Module 6

Module 6: Regulatory Strategy from Development to the Marketplace 7-9 Octo ber 202 4

©The Organisation for Professionals in Regulatory Affairs 202 4 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.

Module 6: Regulatory Strategy from Development to the Market Place

Date: 7 - 9 October 2024

LOCATION: Hilton Hotel, South Quay Square, Marsh Wall, London E14 9SH Module Leader: Vina Mistry

Date: Monday 7 th October 2024

Time

Activity

Speaker

10.00 – 11.30

Welcome & Introduction to the Module Lecture 1: Developing the Brand and Shaping its Market Place (Part 1)

Vina Mistry MTOPRA Pharmistry Consulting Limited

Refreshment Break

11.30 – 12.00

12.00 – 13.15

Lecture 1: Maintaining and Extending Brand Awareness through Product Development. (Part 2)

Vina Mistry MTOPRA Pharmistry Consulting Limited

13.15 – 14.15

Lunch

Christopher Leung, Fieldfisher

Lecture 2: Protecting the Brand: Intellectual Property and Data Exclusivity

14.15 – 15.30

15.30 – 15.45

Refreshment Break

Daniel Jackson, UCB Pharma

15.45 – 17.00

Lecture 3: Demonstrating Value and Market Access

Version: 1

Module 6: Regulatory Strategy from Development to the Market Place

Date: 7 - 9 October 2024

Date: Tuesday, 8 th October 2024

Time

Activity

Speaker

Amalia Alexe, Novartis Pharma

09.00 – 10.15

Lecture 4: Pharmacovigilance and Risk Management

10.15 – 10.45

Refreshment Break

Gaelle Andriantafika European Medicines Agency (EMA)

Lecture 5: An Agency Perspective: The success and failure of a medicinal product in the EU

11.15 – 12.30

12.00 – 13.00

Lunch

Lecture 6: Advertising and Controls on Prescription Only Medicines (POMs)

Carole Pugh CALEA Regulatory Ltd

13.00 – 14.30

14.30 – 15.00

Refreshment Break

15.00 – 17.00

Case Study: Advertising and Controls on Promotional Materials for POMs

Carole Pugh CALEA Regulatory Ltd

Version: 1

Module 6: Regulatory Strategy from Development to the Market Place

Date: 7 - 9 October 2024

Date: Wednesday, 9 th October 2024

Time

Activity

Speaker

Janet Worrell FTOPRA, JensonR+ Group Limited

09.00 – 10.15

Lecture 7: Issue Management

10:15 – 10.45

Refreshment Break

Michelle Gleed, Camdia Ltd

10.45 – 12.00

Lecture 8: Communicating with Patients and Prescribers

12.00 – 13.00

Lunch

Lecture 9: OTC Switching

Helen Erwood FTOPRA, ESPL Regulatory Consulting

13.00 – 14.30

14.30 – 15.00

Refreshment Break

15.00 – 17.00

Helen Erwood FTOPRA, ESPL Regulatory Consulting

Case Study: OTC Workshop & Close

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MSc Module 6: Regulatory Strategy: From Development to the Market Place

Welcome and Introduction to Module 6

7th to 9th October 2024

Vina Mistry

Independent Regulatory Consultant: Pharmistry Consulting Ltd

The Organisation for Professionals in Regulatory Affairs The Organisation for

Professionals in Regulatory Affairs

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Module 6: Aims and Learning Outcomes

Module 6 Aims

• To consider and evaluate practical regulatory aspects of regulatory strategy for commercialising products and maintaining the brand from development stages to registration and throughout the product lifecycle; • To explore and critically debate the regulatory issues likely to arise during commercialisation of products in order to be able to provide effective advice as necessary.

Module 6 Learning Outcomes

• To recognise the needs of marketing colleagues in commercialising products and maintaining brand awareness through new drug development, new indications and switching of legal status; • To demonstrate how the marketing life of a product can be optimised by use of patents, supplementary protection certificates, data exclusivity; • To optimise the needs of pricing and reimbursement committees, such that any commercial advantages may be gained; • To understand the importance of the SmPC as a means of communication with prescribers and as the basis for advertising and patient information; • To understand the constraints of advertising and promotion of pharmaceuticals and OTC medicines; • The responsibilities and requirements for keeping licences current wrt pharmacovigilance and adverse drug reaction and risk management. • Differentiate the internal and external activities and interactions associated with a product issue or during crisis management.

