topic 1 a papers i foresight training pavia 2008 (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

CHMP and Centralised CHMP and Centralised Procedure:Procedure:

future challengesfuture challenges

1

Eric AbadieEric Abadie

CHMP Chair / EMEA and CHMP Chair / EMEA and General General

Directorate/AFSSAPSDirectorate/AFSSAPS

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

2

C. Projects

Product Evaluation

• Acce t icines• Access to New Medicines• SAGs• Transparency and Risk Benefit

3

CHMP Opinions 2006 - 2007

Outcome of initial-evaluation applications (EU market)

7

5158

98203040506070

4

4 798

010

2006 2007

Positive opinions Applications w ithdrawn prior to opinion Negative opinions

CHMP Opinions 2006 - 2007

Positive opinions per therapeutic area (by ATC code), 2006 - 2007

15

13

15

5135

104 3 7

5

123

Alimentary tract BloodCardiovascular Genito-urinaryHormonal Anti-infectiveImmunotherapy and oncology Neurology/Central nervous systemRespiratory Sensory organsVarious

Rapporteurs from October 2006 – June 2008

35

40UK

DE

NL

SE

15

20

25

30

ES

FR

DK

PT

IE

BE

HU

FI

IT

AT

6

0

5

10

UK DE NL SE ES FR DK PT IE BE HU FI IT AT NO EE SL LT PL CZ GR

NO

EE

SL

LT

PL

CZ

GR

Co-Rapporteurs from October 2006 – June 2008

18

20

UK

DE

NL

SE

8

10

12

14

16

18ES

FR

DK

PT

IE

BE

HU

FI

IT

AT

7

0

2

4

6

UK DE NL SE ES FR DK PT IE BE HU FI IT AT NO EE SL LT PL CZ GR

AT

NO

EE

SL

LT

PL

CZ

GR

Peer Review from October 2006 – June 2008

35

40

45

10

15

20

25

30

35

8

0

5

10

DE SE FR DK EE NL PT ES IE CZ NO UK AT HU FI MT LU PL LT BE IT IC GR

Apr 2005-June 2008 Oct 2006-June 2008

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

Conditional Marketing Authorisation (CMA) Requirements

1(28a) of Directive 2001/83/EC, is positive

• (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

9

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

The applicant can show that he is unable to provide comprehensive dataon the efficacy and safety under normal conditions of use, because:

Directive 2001/83/EC as amended, Annex I, Part II (Exceptional Circumstances, EC)

• 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 basis of a reassessment of the

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• Identified programme of studies…. basis of a reassessment of thebenefit/risk profile,• Restricted use• Medical information shall draw the attention …

Specific obligations – inform B/R – improve safe/effective useFulfilment of spec obligation ≠ Lifting of EC

EMEA / CHMP Imposed on MAH

+ve CHMP opinion

100

Adequate Data

“normal” MA

+ve CHMP opinion

11

Data

Time

Exceptional Circumstances

Conditional Approval(Cancer, HIV !)

Sutent Cancer L Sunitinib Impaqtiv Prezista HIV J Darunavir

Diacomit Epilepsy N Stiripentol

Isentress HIV J RaltegravirBreast

12

TyverbBreast Cancer L Lapatinib

Vectibix MCR cancer L Panitumumab

Intelence HIV L Etravirine

Exceptional circumstances(Orphan diseases !) to June

2008

Atryn

CongenitalAntithrombin

deficiencyR-Antithrombin

alfa

Elaprase Hunter Syndrome A Idersulfase

13

Increlex IGFD H Mecasermin

Evoltra ALL L Clofarabine

Pandemrix Pandemic Flu vaccine

Accelerated Assessment

When ?Justification major benefits

•Reserved products major therapeutic interest

When ?

