATION
19 FEBRUARY 2007
DEADLINE FOR COMMENTS
29 MAY 2007
DISCUSSION OF REVISED REPORT BY CHMP
FEBRUARY 2008
24

14. Benefit Risk Assessment:
Recommendations (1)
1) To revise the current benefit-risk assessment section
of the CHMP assessment report templates,
incorporating a structured list of benefit and risk criteria
and guidance
• Pilot phase: before implementation, the modified
templates should be tested (for example, by a small
group of assessors using ongoing or completed
applications) and revised as necessary. The pilot
phase ill also involve P t
phas will als in
Patients, Healthcare
s e t
e
Professionals’ representatives and other stakeholders
as necessary.
• Implementation phase: should consist of regular
training of assessors and monitoring (role of HMA).
25
Benefit Risk Assessment:
Recommendations (2)
2)
To further research the methodology of benefit risk
assessment, involving further experts and assessors.
•
To explore further development in methodologies for
benefit/risk analysis, including a wide range of
quantitative and semi-quantitative tools.
•
The
Th CHMP should continue t i t
h ld
ti
to interact with relevant
t ith l
t
stakeholders on international and European initiatives
related to the benefit-risk assessment methods
•
CHMP need the support of NCA !
26

15. CHMP Projects (3 year term)
1. Legislation – RMP, ATP, Paediatrics, Variations, PhVig
2. New Projects – R/B, Antimicrobials, Microbicides
3.
3 WPs – Revision of Role and Mandate Inter ction PhVWP
Mandate, Interaction
4. Experts WG and SAGs – optimisation of consultation process
5. New Review Procedures – Accelerated Review, Biomarkers etc
6. Interaction other Cttees – PDCO, COMP, HMPC, CMD(h)
7. Assessors Trainings / Workshops
8. Communication and Interaction – publications, Interested
Parties consultation
9. International activities – ICH, IMI, CPATH, WHO, Bilateral
agreements
27
High priorities – projects to be
initiated
• Revision of Role and Mandates
of Working Parties
• Paediatric Regulation and
PDCO/CHMP interactions
• Optimisation of consultation
process of SAGs and
Specialised Experts Groups
• Outcome assessment research
• Microbicides
• New Statistical approaches
• Variations Regulation revision
28

16. Revision of Role and Mandate of
WP
• Objectives
j
– Review of mandates,
composition, terms of
reference, procedures to
take into account
outcomes of previous
discussions
– I
Improvement of efficiency
t f ffi i
taking into account
HMA’s concern about the
resource
implementations of WPs.
• Actions proposed to
meet the objectives
– Create a working group
with members appointed
by the CHMP, including
representatives from the
EMEA S
Secretariat t
t i t to
meet and agree on
present and future CHMP
needs with respect to
WPs. Define a project
plan and mandate for the
group’s activities.
29
Paediatric Regulation and
PDCO/CHMP interactions
•
Objectives
– Ensure other WP, Commi te s
WP Committees
etc are appropriately consulted
on relevant topics to fed into
PDCO deliberations on PIPs
– Robust PDCO Opinion
accepted from both scientific
and regulatory perspectives
– SAWP/CHMP advice and
opinions are scientifically
sound for the paediatric
population.
•
Actions proposed to meet the objectives
– Ide tify deviati n of PD O vi w on
Identify deviation PDCO views n
future PIP opinions from existing CHMP
Guidelines
– Identify deviation of PDCO PIP opinions
from SA
– Involve PDCO members/alternates as
experts for evaluation of paediatric data
resulting from an agreed PIP.
– Involve CHMP Rapporteurs before PIP
finally approved
– Involve SAWP members/alternates as
experts for PIP content
– Involve other WP, as appropriate, in
consideration of paediatric topics
– Clarify the role and responsibilities of the
CHMP members having joint
membership
30

