CRED ERP 25

CRED Navigating European Regulatory Procedures

8 – 9 July 2025

©The Organisation for Professionals in Regulatory Affairs 2025 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

CRED Navigating European Regulatory Procedures 8-9 July 2025

Day One – 8 July 2025

Time (GMT)

Session

Presenter

08.30

Registration and coffee

09.00

Chairman’s Introduction

Kora Doorduyn-van der Stoep Medicines Evaluation Board (MEB)

09.05

Case study introduction

Matthew Sardo

Sardo Trading Limited

• Delegates will be divided into groups for afternoon case study and provided with material.

09.10

Overview of the European Regulations • A brief outline of the Centralised and Mutual Recognition/Decentralised procedures

Kora Doorduyn van der Stoep Medicines Evaluation Board (MEB)

• The role of the regulatory bodies, i.e. EMA, CHMP, COMP, PDCO, SAGs, EU Commission, CMDh, National Authorities, ATMP, PRAC, EMA re-structure • Ongoing update to pharmaceutical legislation • Orphan Drug Regulations • Paediatric Regulations • PRIME and similar initiatives • Considerations for SMEs • The role of patients Developing your Global Filing Strategy • Influencing factors, e.g. product type, strength of data, internal & external initiatives (include in learning objectives) • Scientific advice – where and how to obtain it • Utilising internal and external expertise • Integrating filing strategy with commercial objectives • Choosing a procedure – key factors (default procedure unless otherwise indicated/company preference?) • Orphan Drug Considerations • Paediatric Study Requirements • Accelerated approval programs • Briefly mention pharmacoeconomics and HTA requirements • Other initiatives (e.g. PRIME)

10.10

Ming Ewe

Smarter Biotech Solutions Limited

11.00

Tea/ Coffee break

Time (GMT)

Session

Presenter

11.30

Developing Strategy for Filing Non-NCEs • Bibliographic/ established use • Abridged • Line extensions/generics/hybrids • Biosimilars • Borderline and combination products • Herbals

Jayne Hunt

Arriello S.R.O.

12.30

Lunch

13.30

Decentralised and Mutual Recognition Procedures • Background to mutual recognition concept • Key features and differences of MRP/DCP • Role of the Reference Member State and booking your RMS slot • DCP procedure timetable • Organising your company • Interacting with the Authorities during the procedure • Common problems and pitfalls in DCP • Repeat-use MRP • The role of CMDh • Appealing a negative decision - referral and arbitration • Common problems and pitfalls in MRP

Stephen Smith

MESAVS Regulatory Solutions Ltd

14.30

Networking session

15.00

Finalising your European Regulatory Strategy • Scheduling the submission • Access to procedures • Commercial considerations • Tradename issues • Pre-submission meetings • Timelines • Conditional approvals/exceptional circumstance

Jayne Hunt

Arriello S.R.O.

16.00

Case Study ( Coffee/tea to be taken in case study groups)

Matthew Sardo

16.45

Case Study Feedback

Presentation of results and discussion

17.15

Review of the day

Kora Doorduyn-van der Stoep Medicines Evaluation Board (MEB)

17.30

Close of Day One

Day Two – 9 July 2025

Time

Session

Presenter

08.30

Introduction •

Jenny Horwood

Review of day 1

JMH Regulatory Ltd

Objectives for day 2

•

Ian Thomson

08.40

Key EU Regional Considerations • Electronic dossier format (eCTD) • Labelling and leaflets including readability testing • Translations • Pharmacovigilance Site Master File and Risk Management Plan • Environmental Risk Assessment • Paediatric Investigational Plans • Manufacturing aspects – site inspections, QC testing and QP release

Johnson & Johnson

10.00

Centralised Procedure - The Details • Preparing for a CP (including eCTD compilation) • Managing the procedure • Interacting with the EMEA/(co-)rapporteur/PRAC • The role of the CHMP • The Commission decision making process • Re-examination of an Opinion • Organising your company • Common problems and pitfalls

Alex Yates

Bicycle Therapeutics

11.00

Tea/ coffee break

11.30

Agency perspective on strategic and practical considerations – how to work effectively • Developing and optimising your strategic plan – how to maximise the chances of an early approval • Scientific advice and its impact on a successful application • Validation, responses to questions and end of procedure – best practice advice • Typical dossier deficiencies and how to avoid them (no. of dossiers that go through first time and if not, why not) • Common pitfalls (both practical and strategic) • Real-life procedure timings – where time can be lost in a procedure • Talking to regulatory agencies • Optimising appeals and hearings • Scientific Advice

Kora Doorduyn-van der Stoep or colleague Medicines Evaluation Board (MEB)

12.30

Lunch

Time

Session

Presenter

13:15

New MAAs in the Centralised Procedure – Theory versus Reality • Understanding the potential for deviating from the rule book • Impact of PRAC • Impact of CAT • Impact of ODD • What are the potential outcomes at D181? • Thinking strategically Learning to manage internal expectations

Sahana Rajashkar

Kamet Consulting Group

14:15

Case Study

Matthew Sardo

Sardo Trading Limited

15.45

Case Study Feedback

Presentation of results and discussion

16:15

Review of the day

Jenny Horwood

JMH Regulatory Ltd

16.30

Close of Meeting

Delegates will be encouraged to ask questions throughout the day so as to ensure the meeting is as interactive as possible. There will be an interactive session with each speaker, at the end of each talk to consolidate the key points of each talk, and to allow the delegate to interact with all of the speake rs.