•Unmet needs vs available methods•Extent of ajor

major benefits expected

14

•Public health •Therapeutic innovation

Extent of major impact (medical practice, added value)

January 2006 – June 2008

15

N = 21Positive = 8

Negative = 13

HIV (2/5)

Dar NL / UK - veDar… NL / UK - ve

Atr… DE / FR - ve

Cel… SE / PO + ve

16

Ise… UK / FR + ve

Etr… FR / PO - ve

Oncology (1/6)

Gen ES / FR - veGen… ES / FR ve

Das… DK / PO - ve

Len… FR / SE - ve

T DE / NL

17

Tor… DE / NL - ve

The…Vid…

UK / FR NL / ES

- ve+ ve

Miscellaneous (2/6)

Anaemia FR / DE Epo… - veAnaemia FR / DE Epo… ve

PNH ES / FR Sol… + ve

GvHD SE / ES Orb… - ve

NMB FI / SE Bri… - ve

18

Angioedema SE / UK Fir… + ve

VTE SE / DE Xar… - ve

Scientific Advisory Groups (SAGs)

•• Deliver independent recommendation to specific Deliver independent recommendation to specific questions put by CHMPquestions put by CHMP

R t ill tt dR t ill tt d•• Rapporteur/CoRapporteur/Co--Rapporteur will attend Rapporteur will attend –– To present the issuesTo present the issues–– To provide any additional information on the To provide any additional information on the

dossierdossier•• Possible hearing from applicantPossible hearing from applicant

19

•• SAGs “advise”, CHMP “decide” SAGs “advise”, CHMP “decide” •• SAG position reflected in CHMP Assessment ReportSAG position reflected in CHMP Assessment Report•• Concerns: only one SAG really works Concerns: only one SAG really works

(Oncology+++)(Oncology+++)

Timings of SAG meetings Experience to date

Products Initial MA

Tarceva 180 - 210

Oncology

Nexavar 120 - 121Sutent 120 - 121Avastin 180 - 210Vectibix re-examination Mylotag 180 - 210Ceplene 180 - 210

20

Lenalidomide 180 - 210Gliolan 180 - 210

Genasense re-examinationCerepro re-examinationTyverb 180 - 210

Timings of SAG meetings Experience to date

SAG Categories Initial MA Post Authorisation samples

HIV/Viral Celsentri 180 - 210 Guidelines

CNS

Tysabri 121 - 180

Referral Art.30 LamictalValdoxan Pre+post 210

Endocrinology - -Nutropin AQ

ActosAvandamet

21

AvandametCVS - - Arixtra + Angiox

Diagnostics Luminity 150 - 180 Gadolinium contrast agents + NSF

Anti-Infectives- - Cubicin

Mycograb Pre+Post 210

Interactions

PDCO CMDh

CHMP

WP’s

SAWP/ Pharmacovigilance

COMP HMPC

22

CAT PhVWG CtteeSAG’s

Interactions CHMP/PDCO

• PDCO/C e r ee gs C• PDCO/CHMP: regular meetings Chairs, role CHMP members at PDCO

• PDCO/SAWP: COMP model• PDCO/other CHMP WP: improving their

coordination on overlapping topics, joint

23

pp g p , jWP, PDCO to provide full input into CHMP guidelines

B/R assessment: how to improve transparency and consistency of our opinions ? Results of B/R

CHMP working group

DISCU ON OF DRAFT REPORTDISCUSSION OF DRAFT REPORT OF WORKING GROUP BY CHMP 22 JANUARY 2007

DEADLINE FOR COMMENTS 13 FEBRUARY 2007

ADOPTION FOR RELEASE FOR PUBLIC CONSULTATION 19 FEBRUARY 2007

24

DEADLINE FOR COMMENTS 29 MAY 2007

DISCUSSION OF REVISED REPORT BY CHMP FEBRUARY 2008

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 phas ill als in P t s e t e

25

phase will also involve Patients, Healthcare Professionals’ representatives and other stakeholders as necessary.

• Implementation phase: should consist of regular training of assessors and monitoring (role of HMA).

Benefit Risk Assessment: Recommendations (2)

2) To further research the methodology of benefit risk assessment involvin further ex erts and assessors., g p

• To explore further development in methodologies for benefit/risk analysis, including a wide range of quantitative and semi-quantitative tools.

Th CHMP h ld ti t i t t ith l t

26

• The CHMP should continue to interact with relevant stakeholders on international and European initiatives related to the benefit-risk assessment methods

• CHMP need the support of NCA !