17. Optimisation of SAGs/Exp Groups
consultation process within
review procedure
• Objectives
j
– Review of mandates,
composition in terms of both
the best available expertise
and the number of
members, procedures to
involve SAGs in product
scientific discussions and on
drafting of guidelines
• Actions proposed to
meet the objectives
– Create a working group
with CHMP appointed
members, including
representatives from the
Sec e a a o
EMEA Secretariat to
meet and agree on
proposals with regard to
the topics mentioned as
Objectives.
– Set up a policy concerning
when SAGs/Experts Groups
should be consulted.
– Proposal to address the
issue of the conflict of
interest of SAGs members
31
Variation Regulation Revision
•
Objectives
– Input in propose cl ssification of
proposed classification
changes as Type IA, IB or Type II
variations, with detailed conditions and
dossier requirements (guideline will not
only cover quality changes, but will also
pre-define certain safety/efficacy
changes as Type IA/IB/II variations).
– Input in the proposed procedural
guidance for the handling of the different
types of variations
– Define tasks to be performed by the
Rapporteur and the EMEA.
– Define practical working arrangements
at CHMP level, and in cooperation with
CMD(h) e.g. for worksharing, scientific
classification recommendations and
potential referrals from MRP/DCP.
•
Actions proposed to meet the
objectives
– Clarify timelines and drafting process
with the EC, in order to ensure
adequate planning and pro-active
contributions
– Discuss with the EC the possible
creation of a small drafting group,
including representatives of
MSs/EMEA/WPs.
– EMEA to set up internal
set-up
implementation group similar to what
was done in 2003 to propose detailed
procedural handling of the new
variations, for discussion and
agreement with CHMP. The outcome
of these discussions will be reflected
in an update of the EMEA “PostAuthorisation Procedural Advice”
guidance document.
32

18. Outcome Research Assessment
•
Objectives
•
–
At EMEA level: The purpose
of these projects will be to
assess or improve the
methodologies and outcomes
of EMEA’s scientific activities
–
At CHMP level: to establish
and successfully complete a
range of methodologies
(tools/scales) that would
monitor the outcomes of
CHMP’s actions.
Actions proposed to meet the
objectives
–
–
–
–
CHMP to identify and prioritise
topics for outcomes assessment
projects Prioritisation to be
based on urgency and
relevance of the topic and
feasibility of a project
Identification of topics that seem
to merit/require thorough
methodological assessment
Identification of outcomes that
can serve for further outcomes
assessment and evaluation
Procure resources to conduct
prioritised projects.
33
Microbicides
• Objectives
– Allow EMEA/CHMP to
gain further knowledge
and expertise in this field
– Elaborate over time a
scientific position on
these development
programme without
detailed defining of
registration requirements
– Ensure preparedness for
potential future Art. 58
Opinions and/or MAAs in
the centralised procedure
• Actions proposed to
meet the objectives
– Need to create an expert
group for elaborating the
current thinking on the
development of
microbicides. This will
entail meetings with
stakeholders for
identifying the critical
issues to be addressed
– Attendance of EMEA
representative in relevant
scientific conferences
34

19. New Statistical Approaches in
Clinical trials for efficacy
• Objectives
• Actions proposed to
meet the objectives
– To propose a
strategy in order to
advance the
knowledge and
understanding of
new and existing
biostatistical
approaches among
h
statisticians,
clinicians and
medical researchers
in the network of
European experts
– It is proposed that a
task force is set up
consisting of
regulatory
statisticians and
experts. The main
actions of the task
identify problems in
the implementation
of new statistical
approaches, and to
propose actions on
how to address them
35
High priorities – ongoing projects
• Review and learning
project on RMP
• Advanced Therapies
Regulation
• Interaction with PhVWP
and delegations of tasks
• Evaluation of Benefit
Risk
• Antimicrobial resistance
• Biomarkers Qualification
36

20. Conclusion
• CHMP workplan in line with EMEA priorities and key
objectives for near future
• High quality performance in areas of scientific
advices and evaluation of B/R
• Cooperation between CHMP, its WP and other
Committees is paramount !
• Foster consistency, transparency and communication
in the area of B/R, including rationale for CHMP
opinions
• Introducing successive layers of legislation including
additional Committees increases the workload, not
only at the level of CHMP/EMEA but also within the
Network which should remain the scientific pillar of
CHMP opinions
37

21. First Foresight Training Course
European centralised p ocedu e
u opea ce t a sed procedure
and paediatric regulation
Sergio Dompé - Farmindustria
Pavia, September 2nd 2008
Major changes in Pharma sector
An ageing population in
Advanced Economies
Growing importance of
Emerging Countries
Major patent expiry in
coming years
Price containment
Cost pressure
Increased competition
Growing R&D costs
(higher attrition rate)
Margins squeeze
New demand for
unmet medical needs
(e. g. rare diseases)
Ever more resources
needed for R&D
New cutting-edge
technologies
Move to personalized
medicine (from about
Interdisciplinary R&D
500 molecular targets to
over 10.000 in coming years)
Spillovers into
other sectors
Growing specialisat on
Changes in
the business
environment
+
Technology
“shock”
=
New business models
1