Speaker Biographies

Alex Yates Alex has more than 20 years’ experience in Regulatory Affairs and Drug Development, working in consultancy, large pharma, and currently in small biotech (where he is VP Regulatory Affairs & Development Quality at Bicycle Therapeutics). Alex has led multiple EU procedures and filings for innovative products, orphan drugs, biosimilars and generics, and has experience in strategic engagement with Regulatory Agencies globally. Outside of work Alex is a passionate and published photographer and spends most of his spare time cycling. Jayne Hunt Jayne (FTOPRA) has over 30 years pre and post marketing strategic development & operational regulatory affairs expertise in the EU/UK/US and other countries. This covers experience with ATMPs, biologics, small molecules in a range of semi-virtual, small to medium, and ethical and generic pharmaceutical companies, CROs and consultancy services. Specific experience: European and US pre and post-marketing strategy activities covering: marketing authorisation submissions including legal status considerations and labelling, global clinical trial submission management, CTA & IND submission and ongoing management, orphan drug applications (EU/US), Health Authority Meetings (EMA scientific advice / FDA – Type B-EOP2, Type B, Type C, Health Canada, HPRA, MHRA), fast track & breakthrough & pre-breakthrough applications, PRIME applications and SME support. Matthew Sardo Matthew and has worked within the pharmaceutical industry for 25 years. After starting his career working for the Medicines Control Agency in the UK, he then went on to work for Sanofi-Synthelabo, Alliance Pharmaceuticals and PRA International. During this time he gained experience within pharmacovigilance, medical information, clinical trials, regulatory affairs and quality assurance and has been responsible for advising on regulatory strategy for EU submissions and compilation of MAAs across a number of different therapeutic areas as well as acting as company lead for Scientific Advice meetings. Matthew also has extensive product licence maintenance and technology transfer experience. In addition, through his regulatory work, Matthew has gained experience with a number of QA-related projects including SOP design and authorship, design and setup of Quality Management Systems and various CMC, GDP and GMP-related projects. Matthew moved into consulting ten years ago with his company Sardo Trading Ltd and works with clients on diverse projects including provision of regulatory strategic advice and preparation for Scientific Advice meetings. Through his experience within the quality field Matthew went on to train as a GDP/GMP auditor in 2016 and has assisted and advised upon the setup of EU Quality Management Systems for EU-based clients and conducted GDP/GMP audits. Matthew is also an active member of TOPRA and the Research Quality Association and is the TOPRA Working Party Chair for the European Procedures course run by TOPRA. Matthew can be contacted at: matthew@sardotradinglimited.com Ian Thomson Ian has over 14 years of industry experience in EU and EMEA pharmaceutical Regulatory Affairs (RA). Ian started his career at DLRC regulatory consultancy where he was involved in number of diverse regulatory projects for both generic and innovator pharma companies. Ian then joined the EMEA Oncology/Hematology RA team at Johnson & Johnson (previously Janssen) in 2014 as a Regulatory Scientist and has worked in roles with increasing

responsibility and complexity during this time, particularly in the Hematology therapeutic area. Ian has extensive experience in providing strategic support to clinical development teams for a portfolio of products and has led multiple EU regulatory submissions, including new MAAs, line extensions and indication extensions as well as providing regulatory leadership and support for diverse and complex clinical trial programmes. Ian holds a degree in Biochemistry from the University of Bristol. Kora Doorduyn-van der Stoep Kora works at the Medicines Evaluation Board (MEB) in The Netherlands. Her current position at the MEB is EU representative of the MEB. She held several positions within the MEB, both regulatory and management. From May 2009 – November 2020 she was acting as Member and official representative in the CMDh (Co-ordination Group Mutual Recognition and Decentralised Procedures – Human) on behalf of the MEB. In December 2018 she was elected as Vice-Chairperson of CMDh. In October 2020 she has been elected as Chairperson of CMDh starting in November 2020 and in October 2023 she was re-elected as Chairperson of CMDh She is also participating in several working parties of CMDh with issues related to Pharmacovigilance legislation (like RMPs/PSUSA’s) and variations as an area for special attention. As CMDh chair she is also member of several EMA/HMA Task forces and other groups (like Scientific Coordination Board, EMA/HMA focus groups on resources) She is a member of the HaRP peerreview group which is the group dealing with harmonization of RMPs for the same active substance in the EU. She is coordinator/Rapporteur EU Training Curriculum for Regulatory experts (for CMDh). She graduated MSc Pharmacy (in 1983) and as a pharmacist (in 1985). Steve Smith With a background in Chemistry, having graduated with a PhD in Organic Chemistry in 2003, Steve then worked as a development chemist for Rhodia Pharma Solutions before starting his regulatory career in 2004 at GSK, working in CMC. After leaving GSK, he worked for Seven Seas, Teva Pharmaceuticals and Mundipharma before returning to GSK and after a spell at Amgen, is currently working for Servier. In his regulatory career to date Steve has worked for small, medium sized and large pharma companies covering both the innovator and generics sector, working with small molecules and biologics across all therapeutic areas. This provides him him a wide and extensive knowledge of the regulatory affairs profession. Jenny Horwood Following the completion of a D.Phil. in neuropsychopharmacology at Sussex, and post doc at the CNRS in Paris in electrophysiology and behavioural models, Jenny worked as a senior scientist for Paradigm Therapeutics for 2 years then went on to join Pfizer in 2006 as a neuroscientist. She then quickly (in 2007) moved into the field of regulatory affairs becoming a regulatory clinical trial strategist. From 2007 to 2022 Jenny continued to grow in her role within Regulatory Affairs at Pfizer both in Europe and the US to become a Senior Director and Global Regulatory Portfolio Lead in the therapeutic area of Rare Disease in 2022. In 2024 (after 18 years) Jenny left Pfizer and founded JMH Regulatory Ltd; a regulatory affairs consultancy business, providing services in the development space to a variety of clients to help them navigate the complex and ever-changing regulatory environment and optimise their development strategies. Additionally, she enjoys teaching, both for clients and at TOPRA, using her experience of interactions with FDA, EMA and national authorities, which has included the compilation / submission / review of varying