CHMP Projects (3 year term)

1. Legislation – RMP, ATP, Paediatrics, Variations, PhVig

2. New Projects – R/B, Antimicrobials, Microbicides

3 WPs Revision of Role and Mandate Inter ction PhVWP3. WPs – Revision of Role and Mandate, Interaction PhVWP

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

27

8. Communication and Interaction – publications, Interested Parties consultation

9. International activities – ICH, IMI, CPATH, WHO, Bilateral agreements

High priorities – projects to be initiated

•• Revision of Role and Mandates Revision of Role and Mandates of Working Partiesof Working Parties

•• Paediatric Regulation and Paediatric Regulation and PDCO/CHMP interactionsPDCO/CHMP interactions

•• Optimisation of consultation Optimisation of consultation process of SAGs and process of SAGs and Specialised Experts GroupsSpecialised Experts Groups

•• Outcome assessment researchOutcome assessment research•• MicrobicidesMicrobicides

28

•• MicrobicidesMicrobicides•• New Statistical approachesNew Statistical approaches•• Variations Regulation revisionVariations Regulation revision

Revision of Role and Mandate of WP

• Objectives • Actions proposed toj

– Review of mandates, composition, terms of reference, procedures to take into account outcomes of previous discussionsI t f ffi i

Actions proposed to meet the objectives

– Create a working group with members appointed by the CHMP, including representatives from the EMEA S t i t t

29

– Improvement of efficiency taking into account HMA’s concern about the resource implementations of WPs.

EMEA Secretariat 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.

Paediatric Regulation and PDCO/CHMP interactions

• ObjectivesEnsure other WP Commi te s

• Actions proposed to meet the objectives Ide tify deviati n of PD O vi w n– Ensure other 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.

– Identify deviation of PDCO views on 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

30

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

Optimisation of SAGs/Exp Groups consultation process within

review procedure• Objectives • Actions proposed toj

– 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 EMEA Secretariat to

31

– 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

Sec e a a omeet and agree on proposals with regard to the topics mentioned as Objectives.

Variation Regulation Revision• Objectives

– Input in propose cl ssification of

• Actions proposed to meet the objectives

Input in proposed classification of 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

– 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

32

– 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.

– EMEA to set-up internal 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 “Post-Authorisation Procedural Advice” guidance document.

Outcome Research Assessment

• Objectives • Actions proposed to meet the 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

– 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

33

range of methodologies (tools/scales) that would monitor the outcomes of CHMP’s actions.

methodological assessment– Identification of outcomes that

can serve for further outcomes assessment and evaluation

– Procure resources to conduct prioritised projects.

Microbicides


– Allow EMEA/CHMP to gain further knowledge and expertise in this field

– Elaborate over time a scientific position on these development programme without

– 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

34

programme without detailed defining of registration requirements

– Ensure preparedness for potential future Art. 58 Opinions and/or MAAs in the centralised procedure

identifying the critical issues to be addressed

– Attendance of EMEA representative in relevant scientific conferences

New Statistical Approaches in Clinical trials for efficacy


– To propose a strategy in order to advance the knowledge and understanding of new and existing biostatistical

h

meet the objectives

– It is proposed that a task force is set up consisting of regulatory statisticians and experts. The main actions of the task

35

approaches among statisticians, clinicians and medical researchers in the network of European experts

actions of the task identify problems in the implementation of new statistical approaches, and to propose actions on how to address them

High priorities – ongoing projects• Review and learning

project on RMP• Advanced Therapies

Regulation• Interaction with PhVWP

and delegations of tasks• Evaluation of Benefit

Risk

36

Risk• Antimicrobial resistance• Biomarkers Qualification

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

37

• 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

European centralised procedure

First Foresight Training Course

Pavia, September 2nd 2008

Sergio Dompé - Farmindustria

u opea ce t a sed p ocedu eand paediatric regulation

Major changes in Pharma sector

Growing importance ofEmerging Countries

An ageing population inAdvanced Economies

Major patent expiry in coming years

Price containment

Increased competition

Cost pressure

Changes in

New demand forunmet medical needs(e. g. rare diseases)

Growing R&D costs(higher attrition rate)

coming years

New cutting-edge technologies

Increased competition

Ever more resources needed for R&D

Margins squeeze

Interdisciplinary R&D

Move to personalized medicine (from about 500 molecular targets to

the business environment

+Technology

Interdisciplinary R&D

Spillovers into other sectors Growing specialisat on

over 10.000 in coming years) “shock”

New business models

=

1

Growing with networks in the Life Sciences: an opportunity for Italy

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

1985

2005

gknowledge at international level

1995

up to a few years agocritical mass needed

2

source: ATA

today the difference is in network competitiveness, not only in size

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

Source: PriceWaterHouseCoopers

growth opportunities for many subjects(Big Pharma, SMEs, Public Research, University,…)