22. Growing with networks in the Life
Sciences: an opportunity for Italy
1985
from new technologies: opportunities to
explore leading scientific pathways
from pharmaceutical companies: competencies
to make innovation available
from NHS: cr tical mass and heritage in
g
knowledge at international level
1995
up to a few years ago
critical mass needed
2005
today the difference is in network
competitiveness, not only in size
source: ATA
2
More refined tests and regulation
as means for R&D productivity
New R&D models and integration
with regulation process
improve the access to innovation
new answers to unmet medical needs
growth opportunities for many subjects
(Big Pharma, SMEs, Public Research, University,…)
Source: PriceWaterHouseCoopers
3

23. Aim
where research is the key, remove major bottlenecks in drug
development
Long term objectives
pharmaceutical sector
•increase competitivenes of European p
•foster Europe as the most attractive place for pharma R&D
•enhance access to innovative medicines for patients
IMI will fund pan-European
public-private partnership in
biomedical research
A growing commitment
by pharmaceutical industry in Italy
12
R&D expenditure/pharmacies
sales in pharma companies (%
figures)
Investments +32,5% since 2002
Increase in clinical studies (>10% per year)
11
1,8 billion € investments in Research and
Manufacturing planned for 3 years
10
Red Biotech companies in Italy
9
Before
’70
8
7
20
1971-1975
1976-1980
1990
1995
2000
21
27
2005 ‘07
1981-1985
In few years 147 biotech medicinal
products under development and 99 in
discovery phase
1986-1990
1991-1995
Consolidate growing partnership w th public
research and important incentives
1996-2000
2001-2007
33
52
71
98
168
source: Farmindustria, Blossom-Assobiotec
4

24. EMEA: a regulatory excellence supporting
innovation and R&D growth
•
enhanced role and scope (new chemical and
biotech
drugs for most critical diseases and
orphan drugs)
•
support to research and innovation to stimulate
the development of better medicines, and their
earlier availability to patients and healthcare
professionals
•
upstreaming regulatory cooperation to bring EU
and
US
closer
and
eliminate
unjustified
regulatory divergences
5
EMEA: a stimulus for innovation
SME OFFICE
•
support to innovation, particularly in the field of
new technologies and emerging therapies
•
fee incentives and administrative assistance
SCIENTIFIC ADVICE
•
high
quality
level
advice,
focused
on
development strategies
•
p
q
p
broader scope for request and faster procedure
6

25. EMEA: a stimulus for innovation
ORPHAN DRUGS
•
steady increase in positive COMP opinions
•
44 Marketing Authorisations granted in the EU
INNOVATION TASK FORCE
•
forum for early dialogue with applicants
•
free advice on eligibility for EMEA procedures of
emerging therapies and borderline products
7
Paediatric EU Regulation: opportunity
for public-private partnership
•
Scientific and regulatory measures to encourage
research, development and authorisation of
medicines assessed for paediatric use
•
Incentive measures to support paediatric
investigations into new and older products
•
Paediatric R&D infrastructure (PDCO and clinical
networks) in Europe to establish a central role in
drug development for children
8

26. Better medicines for children:
a challenge for PDCO
Since August 2007
233
•233 Paediatric Investigation Plans and Waivers
applications submitted (17% are orphan medicines)
•31 positive opinions on waivers
•39 positive opinions on PIPs
New opportunities for dialogue and interaction thanks
to cooperation established with Member States
States,
Academia and FDA
9
The answer of pharmaceutical industry to
the EU Paediatric Regulation
Sharing ethical, scientific and research-driven
contents
Within research activities foreseen by the European
Framework Program, cooperation with TEDDY [TASKFORCE IN EUROPE FOR DRUG DEVELOPMENT IN YOUNG] to:
• foster training programs on ethical, scientific and
social aspects of clinical research in children
• facilitate the conduct of clinical trials
• improve the quality of trials
10

27. Pre-Submission
Activities
Hans-Georg Eichler
EMEA
Pavia; September 2008
Pre-submission activities
•Scientific Advice/Protocol assistance
•Orphan Drug Designation
•Marketing Authorisation Application
2

28. The SA/PA pre-submission meeting
• Optional – a service by your friendly regulator
• used by ca. 40% of all applicants/requests (124 PSM’s in 2007)
Why ask for it?
• benefit from the experience available at the EMEA…
• …with possible involvement of co-ordinators and experts
• receive early feedback on content and …
• …improve quality of request, refine your questions
The less experienced the applicant, the higher the value of a PSM
3
With pre-submission meeting
Letter
of
Intent
Pre sub.
Pre-sub.
meeting
Final
docs
Start of
SA/PA
procedure
SAWP
mtg 1
Letter
of
Intent
Final
docs
Without pre-submission meeting
4

