Module 1 2021

©TOPRA ( The Organisation for Professionals in Regulatory Affairs) 2021

Please note that all printed material contained in the course handouts is, unless copyright is assigned elsewhere, the copyright of The Organisation for Professionals in Regulatory Affairs. Such materials are intended for the personal use of the registered students/delegates. Agreement must be reached with the Institute before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form or by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

First Name

Last Name

Company

Country

Altay Veda

Atac

Med Supplies

United Kingdom United Kingdom United Kingdom

Avadhan

GlaxoSmithKline

Fola

ayankogbe

Ethypharm UK

Cabiria

Bellantuono

Sintetica SA

Switzerland

Ulrike

Bindl Bratti

Alexion Pharma

Germany Germany

Monica

Bayer

Tracey

Brett

DKT WomanCare Global Services SAS France

Catherine Burke

Ireland

Agathe Edmar Marion Ariana

Cabarrot Campos

AstraZeneca

United Kingdom

Ipsen Innovation

France France

Carpentier

Alexion Europe SAS PRA Health Sciences

Castro

United Kingdom United Kingdom

Celine

Courtay-Cahen Boyd Consultants

Bettina

Deubner

AbbVie

Germany

Rotem Domany

OPKO Biologics

Israel

Saurabh

Dudhewar

Sandoz

Netherlands

Marina

Dunn Emal

AstraZeneca

United Kingdom

Diba

Barry

Fullard

Invibio

United Kingdom

Elisa

Gramigni

Menarini Ricerche Spa

Italy

Charlotte

Grenier

Alexion Europe SAS

France

Ginette

Hampshire

Eisai

United Kingdom

Alexia

Hulin

EyeD Pharma

Belgium

Vipul

Kamalkar Khawaja

Aurobindo Pharma

United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom

Rizwan Naomi

Elanco

Krikman

IDEA Regulatory

Molly

Lapworth

DLRC DLRC

Alex Ines

Leggatt

Lenic

AstraZeneca

Peggy

Levy

Teva Canada Innovation

Canada Belgium Belgium

Sophie

Missotten

Viatris

Julie

Mutert O'Shea

GALAPAGOS NV EirGen Pharma Lightpoint Medical

Maria Shajel

Ireland

Panchal Soora

United Kingdom

Sandra Marisa Pereira Domingues Bayer Consumer Care

Switzerland

Mai-An Shivani

Pham

AstraZeneca

United Kingdom

Prabhu

Abbott Products Operations

India

Eva

Prevc

Amgen AbbVie

Austria

Zeenat

Raza

United Kingdom United Kingdom

Gwyneth Gabriela

Rodrigues Rodrigues

Merck Sharp & Dohme

DKT WomanCare Global Services SAS France

Carlota

Rovello Saleemi

Athlone Laboratories

Ireland

Iqra

Roche Boots

United Kingdom United Kingdom

Gursharn Sanghera

Manuela

Schneider

Vifor Pharma Management

Switzerland

Alenka Nicola

Skulj

Lek Pharmaceuticals

Slovenia

Smith

Recipharm

United Kingdom United Kingdom United Kingdom

Aneta

Sokolova

Teva

Mark

Stott

Baxter Healthcare

Ann

Tillyer

Niche Generics

Ireland

Estelle

Truchet

Emergent BioSolutions Berna

Switzerland

Andreina

Vallenilla

Grunenthal

Germany

Keri

Wilkie

Vascutek Ltd (t/a Terumo Aortic)

United Kingdom United Kingdom Czech Republic

Abisola Yuanxiu

Williams Zadnik Li

Pharma Research Associates

Pro.Med.CS

Qian

Zhu

Dizal (Jiangsu) Pharmaceutical

China

Module 1: Strategic Planning in Regulatory Affairs 30 th June - 2 July 2021

Online

Module Leaders : Ineke Jonker-Hoogerkamp

Date: Wednesday 30 th June 2021

Time (BST)

Activity

Speaker Chairperson: Ineke Jonker- Hoogerkamp Eagle Pharma Consult Ineke Jonker- Hoogerkamp Eagle Pharma Consult Ineke Jonker- Hoogerkamp Eagle Pharma Consult

09.15– 09.30

Welcome & Introduction Aims and objectives of the module

Lecture 1: Strategic Planning in the Pharmaceutical Industry

09.30 – 10.15

Refreshment Break

10.15 - 10.30

Lecture 2: EU Regulatory Procedures – Strategic Choices

10.30 – 11.30

Connie van Oers Sanofi-Genzyme

11.30 - 12.30

Lecture 3: Japan – Strategic Considerations Considerations for the Japanese market, implications for non-Japanese companies, working with affiliates, CROs. Working with the PMDA