applications including, but not limited to, MAAs, BLAs, IND’s, CTA’s, PIP’s, OD’s & numerous agency meetings for various types.

Ming Ewe Ming is passionate about unleashing a different kind of leadership in the biotech industry to improve the health and wellbeing of humankind. Over the past 25 years in global and European roles, Ming has helped various companies and startups develop their highly innovative drugs including cell and gene therapies (CGTs). She is well versed in handling complexity and ambiguity while helping organisations navigate the complex regulatory jungle and change within growing SMEs. Having frequently experienced how people and organisational issues can significantly affect the overall progress and success of a promising therapy, in some instances derailing entire programs, Ming firmly believes that a more integrative strategic approach is sorely needed. The more aligned your regulatory strategy, organisational and people are, the more likely the right regulatory strategy will be successfully identified and implemented. Ming is currently a mentor on the Bioindustry Association’s (BIA) Women in Biotech mentoring program. She is an active member of The Organisation for Professionals in Regulatory Affairs (TOPRA) where she is the Co-Chair of the Combination Products Special Interest (SPIN) group covering Drugs and Devices/Companion Diagnostics and helps to train young regulatory professionals. Ming now exclusively works with innovative purpose-led early-stage biotech start-ups Sahana Rajashekar With a background in Regulatory Affairs and Biotechnology, having graduated with a Masters in Regulatory Affairs from University of Southern California, Los Angeles in 2017. Sahana works as a Senior Regulatory Affairs Specialist II in Kamet Consulting Group. She worked as a Regulatory Affairs Specialist in Cooper Vision and dons a 510K Submission to the US FDA (K23427) under her name. She has also interned in companies such as Philips Healthcare, Seattle and Foundation Medicine, Massachusetts. She has also worked as Clinical Research Specialist for All of Us Clinical Research Program. She has worked in the field of Pharmacovigilance as a Drug Safety Associate for a CRO by name IQVIA. She has experience in a start up , mid sized and established companies. This provides her with a wide and extensive knowledge of the Regulatory affairs field. through her consultancy, Smarter Biotech Solutions. LinkedIn: https://www.linkedin.com/in/ming-ewe/ Website: https://www.smarterbiotechsolutions.com/

Quick Reference Guide to Decentralised Procedure (DCP)

Background: The DCP was first implemented through Directive 2004/27/EC and introduced in the EU in 2005. It allows for simultaneous submission of an application for a product across several Member States (MS) where there is no existing Marketing Authorisation (MA) for planned marketed product in the EEA yet. The DCP shares similar concepts to the Mutual Recognition Procedure (MRP) in the sense that it permits a harmonised approach/assessment to approval and life cycle management as the core technical details registered are intended to be and remain the same across each MS. Only applicable if no MA’s exist in EEA for the product in question. • Like MRP the assessment is carried out by one MS, defined as Reference Member State (RMS). • Subsequent to this, CMSs review the assessment of the RMS and generate any additional comments if needed. • The applicant responds to the questions raised by RMS and CMSs. • The Co-ordination group for Mutual Recognition and Decentralised procedure – human (CMDh) is responsible for the coordination and processes by issuing e.g., Best Practice Guides/SOPs and discussing specific issues • If consensus is reached at day 210 (could also be earlier than day 210) on the assessment report of the RMS, the procedure ends positively. • This is followed by a National Phase in each MS. • In case no consensus is reached by day 210 of the procedure, the issue for which no consensus is reached will be referred to CMDh. Key Points: •

DCP Flow chart:

Assessment Step 1

Applicant submits application to RMS and each CMS for review

RMS and CMS validates the application

Assessment Step 2

Day -14

CMS reviews the assessment report and generates comments

RMS circulates Day 70 Preliminary Assessment Report

RMS starts procedure, CMS notified via CTS

Day 0

Day 100

Day 70

RMS sends draft assessment report and labelling, PL, SmPC

CMS reviews the assessment report and generates comments

Draft responses up to 3 or 6 months

Clock stops

Day 120

Day 105

Communicate outstanding issues with applicant

Consensus achieved?