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Module 6: To Better Equip You Focused Key Topics to Assist with your Regulatory Strategy

DEFINING THE PRODUCT AND ITS PLACE ON THE MARKET • Developing the Brand and Shaping its Market Place.

LEGAL FRAMEWORK: PROTECTING THE BRAND • Protecting the Brand: Intellectual Property and Data Exclusivity

SUCCESSFULLY LAUNCHING THE PRODUCT ON THE MARKET • Demonstrating Value and Market Access • Pharmacovigilance and Risk Management • Health Authority Engagement and Assessment COMMUNICATING WITH THE MARKET • Advertising and Controls on Prescription Only Medicines • Issue Management • Communicating with Patients and Prescribers

EXTENDING THE LIFECYCLE OF THE PRODUCT • Extend and maintain the brand • OTC Switching

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Student / Delegate Participation

Interactive;

• Ask questions to further understand the subject;

• Speakers will naturally pause to check for questions;

• Attendees online - Use the chat functionality to ask a question;

• Teamwork during case studies;

• A platform to further your knowledge

Enjoy the module ☺

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MSc Module 6: Regulatory Strategy; From Development to the Market Place

Developing the Brand and Shaping its Market Place Part 1

Vina Mistry

Independent Regulatory Consultant: Pharmistry Consulting Ltd

The Organisation for Professionals in Regulatory Affairs The Organisation for

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Learning Outcomes

PART 1

• Key strategic regulatory considerations when defining and shaping a brand throughout the development stages. • To recognise the needs of marketing colleagues in defining and shaping a successful brand throughout the development stages to prepare its place on the market.

PART 2

• Key considerations in maintaining and extending brand awareness

• The input of the regulatory representative in shaping a successful product through to life-cycle management

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Disclaimer

• Most statements and views expressed herein are those of the presenters.

• The focus and perspective taken with this lecture (Part 1 and Part 2):

o Regulatory Perspective

o Majority EU focused with some US thoughts in mind

o Key strategic thinking and planning of the regulatory pathway not operational planning

o Does not cover emerging markets

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This Presentation will Cover

Post-Approval & Life Cycle Management

Development Program MAA Approval & Launch

Maintain and Extend the Brand - Part 2

Define and Shape the Brand - Part 1

Key Marketing Considerations and Constraints

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Integrated Development Plan

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Disease Area Strategy

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Value Proposition

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Target Product Profile and Product Claims

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Regulatory Pathway

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EU Regulatory Early Access Tools

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Product Name

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Key Collaboration and Communication Plans

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Product Launch Activities

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• Future Product / Brand Developments – PART 2 Maintaining and extending the brand

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Key Marketing Considerations and Constraints Whilst defining and shaping the brand

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Key Marketing Considerations From development stages to the market place

Post Launch Marketing

Market Research

Clinical Studies

Regulatory Approval

Product Launch

Considerations from Development to the Market Place

Provide background on market and product potential

Input into clinical development program Define target product profile Define competitors and market landscape

Input on product Labelling

Finalise launch strategy

Monitor perform of launch and sales Adjust strategy and tactics Sequence promotion in accordance with licence obligations Manage product life cycle / future

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Define launch plans

Finalise pricing

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Develop market positioning and branding

Finalise promotion and advertising materials and branding Implement launch plans Finalise field sales plans

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Develop clinical strategy

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changes to the licence or label

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Key Marketing Constraints Throughout development stages

A stringent pre-launch environment.

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• Competitor awareness and intelligence on market share. • Uncertainties of the final indication and product claims. • Uncertainties of the product positioning in the market place. • Cannot promote a product or brand name prior to licence approval. • Cannot always make links to the drug tradename. • Can only make assumptions of expected data results • Can only make certain product claims if supported by data • Timing of publication of key clinical data. • Timing of the licence approval (dependent on filing strategy and other regulatory constraints) • Timing to achieve pricing and reimbursement in certain countries. • Timing of supply of medicinal product ready for launch

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Integrated Development Plan Define and shape the brand

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Integrated Product Development Plan

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Disease Area Strategy Defining the brand

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Disease Area Strategy Define the brand: pre-licence and pre-launch: several questions to resolve !