Mohamed Oubihi Yakumed

12.30 - 13.30

Lunch

13.30 - 14.30

Lecture 4: Regulatory Strategy for the Emerging Markets – Far East, Africa, Middle East, Latin America

Ellliot Simonian Consultant

14.30 - 15.00

Refreshment break

Lecture 5: The USA – Strategic Considerations Considerations for the US market, implications for a non-US company, working with affiliates, CROs, Joint ventures. Working with the FDA

15.00 - 16.00

Marga Oortgiesen UCB

Module 1: Strategic Planning in Regulatory Affairs 30 th June - 2 July 2021

Date : Thursday 1 st July 2021

Chairperson Ineke Jonker-Hoogerkamp

Time (BST)

Activity

Speaker

09.30 - 10.30

Lecture 6: Orphan Drugs – Strategic Considerations Regulatory Strategy in orphan drug development – keep your stakeholders aligned

Liesbeth Hof ProPharma Group

10.30 – 11.00

Refreshment Break

Lecture 7: Electronic Submissions (eCTD) – Strategic Implications Gateways, Electronic data standards, Impact for global roll-out, Implications for smaller companies ; PIM

11.00 - 12.00

Matthew Pazdernik Organon

12.00 – 13.00

Lunch

Module Leader

14.00 – 16.30

Case Study – Global Project Development Strategy with Refreshment Break

Module 1: Strategic Planning in Regulatory Affairs 30 th June - 2 July 2021

Date : Friday 2 nd July 2021 Chairperson Ineke Jonker-Hoogerkamp Time (BST) Activity

Speaker

Lecture 8: Regulatory Intelligence – Implications for Product Development Consider how to use/where to get information and how companies (both big and small) can influence the development of guidance documents Lecture 9: Interaction with Regulatory Agencies – the Industry Perspective Scientific Advice, Protocol assistance, Joint Scientific Advice, SMEs

08.30 – 09.30

Alessandro Lazdins GSK

09.30 – 10.30

Ineke Jonker- Hoogerkamp Eagle Pharma Consult

10:30 – 11.00

Refreshment Break

11.00 – 12.00

Lecture 10: Pharmacoeconomics Pricing and reimbursement strategies within the EU, when/what to build into product

Hayden Holmes York Health Economics Consortium Ltd

12.00 – 13.00

Lecture 11: Medicines for Children – Strategic Considerations Regulatory Issues and strategies

Maaike van Dartel CBG-MEB

13.00 – 14.00

Lunch

Lecture 12: The Relationship between Regulatory Affairs and Project Planning

14.00 – 15.00

Elke Litzlbauer Takeda

Refreshment Break

15.00 – 15.30 15.30 – 16.30

Lecture 13: Life Cycle Management Regulatory issues and strategies

Sjaak Bot Janssen

28-6-2021

Strategic planning in Regulatory Affairs

 A presentation by Ineke Jonker, Independent Consultant, Eagle Pharma Consult

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Learning Outcomes

 Understand the importance of a regulatory strategy  Understand which factors play a role in designing a regulatory strategy  Understand how current trends in pharmaceutical industry may influence the regulatory strategy

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In This presentation we will cover

 What is a regulatory strategy?  Why and when is a regulatory strategy needed?  The aspects of a regulatory strategy

 What are the current trends in pharmaceutical industry?  How will these trends in pharmaceutical industry affect the regulatory strategy?

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What is a Regulatory Strategy?

• Strategic planning: • Process of defining strategy or direction

• Making decisions on resources to pursue this strategy. • control mechanisms for guiding the implementation of the strategy. • Involves many parties and research sources in the analysis of the goal, the organization and its relationship to the environment in which it competes.

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What is a Regulatory Strategy?

• Regulatory Strategy: • Plan for developing the product with the goal of obtaining initial regulatory approval in desired markets • Plan also for lifecycle management including post approval maintenance

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Why a Regulatory Strategy?

• For alignment of development, commercial and regulatory goals: • Development: CMC, non-clinical and clinical development plan • Commercial: key product label attributes and positioning, pharmacovigilance and “fourth hurdle” • Regulatory: scientific advice, procedure, legal basis, exclusivity

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Why a Regulatory Strategy?

• Understand the regulatory landscape • Guidelines • Stakeholders • Emerging policies • Precedences – Public assessment reports • Drive the development and identify hurdles so they can be solved proactively

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Why a Regulatory Strategy?

Tracking tool: summarize key objectives/agreements with project team (target product profile) and with authorities Planning tool: documentation, timelines and topics to be discussed with health authorities Risk management: keep track of issues that may affect timelines, costs or commercial value

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When a Regulatory Strategy?

• Always…… • Development: new molecular entities (chemical and biopharmaceutical), drug rediscovery • Lifecycle management: maintenance of existing products, new indications, new API suppliers, new markets, line- extensions, site transfers

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When a Regulatory Strategy?