Yes

No

Day 150 (Day 30)

Day 195

National marketing authorization in each of the CMS

RMS consults with CMS and discussion with applicant

Yes

Day 210 (Day 90)

Consensus achieved?

Review by Co ordination group

No

Day 270

Quick Reference Guide for the Centralised Procedure (CP)

Background: The CP was first introduced into the European Union (EU) in 1995. It was designed to ensure a harmonised scientific assessment and approval of new medicines across the EU; one submission which results in a single market authorisation for the EEA. (EEA defined as the 27 Member States; the European Free Trade Association or EFTA also include Iceland, Liechtenstein, and Norway.)

Strategy:

For some the applicant can choose either centralised procedure or national/ MRP/ DCP procedure ( “ optional CP scope ” )

Some products can now be authorised only via centralised procedure ( “ mandatory CP scope ” )

Some products are excluded from centralised procedure ( outside CP scope)

“Mandatory scope” CP: • Biotechnological and orphan

medicinal products and for human products containing a new active substance [authorised after 20 May 2004] and advanced therapies • CP is mandatory for products which are intended for the treatment of AIDS, cancer, neurodegenerative disorder or diabetes

“Optional scope” CP:

Key Points: • Centralised Procedure is mandatory when requesting MA’s for certain medicinal products. • The European Medicines Agency (EMA) plays a key role in the coordination of the evaluation of applications. • The Committee for Medicinal Products for Human Use (CHMP) is the EMA ’s committee responsible for human medicines and conducts the assessment of CP applications. A rapporteur and co-rapporteur are allocated to perform assessment of the submitted application and the other CHMP members may comment on these assessment reports. A PRAC rapporteur is appointed assessing Risk Management Plan (RMP). The PRAC rapporteur should be from another MS that the CHMP rapporteurs. • Summary: 1 Application, 1 Market Authorisation, 1 set of Product Information (all EU official languages) for all EU markets.

Centralised Procedure flow chart:

Quick Reference Guide to Legal Basis

Background:

Types of secondary legislation

• Regulation – Binding to all Member States, no National changes, deviations, or differing local transposition allowed. • Directive – Results binding but method of implementation is up to each Member State via transposition into National law. • Decision – Implementing acts or decisions which are binding upon those individual Member States or a subject for which being addressed. • Guidelines – Interpretation of requirements, recommended but not binding. Helps to explain the rules as set out in legislation.

Legal Basis:

Full application - Article 8(3)

•

• Generic, hybrid or similar biological applications - Article 10 o Well-established use application - Article 10a o Fixed combination application - Article 10b o Informed consent application - Article 10c o

A ‘generic’ of a reference medicinal product – Article 10(1) o A so-called ‘hybrid’ of a reference medicinal product – Article 10(3) o A ‘similar’ biological medicinal product of a biological reference product – Article 10(4)

References & Further Reading:

• Volume 2A Procedures for marketing authorisation Chapter 1 Marketing Authorisation July 2019. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol- 2/vol2a_chap1_en.pdf • Legal basis for all types of application is set out in Directive 2001/83/EC (link to Directive in next bullet point) and in Regulation (EC) No 726/2004, version M6 https://ec.europa.eu/health/sites/health/files/files/eudralex/vol- 1/reg_2004_726/reg_2004_726_en.pdf

• Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the community code relating to medicinal products for human use; consolidated version with amendments https://eur lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2001:311:0067:0128:en:PDF

Quick Reference Guide to Mutual Recognition Procedure (MRP)

MRP Background: The MRP was first introduced into the EU in 1995. It was designed to ensure an efficient/harmonised assessment procedure in cases where multiple applications for the same product were made to National Competent Authorities across the EEA.

The need for this harmonisation came about due to difficulties seen in life cycle management where a product approved across different markets was often the subject of differing assessments with resulting divergence in Product Information.

The MRP aimed to introduce efficiency and consistency to assessment process where the same product is authorised Nationally across a number of different Member States and serves to reduce duplication of effort by both Applicants and NCAs both during initial assessment and subsequent life-cycle management.

Key Points: •

There must be an existing approved Marketing Authorisation (MA) in a Member State (MS), referred to as Reference Member State (RM S); this is then subsequently “recognised” by other MS (referred to as Concerned Member States (CMS). • Initial assessment is carried out by one MS (the RMS). • The CMS “mutually recognise” the assessment and marketing authorisation conducted/granted by the RMS. • If there are any major objections raised by the CMS, these must be raised on the grounds of a Potential Serious Risk to Public Health (PSRPH). • The Co-ordination groupfor Mutual recognition and Decentralised procedure – human (CMDh) is responsible for the coordination and processes by issuing e.g. Best Practice Guides/SOPs and discussing specific issues. • The MRP follows a 90-day period at maximum if consensus amongst CMS is reached. • This is followed by a National Phase in each MS. • In case no consensus is reached by day 210 of the procedure, the issue for which no consensus is reached will be referred to CMDh.