3

Aimwhere research is the key, remove major bottlenecks in drug developmentLong term objectives•increase com etitivenes of Euro ean pharmaceutical sector p p 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 public-private partnership in biomedical research

A growing commitment by pharmaceutical industry in Italy

R&D expenditure/pharmacies sales in pharma companies (% figures)

11

12Investments +32,5% since 2002

Increase in clinical studies (>10% per year)

1,8 billion € investments in Research and Manufacturing planned for 3 years

1971-1975

1976-1980

1981-1985

1986-1990

20

21

27

33

52

Red Biotech companies in Italy

1990 1995 2000 2005 ‘077

8

9

10Manufacturing planned for 3 years

In few years 147 biotech medicinal roducts under develo ment and 99 in

Before ’70

1991-1995

1996-2000

2001-2007

71

98

168

source: Farmindustria, Blossom-Assobiotec

Consolidate growing partnership w th public research and important incentives

p pdiscovery phase

4

• enhanced role and scope (new chemical and

biotech drugs for most critical diseases and

orphan drugs)

EMEA: a regulatory excellence supportinginnovation and R&D growth

• 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

SME OFFICE

• support to innovation, particularly in the field of

new technologies and emerging therapies

EMEA: a stimulus for innovation

• fee incentives and administrative assistance

SCIENTIFIC ADVICE

• high quality level advice, focused on

development strategies

• broader scope for request and faster procedurep q p

6

ORPHAN DRUGS

• steady increase in positive COMP opinions

EMEA: a stimulus for innovation

• 44 Marketing Authorisations granted in the EU

INNOVATION TASK FORCE

• forum for early dialogue with applicants

• free advice on eligibility for EMEA procedures of

emer in therapies and borderline productsg g

7

Paediatric EU Regulation: opportunityfor 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

Better medicines for children: a challenge for PDCO

Since August 2007

•233 Paediatric Investigation Plans and Waivers 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 to cooperation established with Member 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 [TASK-

FORCE IN EUROPE FOR DRUG DEVELOPMENT IN YOUNG] to:

• foster training programs on ethical, scientific and social aspects of clinical research in children

10

• facilitate the conduct of clinical trials

• improve the quality of trials

Pre-Submission Activities

Hans-Georg EichlerEMEA

Pavia; September 2008

Pre-submission activities

•Scientific Advice/Protocol assistance

•Orphan Drug Designation

•Marketing Authorisation Application

2

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

3

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

With pre-submission meetingLetter

of FinalPre-sub.ofIntent

Finaldocs

Pre sub.meeting

SAWP mtg 1

Start of SA/PA

procedure

4

Finaldocs

Letterof

Intent

Without pre-submission meeting

The Orphan drug designation pre-submission meeting

• Optional – a service by your friendly regulatorOptional 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…

5

• receive informal early feedback on content and …

• …improve quality of request

• no fee, no delay (unless applicant requires extra time for revision)

PrePre--submissionsubmission

MAA Pre-Submission Activities

-1 m

-18m/-12mRequest Eligibility for Centralised ProcedureRequest Inv nted name review

g

Request ford review

New! Pediatric

Investigational Plan (PIP) compliance check

at least 3 m before MAA

6

-12m to -36mScientific AdvicePipeline information

Request Invented name reviewStart Rapporteur appointment process

Orphan Drug designation

SME designation

EMEA Pre-submission Guidance(example topics)

• When and how are Rap/Co-Rap appointed?

• How, when and to whom shall I submit m a lication?, y pp

• 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 ?

7

Further clarification ? Other questions ? ⇓ Request MeetingRequest Meeting at EMEA via

“Pre-Submission Meeting Request Form”

• 6-7 Months before submission

• Discuss final practical & regulatory aspects of upcoming li ti

Free service

EMEA Pre-submission Meetings

application

• Clarify application-specific issues not addressed in the Pre-Submission Guidance

• Useful step to ensure that application will meet all requirements for Validation

8

• Strongly recommended, even for experienced users of the centralised procedure

Reconfirm various administrative/procedural/legal issues; requirements may have changed

Scientific Advice at EMEA

Hans-Georg EichlerEMEA

Pavia; September 2008

Scientific Advice and MAA outcome2004-2007

advice outcomecompliance ratios* *

218

156113

43

151

14

57

171= 0.33

HR = 2 6

no

noyes

2

62

47

1

41

6

476

= 0.13

HR = 2.6

yes- Endpoint

- Comparator

- Stat/Analysis

*

Scientific Advice: getting the most out of it

We intend to demonstrate the efficac of dru on y [ g]severity of asthma by way of a double-blind, randomised, controlled trial in patients with severe asthma.