• Start early in development, e.g. before regulatory non- clinical studies • Start with the end in mind, e.g. with a target product profile • Regulatory strategy should be a living document

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Aspects of a Regulatory Strategy

• Overview of guidelines and precedents: covered in the lecture on regulatory intelligence • Plan for scientific advice : covered in the lecture on authority consultation • Knowledge on requirements in the regions of interest

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Aspects of a Regulatory Strategy

• Key product label attributes • External influencing • Global submission strategy: know the requirements in each region • Pharmacoeconomic / Reimbursement aspects • Target submission and approval dates • Options for accelerated approval pathways: covered in the lectures for the various regions • Options for small and medium enterprises

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Aspects of a Regulatory Strategy

Provides guidance on how to work with other disciplines: covered in the lecture on the Relationship between Regulatory Affairs and Project Planning

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Aspects of a Regulatory Strategy

What is designing a regulatory strategy about?

or

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Aspects of a Regulatory Strategy

Design of a regulatory strategy requires the regulatory professional to have: *Scientific know-how • Essential technical and scientific aspects of the product to be registered AND *Soft skills: • Negotiation skills • Problem-solving • Creativity and flexibility • Understanding of and insight in interests of stakeholders

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Trends in Pharmaceutical Industry

• Shift to emerging markets • Unmet medical need: Alzheimer’s disease, obesity, diabetes type II • Personalised medicine • Drug-Device combinations e.g. Companion diagnostics • Need for prevention of diseases versus treatment (vaccines for developing countries, e.g. malaria)

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Trends in Pharmaceutical Industry

• Mergers and acquisitions • In- and out-licensing • A big pharma company handles the strategic planning differently than a small enterprise

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Effect of Trends on the Regulatory Strategy

• For personalised medicine, a different regulatory strategy is needed when compared to a blockbuster.

How?

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Effects of trends on the Regulatory Strategy

• Emerging markets are also in the picture for development and manufacturing activities hence requiring management skills.

What are the specifics in the regulatory strategy?

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Effects of Trend on the Regulatory Strategy

• A drug is developed for an unmet medical need.

What are the strategically important aspects?

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In This presentation we covered

 Why and when is a regulatory strategy needed?  The aspects of a regulatory strategy  What are the current trends in pharmaceutical industry?  How will these trends in pharmaceutical industry affect the regulatory strategy?

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Recommended references

 TOPRA Regulatory Rapporteur February 2014  The use of EPARs in regulatory strategy for biologics and advanced therapies; TOPRA Regulatory Rapporteur Vol 17 No 6 June 2020  Regulatory affairs strategic planning: how to do it well; TOPRA Regulatory Rapporteur Vol 17 No 10 Oct 2020  Worldwide Update, FDA and NIH heads outline plan for personalised medicine; RAJ Vol 21 No 8 August 2010, page 520  Porter M.E. (1980) Competitive Strategy; Techniques for Analyzing Industries and Competitors. London, Free Press

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Take home message

 Regulatory strategy is indispensible  As a regulatory professional you are in a unique position: ● You can influence company policy ● You are an active stakeholder in company policy, development and life cycle management ● You contribute to the success of your company! ● You have added value  It is an underestimation to consider the regulatory profession only as filling out forms and shoving paper around.

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QUESTIONS?

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Contact details Name: Ineke Jonker-Hoogerkamp, PhD Tel: + 31 6 27 00 77 79 Email: a.jonker@eaglepharmaconsult.com

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EU Regulatory Procedures Strategic Choices

Connie van Oers – Global RA-CMC Biologics Sanofi Genzyme

The views expressed in this presentation are solely the view of the presenter and do not necessarily reflect the views of Sanofi

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This presentation covers

 Overview of Authorities involved in Marketing Authorisations in the EU  Legal Basis of EU Marketing Authorisations  Overview of EU Regulatory Procedures  Basics of Mutual Recognition/Decentralised/Centralised Procedure  Strategic Factors that may influence the choice of Procedures  Options within the Procedures

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A Marketing Authorisation (MA) in the European Union

 License to sell a medicine  License granted by “Competent Authorities”  Assessment is benefit/risk balance based on:

● Quality; ● Safety; ● Efficacy;  Positive risk-benefit balance in favour of patients and users of products once they reach the market place.