MRP Process Flow chart:

Day -90

Applicant requests RMS to update Assessment Report

Applicant submits application to RMS and CMSs for review

CMS validates the application

Day -14

CMS reviews assessment report and generates comments

RMS starts the procedure

Day 30

Day 0

Applicant sends response to RMS and CMSs

CMS sends remaining comments from Applicant response

Day 40

Day 55

Comments resolved?

Yes

RMS closes procedure

Day 60

No

CMS send their remaining comments to RMS, CMS, and Applicant

Applicant sends response document to CMSs and RMS

Day 75

Consensus reached?

Yes

RMS closes procedure

Day 90

No

Applicant sends English PI and labelling to CMSs

National marketing authorization in each of the CMS

Referred to CHMP for arbitration

Consensus not Reached

Final position adopted by CMDh

Day +5 Post Procedure

Day +30 Post Procedure

Day 150

European Regulatory Procedures: Pre-Read Centralised Procedure

The objective of this pre-read summary of the Centralised Procedure (CP) is to enable you to become familiar with the key features of the approval process related to the CP before attending the TOPRA CRED course on EU Regulatory Procedures. During the course itself, expert speakers will give a brief outline of the different EU regulatory procedures and how they work and will then focus on covering real-life examples of what running these procedures in practice entails, how best to organise your company team internally as well as covering common pitfalls and how to avoid them. In order for you to get the most out of the course and the presentations, a certain amount of background reading and study on your part constitutes helpful preparation. The presenters will assume that you have reviewed the pre-read materials and that you are at least familiar with the following topics:

1. Legal basis for the Centralised Procedure 2. Preparing for a CP (including eCTD compilation) 3. Roles and Responsibilities (EMA; CHMP; PRAC; EC) 4. Managing the procedure 5. Interacting with the EMA/(Co-)Rapporteurs 6. Post submission 7. The Commission decision making process 8. Re-examination of an Opinion 9. Questions for the TOPRA presenters

By ensuring that you have familiarised yourself with this material in advance it will enable the presenters to further elaborate on the reality of how these procedures work in practice versus what is described by regulatory requirements and the Medicinal Products Directive (MPD) 2001/83/EC.

1. Legal basis

The legal basis for the establishment of the Centralised Procedure, created by Council Regulation (EEC) No 2309/93 and implemented on 1 st January 1995, is laid down in Regulation (EC) No 726/2004 and Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 (“the Regulation”) which makes provision for a centralised Community procedure allowing for: • a single application • a single evaluation • a single authorisation • direct access to the single market of the EEA-EFTA Overview of the procedure The procedure is coordinated by the EMA and is assessed by appointed CHMP Rapporteur and Co Rapporteur, PRAC Rapporteur. The PRAC rapporteur should always be a PRAC member from another MS than the CHMP rapporteur The CHMP scientific opinion to grant an opinion – positive or negative - is voted upon by CHMP (1 vote per each of 27 Member States plus 5 co-opted members) with a consensus or simple majority vote (17 votes out of 32)being required. The final decision to grant approval is made by European Commission based upon the CHMP opinion resulting in a single EU-wide Marketing Authorisation issued by the European Commission. Data exclusivity and market protection includes: 8+2 years (8 years data In addition, it makes provision for the establishment of a European Medicines Agency (EMA).

exclusivity/2 years marketing exclusivity) with an additional one year market exclusivity possible for significant new indications approved within the first 8 years). This is applicable for marketing authorisations (MAs) granted based on so called full dossiers (i.e. article 8(3) 10a and 10b of Directive 2001/83/EC.

2. Preparing for the Centralised Procedure – checklist of activities

Eligibility Is your product eligible for review under the CP? Article 3 of Regulation (EC) No 726/2004 defines the scope and eligibility of applications for evaluation under the centralised procedure through which medicinal products must ("mandatory scope") or may ("optional scope" or "Generic/Hybrid") be authorised by the Community. Mandatory for: • Medicinal Products developed by means of biotechnological processes (recombinant DNA technology, hybridoma and monoclonal antibody methods • Advanced Therapy Medicine Products (Gene Therapy, Somatic cell therapy or tissue engineered products) • Orphan products • Biosimilars which are developed by means of one of the biotechnological processes listed in the Annex to Regulation(EC) No 726/2004 • Medicinal products for the treatment of AIDS, cancer, neurodegenerative disorder, diabetes, auto-immune diseases, and other auto-immune dysfunctions and viral diseases. • Significant therapeutic, scientific or technical innovation, or where the granting of a Community Authorisation for the medicinal product is in the interests of patients at the Community level • Generics of reference products approved via Centralised procedure • In some cases generics of reference products approved via National/MRP/DCP procedures (except biosimilars) provided that the conditions, laid down in Article 3(3) of the Regulation are met (e.g. same summary of product characteristics, same name in all the Member States) • Certain paediatric use applications may be eligible, e.g., PUMAs, paediatric indication applications for applications for nationally-approved products Note: A generic or hybrid medicinal product of a reference medicinal product authorised via the centralised procedure has ‘automatic’ access to the centralised procedure under Article 3(3). Multiple/duplicate or informed consent applications from the same or different marketing authorisation holder for a specific medicinal product with an active substance(s) already authorised via the centralised procedure, have automatic access to the centralised procedure. Applications for generics/hybrids of reference products approved via the centralised procedure can also be made using the DCP/MRP procedure. Optional for: • New active substances

Further reading: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/european- medicines-agency-pre-authorisation-procedural-advice-users-centralised-procedure_en-0.pdf

Suitability for the Centralised Procedure Is the CP the best route for your medicinal product?