Unmet Medical Need

Product’s Mechanism of Action

Disease / condition: is it rare, genetic?

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What is the new drug?

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• Target population (prevalence, epidemiology data)?, • How are patients diagnosed and treated today (SOC)? • Is there a severity disease spectrum? • What is the patients prognosis and quality of life • How could patients be treated differently /followed up? • Is there a current standard of care? • What indication can we achieve? • What can we actually achieve in the label, (e.g. oral kinase inhibitor vs syk inhibitor, moderate to severe) • What can be supported by the generated data? • What is scientifically appropriate and meaningful? • Research into all the available clinical guidelines for designing studies in the disease area.

• How does the new drug work? Is it novel, complex, what is the mechanistic pathway? • Would it be short term or long-term treatment • Preventive or treatment? • Where does it fit in the care pathway? • How will the drug be delivered? • Is the drug safe and effective and will the drug be able to work in clinical practice? • Alignment of scientific, commercial and regulatory. • Start laying out the scientific groundwork. • What must be achieved to make the drug marketable; improved efficacy, safety, tolerability, new treatment option, superior claims, better than gold standard. • Develop a ‘Target Product Profile’ (TPP). • You do not want to change messaging mid pre-launch Cross-functional Strategic Alignment

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Value Proposition Defining the brand

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Fundamental Questions to Assess the Value Proposition: Think like a payer

• What is the new drug, and which patients will use it? o Where does it fit into the care pathway? o What is current standard of care (if any)?

Efficacy

Is the drug safe and effective? o

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Does it work in clinical practice?

• Is investing in this drug an efficient use of resources? o

Cost effectiveness, budget impact compared to which alternative?

How confident am I in this assessment? o Is more information / data needed?

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Effectiveness

• What is the full range of impacts to the healthcare system? o What are the other requirements? Capital, training …

• Can I control use once market access is granted? o

Efficiency

Comparison diagnostic, stopping rules, further indications?

Demonstrating Value and Market Access

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Regulatory-HTA Interface Shifting the paradigm

Reference: “How Regulatory Agencies could interact with Health Technology Bodies”, Source: Lonngren et al DIA, Berlin, March 2009.

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Target Product Profile Define and shape the brand

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EXAMPLE: Creating a Target Product Profile

TPP Handout

PRODUCT ATTRIBUTES

TARGET CHARACTERISTICS

Product Description / Type Mechanism of Action

Type of agent / molecule, e.g. ATMP, biological drug, small molecule, monoclonal antibody; first in class; The target the treatment is believed to act upon; how does the drug molecule exert its effects on the target Intended clinical need which the product will address. E.g. Treatment for..; prevention of..; disease; condition; specific severity with specific symptoms; relief of symptoms; first-line or adjunctive therapy. Adult; paediatric; specific age; subpopulation target (e.g. positive identification of genetic markers; antigen or antibodies; patients who failed on other treatments) Dosage form, regimen and level required for therapeutic effect (dictated by pharmacology and potency); Recommended administration route e.g. oral, IV, SC, inhaled (dictated by bioavailability and stability data); Primary and secondary endpoints for phase III clinical study; including variables (e.g. disease state) and specific measures, e.g. all-cause mortality, or cardiac function measured; validation of endpoints

Indication and Usage Unmet Medical Need

Patient Population

Dosage Form, Strength and Administration Route

Clinical Efficacy: Primary and Secondary Endpoints

Clinical Assessment of Success

Percentage of improvement in primary endpoint (specify absolute or relative to baseline) compared to reference or control group required for marketing success; study design options; treatment duration / frequency

Contraindications

Situation(s) in which the drug should not be used because the known risk outweighs any possible benefits; known hazards from clinical studies (not theoretical possibilities) Potency of product; specific values, e.g. NOEL and NOAEL (extrapolated from preclinical testing data); Data from studies; any advantages over other existing treatments; identified risks; special care to be exercised by practitioner for safe and effective use Any serious drug-related adverse reactions, reactions anticipated from preclinical studies; reactions dictated from experience from clinical studies