29. The Orphan drug designation presubmission meeting
• Optional – a service by your friendly regulator
• used by ca. 60-70% of all applicants/requests
• mostly by teleconference
Why ask for it?
• benefit from the experience available at the EMEA…
• receive informal early feedback on content and …
• …improve quality of request
• no fee, no delay (unless applicant requires extra time for
revision)
5
MAA Pre-Submission Activities
PrePre-submission
-1 m
Request for
d review
New! Pediatric
Investigational Plan (PIP)
compliance check
at least 3 m before MAA
g
-18m/-12m
-12m to -36m
Orphan Drug
designation
Request Eligibility for Centralised Procedure
Request Inv nted name review
Invented
Start Rapporteur appointment process
Scientific Advice
Pipeline information
SME
designation
6

30. EMEA Pre-submission Guidance
(example topics)
• When and how are Rap/Co-Rap appointed?
• How, when and to whom shall I submit my application?
,
• When can I expect a GMP inspection?
• How is the fee for my application calculated?
• Do I need to perform User Consultation on the PL?
Further clarification ? Other questions ?
⇓ Request Meeting at EMEA via
“Pre-Submission Meeting Request Form”
7
EMEA Pre-submission Meetings
• 6-7 Months before submission
Free service
• Discuss final practical & regulatory aspects of upcoming
application
li ti
• Clarify application-specific issues not addressed in the PreSubmission Guidance
• Useful step to ensure that application will meet all
requirements for Validation
• Strongly recommended, even for experienced users of the
centralised procedure
Reconfirm various administrative/procedural/legal
issues; requirements may have changed
8

31. Scientific Advice at
EMEA
Hans-Georg Eichler
EMEA
Pavia; September 2008
Scientific Advice and MAA outcome
2004-2007
compliance*
advice*
113
no
218
no
yes
15
- Stat/Analysis
57
171
yes
47
= 0.33
14
HR = 2 6
2.6
1
62
- Comparator
ratios
43
156
*Endpoint
-
outcome
6
41
6
47
= 0.13
2

32. Scientific Advice: getting the most out of it
We intend to demonstrate the efficacy of [drug] on
severity of asthma by way of a double-blind, randomised,
controlled trial in patients with severe asthma.
Does CHMP agree?
A draft clinical trial protocol is attached in appendix 1.
Does CHMP agree with the proposed protocol of the
phase III trial?
Level of input
Level of output !
3

33. EMEA qualification process of innovative
drug development methods
Scope: to address innovative drug development methods
methods.
1st phase: limited to use of Biomarkers developed by
consortia.
Input: Protocols and results of studies performed to
establish use of a biomarker for a specific purpose in drug
development.
Operations: based on existing Scientific Advice procedure
with adaptations: appointment of dedicated team
team,
involvement of experts, allow for internatl collaboration;
public consultation prior to a Qualification Advice.
Output: (i) Scientific Advice on future protocols and studies
to be further for qualification purposes. (ii) Qualification
Advice and assessment (public document).
5

34. Pre-submission activities – biotech and
orphan perspective
Anne Marie Li Kwai Cheung
Associate Director Regulatory
Affairs Genzyme Europe BV
2September 2008
In this talk
Introduction
Pre-submission activities
Pre-submission meetings
Summary
Foresight Training Course 2-4 September 2008

35. Pre-submission activities
Scientific advice/Protocol Assistance at any time during
development and post-approval
–
National or at CHMP
Regulatory strategy meeting (under review)
–
–
18-24 months prior to submission
Bridging advice, interim results and dossier preparation
Pre-submission meeting
–
6-7 months prior to filing
Rapporteur selection
–
Schedule meetings with rapporteur
Trade name acceptability
Foresight Training Course 2-4 September 2008
EMEA Guidance on Pre-submission
meeting for MAA
The EMEA emphasises the importance of Pre-Submission Meetings
with applicants. Pre-Submission Meetings are a vital opportunity for
applicants to obtain procedural, regulatory and legal advice from the
EMEA. This guidance information and successful Pre-Submission.
Meetings should enable applicants to submit applications, which are in
conformity with the legal and regulatory requirements and which can be
validated speedily. Pre-Submission Meetings will also enable applicants
to t bli h
t establish contact with th EMEA staff closely i
t t ith the
t ff l
l involved with th
l d ith the
application as it proceeds
http://www.emea.europa.eu/htms/human/presub/index.htm
Foresight Training Course 2-4 September 2008