Administrative • One application leads to one evaluation/one set of questions, leading to one authorisation in 27 EU Member States + 3 countries of the EFTA (Iceland, Liechtenstein, and Norway) • Transparent evaluation (assessment reports, agendas and meeting minutes) • Results in a single set of product information for healthcare professionals and patients in all the EU official languages • More efficient Europe-wide approval

• Life cycle management resource and cost savings

Regulatory •

Lack of opportunity to select Rapporteur/Co-Rapporteur • “All or Nothing” procedure seen as a risk; if CHMP refuses to approve an MAA, the drug is barred from sale in every EU country • Data package may be more acceptable in some regions than others, i.e., cannot avoid countries with specific issues or concerns Commercial • Prevalence of the disease/medical condition may differ across individual countries; therefore may not be needed in all EU markets; utilise a different procedure (MRP/DCP/National) • Single MA holder, tradename and pack – possible lack of flexibility in marketing? • Pricing and reimbursement – consider interaction between regulators, Health Technology Assessment (HTA) bodies and trade associations. • Review available guidance: ICH and EU guidance, EU legislation and national treatment guidelines • Review EPARs for authorised medicinal products with similar indication(s) or issues • Check comparator(s)/Standard of Care (SOC) used, efficacy endpoints, safety profile, specification limits, stability data, toxicity profile etc. • List all known/potential issues with data package (missing data, unfavourable results etc) and rank in terms of risk to approval (critical, major, minor) • Is the proposed indication appropriately reflective of the population studied and the outcomes? • If you have orphan drug designation have you adequately assessed similarity and significant benefit? Resolved with a post-approval commitment • Justified based on the overall risk-benefit profile and unmet medical need • Determine which issues should be discussed with the (Co-)Rapporteur and/or EMA based upon the criteria assigned based on data package. Determine whether it would be appropriate for the product to be approved under ‘exceptional circumstances’ or ‘conditional approval’ • Eligibility may be subject of CHMP Scientific Advice • Eligibility should be discussed with the EMA at the pre-submission meeting and justified in the MAA. Risk Mitigation Strategy Determine which issues can/should be: • Resolved pre-submission • Data Package Gap Analysis With a cross-functional team (clinical, preclinical, CMC), conduct a gap analysis on the data package to:

eCTD eCTD-format electronic-only submissions are mandatory for centralised submissions

• The eCTD is an electronic version of the Common Technical Document (CTD) • It contains additional technical components which enable the lifecycle of individual files and of the product itself, to be managed • eCTD has:

Folder structure

o o o

Contents

XML backbone

• Amendments/supplements are never incorporated into the original submission but remain entirely separate, with its own XML backbone.

General Points/Recommendations: • Vendors can provide eCTD builder tools and consultancy on eCTD preparation • Document preparation: if documents authored in Word using templates with styles, bookmarks and electronic cross-referencing, then PDF files generated from these can be automatically bookmarked and hyperlinked internally • Recommend securing an electronic document management system • Ensure that electronic source documentation will be available from third parties, e.g., licensing partners and CROs • Study the templates for assessors in order to understand what they are looking for in the responses Further reading: https://www.ema.europa.eu/en/general-regulatory-procedural-guidance https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/marketing-authorisation- guidance-documents https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/assessment-templates guidance#day-80-and-day-120-assessment-report-templates-(containing-guidance)-section https://admin.ich.org/sites/default/files/inline-files/eCTD_Specification_v3_2_2_0.pdf

3. Roles and responsibilities in the Centralised Procedure

European Medicines Agency (EMA) • An Agency of the European Commission • EMA provides the

Committee on Human Medicinal Products (CHMP) • Assessment of MAAs and maintenance activities (e.g., review of variations to MAA)

Pharmacovigilance and Risk Assessment Committee (PRAC) • Primarily responsible for assessing EU Risk Management Plans (RMP) and all aspects of risk management • Determines requirement for post-authorisation safety studies (PASS) • Assesses need for additionalrisk

•

Preparation of the ‘opinion’ of the CHMP on any question relating to the evaluation of medicinal products for human use (opinion provided by EMAto EU Commission) Opinion based upon review of (Co-)Rapporteur Assessment Reports and selected review of MAA

framework within which the scientific committees perform their assessments

•

minimisation measures (e.g., restricted distribution, patient / physician education)

(Co-)Rapporteurs •

EMA Procedure Manager (PM) • Applicant’s primary contact during course of evaluation procedures

EMA Product Lead (EPL) •

Leads the EMA product team Maintains oversight of the medicine throughout its lifecycle Accountable for the overall product knowledge Provides clinical and regulatory science input Supports consolidation of a committee position Facilitates cross-committee discussions and coordinates with the different experts/committees in EMA Reference for the defined products / disease area Should have oversight of all correspondence with Sponsor