Safety Profile Warnings and Precautions

Pertinent Adverse Reactions

Storage and Handling

Storage requirements e.g. temperature, refrigeration, freeze; any specific instructions. Drug product preparation before administration; reconstitution requirements

Regulatory Pathway

Regulatory considerations; data package content; orphan status; PIP requirements; engagement with regulatory agencies; use of any early access tools; intended MAA filing strategy; concessions for any eventual approval; post approval concessions Any involvement of partners for development or marketing; market jurisdictions; intended market exclusivity targets; patent protection status; cost of treatment to bring to market; market size

IP and commercial development considerations

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TPP Handout

Target Product Profile Create early in the development program

A summary of the development : •

TPP provides a summary of the development of a medicinal product in terms of realistic labelling and commercial target concepts and goals (best case and worst case scenarios). A dynamic document, which gets updated as new information unfolds. • Aim is to have one global TPP, but not always possible with divergent regionally health authority opinions.

Ultimate objective: • To develop a drug for an unmet medical need, which physicians want to prescribe, patients want to take, regulators will approve and payors will value. Gain external knowledge, multi-dimensional: • Advisory boards and key opinion leaders • Clinical considerations e.g. review competitors (now and future predictions), key issues in real life setting e.g. managing an emerging safety profile, review of key pivotal clinical data • Commercial considerations: key claims for launch e.g. differentiating factors – what must be achieved to make the drug marketable; Improved efficacy, safety, tolerability…a new treatment option, superior claims, betters gold standard. • Regulatory precedents; clinical guidelines, endpoints, comparators, study designs, learnings from competitors (EPARs).

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Target Product Profile Create early in the development program

Regulatory considerations •

Input into phase III study designs

• Monitor link between TPP, core data sheet and study data • Regulatory filing pathway to approval • Input prior to Scientific Advice

Clinical considerations • Meet the requirements of Regulators, HTABs or both • Types of study / evidence: RCTs, pragmatic study designs, biomarker / surrogate measures, adaptive trial design, indirect comparisons and meta-analyses, observational studies. • Endpoints: Regulators vs HTABs preferred (e.g. clinical endpoint vs QoL, PROs). • Comparators: choice of appropriate comparative (if applicable); head to head, demonstrate absolute or relative efficacy or both. • Analysis: non-inferiority or superiority. Novel statistical analysis models. Extrapolation from adults to paediatrics • Post-approval studies: PAES, PASS - Regulators and HTABs requirements

Proof of Concept (PoC) versus Proof of Value (PoV )

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Handout Decision Tree

Target Product Profile Other considerations: Orphan Drug

• An Orphan Drug is intended to treat patients with a rare (“orphan”) disease

• The orphan drug regulatory framework provides pharma companies with financial, regulatory and marketing incentives to encourage development in rare diseases, which affect smaller populations of patients and represent unmet medical need

• The statutory and regulatory framework for orphan drug designation varies considerably worldwide

• The official benefits differ across regions, but may include:

Tax incentives or Research grants

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• Fee reductions for regulatory procedures (Free advice from EMA)

• Shorter review period for marketing application (accelerated assessment in EU or breakthrough designation / fast-track assessment US)

• Marketing exclusivity (EU & JP: 10 years; US: 7 years)

• Pricing and Reimbursement benefits (e.g. premium pricing; quicker market access via shorter HTA procedures; automatic entitlement to reimbursement for patients).

• Acknowledgement of rarity of disease which can frame HA interactions.

• Development teams to make fundamental decisions on value of orphan status

• The TPP should consider the timelines to obtain orphan drug requirements

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Handout Decision Tree

EU Orphan Drug Designation (ODD)

Strategic Preparation •

Key elements •

Qualitative and quantitative report on the incidences and prevalence of the disease across the EU • Demonstrate there is n o ‘similarity’ to other approved products for same indication i.e. must NOT be identical active substance or active substance with same principle molecular structural features and act via same mechanism of action Demonstrate significant benefit over all existing authorised products or methods for the same indication. Definition of ‘significant benefit’: a clinically relevant advantage or a major contribution to patient care • Based on assumptions at the time of ODD • Examples: new mechanisms of action; improved efficacy; or more convenient administration route; or complimentary safety profile. • •