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 Know the Regulatory Landscape and its options; ● Competent Authorities ● Regulations, Guidelines  Know your product and organisation; ● What are the goals and capabilities of your organisation ● Are specific guidelines applicable to your product or indication  Be aware of the consequences of a choice for future development, and (post-)marketing; ● Is it possible to meet commitments made ● What are the marketing and manufacturing capabilities ● Have Health economics or reimbursement been taken into account Some considerations for Strategic Choices to obtain a Marketing Authorisation in the EU

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 National Authorities in each Member State; ● Exact Roles and Tasks differ between countries ● Network through Heads of Medicines Agencies; Competent Authorities

 CMDh (Commission for Mutual Recognition and Decentralised Procedure (human) ; ● Examination of any query related to a marketing authorisation of a medicinal product in 2 or more member states. ● Representatives of all EU MSs plus Norway, Iceland and Lichtenstein – EU Law applies in the UK only to the territory of Northern Ireland

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 Protection and Promotion of Public and Animal Health  Marketing Authorisations  EU’s safety-monitoring or ‘pharmacovigilance’ system  Referrals  Coordinating inspections: GMP, GCP, GLP, PhV  Stimulating Innovation and research ● Scientific Advice, Guideline, Small Medium Enterprises Office, Orphan Designations, Innovation Task Force, PRIME designation; The European Medicines Agency

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Scientific Committees EMA

 Committee for Medicinal Product for Human Use (CHMP) and its working Parties • Tasks – Initial Assessment of EU Marketing Authorisation; Assessing Variations or extensions; Considers recommendation of the PRAC; Scientific Advice; Scientific Guidelines; Referrals; European Public Assessment Reports • Composition – Chair; Harald Enzmann (BfARM; Germany)) – 1 member plus alternate from 27 EU MSs; one member plus alternate from Iceland and Norway; 5 co-opted members;  Pharmacovigilance Risk Assessment Committee (PRAC)

 Committee Advanced Therapies (CAT)

 Committee for Orphan Medicinal products (COMP)

 Paediatric Committee (PDCO)

 Several Working Parties and Other Groups

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 National • Application in individual countries;  Mutual Recognition (MRP)/Decentralised (DCP) Procedure • National Application intended for more than one country  Centralised Procedure • 1 application in all EU Member States • 1 marketing authorisation; • 1 (invented) name • 1 common product information How to obtain a marketing Authorisation

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Legal Basis

 Article 8(3) Full Application ● Full Dossier; quality, nonclinical and clinical data ● “Full-mixed”; combination of non-clinical/clinical studies and bibliographical references

 Article 10(1) Generic ● Reference product on the market no less than 8 years; ● Same qualitative, quantitative composition; ● Same pharmaceutical form; ● Bioequivalence

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 Article 10 (3) Hybrid (mixed) Application ● Additional non-clinical/clinical data in case – Product does not meet definition of generic – No bioequivalence – in case of changes in the active substance(s), – Change to active substance, therapeutic indications, strength, pharmaceutical form or route of administration  Article 10(4) Biosimilars ● Additional non-clinical/clinical data required in case of: – Product does not meet definition of generic, esp. differences relating to raw materials or differences in manufacturing processes of biological product and reference biological product Legal Basis

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Legal Basis

 Article 10(a) Well Established use ● Well established medicinal use of active substance for at least 10 years; ● Non-clinical and clinical trial results replaced by appropriate scientific literature;  Article 10(b) Fixed combination products ● Active substances used in composition of authorised medicinal products but not in combination; ● New non-clinical and clinical data relating to the combination are required;  Article 10(c) Informed consent / Duplicate ● MAH allows reference to data on file to support assessment of other medicinal products with the same qualitative and quantitative composition of active substance and same pharmaceutical form

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 Combination of a medicinal Product plus a Medical device ● Single integral, combined, non-reuseable; ● To be Approved as a Medicinal Product; ● No CE Mark for the Device required;  Combination of Medical Device with Ancilliary substance ● To be approved by Notified body; ● CE Mark; ● Notified Body will ask for opinion on the ancilliary substance from a competent authority for pharmaceuticals  Combination Package ● Approved Medicinal Product and Medical Device packed together Combination products – Medical device regulation drug device drug device drug device + drug drug +

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National Procedure

 Until 1998 (national in multiple EU countries)  Currently only for: ● Marketing authorisation in a single EU Member State (No MA in any other Member State and no pending application in a member State); ● National Phase Mutual Recognition Procedure  Timelines National  Result: ● National approval, national SPC, country specific name; ● Difference between member states (indications, dosing, legal status (prescription or OTC);

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 Principle of Mutual Recognition/ Decentralised procedure • A marketing Authorisation in one Member State ought in principle to be recognised by the authorities of other member states; – As opposed to CHMP opinion by majority of votes (CP); – As opposed to every HA doing their own procedure, assessment (national)  Mutual Recognition Procedure (MRP) • Where the medicinal product has already received a Marketing Authorisation in a Member State at the time of application;  Decentralised Procedure (DCP) (MRP) • Where the medicinal product has not received a Marketing Authorisation in a Member State at the time of application; Mutual Recognition Procedure (MRP) Decentralised Procedure (DCP)