36. MAA Pre-submission meeting
Aimed to provide information to finalize MAA
– Legal issues
– Regulatory issues
– Scientific issues
Should be held 6-7 months prior to MAA submission
http://www.emea.europa.eu/htms/human/presub/38271206en.pdf
http://www.emea.europa.eu/htms/human/presub/list.htm
Foresight Training Course 2-4 September 2008
EMEA Participants
Product team Leader (PTL)
Project Team members from
Quality
– Safety and efficacy
– Regulatory Affairs
– Specialized Group Leader therapeutic area
Possible other attendees from: Orphan Drugs,
SME, Pediatrics, Inspections, Medical Information,
Risk Management, Central Information Group and
post-authorisation Safety and efficacy
–
Foresight Training Course 2-4 September 2008

37. Meeting documents
Pre-submission request form
Overview of development programme
Draft Table of contents
Draft product information (CTD M1.3)
Draft application form
Topic specific information
–
E.g. justification for accelerated review
Foresight Training Course 2-4 September 2008
Meeting
Pre-submission request form serves as agenda
–
–
–
–
–
–
Quality and GMP
Non-clinical, Clinical, GLP and GCP
Pharmacovigilance
Regulatory and Procedural;
Product Information and Transparency
Administrative
Applicant allowed a 20-30 minutes presentation at start meeting
Meeting minutes to be prepared by sponsor within 2 weeks
–
EMEA will review within 2 weeks
Foresight Training Course 2-4 September 2008

38. Our experience
EMEA staff well prepared
Good guidance that supported smooth validation
Great opportunity to meet EMEA team involved in
review of your MAA
Do not think that you know how it works from the
experience on your last MAA – things may change
Work with PTL to schedule meeting with (Co)
(Co)Rapporteur and assessment team on national level
prior to MAA submission
–
–
May be relevant for determining exact submission time
First opportunity to go through development program and
data
Foresight Training Course 2-4 September 2008
Rapporteur Selection

39. Role (Co)- Rapporteur
For any scientific evaluation, a Rapporteur, and if
relevant a Co-Rapporteur, shall be appointed from
amongst the members of the CHMP
The Rapporteur/Co-Rapporteur is supported by a
team of assessors/experts (assessment team)
In the pre-authorisation phase of the MAA, two
pp
(i.e. a Rapporteur and a Co-Rapporteur)
pp
pp
)
Rapporteurs (
are appointed.
Normally, the Rapporteur (and her/his assessment
team) would be the leader in the centralised postauthorisation phase.
Foresight Training Course 2-4 September 2008
Appointment process
initiated following the receipt of the letter of
intention to submit the MAA and the request
to assign Rapporteurs.
Will not be initiated until 7 months prior to the
MAA intended submission date.
Contrary to the past, sponsor’s proposals/
preferences will not be considered
Selection will be based on objective criteria
http://www.emea.europa.eu/htms/human/presub/q07.htm
Foresight Training Course 2-4 September 2008

40. Our experience
Important to submit request timely
Knowing your Rapporteur early allows setting
up meetings with assessment teams at
national level prior to MAA submission
Foresight Training Course 2-4 September 2008
Trade Name acceptability

41. Background
According to Article 1(20) of Directive 2001/83/EC, as
amended, the name of the medicinal product “may be
either an invented name not liable to confusion with
the common name, or a common name or scientific
name accompanied by a trademark or the name of
the Marketing Authorisation Holder”.
This may include the “The international nonproprietary name (INN) recommended b th W ld
d d by the World
Health Organisation, or, if one does not exist, the
usual common name”.
Important for commercial purposes
Foresight Training Course 2-4 September 2008
Why CHMP assesses invented names
Assess whether the invented name proposed for a medicinal
product could create a public-health concern or potential
safety risks.
In particular, the invented name of a medicinal product:
–
–
–
should not be liable to cause confusion in print, handwriting or
speech with the invented name of an existing medicinal product
should not convey misleading therapeutic or pharmaceutical
connotations
should not be misleading with respect to the composition of the
product
Role for Invented Name Review Group (NRG)
Foresight Training Course 2-4 September 2008

42. Foresight Training Course 2-4 September 2008
Process for invented name review
At the earliest 18 months prior to intended submission
trade name acceptability can be asked for
Documents needed:
–
–
Proposed invented name request form
Product profile or draft SmPC
NRG will ensure consultation with the Member States
and WHO
–
NRG discussion with CHMP adoption
Appeal possible
http://www.emea.europa.eu/htms/human/presub/q04.htm
Foresight Training Course 2-4 September 2008

43. Our experience
Start early is important to avoid challenges
during MAA review
A product available in one member State
may lead to discussion if considered to close
in name
Foresight Training Course 2-4 September 2008
Conclusion
There are many important pre-submission
activities in the later stages that are
dependent on the intended submission date.
Be proactive and try to avoid delays and/or
try to get the knowledge on potential
challenges early to facilitate a smooth filing
and validation.
Foresight Training Course 2-4 September 2008