EU Regulation (EC) No.141/2000

Fulfil ODD criteria for the rare condition •

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Medicine must treat, prevent, or diagnose a disease which is life-threatening or chronically debilitating, or it is unlikely that the medicine will generate sufficient returns to justify the investment needed for its development. The disease must not affect more than 5 in 10,000 people across EU. No satisfactory method of diagnosis, prevention or treatment exists, or if such a method already exists, the medicine must be of significant additional benefit to those affected by the condition

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Examination by the EMA COMP • No fee •

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90 days assessment from validation COMP opinion sent to EU Commission who grants ODD

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Over authorised product (=satisfactory methods) Re-confirm prior to MAA to maintain ODD status - ‘Maintenance Report’. A much higher level of evidence required at time of MAA compared to time of ODD application, which is aligned to development stages.

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Entry in the EU ODD register

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• Submission of ‘annual reports’ summarising status of development

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Target Product Profile Other considerations: Paediatric population

Paediatric Regulation 1901/2006

• TPP needs to consider the different paediatric population (all age range) wrt to target indication, treatment and duration of completing clinical studies in paediatric population. • Paediatric Investigation Plan (PIP) consisting of clear clinical study designs, timelines, measures with statistical plan will need to be devised and agreed by EMA Paediatric Committee. Submission ideally after adult PK studies are completed. • If development is too early to plan then a PIP deferral is required to be devised in time for the adult MAA filing. • If disease, condition or treatment is not intended for the paediatric population then a wavier (part or full) needs to be applied. • Clinical development must be in accordance with an agreed PIP. Modification of the PIP is allowed within justified scientific reasoning. The development plan should plan for the timelines for anticipated PIP modifications. • All MAAs with proposed paediatric indication requires a completed approved PIP with successful compliance check. • Incentives: 6 months SPC extension. PUMA: 8+2+1 data protection rule. Paediatric orphan drug: extra 2 years market exclusivity.

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Target Product Profile Summary

• TPP is useful resource for industry and agencies for first MA and line extensions

Agency

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• TPP can allow constructive dialogue regarding proposed promotional claims

• Efficient use of agency meeting time

• Useful in scientific advice meeting with regulatory agencies

Industry

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• Provides a clear link to ensure teams constantly ensure that the data support the appropriate claims

• Can facilitate production of an annotated label and identify gaps in the development

Useful Reference: FDA Guidance for Industry Target Product Profile — A Strategic Development Process Tool

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Regulatory Pathway Mapping the journey to MAA

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Regulatory Pathway Plan Key considerations from development to market

Post Launch Marketing

Market Research

Clinical Studies

Regulatory Approval

Product Launch

Develop a Project Plan: Map the Regulatory Journey from Development to the Market Place

Provide regulatory background on disease area, competitors labels and clinical study design

Input into clinical development program Request and prepare for scientific advice

MAA submission and assessment to desired TPP

Launch Ready

Assure licence obligations and post approval commitments Manage product life cycle / future changes to the licence or label

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Assist with HTAs

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Review and finalise promotion and advertising materials

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PIP compliance check

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Input in TPP

Orphan Maintenance (if applicable) Input on product Labelling to desired TPP

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Develop global regulatory strategy and filing plan

Implement label

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Clinical guidelines

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PIP Obligations

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Post-approval plans

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PRIME (if applicable)

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Input into launch plans including drug product and packaging readiness

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Orphan (if applicable)

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Tradename

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Regulatory Pathway Plan Obtaining scientific advice with agencies can help mitigate regulatory riskd

Considerations

Challenges

Identify which agency

A high resourced team required

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• National; EMA; FDA; JP; EMA/HTA; EMA/FDA,

• Preparation and delivery to short timelines: briefing package; A-LoQs • Development plans are too premature to discuss with the agency,

• Identify the appropriate stages during development and the actual timing: PRIME; Ph2; Ph3; MAA ready

Identify gaps in the development plan

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Data not ready to share with the agency

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Identify the topics of engagement