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Eligibility

 Applications for MA in more than one member state  Open for all applications not falling under mandatory scope of the Centralised procedure ● New active substances; generic medicinal products; informed consent applications; bibliographic applications; known substances in new combinations; line extensions; herbal medicinal products; homeopathic products ;  Flexibility ● Choice of MSs ● Different trade names in different MSs ● Different MA Holders in different Member States;  Applicant to choose RMS  Possibility of Repeating Procedures

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Overview of MRP and DCP DCP

MRP ● National registration in RMS ● (Updated) Assessment Report ● Dossier submission to CMS

● submission to RMS and CMS;

● Validation (14 days) ● Assessment I -120 days ● Assessment II – 90 days ● Discussion at CMDh (if necessary);

● Validation (14 days) ● 90 day assessment;

● Discussion at CMDh (if necessary) Total time 90 days (excluding clock stops)

Total time 210 days (excluding clock stops);

● National Phase;

● National Phase;

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Role of Reference Member State

 Regulatory Advisor to Applicant  Scientific Advisor of Dossier

CMS

 Moderator between applicant and CMS • Provides regulatory and scientific advice • Decides timetable • Scientific assessment –assessment report • Evaluation Responses; • Central point between applicant and CMS • Organises and chairs break-out sessions, instruct applicant • Refers to CMDh • Informs EMA if after referral no consensus • Informs applicant and CMS after positive conclusion and prepares final assessment report • Public assessment report

CMS

CMS

RMS

CMS

CMS

CMS

Applicant

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 To include further CMSs  All ongoing procedures (e.g. variations) to be finalised and dossier updated  Dossier update to include • Responses to previous procedures; • Commitments fulfilled • Additional data to comply with recent regulatory requirements e.g Risk Management Plan, Environmental Risk Assessment; • Consider new studies according to current standards, or provide updated evaluation of risk-benefit  Discuss with RMS before submission of RU-MRP  Multiple Repeat Use procedures possible Repeat-use MRP

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Centralised Procedure

 EU Marketing Authorisation through Centralised Procedure ● 1 marketing authorisation; ● 1 (invented) name ● 1 common product information  Dossier submission to EMA ● Initial Assessment by Rapporteur and Co-Rapporteur ● Discussion in the CHMP ● Scientific Opinion by CHMP; Positive opinion by absolute majority of votes ● Final Approval given as Decision by the European Commission

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 Biopharmaceuticals • Recombinant DNA Technology • Controlled expression of genes encoding for biologically active proteins • Hybridoma and monoclonal antibodies cells • Biosimilars;  Advanced therapy Medicinal Products (ATMPs) ● Gene Therapy medicinal products; ● Somatic Cell therapy medicinal products ● Tissue engineered products  Certain therapeutics areas ● AIDS, Cancer, Neurodegenerative disorders, Diabetes, Autoimmune diseases, Viral Diseases  Orphan medicinal products Centralised Procedure;Mandatory Scope

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Centralised Procedure; Optional Scope

 New active substances (outside mandatory scope indications) ● A new chemical, biological or radiopharmaceutical active substance as not previously authorised as a medicinal product in the European Union  Product offering significant therapeuic, scientific or technical innovation • Granting of a community authorisation is in the interests of patients at community level • Generics/Hybrid of centrally authorised products • Multiple/Duplicate • Paediatric use in accordance with paediatric regulation (EC 1901/2006)

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Centralised Procedure steps to take

 Submission of eligibility Request ● Between 18 to 7 months before submission  Notification of intention to submit an application ● At least 7 months before submission  Appointment of Rapporteurs ● 7 months before submission  Pre-Submission Meeting

● 7 months before submission  Submission of Application  Scientific Evaluation ● 210 days of assessment (excl clock-stops)  CHMP Opinion  European Commission decision

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Centralised Procedure

For ATMPs: Commision Advanced Therapies (CAT) involved

• Day 1 - Start of Procedure • Day 80 - Preliminary Assessment Reports by Rapporteur an Co-Rapporteur (sent to CHMP and applicant) • (before Day 120 PRAC Risk Management Plan Assessment report and List of Questions prepared) • Day 120 - List of Questions adopted by CHMP Clockstop • Day 120 - Submission Responses • Day 157 - joint Assessment Report from CHMP and PRAC (Co-)Rapp • Day 180 - CHMP Discussion on the need for adoption or list of outstanding issues Clockstop • Day 181 - submission of responses or oral explanation • Day 194 - CHMP (Co-) Rapp/PRAC Rapp joint Assessment Report • Day 210 - Adoption of CHMP Opinion

