1ST FORESIGHT TRAINING COURSE
In collaboration with
“Master in Regulatory Sciences - GIANNI BENZI” (University of Pavia)
“...
CHMP and Centralised
Procedure:
future challenges

Eric Abadie
CHMP Chair / EMEA and
General
Directorate/AFSSAPS
1

Overvi...
Product Evaluation
• Acce t New Medicines
Access to
icines
• SAGs
• Transparency and Risk Benefit

3

CHMP Opinions 2006 -...
CHMP Opinions 2006 - 2007
Positive opinions per therapeutic area (by ATC code), 2006 - 2007
4

10

7

3

15
13

15
35

1 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...
Conditional Marketing Authorisation
(CMA) Requirements
Art 4: a conditional approval may be granted where although compreh...
EMEA / CHMP Imposed on
MAH
+ve CHMP
opinion
“normal” MA

100

+ve CHMP
opinion

Adequate
Data

Exceptional
Circumstances

...
Exceptional circumstances
(Orphan diseases !) to June
2008

Atryn

Congenital
Antithrombin
deficiency

Elaprase

Hunter Sy...
January 2006 – June 2008

N = 21
Positive = 8
Negative = 13
15

HIV (2/5)
Dar…
Dar

NL / UK

- ve

Atr…

DE / FR

- ve

Ce...
Oncology (1/6)

Gen…
Gen

ES / FR

- ve

Das…

DK / PO

- ve

Len…

FR / SE

- ve

Tor…
T

DE / NL

- ve

The…
Vid…

UK / ...
Scientific Advisory Groups (SAGs)
• Deliver independent recommendation to specific
questions put by CHMP
• Rapporteur/Co-R...
Timings of SAG meetings
Experience to date
SAG Categories
HIV/Viral

Initial MA

Post Authorisation samples

Celsentri

18...
Interactions CHMP/PDCO
• PDCO/C
PDCO/CHMP: regular meetings C
e
r ee gs Chairs,
role CHMP members at PDCO
• PDCO/SAWP: COM...
Benefit Risk Assessment:
Recommendations (1)
1) To revise the current benefit-risk assessment section
of the CHMP assessme...
CHMP Projects (3 year term)
1. Legislation – RMP, ATP, Paediatrics, Variations, PhVig
2. New Projects – R/B, Antimicrobial...
Revision of Role and Mandate of
WP
• Objectives
j
– Review of mandates,
composition, terms of
reference, procedures to
tak...
Optimisation of SAGs/Exp Groups
consultation process within
review procedure
• Objectives
j
– Review of mandates,
composit...
Outcome Research Assessment
•

Objectives

•

–

At EMEA level: The purpose
of these projects will be to
assess or improve...
New Statistical Approaches in
Clinical trials for efficacy
• Objectives

• Actions proposed to
meet the objectives

– To p...
Conclusion
• CHMP workplan in line with EMEA priorities and key
objectives for near future
• High quality performance in a...
First Foresight Training Course
European centralised p ocedu e
u opea ce t a sed procedure
and paediatric regulation
Sergi...
Growing with networks in the Life
Sciences: an opportunity for Italy
1985

from new technologies: opportunities to
explore...
Aim
where research is the key, remove major bottlenecks in drug
development
Long term objectives
pharmaceutical sector
•in...
EMEA: a regulatory excellence supporting
innovation and R&D growth
•

enhanced role and scope (new chemical and
biotech

d...
EMEA: a stimulus for innovation
ORPHAN DRUGS
•

steady increase in positive COMP opinions

•

44 Marketing Authorisations ...
Better medicines for children:
a challenge for PDCO
Since August 2007
233
•233 Paediatric Investigation Plans and Waivers
...
Pre-Submission
Activities

Hans-Georg Eichler
EMEA
Pavia; September 2008

Pre-submission activities
•Scientific Advice/Pro...
The SA/PA pre-submission meeting
• Optional – a service by your friendly regulator
• used by ca. 40% of all applicants/req...
The Orphan drug designation presubmission meeting
• Optional – a service by your friendly regulator
• used by ca. 60-70% o...
EMEA Pre-submission Guidance
(example topics)
• When and how are Rap/Co-Rap appointed?
• How, when and to whom shall I sub...
Scientific Advice at
EMEA

Hans-Georg Eichler
EMEA
Pavia; September 2008

Scientific Advice and MAA outcome
2004-2007
comp...
Scientific Advice: getting the most out of it
We intend to demonstrate the efficacy of [drug] on
severity of asthma by way...
EMEA qualification process of innovative
drug development methods
Scope: to address innovative drug development methods
me...
Pre-submission activities – biotech and
orphan perspective

Anne Marie Li Kwai Cheung
Associate Director Regulatory
Affair...
Pre-submission activities
Scientific advice/Protocol Assistance at any time during
development and post-approval
–

Nation...
MAA Pre-submission meeting
Aimed to provide information to finalize MAA
– Legal issues
– Regulatory issues
– Scientific is...
Meeting documents
Pre-submission request form
Overview of development programme
Draft Table of contents
Draft product info...
Our experience
EMEA staff well prepared
Good guidance that supported smooth validation
Great opportunity to meet EMEA team...
Role (Co)- Rapporteur
For any scientific evaluation, a Rapporteur, and if
relevant a Co-Rapporteur, shall be appointed fro...
Our experience
Important to submit request timely
Knowing your Rapporteur early allows setting
up meetings with assessment...
Background
According to Article 1(20) of Directive 2001/83/EC, as
amended, the name of the medicinal product “may be
eithe...
Foresight Training Course 2-4 September 2008

Process for invented name review
At the earliest 18 months prior to intended...
Our experience
Start early is important to avoid challenges
during MAA review
A product available in one member State
may ...
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Topic 1 a papers i foresight training pavia 2008 (1)

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I Foresight Training Course (Pavia, 2-4 settembre 2008)

European Centralised Procedure and Paediatric Regulation.

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

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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