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• Readiness to discuss key decisions on certain aspects of the development plans with the agency. In some cases substantial detail is required • Willingness to change development plans upon health authority discussions (otherwise justified) • PRIME: EMA PRIME coordinator and Rapporteur updated periodically on development plans and dates of future engagement timelines and topics and progress check on changes. Important when product is earlier in development and engagement may be less frequent. • Resolving divergences between HA vs HTABs

• Identify whether the company is ready to share any data: preclinical, clinical, pharmacology, quality. Ideal to seek endorsement • Define company position for each topic of engagement and be ready to present the development plans • Frame the questions in way to spark scientific discussion. Avoid posing too many “ Do you agree….” type questions. • Planning is key. E.g.: EU CHMP SA can take up to 7 to 8 months from briefing book preparation to actual CHMP written advice.

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Clinical Development Strategy: Define Pathway to MA Acceleration to MA is dependent on designs, disease and development

Traditional development pathway • Distinct clinical phases

Accelerated development pathway • Unique adaptive clinical trial designs that combines Ph1 & Ph2 evaluates can help to accelerate the product development and thus could meet the unmedical need earlier Potential to apply for acceleration of MA with or without EMA PRIME assistance or FDA breakthrough •

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EU Regulatory Early Access Tools Helping to shape the brand

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EU Regulatory Early Access Tools To help expedite drug approval

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EU Regulatory Early Access Tools Stages throughout development

Compassionate Use

PRIME Adaptive Pathways

Post Authorisation

Non-clinical

Phase I

Exploratory

Confirmatory

Evaluation

Discuss opportunities for Accelerated Assessment and Conditional MAA

Accelerated Assessment

MAA under Exceptional Circumstances

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Conditional Approval

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EU Regulatory Early Access Tools Benefits patients with unmet medical needs

Compassionate Use

PRIME Scheme

Reference: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000856.jsp&mid=WC0b01ac0580b18c78

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EU Regulatory Early Access Tools Benefits patients with unmet medical needs

Conditional MA

Accelerated Assessment

Reference: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000856.jsp&mid=WC0b01ac0580b18c78

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Comparison of PRIME vs BTD

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Comparison Regulatory Early Access Tools: EU vs US

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Product Name

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Product Name Application timing is key. Ideally aim for one global tradename

Benefits of having one global tradename:

• Economies of scale (production and distribution)

Lower marketing costs

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• Increases international media reach via the internet

• Maintains consistent global branding and image

• Lays the groundwork for future extensions worldwide

Constraints of not achieving one global tradename

• Different meanings in different countries

• Differences in patent office versus regulatory agency assessment: • Patent offices do not evaluate safety and efficacy of a drug and do not consider promotional aspects of a brand. • Regulators review proposed invented name wrt scientific claims and may detect misleading manner in a tradename.

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Product Name Choosing and obtaining a name

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Key Collaboration and Communication Plans

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Key Collaboration and Communication Plans Key considerations

The Patient is a key customer in defining and shaping the brand.

Engaging with patient groups

Understand the needs of patients

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• Practicalities of disease management e.g. pain management for cancer patients

• Raise awareness, carefully (e.g. via educational campaigns)

Well informed patients

• Increased transparency: Disease help lines, clinical trial websites, charity groups, GP consultations, published CSRs.

• Educational materials to enhance their understanding of the drug development process

• Patient leaflets and communications, readability of leaflets

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Key Collaboration and Communication Plans Key considerations

External Stakeholders are key customers too

• Proactive co-ordinated communication globally

• Governance of reporting to financial markets vs. relationship with regulatory agency

• Co-ordinating release of phase III study results with major congresses and link with regulatory agency communication

▪ Phase III manuscripts/ Satellite symposium/ Congresses

─ Speaker may not hold the same view as the company

─ Study investigators need to express their view on the data since they are the experts

• Publications externally serves different purposes

Limitations on advertising

May need prior health authority vetting /approval.

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▪ A mechanism for providing additional information to prescribers, i.e. QoL data not covered in label, ADR reporting requirements

• Different types of journals – Timing is key !