• Day 277 - days Final Commission Decision

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 Appointed from the CHMP Members ● Applicant’s proposal/preference not considered ● Appointment (usually) in accordance with expertise (therapeutic area) ● ATMPs: (Co) Rapporteurs appointed amongst CAT Members ● PRAC Rapporteur and Co-Rapporteur Appointed  Spokesperson of the CHMP  Prepares initial Assessment Report  Important for the Applicant ● Maintain good and Open Relationship;  Supported by Product Team ● National experts ● Product Team Lead nominated by EMA; primary contact applicant; liaison between EMA, Rapporteur, Applicant Rapporteur

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 PRIME – Priority Medicine ● Early Dialogue with HA and support during development  Innovation Task Force ● Early Dialogue for emerging therapies (ATMPs), emerging technologies, and borderline therapeutics (pharmaceuticals plus devices) for which there is no established EMA experience  Accelerated Review ● 150 day procedure instead of 210 days  Exceptional circumstances ● If it is not possible to collect comprehensive data (i.e. ultra rare diseases)  Conditional Approval ● Package not complete at time of submission  Orphan Medicinal products, Options for Small Medium Enterprises, Paediatric Medicines  Rolling review ● Ad-hoc procedure in the context of a public health emergency Options with EMA -Centralised Procedure

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PRIME: Priority Medicines Strategic Choice

 Enhanced support for development ● Voluntary, to be requested ● Medicines that target an unmet medical need; ● May offer major therapeutic advantage, or benefit patient without treatment options ● Based on enhanced interaction and early dialogue with developers of promising medicines; – Scientific Advice – Accelerated Assessment;  Regular Meetings ● Rapporteur from CHMP/CAT to help build knowledge ● Guidance on overall development plan and regulatory Strategy; ● Scientific Advice at key development milestones;

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How to liaise options for dialogue National or EMA

 Scientific advice

• Early in development • can (and should) be repeated • national HA or EMA  Combined Scientific Advice with HTA • with EMA • possibilities on national level  Pre-submission meeting • first opportunity to meet product team

 Clarification meeting,  Oral explanation, SAG  Every Meeting to be prepared, attended and followed-up on as appropriate

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 Examples of offers from National Authorities;  Medicines Evaluation Board, The Netherlands Alternatives for Early Dialogue Strategic Choice

• “Advies op maat”: personalised advice • Scientific Advice for small companies, • Primarily concerns pharmaceutical or pre-clinical aspects in early phases of development  Paul Ehrlich Institut, Germany ● Pre-Advice: – very early stage of development; – general (scientific) guidance and regulatory orientation – Informal exchange on general issues with regard to the medicinal product class;

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ATMP Classification

 consult EMA to determine if a medicine they are developing is an ATMP. The procedure allows them to receive confirmation that a medicine, which is based on genes, cells or tissues, meets the scientific criteria for defining an ATMP.  The classification procedure is optional.  EMA established the procedure to address questions on borderline classification with other areas, such as medical devices, as early as possible.  EMA's Committee for Advanced Therapies (CAT) delivers scientific recommendations on ATMP classification after consultation with the European Commission within 60 days after receipt of the request.  Request form and background information including background information on scientific, legal, regulatory and medical aspects

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Accelerated Assessment Strategic Choice

 Request before submission, (2 to 3 months)  Reduces Timelines from 210 to 150 days • 90+30+30 days; 1 month clock stop after day 90  Major Public health Interest ● Particularly from the point of view of therapeutic innovation;  Justification of Public Health Interest

● Unmet medical need, new methods of therapy, improves on existing methods;  If at day 120 or 150 CHMP or Applicant consider accelerated assessment no longer appropriate, assessment may continue under standard timelines  Applicant needs to be ready to submit responses in short period

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Conditional Approval Strategic Choice

 Extensive Studies/data may not be required in case of: • Serious debilitating/ life-threatening diseases; • Orphans; • Incomplete non-clinical and/or quality data only in emergency situations  Requirements: • Positive benefit/risk balance; • Unmet medical need; • Possibility to provide comprehensive data; • Benefit to immediate availability on the market outweighs the risks of placing on market without comprehensive studies;

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Conditional Approval Strategic Choice

 MA subject to specific obligations (to provide comprehensive data) • Valid for 1 year on a renewable basis  Strategic Choice instead of way-out if too many questions can not yet be answered ! ● Request at pre-submission meeting

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 Principle: ● CHMP and PRAC, with the support of the COVID-ETF, review data as they become available on a rolling basis, while development is still ongoing ● Assessment performed by Rapporteur and Co-Rapporteur; outcome adopted by CHMP  Eligibility: ● Applicants should email 2019-ncov@ema.europa.eu with: – a justification for assessing the product via a rapid procedure; – data supporting the proposed role of the product in the COVID 19 setting; – data supporting proof of concept. – Applicants can submit it together or after the request for eligibility to the centralized procedure  Several rolling review cycles possible ● Each cycle a minimum of 2 weeks depending on amount of data  Submission formal MAA ● Once CHMP considers data package sufficient complete ● Shortened timetable depending on remaining data to be assessed Rolling Review

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Strategic choices Type of Application

• Mandatory scope of Centralised Procedure • Legal Basis • Complete • Bibliographic • Generic • Biosimilar • ……..