A draft clinical trial protocol is attached in appendix 1. Does CHMP agree?

3

Does CHMP agree with the proposed protocol of the phase III trial?

Level of input Level of output !

EMEA qualification process of innovative drug development methods

Scope: to address innovative drug development methodsScope: to address innovative drug development 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

5

with adaptations: appointment of dedicated 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).

Pre-submission activities – biotech and orphan perspective

Anne Marie Li Kwai CheungAssociate Director Regulatory Affairs Genzyme Europe BV

2September 20082September 2008

In this talk

IntroductionPre-submission activitiesPre-submission meetingsSummary

Foresight Training Course 2-4 September 2008

Pre-submission activities

Scientific advice/Protocol Assistance at any time during development and post-approval

– National or at CHMPRegulatory 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 filingRapporteur selection

– Schedule meetings with rapporteurTrade name acceptability

EMEA Guidance on Pre-submission meeting for MAA

The EMEA emphasises the importance of Pre-Submission Meetingswith applicants. Pre-Submission Meetings are a vital opportunity forapplicants to obtain procedural, regulatory and legal advice from theEMEA. This guidance information and successful Pre-Submission.Meetings should enable applicants to submit applications, which are inconformity with the legal and regulatory requirements and which can bevalidated speedily. Pre-Submission Meetings will also enable applicantst t bli h t t ith th EMEA t ff l l i l d ith th


to establish contact with the EMEA staff closely involved with theapplication as it proceeds

http://www.emea.europa.eu/htms/human/presub/index.htm

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.pdfhttp://www.emea.europa.eu/htms/human/presub/list.htm

EMEA Participants

Product team Leader (PTL)Project Team members from– Quality– Safety and efficacy– Regulatory Affairs

Specialized Group Leader therapeutic area


– Specialized Group Leader therapeutic areaPossible other attendees from: Orphan Drugs, SME, Pediatrics, Inspections, Medical Information, Risk Management, Central Information Group and post-authorisation Safety and efficacy

Meeting documents

Pre-submission request formOverview of development programmeDraft Table of contents Draft product information (CTD M1.3)Draft application form


Draft application formTopic specific information– E.g. justification for accelerated review

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 meetingMeeting minutes to be prepared by sponsor within 2 weeks

– EMEA will review within 2 weeks

Our experience

EMEA staff well preparedGood guidance that supported smooth validationGreat opportunity to meet EMEA team involved in review of your MAADo not think that you know how it works from the experience on your last MAA – things may changeWork with PTL to schedule meeting with (Co)


Work with PTL to schedule meeting with (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

Rapporteur Selection

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 Rapporteurs (i.e. a Rapporteur and a Co-Rapporteur)


pp ( pp pp )are appointed.Normally, the Rapporteur (and her/his assessment team) would be the leader in the centralised post-authorisation phase.

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 consideredSelection will be based on objective criteriahttp://www.emea.europa.eu/htms/human/presub/q07.htm

Our experience

Important to submit request timelyKnowing your Rapporteur early allows setting up meetings with assessment teams at national level prior to MAA submission


Trade Name acceptability

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 non-

(INN) d d b th W ld


proprietary name (INN) recommended by the World Health Organisation, or, if one does not exist, the usual common name”. Important for commercial purposes

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


connotations – should not be misleading with respect to the composition of the

product Role for Invented Name Review Group (NRG)


Process for invented name review

At the earliest 18 months prior to intended submission trade name acceptability can be asked forDocuments 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 possiblehttp://www.emea.europa.eu/htms/human/presub/q04.htm

Our experience

Start early is important to avoid challenges during MAA reviewA product available in one member State may lead to discussion if considered to close in name


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 tr to et the knowled e on otential


y g g pchallenges early to facilitate a smooth filing and validation.

topic 1 a papers i foresight training pavia 2008 (1)

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