High impact journals; Lancet, NEJM

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▪ Specialised journals; ophthalmology, neuroscience

One Q&A co-ordinated global messaging

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▪ Be ready to proactively and reactively answer questions to Journalists, media press releases, healthcare professionals, patients, shareholders

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Key Product Launch Activities

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Product Launch Activities Key considerations

• Centralised procedure dictates identical packs

• MAA contains English and worst case pack layouts, ( e.g. triple language packs )

• All packs, contents, layout, words are part of approval process.

• Blue box wording ( price, bar code, identification and authenticity, legal status code or wording ) requirements should conform to the each MS local requirements. • The planning of country shared packs should be confirmed early in the MAA and before approval • Commercial considerations of volumes and profit margins so that production schedules can be planned accordingly • Regulatory need to balance commercial launch plans with length of different pricing procedures. These timelines should be built into the overall regulatory pathway timelines • You do not need to launch in all markets but there is a Sunset Clause. Inform EMA. • Implementation of approved risk minimisation plans, i.e. educational materials for physicians and /or patients • Plan for other launches in emerging markets sequentially; Middle East, Africa, China,. Some countries rely on the approval from the US or EU as part of their assessment procedure. • Assisting with health technology appraisals to achieve the right pricing and reimbursement strategy

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Future Product Development Extend & Maintain the Brand

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In this presentation we covered

PART 1

• Key strategic regulatory considerations when defining and shaping a brand throughout the development stages. • To recognise the needs of marketing colleagues in defining and shaping a successful brand throughout the development stages to prepare its place on the market.

PART 2

• Key considerations in maintaining and extending brand awareness

• The input of the regulatory representative in shaping a successful product through to life-cycle management

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Any Questions?

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Recommended References

• Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on Orphan Medicinal Products. Official Journal of the European Communities . • Commission Regulation (EC) No 847/2000 of 27 April 2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and ‘clinical su per iority’. Official Journal of the European Communities . • Communication from the Commission on Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products (2003/C 178/02). Official Journal of the European Union. • Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Official Journal of the European Union. • EMA Paediatrics Investigational Plans Overview Webpages. Available from: https://www.ema.europa.eu/en/human-regulatory/research development/paediatric-medicines/paediatric-investigation-plans • EMA Guideline on the acceptability of names for human medicinal products processed through the centralised procedure. EMA/CHMP/287710/2014 – Rev 6. 22 May 2014 • FDA Electronic code of federal regulations, Subpart C, Designation of an Orphan Drug, Part 316; Orphan Drugs. Available From: https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/e-cfr-21-part-316-orphan-drug-orphan-drug-act 1983 • EMA CHMP Guidance (7 May 2018): Enhance early dialogue to facilitate accelerated assessment of priority medicines (PRIME), EMA/CHMP/57760/2015, Rev. 1: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/enhanced-early-dialogue facilitate-accelerated-assessment-priority-medicines-prime_en.pdf • EMA Guidance (07-May 2018): EMA guidance for applicants seeking access to PRIME scheme. EMA/191104/2015: https://www.ema.europa.eu/en/documents/other/european-medicines-agency-guidance-applicants-seeking-access-prime-scheme_en.pdf • EMA Support for early access overview webpages. Available from: https://www.ema.europa.eu/en/human-regulatory/overview/support early-access • EMA PRIME overview website: https://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicines

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MSc Module 6: Regulatory Strategy; From Development to the Market Place

Awareness of Maintaining and Extending the Brand through continued Product Development: Part 2

Vina Mistry

Independent Regulatory Consultant: Pharmistry Consulting Ltd

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Learning Outcomes

• Key considerations in maintaining and extending brand awareness

• The input of the regulatory representative in shaping a successful product through to life-cycle management

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Maintaining and Extending the Brand Several elements during life-cycle management

MAA approval

Lifecycle Strategy

Benefit / Risk Assessment

Efficacy

Safety

PIP & ODD maintenance

New Indications

Minimizing risks

Maximizing Patients

Label enhancements

PAMs

PASS

PAES

Quality

Essential compliance activities: ▪ PSMF ▪ Marketing status reports ▪ GxP Inspections

New formulations

New dosage strengths

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Maintaining and Extending the Brand 4 key areas to maintain and extend the new medicinal product

Maximising Patients

• Special populations (renal, hepatic, ethnic, pregnancy, DDIs) • New clinical indication • New patient population (e.g. paediatrics, elderly) • New formulation