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Article 117 medical device regulation Medical Device Regulation: came into force 26 May 2021

Article 117 of the EU MDR is about the drug-device combination products. The objective of Article 117 of the EU MDR is to involve the right stakeholders in the review process of the device by Notiffied Body (NB) and to also meet the expectations of the EMA and/or National Competent Auhtorities: -the MAA dossier should include results of the assessment of conformity or the relevant certificate issued by a notified body needed to affix a CE marling -an opinion on the conformity of the device part issued by a notified body

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Strategic Options RMS, CMSs, Rapporteur, (Co)-Rapporteur

 Based on Regulatory, Strategic and commercial reasons  Availability of RMS in DCP • Where they supportive of product/dossier scientific advice • Expertise of RMS for certain type of Products • Availability of Slot;  For MRP, RMS is where dossier was filed and approved nationally  Centralised Procedure – (Co-)Rapporteur Appointed • No Influence of Applicant • Supportive of product dossier during scientific Advice; Should you try to influence the choice of Rapporteur ?

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Strategic Choices- Market Considerations

 Where will the product be marketed ?  All EU member states

Limited number of countries

 Expand later: repeat use MRP • Decentralised Procedure to target main markets. • Repeat Mutual Recognition procedure(s) to add new Member States as required  Capability of the organisation • Ability to market throughout EU • CP more efficient to market in all or majority of MS  Existing license in one MS Mutual Recognition Procedure

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 Centralised Procedure ● One fee for all EU Countries; Strategic Choices Fees

 Mutual Recognition, Decentralised Procedure ● Fee Per Member State ● Fee RMS, Fee CMS;

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Strategic Options Timelines

 Is there a faster Procedure?

 MRP: National plus 90 days ● National Timelines before MRP not defined

 DCP: 210 days

 Centralised Procedure ● Possibility of Accelerated Assessment: from 210 to 150 days;

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Strategic choices Procedure

 Is there an ‘easier’ procedure? ● Only Data count; ● Withdrawal of a MS in MRP/DCP; ● Withdrawal or negative opinion in CP;

 Conditional Approval ● Not to be mistaken for an easier option when in fact data are deficient;

● Need sufficient data for positive risk/benefit ● Conditions imposed should be able to be met

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Name of the product Strategic Choice

 Name of the Medicinal Product (art 1(20+21) Dir 2001/83/EC) ● 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; ● Common name; International non-proprietary name (INN) recommended by the WHO;  Centralised Procedure ● 1 Name in the EU; ● Multiple/Duplicate Applications Possible;  MRP/DCP ● Different Names in different EU Countries ● Name Flexibility ● Multiple/Duplicate Applications Possible

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 Centralised Procedure ● Variations submitted as one package to EMA; ● Single List of Questions received from EMA;  MRP/DCP ● Package submitted to RMS and all CMS; ● Questions raised by RMS and CMS;  Post Approval Commitments - Conditional Approval or others  Annual reassessment – Exceptional circumstances Post- Marketing Considerations

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Statistics –EMA 2020

Medicine evaluation figures | European Medicines Agency (europa.eu)

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Statistics EMA

Medicine evaluation figures | European Medicines Agency (europa.eu)

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Statistics –CMDh 2020

CMDh statistics (hma.eu)

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Statistics – CMDh 2020

CMDh statistics (hma.eu)

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Statistics –CMDh 2020

CMDh statistics (hma.eu)

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Recommended references

 www.ema.europa.eu ● Marketing Authorisation: Pre-authorisation Guidance Q&A ● Research & Development: scientific guidelines  ec.europa.eu/health/documents/eudralex/ ● The rules governing medicinal product in the EU; – Volume 2, Pharmaceutical legislation on notice to applicants and regulatory guidelines for medicinal products for human use  www.hma.eu/ ● Heads of Medicines Agency  http://www.hma.eu/cmdh.html ● CMDh website

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Learning Outcomes: Recap

 Overview Centralised Procedure;  Overview of Mutual Recognition Procedure/ Decentralised Procedure;  Understanding factors to consider when chosing a EU MA Procedure  Strategic Choices to make before submission;

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Pharmaceutical Drug Development in Japan