Rapporteur and co- Rapporteurs are CHMP members assigned to lead the assessment of the MAA Responsible for the scientific assessment of the dossier Prepare separate Day 80 AR, Day 87 AR Prepare Joint Day 150 AR Propose positive / negative opinion, scientifically justifiable SmPC, conditionsfor use, obligations, RMP Identify need for input from external experts / SAG

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Provision of regulatory procedural guidance Ensures adherence to procedural guidelines and timelines Regulatory scientific support in simpler procedures Maintains process performance metrics Appointed at start of procedure

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Oversees management of procedure

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European Commission • The EC reviews the

Scientific Advisory Group (SAG) • Independent expert scientific advisory group • Convened by CHMP if external expert advice is

‘opinion’ of the EMA and prepares and issues the Final Commission Decision (the EU Marketing Authorisation)

required on specific assessment issue(s) CHMP ask SAG specific question(s) Normally occurs prior to CHMP discussion on the review

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Closed meeting (unlike US advisory committees) Sponsor invited to provide their point of view on issue being addressed Advice given by SAG may be disregarded by CHMP

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4. Managing the Procedure: Pre-Submission to Approval

Procedure overview:

Pre-submission -18 months before start of procedure Submit invented names to Name Review Group (NRG) -6/7 months Eligibility Justification and Notification of Intent to File

Pre-submission meeting request EMA Pre-submission meeting

-6 months

Intent to submit multiple applications (Co-)Rapporteur and peer review appointed Intent to apply for (partial) fee waiver deferral Submission of MAA to EMA and (Co-)Rapporteur

-2 months

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EMA Pre-submission meeting The meeting is intended to address issues peculiar to the planned MAA that have not been addressed in the Pre-Submission Guidance (PSG) Q&A document or other guidance. Assists applicants in “finalisation of upcoming MAA”. In order to apply for a meeting, applicants must complete the pre-submission meeting request form: https://www.ema.europa.eu/en/pre-submission-request-form

The form consists of the following areas: • Quality + GMP • Non-clinical + Clinical + GLP + GCP • Pharmacovigilance • Regulatory + procedural • Product information + transparency • Administrative

Information on the product and development programme should also be provided and using this information, the EMA will decide what needs to be discussed at the meeting.

Focus on key issues within dossier; try not to cover too many topics and ensure the company’s interpretation of the relevant legislation and/or guidance is provided along with the company position.

It is advisable to review available European Product Assessment Reports (EPARs) to determine whether a precedent has been set with another medicinal product in relation to an issue.

If ‘conditional approval’ or approval under ‘exceptional circumstances’ is requested, this should be justified in a pre-authorisation or pre-submission meeting request form and discussed at the meeting.

Further reading: Guidance on pre-submission meetings and Q&A available at: https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/pre-authorisation-guidance

5. Interacting with the EMA/(co-)Rapporteurs

(Co-)Rapporteur Pre-Submission Meeting(s) These meetings are important because they serve to build a dialogue between the Rapporteurs and the applicant. This is important because the Rapporteurs will act as primary reviewer and product champion when discussing issues with the CHMP. The better briefed the Rapporteurs are on the key issues and the company position on them, the better they can explain and discuss these issues when they are under review by the CHMP. For differences in content and structure for advanced therapy filings, EMA recommends early pre-submission meetings and requesting appointment of rapporteurs as early as possible to facilitate dialogue during the MAA preparation. Key points: • Determine whether joint or separate (Co-)Rapporteur meeting(s) is appropriate taking (Co-)Rapporteur preferences into consideration • Face-to-face meetings are normally preferable depending on availability • Invite/keep the EMA Project Manager informed • Provide the briefing package to the (Co-)Rapporteur as far in advance as possible of the meeting • Agree timelines with (Co-)Rapporteur, generally 2-4 weeks in advance o Contact (Co-)Rapporteur in advance to determine preferred meeting structure o Presentation and discussion versus discussion only o Level of background discussion required prior to issues discussion • Provide a summary of relevant quality, non-clinical & clinical data • Summarise main issues with supporting data package, associated list of questions and accompanying company position • Be transparent and honest about the issues • Be strategic about questions posed; do not ask questions for which company is not prepared for the answer; focus on what needs to be addressed • General rule – do not ask for “open” advice if the company is not prepared to follow it • Ensure appropriate functional area representation in order to be able to address issues raised (the number of attendees is limited; do not bring more company representatives than there are authority attendees) • Determine (Co-)Rapporteur level of concern and/or position on individual issues by review ofinformation in the public domain o EPARs o Guidance they might have provided input on o Colleagues ’ experience of the agencies • Provide draft minutes of meeting to (Co-)Rapporteur and EMA • Include minutes of meeting in MAA.