Benefit / Risk Assessment

• Conditional Marketing Authorisation (MA) obligations • Renewals • Post-approval commitments • Post-approval safety or efficacy studies, registry data

Minimising Risk

New safety updates (pharmacovigilance) Periodic Safety Update Reports (PSURs)

• •

• Risk Management Plan (RMP) incl. Direct Healthcare Professional Communications (DHPCs) & Education

Maintaining Compliance

Sunset clause monitoring

• • •

GxP Inspections

Pharmacovigilance System Master File (PSMF) • General maintenance: quality variations, labelling

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Extend and Protect the Brand Look for opportunities to expand the potential of the new medicinal product

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Reach More Patients and Extend the Clinical Indication Maximise the potential of the approved new medicinal product

Treat more patients • Completely new indication* e.g. RA, MS, CD • New population; paediatrics, elderly • Different “stages” of the disease e.g. Relapsing -remitting MS, Primary-progressive MS, mod-severe

Treat earlier • Treatment line of clinical use e.g. 2nd to 1st

Improved or new therapy • Monotherapy or combination therapy, • e.g. use with SoC i.e. anti-TNF + methotrexate in RA • New target therapy: e.g. Xalkori NSCLC, ALK+ve to ROS1+ve Maximise treatment effects • Treatment will make a difference to patients • Sub-populations (e.g. new age ranges, neonatal) • Optimise B/R considerations • Support effectiveness (HTA, pricing &reimbursement)

How is the licence extended? • Need supportive data: new direct clinical study data evaluating efficacy and safety, extrapolation (PK, PD, popPK), literature review • Submission of Type II complex variation (90 day agency review for changes to or addition of a new indication)

Extend Intellectual Protection (IP) • e.g. extra time, + 1 year EU Regulatory Data Protection to avoid

generic applications from being filed • Added “significant benefit” if orphan

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Alzheimer’s Disease Targeting different clinical stages of the disease spectrum over time

Dementia stages

Pre-dementia stage

MCI due to AD

Pre-Clinical

Mild

Moderate

Severe

• Clinically treat different stages of the Alzheimer’s disease spectrum • Presentation of the diseases changes over time • Early onset predementia stage, measured using the ‘Alzheimer’s Disease assessment scale’ (ADAS). • Mild cognitive impairment (MCI), mild to moderate to severe disease measured by using the ‘clinical dementia rating’ (CDR) • Magnitude of the biomarker increases as the disease worsens.

Source: Jack, et al. Lancet Neurol (2013)

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Examples Maximise the potential opportunities to extend the new medicinal product

Indirectly broadening treated patient population: • Removing historical barriers, e.g. Tysabri for Disease Modifying Therapy (DMT) switch

Treat different stage of disease: • Moving to earlier line of treatment e.g. Zytiga for m etastatic castration resistant prostate cancer ( mCRPC) w/disease progression to mCRPC asymptomatic / mildly symptomatic • Zykadia, NSCLC, broadened indication to include 1st line therapy Monotherapy / combination therapy: • Victoza: Type II diabetes, combination therapy to monotherapy • Enbrel: RA monotherapy to combination with methotrexate, updated standard of care (SoC)

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Example: Keytruda (active pembrolizumab) for Cancer Maximise the potential opportunities to extend the medicinal product

Mechanism of Action: •

Pembrolizumab, is a monoclonal antibody, a protein that has been designed to recognise and block a receptor (‘target’) called PD -1. Some cancers can make a protein (PD-L1) that combines with PD-1 to switch off the activity of certain cells of the immune system (the body’s natural defences) preventing them from attacking the cancer. By blocking PD -1, pembrolizumab stops the cancer switching off these immune cells, thereby increasing the immune system’s ability to kill the cancer cells. Initial Marketing Authorisation approved to treat: • Metastatic melanoma, a skin cancer and then later the licence extended to stage III melanoma with combo with ipilimumab

Posology: •

Intravenous injection.

• Keytruda monotherapy the adult dose is either 200 mg every 3-weeks or 400 mg every 6-weeks. • Administered in combination with other cancer medicines, the adult dose is always 200 mg every 3-weeks. • The dose for children is based on their body weight.

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