Japan Bio and Pharma Experts

YAKUMED Japan

YAKUMED LIMITED BUILDING 220, WHARFEDALE ROAD, WOKINGHAM RG41 5TP, BERKSHIRE, UK PHONE: +44 (0) 1189654037

6F NUKARIYA BUILDING. 1-16-20 MINAMI IKEBUKURO TOSHIMA-KU TOKYO 171-0022 , JAPAN

Phone: +81 (0) 3-5326-3385

Distribution to third parties is not allowed

1

Presentation Outline

Introduction to Japanese Market

PMDA Scientific Advice

Clinical Trials in Japan vs Europe

Recent Updates & Regulatory Pathways

Cultural Considerations

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Presentation Outline

Introduction to Japanese Market

PMDA Scientific Advice

Clinical Trials in Japan vs Europe

Recent Updates & Regulatory Pathways

Cultural Considerations

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Attractiveness of Japan for Drug Development

- Strong Economy (world number 3)

- Increasing Elderly population

- World-class reimbursement system

- Advanced Infrastructure for Clinical trials

- Highly Qualified work-force

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Strong Economic Power

Strong Economy (world number 3)

-

- Third Largest Economic Power - GDP (2018) = USD 5.2 trillion - Third Largest Pharmaceutical Market

-

Increasing Elderly population

-

World-class reimbursement system

-

Advanced Infrastructure for Clinical trials

-

Highly Qualified work- force

JETRO

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Fast Aging Population

-

Strong Economy (world number 3)

Increasing Elderly population

-

-

World-class reimbursement system

-

Advanced Infrastructure for Clinical trials

-

Highly Qualified work- force

- Population started shrinking after 2010

- Now 29% of population is over 65

- 2040 36% of population will be over 65

MHLW

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Leading Causes of Death

-

Strong Economy (world number 3)

Increasing Elderly population

-

-

World-class reimbursement system

-

Advanced Infrastructure for Clinical trials

-

Highly Qualified work- force

MHLW 2014

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Japanese Healthcare System

-

Strong Economy (world number 3) Increasing Elderly population World-class reimbursement system Advanced Infrastructure for Clinical trials

-

-

Universal Free Access to healthcare Contributed to the outstanding health of Japanese -Life expectancy is the longest in developed countries -Infant mortality is the second lowest in the world

-

-

Highly Qualified work- force

Relatively efficient: Favorable health status compared with expenditure

Reimbursement system in Japan is quick and predictable despite recent government initiative to introduce Health Technology Assessment.

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Clinical Trial Infrastructure (1)

-

Strong Economy (world number 3)

-

Increasing Elderly population

-

World-class reimbursement system

Advanced Infrastructure for Clinical trials

-

-

Highly Qualified work- force

Source: OECD Health 2008, 2009, 2010 Data

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Clinical Trial Infrastructure (2)

-

Strong Economy (world number 3) Increasing Elderly population World-class reimbursement system

-

-

Advanced Infrastructure for Clinical trials

-

Source: OECD Health 2008, 2009, 2010 Data

-

Highly Qualified work- force

Denmark

Japan UK Germany France Sweden Spain Denmark

Nurses, Density per 1000 population

Spain

Nurse graduates per 100.000 population Medical graduates

Sweden

France

Physicians, Density per 1 000 population (head counts)

Germany

per 100.000 population

UK

Japan

0 10 20

0 20 40 60 80

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Strong R&D Infrastructure

-

Strong Economy (world number 3) Increasing Elderly population

-

-

World-class reimbursement system

-

Advanced Infrastructure for Clinical trials Highly Qualified work-force

-

JETRO

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Highly Qualified Labour

-

Strong Economy (world number 3) Increasing Elderly population

-

-

World-class reimbursement system

-

Advanced Infrastructure for Clinical trials Highly Qualified work-force

-

JETRO

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Japanese Regulatory Authorities

MHLW

PMDA

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MHLW

MHLW (Ministry of Health Labor and Welfare)

 Healthcare Policy

 Enforcement of administrative measures, eg: approval of JNDAs

 Guidelines

 Pricing (Health policy Bureau)

 Safety measures for emergency cases

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PMDA

PMDA (Pharmaceutical and Medical Device Agency)

 Consultations

 Implementation of work such as review of CTN/JNDA

 Interface with applicants during review

 GCP/GMP Inspections

 Document compliance review

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PMDA Structure

Office for Promotion of regulatory Sciences Office of General affairs/ Finance/Planning

Chief Management Officer

Auditor

Office of Quality Control Office of Safety I, II Office of Conformity Audit Office of Medical Devices I, II Office of OTC/Generic Drugs Office of Biologics I,II Office of New Drug I - V Office Review Administration Office of Review Management Office of Relief Funds Office International programs

Sr Ex. Director

Auditor

Chief Relief Officer

Chief Executive

Center Review Director

Ex. Director

Ex. Director

Chief Safety Officer

Inspection Office

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