6. Submission Procedure

Time Day 1

Procedural step Start of Procedure

Day 80 Day 115

Preliminary assessment Report

Receipt of draft list of questions from Rapporteur, co-Rapporteur, CHMP members and EMA Receipt of CHMP adopted list of questions, as well as the overall conclusions and review of the scientific data Adoption of request for inspection

Day 120

Clock Stop Day 121

Submission of the responses and restart of the clock

Day 150 Day 180

Preliminary Joint Assessment Report

CHMP discussion and decision on the need for adopting a list of “outstanding issues” (questions) and/or an oral explanation by the applicant. If an oral explanation is needed, the clock is stopped. Final inspection report

Day 181

Oral explanation by applicant if needed / Responses to List of Outstanding Issues Final draft of English Product Information submitted by applicant Adoption of CHMP opinion and CHMP Assessment Report

Day 181 – 210

Day 210 Day 215 Day 232 Day 239 Day 261 Day 277

Draft translated labelling and Annexes Final translated labelling and Annexes Start of “Standing Commission Consultation” End of “Standing Commission Consultation” Commission Decision issued/End of Procedure

Day 80 (provided to sponsor for information only) • Day 80 (Day 87 for PRAC Report) •

Schedule a team meeting to review the preliminary Assessment Report(s) • Develop strategy for addressing identified issues ensuring cross-functional agreement is obtained on how to address issues raised • Start drafting responses where possible and practicable. Day 120 • There is a clock-stop in the procedure following Day 120 whilst the applicant prepares its responses to the CHMP’s list of questions • Schedule a project team meeting to review the CHMP adopted list of questions • Further develop strategy for addressing identified issues • Provide responses: o A separate document for each discipline should be used: (Clinical, Non-clinical, Quality, Risk Management Plan). The templates can be set up such that there is one question per page however these page breaks can be removed once responses are finalised • Consider alternate strategy, e.g., withdrawal of MAA, post-approval commitment, conditional approval, etc. • Remember that, in general, no substantial data derived from new studies should be introduced in the responses. However, new analysis may be included, e.g., follow-up data from previously submitted studies • Identify questions that require clarification/discussion with the EMA/(Co-)Rapporteur • Submit a written request for a Clarification Meeting if required.

Day 120 LoQ Clarification Meeting • Should be a joint meeting between applicant, (Co-)Rapporteurs, and the EMA • Consider conducting meeting at EMA during CHMP week versus meeting/teleconference at agency (to enable assessment team to attend) • Aim of meeting: o Clarify scientific rationale of questions which are unclear o Provide guidance on proposed response strategy o Discuss timelines implications o It is not a meeting to discuss all responses to all questions o Do not try to review an exhaustive list of questions and proposed responses o Do try to address the strategy for responding to major objections o Consider addressing questions related to post-approval commitments or risk management strategies o At the end of the meeting, you should aim to understand: • What issues have a major impact on the approvability of the data package • What issues need to be resolved in the responses to Day 120/180 questions and which issues can be addressed as a post-approval commitment • Whether an extension to the standard 3-month clock stop is required o If required, a written request for an extension will need to be addressed to the Chairman of CHMP as soon as possible after Day 120 o Clock stop beyond 6 months not normally accepted

Secondary evaluation phase

* Comments from CHMP and PRAC members not made available to applicants

Day 150 and Day 180:

Day 150 (provided to sponsor for information only) • Schedule a project team meeting to review the draft Response Assessment Report(s) • Develop strategy for addressing identified issues ensuring cross-functional agreement is obtained on how to address issues raised • Start drafting responses where possible and practicable. Day 180 • Schedule a project team meeting to review the List of Outstanding Issues (LOI) • Finalise strategy for addressing identified issues • Prepare for oral explanation/SAG if need has been identified (where responses have failed to convincethe CHMP) • Important to ensure company agrees on position to take at the Oral Explanation (OE) • Consider bringing in external experts to provide support at the OE • Clock stop: 1-3 months (1 month recommended). If able to respond quickly to, RSI timetable with no clock stop could be considered to shorten overall review time and enable CHMP opinion at Day 180. No clock stop response timetable would need to be discussed with the EMA ahead of submission. • Use EMA published timetable: RSI 30 day timetable with clock stop to calculate downstream timelines. Usually midday Friday, day after CHMP Meeting concludes o Company issues Press Release and must correctly represent Regulatory Status. Not to be released until after closure of CHMP meeting. • Linguistic Review – Update translations on receipt of Day 210 label text. • Ensure potential Post Authorisation Measures are acceptable and can be undertaken within the agreed timelines. • Prepare for Commission Decision Phase. • Prepare for EPAR review. Preparing for an Oral Explanation Step 1 (Day 180) If the CHMP deems an OE necessary, the company is advised and the proposed timelines communicated (30 day clock stop standard; 60-90 day clock stop reserved for extensive LOI) CHMP determines need to consult Working Parties or Expert Group(s). EMA contact point confirms timeslot of oral explanation, no later than seven working days in advance, specifying number of participants allowed to attend (typically should not exceed 10). Step 2 Following LOI adoption, the applicant may request a clarification meeting with (Co)Rapporteur. The applicant then provides responses to LOI including amended SmPC, follow-up measures and specific obligations, draft presentation and list of participants for the OE. Day 210 and beyond • CHMP Opinion issued in CHMP Press Release o

Step 3 CHMP discuss applicant’s responses to LOI and refines the LOI for the OE.

Step 4 (Participation in the OE) OE: the applicant addresses each item on the LOI, SmPC amendments, proposed follow-up measures